Renewing Ranobe for Tomorrow: An Integrated Approach to Sustainable Development in Madagascar

The Spiny Forest in southwest Madagascar is home to a 90% endemic array of species and the village of Ranobe. Climate change and deforestation through charcoal production, agricultural use, and development, have degraded 43% of land cover in the last decade. This project collaborated with Ho Avy, a local nonprofit, to design a sustainable development plan for the community. The plan is based on five key perspectives: 1) land use/land cover change management, 2) energy potential, 3) water and health, 4) food security, and 5) economic growth. The plan recommends increased education, shifting incentives, and investment in renewable technologies to be implemented in Ranobe to improve the health of the region’s population and unique environment.Master of ScienceNatural Resources and EnvironmentUniversity of Michiganhttp://deepblue.lib.umich.edu/bitstream/2027.42/83529/1/RenewingRanobeforTomorrow_SNRE_20110419.pd

Sparrow Nest Survival in Relation to Prescribed Fire and Woody Plant Invasion in a Northern Mixed-Grass Prairie

Prescribed fire is used to reverse invasion by woody vegetation on grasslands, but managers often are uncertain whether influences of shrub and tree reduction outweigh potential effects of fire on nest survival of grassland birds. During the 2001–2003 breeding seasons, we examined relationships of prescribed fire and woody vegetation to nest survival of clay-colored sparrow (Spizella pallida) and Savannah sparrow (Passerculus sandwichensis) in mixed-grass prairie at Des Lacs National Wildlife Refuge in northwestern North Dakota, USA.We assessed relationships of nest survival to 1) recent fire history, in terms of number of breeding seasons (2, 3, or 4–5) since the last prescribed fire, and 2) prevalence of trees and tall (\u3e1.5 m) shrubs in the landscape and of low (≤1.5 m) shrubs within 5 m of nests. Nest survival of both species exhibited distinct patterns related to age of the nest and day of year, but bore no relationship to fire history. Survival of clay-colored sparrow nests declined as the amount of trees and tall shrubs within 100 m increased, but we found no relationship to suggest nest parasitism by brown-headed cowbirds (Molothrus ater) as an underlying mechanism. We found little evidence linking nest survival of Savannah sparrow to woody vegetation. Our results suggest that fire can be used to restore northern mixed-grass prairies without adversely affecting nest survival of ≥2 widespread passerine species. Survival of nests of clay-colored sparrow may increase when tall woody cover is reduced by fire. Our data lend support to the use of fire for reducing scattered patches of tall woody cover to enhance survival of nests of ≥1 grassland bird species in northern mixed-grass prairies, but further study is needed that incorporates experimental approaches and assessments of shorter term effects of fire on survival of nests of grassland passerines

ADAM22/LGI1 complex as a new actionable target for breast cancer brain metastasis

Background: Metastatic breast cancer is a major cause of cancer-related deaths in woman. Brain metastasis is a common and devastating site of relapse for several breast cancer molecular subtypes, including oestrogen receptor-positive disease, with life expectancy of less than a year. While efforts have been devoted to developing therapeutics for extra-cranial metastasis, drug penetration of blood–brain barrier (BBB) remains a major clinical challenge. Defining molecular alterations in breast cancer brain metastasis enables the identification of novel actionable targets.Methods: Global transcriptomic analysis of matched primary and metastatic patient tumours (n = 35 patients, 70 tumour samples) identified a putative new actionable target for advanced breast cancer which was further validated in vivo and in breast cancer patient tumour tissue (n = 843 patients). A peptide mimetic of the target's natural ligand was designed in silico and its efficacy assessed in in vitro, ex vivo and in vivo models of breast cancer metastasis.Results: Bioinformatic analysis of over-represented pathways in metastatic breast cancer identified ADAM22 as a top ranked member of the ECM-related druggable genome specific to brain metastases. ADAM22 was validated as an actionable target in in vitro, ex vivo and in patient tumour tissue (n = 843 patients). A peptide mimetic of the ADAM22 ligand LGI1, LGI1MIM, was designed in silico. The efficacy of LGI1MIM and its ability to penetrate the BBB were assessed in vitro, ex vivo and in brain metastasis BBB 3D biometric biohybrid models, respectively. Treatment with LGI1MIM in vivo inhibited disease progression, in particular the development of brain metastasis.Conclusion: ADAM22 expression in advanced breast cancer supports development of breast cancer brain metastasis. Targeting ADAM22 with a peptide mimetic LGI1MIM represents a new therapeutic option to treat metastatic brain disease

Integrated Lipidomics and Proteomics Point to Early Blood-Based Changes in Childhood Preceding Later Development of Psychotic Experiences: Evidence From the Avon Longitudinal Study of Parents and Children

Background: The identification of early biomarkers of psychotic experiences (PEs) is of interest because early diagnosis and treatment of those at risk of future disorder is associated with improved outcomes. The current study investigated early lipidomic and coagulation pathway protein signatures of later PEs in subjects from the Avon Longitudinal Study of Parents and Children cohort.Methods: Plasma of 115 children (12 years of age) who were first identified as experiencing PEs at 18 years of age (48 cases and 67 controls) were assessed through integrated and targeted lipidomics and semitargeted proteomics approaches. We assessed the lipids, lysophosphatidylcholines (n = 11) and phosphatidylcholines (n = 61), and the protein members of the coagulation pathway (n = 22) and integrated these data with complement pathway protein data already available on these subjects.Results: Twelve phosphatidylcholines, four lysophosphatidylcholines, and the coagulation protein plasminogen were altered between the control and PEs groups after correction for multiple comparisons. Lipidomic and proteomic datasets were integrated into a multivariate network displaying a strong relationship between most lipids that were significantly associated with PEs and plasminogen. Finally, an unsupervised clustering approach identified four different clusters, with one of the clusters presenting the highest case-control ratio (p Conclusions: Our findings indicate that the lipidome and proteome of subjects who report PEs at 18 years of age are already altered at 12 years of age, indicating that metabolic dysregulation may contribute to an early vulnerability to PEs and suggesting crosstalk between these lysophosphatidylcholines, phosphatidylcholines, and coagulation and complement proteins.</p

Integrated lipidomics and proteomics point to early blood-based changes in childhood preceding later development of psychotic experiences: evidence from the Avon Longitudinal Study of Parents and Children

Background The identification of early biomarkers of psychotic experiences (PEs) is of interest as early diagnosis and treatment of those at risk of future disorder is associated with improved outcomes. The current study investigated early lipidomic and coagulation pathway protein signatures of later PEs in subjects from the Avon Longitudinal Study of Parents and Children cohort. Methods Plasma of 115 children (age 12) who were first identified as experiencing PEs at age 18 (48 cases and 67 controls) were assessed through integrated and targeted lipidomics and semi-targeted proteomics approaches. We assessed the lipids, LPCs (n=11) and PCs (n=61), and the protein members of the coagulation pathway (n=22) and integrated this data with complement pathway protein data already available on these subjects. Results Twelve PCs, four LPCs and the coagulation protein plasminogen were altered between the control and PE group after correction for multiple comparisons. Lipidomic and proteomic datasets were integrated into a multivariate network displaying a strong relationship between most lipids that were significantly associated to PEs and plasminogen. Finally, an unsupervised clustering approach identified four different clusters with one of the clusters presenting the highest ratio cases:controls (P < 0.01) and associated with a higher concentration of smaller LDL cholesterol particles. Conclusions Our findings indicate that the lipidome and proteome of subjects who report PEs at age 18 is already altered at age 12 indicating that metabolic dysregulation may contribute to an early vulnerability to PEs and suggesting cross-talk between these LPCs, PCs and coagulation and complement proteins

Reduced response to IKr blockade and altered hERG1a/1b stoichiometryin human heart failure

Heart failure (HF) claims 250,000 lives per year in the US, and nearly half of these deaths are sudden and presumably due to ventricular tachyarrhythmias. QT interval and action potential (AP) prolongation are hallmark proarrhythmic changes in the failing myocardium, which potentially result from alterations in repolarizing potassium currents. Thus,we aimed to examinewhether decreased expression of the rapid delayed rectifier potassiumcurrent, IKr, contributes to repolarization abnormalities in human HF. Tomap functional IKr expression across the left ventricle (LV), we optically imaged coronary-perfused LV free wall from donor and end-stage failing human hearts. The LV wedge preparation was used to examine transmural AP durations at 80% repolarization (APD80), and treatment with the IKr-blocking drug, E-4031, was utilized to interrogate functional expression. We assessed the percent change in APD80 post-IKr blockade relative to baseline APD80 (&#916;APD80) and found that &#916;APD80s are reduced in failing versus donor hearts in each transmural region, with 0.35-, 0.43-, and 0.41-fold reductions in endo-, mid-, and epicardium, respectively (p = 0.008, 0.037, and 0.022). We then assessed hERG1 isoform gene and protein expression levels using qPCR and Western blot. While we did not observe differences in hERG1a or hERG1b gene expression between donor and failing hearts, we found a shift in the hERG1a:hERG1b isoform stoichiometry at the protein level. Computer simulations were then conducted to assess IKr block under E-4031 influence in failing and nonfailing conditions. Our results confirmed the experimental observations and E-4031-induced relative APD80 prolongationwas greater in normal conditions than in failing conditions, provided that the cellularmodel of HF included a significant downregulation of IKr. In humanHF, the response to IKr blockade is reduced, suggesting decreased functional IKr expression. This attenuated functional response is associated with altered hERG1a:hERG1b protein stoichiometry in the failing human LV, and failing cardiomyoctye simulations support the experimental findings. Thus, of IKr protein and functional expression may be important determinants of repolarization remodeling in the failing human LV.We thank the Translational Cardiovascular Biobank & Repository (TCBR) at Washington University for provision of donor/patient records. The TCBR is supported by the NIH/CTSA (UL1 TR000448), Children's Discovery Institute, and Richard J. Wilkinson Trust. We also thank the laboratory of Dr. Sakiyama-Elbert for the use of the StepOnePlus equipment We appreciate the critical feedback on the manuscript by Dr. Jeanne Nerbonne. This work has been supported by the National Heart, Lung & Blood Institute (NHLBI, R01 HL114395). K. Holzem has been supported by the American Heart Association (12PRE12050315) and the NHLBI (F30 HL114310).Holzem, KM.; Gómez García, JF.; Glukhov, AV.; Madden, EJ.; Koppel, AC.; Ewald, GA.; Trénor Gomis, BA.... (2016). Reduced response to IKr blockade and altered hERG1a/1b stoichiometryin human heart failure. Journal of Molecular and Cellular Cardiology. 96:82-92. https://doi.org/10.1016/j.yjmcc.2015.06.008S82929

Psychiatric and medical comorbidities of eating disorders : findings from a rapid review of the literature

Background: Eating disorders (EDs) are potentially severe, complex, and life-threatening illnesses. The mortality rate of EDs is signifcantly elevated compared to other psychiatric conditions, primarily due to medical complications and suicide. The current rapid review aimed to summarise the literature and identify gaps in knowledge relating to any psychiatric and medical comorbidities of eating disorders. Methods: This paper forms part of a rapid review) series scoping the evidence base for the feld of EDs, conducted to inform the Australian National Eating Disorders Research and Translation Strategy 2021–2031, funded and released by the Australian Government. ScienceDirect, PubMed and Ovid/Medline were searched for English-language studies focused on the psychiatric and medical comorbidities of EDs, published between 2009 and 2021. High-level evidence such as meta-analyses, large population studies and Randomised Control Trials were prioritised. Results: A total of 202 studies were included in this review, with 58% pertaining to psychiatric comorbidities and 42% to medical comorbidities. For EDs in general, the most prevalent psychiatric comorbidities were anxiety (up to 62%), mood (up to 54%) and substance use and post-traumatic stress disorders (similar comorbidity rates up to 27%). The review also noted associations between specifc EDs and non-suicidal self-injury, personality disorders, and neurodevelopmental disorders. EDs were complicated by medical comorbidities across the neuroendocrine, skeletal, nutritional, gastrointestinal, dental, and reproductive systems. Medical comorbidities can precede, occur alongside or emerge as a complication of the ED. Conclusions: This review provides a thorough overview of the comorbid psychiatric and medical conditions cooccurring with EDs. High psychiatric and medical comorbidity rates were observed in people with EDs, with comorbidities contributing to increased ED symptom severity, maintenance of some ED behaviours, and poorer functioning as well as treatment outcomes. Early identifcation and management of psychiatric and medical comorbidities in people with an ED may improve response to treatment and overall outcomes