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Brianna L Combs, Arthur G Cox Department of Pharmaceutical Sciences, Sullivan University College of Pharmacy, Louisville, KY, USA Abstract: Parkinson’s disease (PD) has a prevalence of nearly 1 million people in the USA, with increasing incidence in the elderly population. Generally, the age of presentation is between 55 and 65 years, with the likelihood of diagnosis increasing as patients reach the age of 80 years or above. Some of the common treatments for PD increase dopamine levels in the brain. Dopaminergic therapy helps to improve motor and non-motor symptoms, but it is not without risks. Dopaminergic therapy can cause confusion, delirium, and psychotic-like behavior. It is recommended that these agents are used cautiously in patients with a history of psychosis due to the risk of exacerbation. It is unclear whether Parkinson’s disease psychosis (PDP) is due to the disease itself, the treatment, or a combination of both, but it is clear that a safe, effective treatment is necessary. Second-generation (atypical) antipsychotics are the current choice of therapy for PDP. All of these agents have a black box warning from the US Food and Drug Administration (FDA) for elevated risk of mortality in elderly patients with dementia-related psychosis. Pimavanserin (Nuplazid®) received its novel drug approval by the FDA on April 29, 2016, to treat hallucinations and delusions associated with psychosis experienced by some people with PD. We review in this article the new research that led to this approval as well as its potential place in therapy. Keywords: pimavanserin, Parkinson’s disease psychosis, Parkinson’s disease

The optical transparency of zebrafish larvae enables visualization of subcellular structures in intact organs, and these vertebrates are widely used to study lipid biology and liver disease. Lipid droplet (LD) presence is a prevalent feature of healthy cells but under conditions such as nutrient excess, toxicant exposure or metabolic imbalance, LD accumulation in hepatocytes can be a harbinger of more severe forms of liver disease. We undertook a comprehensive analysis of approaches useful to investigate LD distribution and dynamics in physiological and pathological conditions in the liver of zebrafish larvae. This comparative analysis of the lipid dyes oil red O (ORO), Nile Red (NR), LipidTox and LipidSpot as well as transgenic LD reporters that rely on EGFP fusions of the LD decorating protein perilipin 2 (PLIN2) demonstrate the strengths and limitations of each approach. These protocols are amenable to detection methods ranging from low resolution stereomicroscopy to confocal imaging, which enables measurements of hepatic LD size, number and dynamics at cellular resolution in live and fixed animals. This resource will benefit investigators studying LD biology in zebrafish disease models., (© 2024. Published by The Company of Biologists Ltd.)

The liver is a remarkable organ that can regenerate in response to injury. Depending on the extent of injury, the liver can undergo compensatory hyperplasia or fibrosis. Despite decades of research, the molecular mechanisms underlying these processes are poorly understood. Here, we developed a new model to study liver regeneration based on cryoinjury. To visualise liver regeneration at cellular resolution, we adapted the CUBIC tissue-clearing approach. Hepatic cryoinjury induced a localised necrotic and apoptotic lesion characterised by inflammation and infiltration of innate immune cells. After this initial phase, we observed fibrosis, which resolved as regeneration re-established homeostasis in 30 days. Importantly, this approach enables the comparison of healthy and injured parenchyma within an individual animal, providing unique advantages to previous models. In summary, the hepatic cryoinjury model provides a fast and reproducible method for studying the cellular and molecular pathways underpinning fibrosis and liver regeneration., Competing Interests: Competing interests The authors declare no competing or financial interests., (© 2024. Published by The Company of Biologists Ltd.)

The liver exhibits a remarkable capacity to regenerate following injury. Despite this unique attribute, toxic injury is a leading cause of liver failure. The temporal processes by which the liver senses injury and initiates regeneration remain unclear. Here, we developed a transgenic zebrafish model wherein hepatocyte-specific expression of uracil phosphoribosyltransferase (UPRT) enabled the implementation of SLAM-ITseq to investigate the nascent transcriptome during initiation of liver injury and regeneration. Using this approach, we identified a rapid metabolic transition from the fed to the fasted state that was followed by induction of the nuclear erythroid 2-related factor (Nrf2) antioxidant program. We find that activation of Nrf2 in hepatocytes is required to induce the pentose phosphate pathway (PPP) and improve survival following liver injury. Mechanistically, we demonstrate that inhibition of the PPP disrupts nucleotide biosynthesis to prevent liver regeneration. Together, these studies provide fundamental insights into the mechanism by which early metabolic adaptation to injury facilitates tissue regeneration., Competing Interests: Declaration of interests M.A.D. has been a member of advisory boards for GSK, CTX CRC, Storm Therapeutics, Celgene, and Cambridge Epigenetix. The Dawson Laboratory is a recipient of grant funding through the emerging science fund administered through Pfizer., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

The Hippo signaling pathway regulates developmental organ growth, regeneration, and cell fate decisions. Although the role of the Hippo pathway, and its transcriptional effectors YAP and TAZ, has been well documented in many cell types and species, only recently have the roles for this pathway come to light in vascular development and disease. Experiments in mice, zebrafish, and in vitro have uncovered roles for the Hippo pathway, YAP, and TAZ in vasculogenesis, angiogenesis, and lymphangiogenesis. In addition, the Hippo pathway has been implicated in vascular cancers and cardiovascular diseases, thus identifying it as a potential therapeutic target for the treatment of these conditions. However, despite recent advances, Hippo's role in the vasculature is still underappreciated compared with its role in epithelial tissues. In this review, we appraise our current understanding of the Hippo pathway in blood and lymphatic vessel development and highlight the current knowledge gaps and opportunities for further research., Competing Interests: Declaration of interests K.F.H. is a member of the Developmental Cell advisory board., (Copyright © 2023 Elsevier Inc. All rights reserved.)

The maintenance of redox and metabolic homeostasis is integral to embryonic development. Nuclear factor erythroid 2-related factor 2 (NRF2) is a stress-induced transcription factor that plays a central role in the regulation of redox balance and cellular metabolism. Under homeostatic conditions, NRF2 is repressed by Kelch-like ECH-associated protein 1 (KEAP1). Here, we demonstrate that Keap1 deficiency induces Nrf2 activation and postdevelopmental lethality. Loss of viability is preceded by severe liver abnormalities characterized by an accumulation of lysosomes. Mechanistically, we demonstrate that loss of Keap1 promotes aberrant activation of transcription factor EB (TFEB)/transcription factor binding to IGHM Enhancer 3 (TFE3)-dependent lysosomal biogenesis. Importantly, we find that NRF2-dependent regulation of lysosomal biogenesis is cell autonomous and evolutionarily conserved. These studies identify a role for the KEAP1-NRF2 pathway in the regulation of lysosomal biogenesis and suggest that maintenance of lysosomal homeostasis is required during embryonic development.

Purpose: This wisdom of experience commentary, from peer academic reviewers serving on accreditation teams, will discuss benefits and challenges of international and national virtual accreditation visits (VAVs) using a "What? So What? Now What?" reflective model., Description: Onsite accreditation reviews for health professional education programs require investments in time, effort, and money to maintain program alignment with accreditation standards and continuously generate quality practitioners. When COVID-19 entered the accreditation world, reviewers had to pivot modalities to a VAV format., Analysis/interpretation: Adaptation and expectations of VAVs present several challenges. Barriers and advantages will be discussed as well as implications for the future. While medical and pharmacy education standardization has long been established, the authors propose national and international accrediting bodies will utilize the ingenuity of emergency COVID-19-driven onsite accreditation alternatives to develop protocols for novel accreditation methodology., Conclusions: Whether the continued mutation of COVID-19 prevents the return to previous accreditation visits or not, the experiences gained from the emergency-driven VAV, can inform and enrich accrediting bodies knowledge, theories, and practices of future VAVs., Implications: Higher-education institutions, accreditation bodies, and government entities will use experiences during COVID-19 to transform and improve academic requirements and future practices. Even if there is a full return to onsite reviews, such guidelines or improved versions of them can be applied to situations where immobility or restricted mobility is an issue, such as in illness, pregnancy, travel, war, etc. It is crucial for educators and accrediting bodies to evolve as we navigate these unprecedented times., (Copyright © 2022. Published by Elsevier Inc.)

The coordinated regulation of growth control and metabolic pathways is required to meet the energetic and biosynthetic demands associated with proliferation. Emerging evidence suggests that the Hippo pathway effector Yes-associated protein 1 (YAP) reprograms cellular metabolism to meet the anabolic demands of growth, although the mechanisms involved are poorly understood. Here, we demonstrate that YAP co-opts the sterol regulatory element-binding protein (SREBP)-dependent lipogenic program to facilitate proliferation and tissue growth. Mechanistically, YAP stimulates de novo lipogenesis via mechanistic target of rapamcyin (mTOR) complex 1 (mTORC1) signaling and subsequent activation of SREBP. Importantly, YAP-dependent regulation of serum- and glucocorticoid-regulated kinase 1 (SGK1) is required to activate mTORC1/SREBP and stimulate de novo lipogenesis. We also find that the SREBP target genes fatty acid synthase (FASN) and stearoyl-CoA desaturase (SCD) are conditionally required to support YAP-dependent proliferation and tissue growth. These studies reveal that de novo lipogenesis is a metabolic vulnerability that can be targeted to disrupt YAP-dependent proliferation and tissue growth., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Cancer cell metabolism is increasingly recognized as providing an exciting therapeutic opportunity. However, a drug that directly couples targeting of a metabolic dependency with the induction of cell death in cancer cells has largely remained elusive. Here we report that the drug-like small-molecule ironomycin reduces the mitochondrial iron load, resulting in the potent disruption of mitochondrial metabolism. Ironomycin promotes the recruitment and activation of BAX/BAK, but the resulting mitochondrial outer membrane permeabilization (MOMP) does not lead to potent activation of the apoptotic caspases, nor is the ensuing cell death prevented by inhibiting the previously established pathways of programmed cell death. Consistent with the fact that ironomycin and BH3 mimetics induce MOMP through independent nonredundant pathways, we find that ironomycin exhibits marked in vitro and in vivo synergy with venetoclax and overcomes venetoclax resistance in primary patient samples., Significance: Ironomycin couples targeting of cellular metabolism with cell death by reducing mitochondrial iron, resulting in the alteration of mitochondrial metabolism and the activation of BAX/BAK. Ironomycin induces MOMP through a different mechanism to BH3 mimetics, and consequently combination therapy has marked synergy in cancers such as acute myeloid leukemia. This article is highlighted in the In This Issue feature, p. 587., (©2021 The Authors; Published by the American Association for Cancer Research.)

The utility of in vitro human disease models is mainly dependent on the availability and functional maturity of tissue-specific cell types. We have previously screened for and identified small molecules that can enhance hepatocyte function in vitro . Here, we characterize the functional effects of one of the hits, FH1, on primary human hepatocytes in vitro , and also in vivo on primary hepatocytes in a zebrafish model. Furthermore, we conducted an analogue screen to establish the structure-activity relationship of FH1. We performed affinity-purification proteomics that identified NQO2 to be a potential binding target for this small molecule, revealing a possible link between inflammatory signaling and hepatocellular function in zebrafish and human hepatocyte model systems.

Obesity is a major risk factor underlying the development of metabolic disease and a growing public health concern globally. Strategies to promote skeletal muscle metabolism can be effective to limit the progression of metabolic disease. Here, we demonstrate that the levels of the Hippo pathway transcriptional co-activator YAP are decreased in muscle biopsies from obese, insulin-resistant humans and mice. Targeted disruption of Yap in adult skeletal muscle resulted in incomplete oxidation of fatty acids and lipotoxicity. Integrated 'omics analysis from isolated adult muscle nuclei revealed that Yap regulates a transcriptional profile associated with metabolic substrate utilisation. In line with these findings, increasing Yap abundance in the striated muscle of obese (db/db) mice enhanced energy expenditure and attenuated adiposity. Our results demonstrate a vital role for Yap as a mediator of skeletal muscle metabolism. Strategies to enhance Yap activity in skeletal muscle warrant consideration as part of comprehensive approaches to treat metabolic disease.

Sulforaphane, an isothiocyanate found in cruciferous vegetables such as broccoli, shows promise as an adjuvant therapy for preeclampsia. To inform future clinical trials, we set out to determine the bioavailability of sulforaphane in non-pregnant and preeclamptic women. In six healthy female volunteers, we performed a crossover trial to compare the bioavailability of sulforaphane and metabolites afforded by an activated and non-activated broccoli extract preparation. We then undertook a dose escalation study of the activated broccoli extract in 12 women with pregnancy hypertension. In non-pregnant women, an equivalent dose of activated broccoli extract gave higher levels of sulforaphane and metabolites than a non-activated extract (p < 0.0001) and greater area under the curve (AUC) (3559 nM vs. 2172 nM, p = 0.03). Compared to non-pregnant women, in women with preeclampsia, the same dose of activated extract gave lower levels of total metabolites (p < 0.000) and AUC (3559 nM vs. 1653 nM, p = 0.007). Doubling the dose of the activated extract in women with preeclampsia doubled levels of sulforaphane and metabolites (p = 0.02) and AUC (1653 nM vs. 3333 nM, p = 0.02). In women with preeclampsia, activated broccoli extract was associated with modest decreases in diastolic blood pressure (p = 0.05) and circulating levels of sFlt-1 (p = 0.0002). A myrosinase-activated sulforaphane formulation affords better sulforaphane bioavailability than a non-activated formulation. Higher doses of sulforaphane are required to achieve likely effective doses in pregnant women than in non-pregnant women. Sulforaphane may improve endothelial function and blood pressure in women with pregnancy hypertension.

Malignant tumors exhibit high degrees of genomic heterogeneity at the cellular level, leading to the view that subpopulations of tumor cells drive growth and treatment resistance. To examine the degree to which tumors also exhibit metabolic heterogeneity at the level of individual cells, we employed multi-isotope imaging mass spectrometry (MIMS) to quantify utilization of stable isotopes of glucose and glutamine along with a label for cell division. Mouse models of melanoma and malignant peripheral nerve sheath tumors (MPNSTs) exhibited striking heterogeneity of substrate utilization, evident in both proliferating and non-proliferating cells. We identified a correlation between metabolic heterogeneity, proliferation, and therapeutic resistance. Heterogeneity in metabolic substrate usage as revealed by incorporation of glucose and glutamine tracers is thus a marker for tumor proliferation. Collectively, our data demonstrate that MIMS provides a powerful tool with which to dissect metabolic functions of individual cells within the native tumor environment., Competing Interests: Declaration of Interests Competing interest reported C.G.: current employment (Zeiss); O.M.: current employment (Novartis); W.G.: consulting (Camp4); K.C.: consulting (Genentech); M.L.S.: consulting (Regeneron, Amgen)., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Hematopoietic stem and progenitor cells (HSPCs), first specified from hemogenic endothelium (HE) in the ventral dorsal aorta (VDA), support lifelong hematopoiesis. Their de novo production promises significant therapeutic value; however, current in vitro approaches cannot efficiently generate multipotent long-lived HSPCs. Presuming this reflects a lack of extrinsic cues normally impacting the VDA, we devised a human dorsal aorta-on-a-chip platform that identified Yes-activated protein (YAP) as a cyclic stretch-induced regulator of HSPC formation. In the zebrafish VDA, inducible Yap overexpression significantly increased runx1 expression in vivo and the number of CD41 + HSPCs downstream of HE specification. Endogenous Yap activation by lats1/2 knockdown or Rho-GTPase stimulation mimicked Yap overexpression and induced HSPCs in embryos lacking blood flow. Notably, in static human induced pluripotent stem cell (iPSC)-derived HE culture, compound-mediated YAP activation enhanced RUNX1 levels and hematopoietic colony-forming potential. Together, our findings reveal a potent impact of hemodynamic Rho-YAP mechanotransduction on HE fate, relevant to de novo human HSPC production., Competing Interests: Declaration of Interests V.L. is currently at the Karolinska Institutet, L.N.T. is at Sanofi, and A.G.C. is at the Peter MacCallum Cancer Centre. G.Q.D. holds equity interest in True North Therapeutics and 28/7 Therapeutics; D.E.I. holds equity in Emulate Inc. and chairs its scientific advisory board., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Objective: Higher rates of neonatal morbidity and mortality at term combined with earlier spontaneous delivery have led to the hypothesis that babies born to South Asian born (SA-born) women may mature earlier and/or their placental function decreases earlier than babies born to Australian and New Zealand born (Aus/NZ-born) women. Whether babies born to SA-born women do better in the preterm period, however, has yet to be evaluated. In this study we investigated respiratory outcomes, indicative of functional maturity, of preterm babies born to SA-born women compared with those of Aus/NZ-born women to explore this hypothesis further., Study Design and Setting: This retrospective cohort study was conducted at Monash Health., Patients: Data were collected from neonatal and birth records of moderate-late preterm (32-36 weeks) infants born between 2012 and 2015 to SA-born and Aus/NZ-born women., Outcome Measures: Rates of nursery admissions and neonatal respiratory outcomes were compared., Results: Babies born to Aus/NZ-born women were more likely to be admitted to a nursery (80%) compared with SA-born babies (72%, p=0.004). Babies born to SA-born mothers experienced significantly less hyaline membrane disease (7.8%), required less resuscitation at birth (28.6%) and were less likely to require ventilation (20%) than babies born to Aus/NZ-born mothers (18%, 42.2%, 34.6%; p<0.001). There was no difference in the duration of ventilation or length of stay in hospital., Conclusions: Moderate-late preterm babies born to SA-born women appear to have earlier functional maturity, as indicated by respiratory outcomes, than Aus/NZ-born babies. Our findings support the hypothesis of earlier fetal maturation in SA-born women., Competing Interests: Competing interests: MD-T has a secondment 1 day per week to CCOPMM and EW is a CEO of Safer Care Victoria, Department of Health., (© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective. To describe an intersession remediation process in an accelerated three-year Doctor of Pharmacy (PharmD) program and to determine if the remediation process reduced attrition rates, including program withdrawals, progression to advanced pharmacy practice experiences (APPEs), and on-time graduation rates. Methods. Attrition was defined as dismissal, withdrawal, leave of absence, and/or change in graduation date. Progression data from students who matriculated between 2008 to 2016, with data available through spring 2017, were analyzed for number of course failures and successful intersession remediation. Other factors such as pharmacy year (first or second year), course subject, and course repeats were evaluated to characterize successful remediation attempts and identify elements that foster student success. Results. Of the 812 matriculated students across the time period analyzed, 18% (n=146) failed at least one didactic course (defined as course average <69.5%). Overall, 74.7% (n=109) of the students who failed a course remediated, with 75.2% (n=82) of those able to remediate being successful, remaining on-time for graduation. If students who remediated were instead required to repeat coursework, the college attrition rate would have averaged over 10 percentage points higher for the time period analyzed than the actual rate of 13.4%. Conclusion. Our study demonstrated that the majority of students who qualified for remediation were successful and graduated on time. Further studies in this area are needed to fully elucidate the effect of remediation processes on learning and retention of knowledge and skills., (© 2019 American Association of Colleges of Pharmacy.)

Introduction: Preeclampsia is a leading cause of maternal and perinatal morbidity and mortality. There is a need for adjuvant, targeted therapies to improve outcomes. Broccoli sprout extract, rich in the antioxidant sulforaphane, reduces oxidative stress and placental secretion of the antiangiogenic factors that contribute to vascular dysfunction in preeclampsia. We propose a phase III trial investigating broccoli sprout extract. We will assess broccoli sprout extract in women with early onset (<34 weeks) preeclampsia, investigating (1) the interval between enrolment and delivery (days), (2) biomarkers of placental and endothelial function and (3) maternal and fetal outcomes., Methods: A double-blind, placebo-controlled randomised trial will be conducted at Monash Health, Melbourne, Australia. One hundred and eighty women (45 each arm of each stratum) with early onset preeclampsia (defined as per Society for Obstetric Medicine of Australia and New Zealand guidelines) will be recruited. Consenting women will be randomised to receive an oral dose of either broccoli sprout extract (24 mg of activated sulforaphane) or identical placebo, twice daily until delivery. Maternal blood will be collected antenatally for measurement of biomarkers of preeclampsia, including soluble fms-like tyrosine kinase 1 (sFlt-1), placental growth factor (PlGF), soluble endoglin (sEng) and activin A, as well as circulating sulforaphane metabolites. Maternal and perinatal outcomes will be monitored throughout. All clinical care decisions, including the timing of delivery, will be made by the treating team, blinded to treatment allocation. Participation in this trial will not affect routine care. At delivery, maternal and cord blood and placentae will be collected to measure sulforaphane metabolites and sFlt-1, PlGF, sEng and activin A., Ethics and Dissemination: Approval to conduct the trial has been granted by Monash Health Human Research and Ethics Committee (RES-18-0000-109A). Deidentified data will be published in peer-reviewed journals and presented at learnt society conferences, both nationally and internationally. This study has not yet commenced and is pre-results. Trial registration number ACTRN12618000216213., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Pancreatic ductal adenocarcinoma is an aggressive cancer with limited treatment options 1 . Approximately 10% of cases exhibit familial predisposition, but causative genes are not known in most families 2 . We perform whole-genome sequence analysis in a family with multiple cases of pancreatic ductal adenocarcinoma and identify a germline truncating mutation in the member of the RAS oncogene family-like 3 (RABL3) gene. Heterozygous rabl3 mutant zebrafish show increased susceptibility to cancer formation. Transcriptomic and mass spectrometry approaches implicate RABL3 in RAS pathway regulation and identify an interaction with RAP1GDS1 (SmgGDS), a chaperone regulating prenylation of RAS GTPases 3 . Indeed, the truncated mutant RABL3 protein accelerates KRAS prenylation and requires RAS proteins to promote cell proliferation. Finally, evidence in patient cohorts with developmental disorders implicates germline RABL3 mutations in RASopathy syndromes. Our studies identify RABL3 mutations as a target for genetic testing in cancer families and uncover a mechanism for dysregulated RAS activity in development and cancer.

Background & Aims: Patients with cirrhosis are at high risk for hepatocellular carcinoma (HCC) and often have increased serum levels of estrogen. It is not clear how estrogen promotes hepatic growth. We investigated the effects of estrogen on hepatocyte proliferation during zebrafish development, liver regeneration, and carcinogenesis. We also studied human hepatocytes and liver tissues., Methods: Zebrafish were exposed to selective modifiers of estrogen signaling at larval and adult stages. Liver growth was assessed by gene expression, fluorescent imaging, and histologic analyses. We monitored liver regeneration after hepatocyte ablation and HCC development after administration of chemical carcinogens (dimethylbenzanthrazene). Proliferation of human hepatocytes was measured in a coculture system. We measured levels of G-protein-coupled estrogen receptor (GPER1) in HCC and nontumor liver tissues from 68 patients by immunohistochemistry., Results: Exposure to 17β-estradiol (E2) increased proliferation of hepatocytes and liver volume and mass in larval and adult zebrafish. Chemical genetic and epistasis experiments showed that GPER1 mediates the effects of E2 via the phosphoinositide 3-kinase-protein kinase B-mechanistic target of rapamycin pathway: gper1-knockout and mtor-knockout zebrafish did not increase liver growth in response to E2. HCC samples from patients had increased levels of GPER1 compared with nontumor tissue samples; estrogen promoted proliferation of human primary hepatocytes. Estrogen accelerated hepatocarcinogenesis specifically in male zebrafish. Chemical inhibition or genetic loss of GPER1 significantly reduced tumor development in the zebrafish., Conclusions: In an analysis of zebrafish and human liver cells and tissues, we found GPER1 to be a hepatic estrogen sensor that regulates liver growth during development, regeneration, and tumorigenesis. Inhibitors of GPER1 might be developed for liver cancer prevention or treatment., Transcript Profiling: The accession number in the Gene Expression Omnibus is GSE92544., (Copyright © 2019 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Lymphatic vascular development involves specification of lymphatic endothelial progenitors that subsequently undergo sprouting, proliferation and tissue growth to form a complex second vasculature. The Hippo pathway and effectors Yap and Taz control organ growth and regulate morphogenesis and cellular proliferation. Yap and Taz control angiogenesis but a role in lymphangiogenesis remains to be fully elucidated. Here we show that YAP displays dynamic changes in lymphatic progenitors and Yap1 is essential for lymphatic vascular development in zebrafish. Maternal and Zygotic (MZ) yap1 mutants show normal specification of lymphatic progenitors, abnormal cellular sprouting and reduced numbers of lymphatic progenitors emerging from the cardinal vein during lymphangiogenesis. Furthermore, Yap1 is indispensable for Vegfc-induced proliferation in a transgenic model of Vegfc overexpression. Paracrine Vegfc-signalling ultimately increases nuclear YAP in lymphatic progenitors to control lymphatic development. We thus identify a role for Yap in lymphangiogenesis, acting downstream of Vegfc to promote expansion of this vascular lineage., Competing Interests: LG, HN, SC, NB, KO, AC, NH, KK, NM, BH No competing interests declared, (© 2019, Grimm et al.)

Introduction: Preeclampsia is a disease specific to pregnancy characterised by new onset hypertension with maternal organ dysfunction and/or fetal growth restriction. It remains a major cause of maternal and perinatal morbidity and mortality. For fifty years, antihypertensives have been the mainstay of treating preeclampsia, reducing maternal morbidity and mortality. With increased knowledge of the mechanisms underlying the disease has come opportunities for novel therapies that complement antihypertensives by protecting the maternal vasculature. Areas covered: In this review, the authors consider, in detail, the antihypertensives commonly used today in the emergency care of women with severe preeclampsia. They also review less common anti-hypertensive agents and discuss the role of magnesium sulphate in the management of preeclampsia and the prevention of eclampsia. Finally, they explore novel therapeutics for the acute management of preeclampsia. Expert opinion: The rapid control of maternal hypertension will, and must, remain the mainstay of emergency treatment for women with severe preeclampsia. The role of magnesium sulphate as a primary prevention for eclampsia is context dependant and should not displace a focus on correcting blood pressure safely. The exploration of novel adjuvant therapies will likely allow us to prolong pregnancy longer and improve perinatal outcomes safely for the mother.

Introduction: The maternal endothelial dysfunction characteristic of preeclampsia arises, in part, from excessive placental production of anti-angiogenic factors, including soluble Flt-1, soluble endoglin and activin A, inducing oxidative stress. We assessed whether the antioxidant and NRF2-activator sulforaphane could mitigate endothelial and trophoblast dysfunction in vitro., Methods: We induced dysfunction in human umbilical vein endothelial cells (HUVECs) with TNF-α, assessing endothelial activation and dysfunction (endothelin-1, vascular cell adhesion molecule; VCAM1, intracellular adhesion molecule; ICAM1, e-selectin and endothelial permeability) in the presence or absence of sulforaphane. We also assessed the effects of sulforaphane in mitigating hypoxic and hyperoxic injury in term placental explants by measuring secretion of anti-angiogenic factors. To assess the role of NRF2 we silenced NRF2 in HUVECs and primary trophoblast cells., Results: Sulforaphane reduced TNF-α mediated HUVEC secretion of endothelin-1, VCAM1, ICAM1 and E-selectin, and prevented increased endothelial permeability. In placental explants, sulforaphane reduced the secretion of soluble Flt-1, soluble endoglin and activin A. Sulforaphane induced activation and nuclear translocation of NRF2 in HUVECs, inducing heme oxygenase 1. NRF2 silencing blocked some but not all of sulforaphane's effects in HUVECs. NRF2 silencing did not prevent sulforaphane's inhibition of trophobast secretion of soluble Flt-1 or activin A., Conclusion: In reducing placental and endothelial oxidative stress, sulforaphane may offer a new adjuvant therapeutic approach for the treatment of preeclampsia., (Copyright © 2019 International Society for the Study of Hypertension in Pregnancy. Published by Elsevier B.V. All rights reserved.)

Zebrafish ( Danio rerio ) are becoming an increasingly powerful model organism to study the role of metabolism in disease. Since its inception, the zebrafish model has relied on unique attributes such as the transparency of embryos, high fecundity and conservation with higher vertebrates, to perform phenotype-driven chemical and genetic screens. In this review, we describe how zebrafish have been used to reveal novel mechanisms by which metabolism regulates embryonic development, obesity, fatty liver disease and cancer. In addition, we will highlight how new approaches in advanced microscopy, transcriptomics and metabolomics using zebrafish as a model system have yielded fundamental insights into the mechanistic underpinnings of disease., (© 2019 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.)

Preeclampsia is a pregnancy-specific disorder, primarily characterized by new-onset hypertension in combination with a variety of other maternal or fetal signs. The pathophysiological mechanisms underlying the disease are still not entirely clear. Systemic maternal vascular dysfunction underlies the clinical features of preeclampsia. It is a result of oxidative stress and the actions of excessive anti-angiogenic factors, such as soluble fms-like tyrosine kinase, soluble endoglin, and activin A, released by a dysfunctional placenta. The vascular dysfunction then leads to impaired regulation and secretion of relaxation factors and an increase in sensitivity/production of constrictors. This results in a more constricted vasculature rather than the relaxed vasodilated state associated with normal pregnancy. Currently, the only effective "treatment" for preeclampsia is delivery of the placenta and therefore the baby. Often, this means a preterm delivery to save the life of the mother, with all the attendant risks and burdens associated with fetal prematurity. To lessen this burden, there is a pressing need for more effective treatments that target the maternal vascular dysfunction that underlies the hypertension. This review details the vascular effects of key drugs undergoing clinical assessment as potential treatments for women with preeclampsia., (© 2018 John Wiley & Sons Ltd.)

The Hippo pathway and its nuclear effector Yap regulate organ size and cancer formation. While many modulators of Hippo activity have been identified, little is known about the Yap target genes that mediate these growth effects. Here, we show that yap -/- mutant zebrafish exhibit defects in hepatic progenitor potential and liver growth due to impaired glucose transport and nucleotide biosynthesis. Transcriptomic and metabolomic analyses reveal that Yap regulates expression of glucose transporter glut1, causing decreased glucose uptake and use for nucleotide biosynthesis in yap -/- mutants, and impaired glucose tolerance in adults. Nucleotide supplementation improves Yap deficiency phenotypes, indicating functional importance of glucose-fueled nucleotide biosynthesis. Yap-regulated glut1 expression and glucose uptake are conserved in mammals, suggesting that stimulation of anabolic glucose metabolism is an evolutionarily conserved mechanism by which the Hippo pathway controls organ growth. Together, our results reveal a central role for Hippo signaling in glucose metabolic homeostasis., (© 2018 The Authors.)

Introduction: Maternal endothelial dysfunction underlying preeclampsia arises from excessive placental release of anti-angiogenic factors, such as soluble fms-like tyrosine kinase-1 (sFlt1), soluble endoglin (sEng) and activin A. Resveratrol, an activator of the nuclear factor erythroid 2-related factor-2 (Nrf2) transcription factor, mediates the gene expression of antioxidant and vasoprotective factors that may counter the endothelial damage imposed by these anti-angiogenic factors. The objective of this study was to assess whether resveratrol could reduce placental oxidative stress and production of anti-angiogenic factors in vitro and/or improve in vitro markers of endothelial dysfunction via Nrf2 activation., Method: We used in vitro term placental explants to assess the effects of resveratrol on placental oxidative stress and production of sFlt1, sEng and activin A. Using human umbilical vein endothelial cells we investigated the effects of resveratrol on markers of in vitro endothelial dysfunction, including the expression of intercellular adhesion molecule 1 (ICAM1), vascular cell adhesion molecule 1 (VCAM1), E-selectin and endothelin-1, and endothelial permeability. To confirm that resveratrol mediated its effects via Nrf2, we examined the impact of resveratrol on the same in vitro markers of endothelial and placental dysfunction following Nrf2 knockdown., Results: Resveratrol significantly decreased placental oxidative stress and the production of sFlt1 and activin A. Resveratrol significantly mitigated tumor necrosis factor-α stimulated endothelial expression of ICAM1, VCAM1, E-selectin and endothelin-1 and prevented an increase in endothelial monolayer permeability. Nrf2 knockdown abolished some of the protective effects of resveratrol on endothelial cells, but not in primary trophoblast cells., Conclusion: Features of placental and endothelial dysfunction characteristic of preeclampsia are improved by resveratrol in vitro, partially via the modulation of Nrf2., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Peripheral quantitative computed tomography (QCT) has been used in poultry bone research in recent years to analyze cortical and cross-sectional geometry. For QCT to be used as a standard research tool for analysis of bones of laying hens (cortical thickness <2 mm), the accuracy of the scans must be assessed. The primary difference between the QCT and micro-computed tomography (micro-CT) is image resolution. Image resolution is inversely related to the pixel size. The aim of the current study was to correlate the cortical parameters measured using clinical CT scans with the measurements from micro-CT, the current gold standard. A total of 15 tibiae and 14 humeri of Lohmann White hens was scanned using clinical CT and micro-CT. Reconstruction of the scans generated images with final voxel resolution of 195 μm for clinical CT scans and 46 μm for micro-CT scans. Cortical and total area were measured using MIMICS® software at proximal, middle, and distal locations of 20 mm sections of humerus diaphysis and 30 mm sections of tibia diaphysis. The total area for proximal and middle locations as well as proximal cortical area measurements for humeri produced strong correlation coefficients (R ≥ 0.70). Moderate strength correlation coefficients (R = 0.40 to 0.60) in humeri were seen in middle and distal cortical areas. Distal total area in humeri displayed a weak correlation coefficient (R ≤ 0.3; P = 0.25). Overall, tibiae demonstrated a weaker correlation. Proximal and middle cortical areas indicated moderate correlation coefficients (R = 0.40 to 0.60), while proximal and middle total areas accompanied by distal cortical and total area displayed weak correlation coefficients (R ≤ 0.3). Only the middle cortical area measurement for tibiae was significant (P = 0.03). These results indicate stronger correlation for humeri measurements among the scans than tibia. Overall, cross-sectional area measurements were only low to moderately correlated between clinical and micro-CT scans., (© 2017 Poultry Science Association Inc.)

As part of the 2014-15 Academic Leadership Fellows Program, the cohort teams presented debates on topics relevant to academic pharmacy at a public forum during the 2015 American Association of Colleges of Pharmacy Interim Meeting. The topic of one of the debates was "Academic Freedom Should Be Redefined." The "point" of the debate focused on important issues such as the fundamental definition of academic freedom as it was written in the 1940 American Association of University Professors' Statement and the need for redefinition as a consequence of many misunderstandings and misinterpretations that have arisen over time. The "counterpoint" received the greatest support, and it asserted that redefinition is not necessary, but rather the need is to clearly articulate the intended meaning of academic freedom through education, discussion, and by not supporting inappropriate behaviors in the name of "academic freedom." Reinforced clarity and operational guidance from the academy and academic institutions may add further clarification and may be the best approach to address the concerns related to academic freedom.

Selenium, an essential micronutrient known for its cancer prevention properties, is incorporated into a class of selenocysteine-containing proteins (selenoproteins). Selenoprotein H (SepH) is a recently identified nucleolar oxidoreductase whose function is not well understood. Here we report that seph is an essential gene regulating organ development in zebrafish. Metabolite profiling by targeted LC-MS/MS demonstrated that SepH deficiency impairs redox balance by reducing the levels of ascorbate and methionine, while increasing methionine sulfoxide. Transcriptome analysis revealed that SepH deficiency induces an inflammatory response and activates the p53 pathway. Consequently, loss of seph renders larvae susceptible to oxidative stress and DNA damage. Finally, we demonstrate that seph interacts with p53 deficiency in adulthood to accelerate gastrointestinal tumor development. Overall, our findings establish that seph regulates redox homeostasis and suppresses DNA damage. We hypothesize that SepH deficiency may contribute to the increased cancer risk observed in cohorts with low selenium levels., Competing Interests: The authors declare no conflict of interest.