40 results on '"L. McRae"'
Search Results
2. Decreased Protein C Pathway Activity in COVID-19 Compared to Non-COVID Sepsis: An Observational and Comparative Cohort Study
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Heiko Rühl, Christian Bode, Tobias Becher, Sebastian Eckert, Ghaith Mohsen, Hannah L. McRae, Jens Müller, Sara Reda, Dirk Loßnitzer, Johannes Oldenburg, Christian Putensen, and Bernd Pötzsch
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COVID-19 ,protein C ,sepsis ,thrombin ,thrombophilia ,Biology (General) ,QH301-705.5 - Abstract
Sepsis-associated coagulopathy increases risk of mortality. Impairment of the anticoagulant protein C (PC) pathway may contribute to the thrombotic phenotype in coronavirus disease 2019 (COVID-19) sepsis. This study assessed the functionality of this pathway in COVID-19 and non-COVID sepsis by measuring its key enzymes, thrombin and activated PC (APC). The study population included 30 patients with COVID-19, 47 patients with non-COVID sepsis, and 40 healthy controls. In healthy controls, coagulation activation and subsequent APC formation was induced by 15 µg/kg recombinant activated factor VII one hour before blood sampling. APC and thrombin in plasma were measured using oligonucleotide-based enzyme capture assays. The indirect thrombin markers prothrombin-fragment 1+2 (F1+2) and thrombin-antithrombin complex (TAT) were also measured. Compared with stimulated healthy controls, median thrombin, F1+2, and TAT levels were higher in patients with COVID-19 (up to 6-fold, p < 2 × 10−6) and non-COVID sepsis (up to 4.7-fold, p < 0.010). APC levels were 2.4-fold higher in patients with COVID-19 (7.44 pmol/L, p = 0.011) and 3.4-fold higher in non-COVID sepsis patients (10.45 pmol/L, p = 2 × 10−4) than in controls (3.08 pmol/L). Thrombin markers and APC showed correlation in both COVID-19 (r = 0.364–0.661) and non-COVID sepsis patients (r = 0.535–0.711). After adjustment for PC levels, median APC/thrombin, APC/F1+2, and APC/TAT ratios were 2-fold (p = 0.036), 6-fold (p = 3 × 10−7) and 3-fold (p = 8 × 10−4) lower in the COVID-19 group than in the non-COVID sepsis group, and the latter two were also lower in the COVID-19 group than in stimulated healthy controls. In conclusion, it was found that a comparatively lower anticoagulant APC response in COVID-19 patients as compared to non-COVID sepsis patients, potentially linked to endothelial dysfunction, contributes to the prothrombotic phenotype of COVID-19 sepsis.
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- 2024
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3. Dynamics of necroptosis in kidney ischemia-reperfusion injury
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Aspasia Pefanis, Anjan K. Bongoni, Jennifer L. McRae, Evelyn J. Salvaris, Nella Fisicaro, James M. Murphy, Francesco L. Ierino, and Peter J. Cowan
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necroptosis ,ischemia-reperfusion ,necroinflammation ,mlkl ,acute kidney injury ,chronic kidney disease ,Immunologic diseases. Allergy ,RC581-607 - Abstract
Necroptosis, a pathway of regulated necrosis, involves recruitment and activation of RIPK1, RIPK3 and MLKL, leading to cell membrane rupture, cell death and release of intracellular contents causing further injury and inflammation. Necroptosis is believed to play an important role in the pathogenesis of kidney ischemia-reperfusion injury (IRI). However, the dynamics of necroptosis in kidney IRI is poorly understood, in part due to difficulties in detecting phosphorylated MLKL (pMLKL), the executioner of the necroptosis pathway. Here, we investigated the temporal and spatial activation of necroptosis in a mouse model of unilateral warm kidney IRI, using a robust method to stain pMLKL. We identified the period 3-12 hrs after reperfusion as a critical phase for the activation of necroptosis in proximal tubular cells. After 12 hrs, the predominant pattern of pMLKL staining shifted from cytoplasmic to membrane, indicating progression to the terminal phase of necroptotic cell death. Mlkl-ko mice exhibited reduced kidney inflammation at 12 hrs and lower serum creatinine and tubular injury at 24 hrs compared to wild-type littermates. Interestingly, we observed increased apoptosis in the injured kidneys of Mlkl-ko mice, suggesting a relationship between necroptosis and apoptosis in kidney IRI. Together, our findings confirm the role of necroptosis and necroinflammation in kidney IRI, and identify the first 3 hrs following reperfusion as a potential window for targeted treatments.
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- 2023
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4. Consideration of sex and gender differences in addiction medication response
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Sherry A. McKee and Aimee L. McRae-Clark
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Sex ,Gender ,Addiction ,Substance ,Medication development ,Nicotine ,Medicine ,Physiology ,QP1-981 - Abstract
Highlights Substance use continues to contribute to significant morbidity and mortality in the United States. To reduce the public health burden attributable to substances, the National Institute on Drug Abuse and the National Institute on Alcohol Abuse and Alcoholism have identified that medication development for substance use disorder is a high priority research area. We reviewed major classes of abused substances (nicotine, alcohol, cocaine, cannabis, opioids) demonstrating that, sex and gender have not been well-considered in addiction medication development research. When adequate data on sex and gender differences have been evaluated (i.e., in tobacco cessation), clinically significant differences in response have been identified between women and men. However, these data are not at all considered in clinical care guidelines. We recommend improved access to publicly available sex-stratified data from medication development investigations, to inform clinical practice and to improve treatment provided to women with substance use disorders.
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- 2022
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5. Differential prevalence of Adverse Childhood Experiences (ACEs) by gender and substance used in individuals with cannabis, cocaine, opioid, and tobacco use disorders
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Erin L. Martin, Brian Neelon, Kathleen T. Brady, Constance Guille, Nathaniel L. Baker, Viswanathan Ramakrishnan, Kevin M. Gray, Michael E. Saladin, and Aimee L. McRae-Clark
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Psychiatry and Mental health ,Clinical Psychology ,Medicine (miscellaneous) ,Article - Abstract
BACKGROUND: Adverse childhood experiences (ACEs) show a graded association with the development of substance use disorders and engagement in risky substance use behaviors. Women are overrepresented among individuals with more severe childhood adversity (≥4 types of ACEs) and may be at particular risk for aberrant substance use. OBJECTIVES: To assess the prevalence of ACEs among men and women with cannabis, opioid, cocaine, and tobacco use disorders. METHODS: Non-treatment-seeking individuals participating in clinical addiction research at a single site completed the ACE questionnaire and provided a detailed substance use history. Data were analyzed using proportional odds models and logistic regression. RESULTS: Most participants (424/565; 75%) reported at least one ACE, and more than one-quarter (156/565; 27%) reported severe childhood adversity. Relative to men (n=283), women (n=282) reported more ACEs (OR=1.49; p=0.01) and more experiences of emotional/physical abuse (OR=1.52; p=0.02), sexual abuse (OR=4.08; p=0.04), and neglect (OR=2.30; p
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- 2023
6. Ex Vivo Modeling of the PC (Protein C) Pathway Using Endothelial Cells and Plasma: A Personalized Approach
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Nadine Schwarz, Jens Müller, Hamideh Yadegari, Hannah L. McRae, Sara Reda, Nasim Shahidi Hamedani, Johannes Oldenburg, Bernd Pötzsch, and Heiko Rühl
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Thrombin ,Humans ,Endothelial Cells ,Cardiology and Cardiovascular Medicine ,Blood Coagulation ,Protein C - Abstract
Background: The endothelial cell–dependent PC (protein C) pathway is critically involved in the regulation of coagulation, anti-inflammatory, and cytoprotective signaling. Its reactivity shows high interindividual variability, and it contributes to prothrombotic disorders, such as the FVL (factor V Leiden) mutation. Methods: Endothelial colony–forming cells (ECFCs) were isolated from heparinized peripheral blood from healthy individuals and FVL carriers. Confluent monolayers of ECFCs were overlaid with plasma, and thrombin formation was initiated by addition of tissue factor (1 pmol/L). Subsequently, thrombin and APC (activated PC) formation rates were measured over time using oligonucleotide-based enzyme capture assays. To induce downregulation of TM (thrombomodulin) expression, ECFCs were stimulated with IL-1β (interleukin 1β). In vivo APC response rates were monitored in study participants after infusion of low-dose rFVIIa (recombinant activated factor VII). Results: The median peak APC concentration was 1.12 nmol/L in experiments with IL-1β stimulated ECFCs and 3.66 nmol/L without IL-1β. Although thrombin formation rates were comparable, APC formation rates were significantly higher in FVL carriers (n=6) compared to noncarriers (n=5) as evidenced by a higher ratio between the area under the curve of APC generation to the area under the curve of thrombin generation (median 0.090 versus 0.031, P =0.017). These ex vivo results were correlated with an increased APC response to rFVIIa-induced thrombin formation in FVL carriers in vivo. Conclusions: Patient-specific ex vivo modeling of the PC pathway was achieved using blood-derived ECFCs. The correlation between in and ex vivo APC response rates confirms that the autologous PC model accurately depicts the in vivo situation.
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- 2023
7. DNA sensor-associated type I interferon signaling is increased in ulcerative colitis and induces JAK-dependent inflammatory cell death in colonic organoids
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Peter Flood, Aine Fanning, Jerzy A. Woznicki, Tadhg Crowley, Andrea Christopher, Alessandra Vaccaro, Aileen Houston, Sheila McSweeney, Sarah Ross, Aileen Hogan, Elizabeth Brint, Agnieszka Skowyra, Milan Bustamante, Monica Ambrose, Gerard Moloney, John MacSharry, Marie-Louise Hammarström, Margot Hurley, Christine Fitzgibbons, Eamonn M. M. Quigley, Fergus Shanahan, Syed A. Zulquernain, Jane McCarthy, G. Steven Dodson, Karim Dabbagh, Bradford L. McRae, Silvia Melgar, and Ken Nally
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Inflammasomes ,Physiology ,Epithelium ,Inflammasome ,Physiology (medical) ,NLR Family, Pyrin Domain-Containing 3 Protein ,Humans ,Janus Kinase Inhibitors ,Cell Death ,Hepatology ,Tumor Necrosis Factor-alpha ,Caspase 1 ,Interleukin-18 ,Gastroenterology ,DNA ,Pyrin ,Caspase Inhibitors ,Nucleotidyltransferases ,Antigens, Differentiation ,Organoids ,DNA-Binding Proteins ,Ulcerative colitis ,JAK inhibitor ,Interferon Type I ,Interferon ,Colitis, Ulcerative - Abstract
DNA sensor pathways can initiate inflammasome, cell death and type I interferon (IFN) signalling in immune-mediated inflammatory diseases (IMIDs); including type I interferonopathies. We investigated the involvement of these pathways in the pathogenesis of ulcerative colitis (UC); by analysing expression of DNA sensor, inflammasome, and type I IFN biomarker genes in colonic mucosal biopsy tissue from control (n=31), inactive UC (n=31), active UC (n=33) and a UC single cell RNA-Seq dataset. The effects of type I IFN (IFN-β), IFN-γ and TNF-α on gene expression, cytokine production and cell death were investigated in human colonic organoids. In organoids treated with cytokines alone, or in combination with NLRP3, caspase or JAK inhibitors, cell death was measured, and supernatants were assayed for IL-1β/IL-18/CXCL10. The expression of DNA sensor pathway genes - PYHIN family members (AIM2, IFI16, MNDA, PYHIN1), as well as ZBP1, cGAS and DDX41 were increased in active UC and expressed in a cell type restricted pattern. Inflammasome genes (CASP1, IL1B, IL18), type I IFN inducers (STING, TBK1, IRF3), IFNB1 and type I IFN biomarker genes (OAS2, IFIT2, MX2) were also increased in active UC. Co-treatment of organoids with IFN-β or IFN-γ and TNFα increased expression of IFI16, ZBP1, CASP1, cGAS and STING, induced cell death and IL-1β/IL-18 secretion. This inflammatory cell death was blocked by the JAK inhibitor tofacitinib but not by inflammasome or caspase inhibitors. Increased type I IFN activity may drive elevated expression of DNA sensor genes and JAK-dependent but inflammasome-independent inflammatory cell death of colonic epithelial cells in UC.
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- 2022
8. Assay for ADAMTS-13 Activity with Flow Cytometric Readout
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Jens Müller, Nasim Shahidi Hamedani, Hannah L. McRae, Heiko Rühl, Johannes Oldenburg, and Bernd Pötzsch
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General Chemical Engineering ,General Chemistry - Abstract
A disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 (ADAMTS-13) is a metalloprotease that regulates the size of circulating von Willebrand factor (vWF) multimers. Severe lack of ADAMTS-13 activity [10% of normal (0.1 IU/mL)] leads to thrombotic thrombocytopenic purpura (TTP), a specific type of thrombotic microangiopathy (TMA). Timely determination of plasma ADAMTS-13 activity is essential to discriminate TTP from other types of TMA with respect to adequate treatment. Identification of the minimal substrate motif for ADAMTS-13 within the A2 domain of vWF (vWF73) as well as the generation of monoclonal antibodies (mAbs) that specifically recognize the ADAMTS-13 cleavage site enabled the development of a variety of methods for determination of plasma ADAMTS-13 activity. In order to further extend the range of analytical platforms applicable for quantitative determination of plasma ADAMTS-13 activity, a specific, vWF/mAb-based assay with flow cytometric readout was developed and validated. Basic assay characteristics include a total assay time of 80 to 90 min, a near linear dynamic range from 0.005 (lower limit of quantification) to 0.2 IU/mL, and intra- and interassay coefficients of variation below 5 and 30% at input plasma ADAMTS-13 activities of 0.015 and ≤0.050 IU/mL, respectively. When compared to the results obtained with a commercially available quantitative ADAMTS-13 activity ELISA, analysis of 18 plasma samples obtained from patients with suspected TTP revealed full agreement of results with respect to the clinical 0.1 IU/mL TTP threshold. Based on these data, it is assumed that the described assay principle can be successfully transferred to virtually all laboratories that have a flow cytometer available.
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- 2022
9. Evaluating cannabis use risk reduction as an alternative clinical outcome for cannabis use disorder
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Jacob T. Borodovsky, Aimee L. McRae-Clark, Kevin M. Gray, Brian J. Sherman, Michael J. Sofis, and Alan J. Budney
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Adult ,Male ,Marijuana Abuse ,medicine.medical_specialty ,media_common.quotation_subject ,Medicine (miscellaneous) ,Hospital Anxiety and Depression Scale ,Double-Blind Method ,Internal medicine ,medicine ,Humans ,Child ,Depression (differential diagnoses) ,Cannabis ,media_common ,biology ,Repeated measures design ,Cannabis use ,Abstinence ,biology.organism_classification ,Clinical trial ,Psychiatry and Mental health ,Clinical Psychology ,Treatment Outcome ,Anxiety ,Female ,medicine.symptom ,Psychology ,Risk Reduction Behavior - Abstract
OBJECTIVE Abstinence is rarely achieved in clinical trials for cannabis use disorder (CUD). Cannabis reduction is associated with functional improvement, but reduction endpoints have not been established, indicating a need to identify and validate clinically meaningful reduction endpoints for assessing treatment efficacy. METHOD Data from a 12-week double-blind randomized placebo-controlled medication trial for cannabis cessation (NCT01675661) were analyzed. Participants (N = 225) were treatment-seeking adults, M = 30.6 (8.9) years old, 70.2% male, and 42.2% Non-White, with CUD who completed 12 weeks of treatment. Frequency (days of use per week) and quantity (grams per using day) were used to define high-, medium-, and low-risk levels. Anxiety and depression were assessed using the Hospital Anxiety and Depression Scale and cannabis-related problems were assessed using the Marijuana Problems Scale. General linear models for repeated measures tested associations between the magnitude of risk reduction and functional outcomes from baseline (BL) to end-of-treatment (EOT). RESULTS Cannabis risk levels were sensitive to reductions in use from BL to EOT for frequency- (χ² = 19.35, p = .004) and quantity-based (χ² = 52.06, p < .001) metrics. Magnitude reduction in frequency-based risk level was associated with magnitude decrease in depression (F = 2.76, p = .043, ηp² = .04), anxiety (F = 3.70, p = .013, ηp² = .05), and cannabis-related problems (F = 8.95, p < .001, ηp² = .12). Magnitude reduction in quantity-based risk level was associated with magnitude decrease in anxiety (F = 3.02, p = .031, ηp² = .04) and cannabis-related problems (F = 3.24, p = .023, ηp² = .05). CONCLUSIONS Cannabis use risk levels, as operationalized in this study, captured reductions in use during a clinical trial. Risk level reduction was associated with functional improvement suggesting that identifying risk levels and measuring the change in levels over time may be a viable and clinically meaningful endpoint for determining treatment efficacy. (PsycInfo Database Record (c) 2021 APA, all rights reserved).
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- 2022
10. Sex and drug differences in stress, craving and cortisol response to the trier social stress task
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Nathaniel L. Baker, Brian Neelon, Viswanathan Ramakrishnan, Kathleen T. Brady, Kevin M. Gray, Michael E. Saladin, Sudie E. Back, Julianne C. Flanagan, Constance Guille, and Aimee L McRae-Clark
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Pharmacology - Published
- 2022
11. OP073 [Post PICU » Post PICU Psychological Impact]: THE CARING INTENSIVELY STUDY: EXPLORING FAMILY MEMBERS’ PERCEPTIONS OF PSYCHOLOGICAL OUTCOMES 3-YEARS FOLLOWING PICU HOSPITALIZATION
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J. E. Rennick, A. M. Knox, K. Dryden Palmer, M. Campbell Yeo, C. Chambers, D. M. Stack, G. Dougherty, S. C. Treherne, L. Mcrae, M. Ho, and R. Stremler
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Pediatrics, Perinatology and Child Health ,Critical Care and Intensive Care Medicine - Published
- 2022
12. Developmental trajectories of alcohol and cannabis concurrent use in a nationally representative sample of United States youths
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Walter Roberts, Melissa R. Schick, Rachel L. Tomko, Aimee L. McRae-Clark, Brian Pittmann, Ralitza Gueorgieva, and Sherry A. McKee
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Pharmacology ,Psychiatry and Mental health ,Pharmacology (medical) ,Toxicology - Published
- 2023
13. Correction to: Consideration of sex and gender differences in addiction medication response
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Sherry A. McKee and Aimee L. McRae-Clark
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Gender Studies ,Endocrinology - Published
- 2022
14. Epithelial dysfunction is prevented by IL-22 treatment in a Citrobacter rodentium-induced colitis model that shares similarities with inflammatory bowel disease
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Qifan Zhu, Daniel Korenfeld, Abel Suarez-Fueyo, Sean Graham, Liang Jin, Shivesh Punit, Rachael Duffy, Munish Puri, Andrew Caruso, Chenqi Hu, Yu Tian, Bradford L. McRae, Raj Kamath, Lucy Phillips, Annette J. Schwartz-Sterman, Susan Westmoreland, Xiaohong Cao, Marc C. Levesque, Yingtao Bi, Jesus Paez-Cortez, and Radhika Goenka
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Intestines ,Mice, Inbred C57BL ,Mice ,Interleukins ,Immunology ,Enterobacteriaceae Infections ,Immunology and Allergy ,Animals ,Citrobacter rodentium ,Intestinal Mucosa ,Colitis ,Inflammatory Bowel Diseases - Abstract
Inflammatory bowel disease (IBD) is characterized by a dysregulated intestinal epithelial barrier leading to breach of barrier immunity. Here we identified similar protein expression changes between IBD and Citrobacter rodentium-infected FVB mice with respect to dysregulation of solute transporters as well as components critical for intestinal barrier integrity. We attribute the disease associated changes in the model to the emergence of undifferentiated intermediate intestinal epithelial cells. Prophylactic treatment with IL-22.Fc in C. rodentium-infected FVB mice reduced disease severity and rescued the mice from lethality. Multi-omics and solute analyses revealed that IL-22.Fc treatment prevented disease-associated changes including disruption of the solute transporter machinery and restored proper physiological functions of the intestine, respectively. Taken together, we established the disease relevance of the C. rodentium-induced colitis model to IBD, demonstrated the protective role of IL-22 in amelioration of epithelial dysfunction and elucidated the molecular mechanisms with IL-22's effect on intestinal epithelial cells.
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- 2021
15. Essential Role of Rho-Associated Kinase in ABO Immune Complex-Mediated Endothelial Barrier Disruption
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Hannah L. McRae, Michelle Warren Millar, Spencer A. Slavin, Neil Blumberg, Arshad Rahman, and Majed A. Refaai
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congenital, hereditary, and neonatal diseases and abnormalities ,QH301-705.5 ,Medicine (miscellaneous) ,vascular biology ,ABO blood groups ,Article ,endothelial cells ,General Biochemistry, Genetics and Molecular Biology ,biological factors ,immune complexes ,transfusion ,hemic and lymphatic diseases ,parasitic diseases ,Biology (General) - Abstract
ABO immune complexes (ABO-IC) formed by ABO-incompatible antigen-antibody interaction are associated with hemolysis and platelet destruction in patients transfused with ABO-nonidentical blood products. However, the effects of ABO-IC on endothelial cells (EC) are unclear. ABO-IC were formed in vitro from normal donor-derived plasma and serum. Human pulmonary artery EC (HPAEC) were cultured and treated with media, ABO-identical and –non-identical plasma, and ABO-IC. EC barrier integrity was evaluated using transendothelial electrical resistance (TEER), scanning electron microscopy (SEM), vascular endothelial (VE)-cadherin and phalloidin staining, and Rho-associated Kinase (ROCK) inhibitor treatment. TEER revealed significant/irreversible barrier disruption within 1–2 h of exposure to ABO non-identical plasma and ABO-IC; this occurred independently of EC ABO type. Treatment with ABO-IC resulted in decreased VE-cadherin staining and increased phalloidin staining in a time-dependent manner, suggesting that the resultant increased EC barrier permeability is secondary to actin stress fiber formation and loss of cell surface VE-cadherin. Inhibition of ROCK was effective in protecting against IC-induced barrier disruption even two hours after ABO-IC exposure. ABO-IC causes increased EC barrier permeability by decreasing cell surface VE-cadherin and promoting stress fiber formation, which is preventable by inhibiting ROCK activation to protect against EC contraction and gap formation.
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- 2021
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16. Chronic cannabis smoking-enriched oral pathobiont drives behavioral changes, macrophage infiltration, and increases β-amyloid protein production in the brain
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Wangbin Ning, Xu Wang, Catrina Robinson, Lei Huang, Amanda Wagner, Andreana Benitez, Nicholas T. Funderburg, Jeremy Y. Yu, Bethany J. Wolf, Wei Jiang, Eric D. Hamlett, Min Li, Xiaoyu Fu, Davide Amato, Wanli Xu, Xue-Zhong Yu, Aimee L. McRae-Clark, Xiaomei Cong, Yongxia Wu, Kendra Maas, Zejun Zhou, Zhenwu Luo, Sylvia Fitting, and Alison J. Scott
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DNA, Bacterial ,Saliva ,Medicine (General) ,Research paper ,Cannabis smoking ,medicine.medical_treatment ,Physiology ,Marijuana Smoking ,medicine.disease_cause ,DNA, Ribosomal ,General Biochemistry, Genetics and Molecular Biology ,Cell Line ,Mice ,R5-920 ,RNA, Ribosomal, 16S ,medicine ,Animals ,Humans ,Microbiome ,Neisseria elongata ,Phylogeny ,Amyloid beta-Peptides ,Bacteria ,biology ,Streptococcus ,business.industry ,β-amyloid ,Macrophages ,Brain ,Sequence Analysis, DNA ,General Medicine ,biology.organism_classification ,Oral microbiome ,Disease Models, Animal ,stomatognathic diseases ,Case-Control Studies ,Actinomyces meyeri ,Medicine ,Female ,Oral Microbiome ,Neisseria ,Cannabis ,business - Abstract
Background Little is known about chronic cannabis smoking-associated oral microbiome and its effects on central nervous system (CNS) functions. Methods In the current study, we have analyzed the saliva microbiome in individuals who chronically smoked cannabis with cannabis use disorder (n = 16) and in non-smoking controls (n = 27). The saliva microbiome was analyzed using microbial 16S rRNA sequencing. To investigate the function of cannabis use-associated oral microbiome, mice were orally inoculated with live Actinomyces meyeri, Actinomyces odontolyticus, or Neisseria elongata twice per week for six months, which mimicked human conditions. Findings We found that cannabis smoking in humans was associated with oral microbial dysbiosis. The most increased oral bacteria were Streptococcus and Actinomyces genus and the most decreased bacteria were Neisseria genus in chronic cannabis smokers compared to those in non-smokers. Among the distinct species bacteria in cannabis smokers, the enrichment of Actinomyces meyeri was inversely associated with the age of first cannabis smoking. Strikingly, oral exposure of Actinomyces meyeri, an oral pathobiont, but not the other two control bacteria, decreased global activity, increased macrophage infiltration, and increased β-amyloid 42 protein production in the mouse brains. Interpretation This is the first study to reveal that long-term oral cannabis exposure is associated oral enrichment of Actinomyces meyeri and its contributions to CNS abnormalities.
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- 2021
17. A preliminary investigation of the role of intraindividual sleep variability in substance use treatment outcomes
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Melissa R. Schick, Danica C. Slavish, Jessica R. Dietch, Sara M. Witcraft, Richard O. Simmons, Daniel J. Taylor, Joshua P. Smith, Sarah W. Book, Aimee L. McRae-Clark, and Allison K. Wilkerson
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Adult ,Male ,Psychiatry and Mental health ,Clinical Psychology ,Recurrence ,Substance-Related Disorders ,Sleep Initiation and Maintenance Disorders ,Medicine (miscellaneous) ,Humans ,Female ,Toxicology ,Sleep ,Actigraphy - Abstract
Poor sleep health is common among individuals in early treatment for substance use disorders (SUDs) and may serve an important role in predicting SUD outcomes. However, sleep parameters have been inconsistently linked with risk of relapse, perhaps because previous research has focused on mean values of sleep parameters (e.g., total sleep time [TST], sleep efficiency [SE], and sleep midpoint [SM]) across multiple nights rather than night-to-night fluctuations (i.e., intraindividual variability [IIV]). The current study assessed sleep across the first week of SUD treatment, with the aim of prospectively examining the relationship between mean and IIV of TST, SE, and SM and treatment completion and relapse within one-month post-treatment.Treatment-seeking adults (N = 23, MGreater IIV in TST was associated with higher odds of relapse (OR = 3.55, p =.028). Greater IIV in SM was associated with lower odds of treatment completion, but only when removing mean SM from the model (OR = 0.75, p =.046).Night-to-night variability in actigraphy-measured TST is more strongly associated with SUD treatment outcomes than average sleep patterns across the week. Integrating circadian regulation into treatment efforts to improve SUD treatment outcomes may be warranted. Given the small sample size utilized in the present study, replication of these analyses with a larger sample is warranted.
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- 2021
18. A potent truncated form of human soluble CR1 is protective in a mouse model of renal ischemia–reperfusion injury
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Jennifer L. McRae, Matthew P. Hardy, Martin J. Pearse, Anjan K. Bongoni, Sandra Wymann, Peter J. Cowan, Tony Rowe, Ingela Vikstrom, Nella Fisicaro, Evelyn J Salvaris, and Adriana Baz Morelli
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Male ,Physiology ,Science ,Complement receptor 1 ,Immunology ,Diseases ,Pathogenesis ,Pharmacology ,Kidney ,Article ,Mice ,Mediator ,Pharmacokinetics ,In vivo ,medicine ,Animals ,Humans ,Complement Activation ,Multidisciplinary ,biology ,Renal ischemia ,Chemistry ,medicine.disease ,Kidney Transplantation ,Peptide Fragments ,Complement system ,Mice, Inbred C57BL ,Transplantation ,Disease Models, Animal ,Solubility ,Nephrology ,Reperfusion Injury ,Receptors, Complement 3b ,Medicine ,biology.gene ,Kidney disease - Abstract
The complement system is a potent mediator of ischemia–reperfusion injury (IRI), which detrimentally affects the function and survival of transplanted kidneys. Human complement receptor 1 (HuCR1) is an integral membrane protein that inhibits complement activation by blocking the convertases that activate C3 and C5. We have previously reported that CSL040, a truncated form of recombinant soluble HuCR1 (sHuCR1), has enhanced complement inhibitory activity and improved pharmacokinetic properties compared to the parent molecule. Here, we compared the capacity of CSL040 and full-length sHuCR1 to suppress complement-mediated organ damage in a mouse model of warm renal IRI. Mice were treated with two doses of CSL040 or sHuCR1, given 1 h prior to 22 min unilateral renal ischemia and again 3 h later. 24 h after reperfusion, mice treated with CSL040 were protected against warm renal IRI in a dose-dependent manner, with the highest dose of 60 mg/kg significantly reducing renal dysfunction, tubular injury, complement activation, endothelial damage, and leukocyte infiltration. In contrast, treatment with sHuCR1 at a molar equivalent dose to 60 mg/kg CSL040 did not confer significant protection. Our results identify CSL040 as a promising therapeutic candidate to attenuate renal IRI and demonstrate its superior efficacy over full-length sHuCR1 in vivo.
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- 2021
19. Evaluation of solvent/detergent-treated plasma safety and efficacy in orthotopic liver transplant and thrombotic thrombocytopenic purpura patients: A single center experience
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Hannah L. McRae, Chelsea Milito, Catherine A. Klapheke, and Majed A. Refaai
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Plasma Exchange ,Purpura, Thrombotic Thrombocytopenic ,Immunology ,Detergents ,Solvents ,Immunology and Allergy ,Humans ,Hematology ,Prospective Studies ,Liver Transplantation - Abstract
Solvent/detergent-treated, pooled plasma (SDP) is approved for use in orthotopic liver transplantation (OLT) and thrombotic thrombocytopenic purpura (TTP) patients; however, studies evaluating safety and effectiveness of SDP in these populations are limited.This prospective study included two cohorts: OLT patients (n = 40) who received either SDP (n = 20) or FFP (control group) (n = 20), and TTP patients (n = 20) who received either SDP (n = 10) or FFP (control group) (n = 10) throughout hospitalization. Medical, laboratory, and blood bank records were retroactively assessed for both cohorts for differences in clinical outcomes, laboratory values, and transfusion data from admission to discharge.In the OLT cohort, significant changes in AST and ALP were observed in the control group as compared to SDP (p .05 each), and creatinine levels improved significantly in the SDP group as compared to the control group (p .05) from admission to discharge. In the TTP cohort, platelet counts were significantly improved within the control and SDP groups from admission to discharge, but there were no significant differences between groups (p = .31). LDH levels improved between admission and discharge for both groups (70% decrease in the control group, p .001, and 80% decrease in the SDP group, p = .001). There were no significant differences detected in clinical outcomes in either cohort.As evidenced by the lack of adverse events in either cohort and similar clinical outcomes, we conclude that SDP is comparable in safety and effectiveness to FFP in OLT and TTP patients. Further studies are needed to evaluate the potential for improved safety with SDP.
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- 2021
20. A pilot trial applying 18-sessions of repetitive transcranial magnetic stimulation to the dorsolateral prefrontal cortex of participants undergoing acute medically-managed withdrawal from opioids over three-days
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Aimee L. McRae-Clark, Mark S. George, Gregory L. Sahlem, Lauren A. Campbell, and Chanda D. Funcell
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medicine.medical_specialty ,business.industry ,General Neuroscience ,medicine.medical_treatment ,Biophysics ,Craving ,Opioid use disorder ,Neurosciences. Biological psychiatry. Neuropsychiatry ,medicine.disease ,Clinical trial ,Dorsolateral prefrontal cortex ,Transcranial magnetic stimulation ,medicine.anatomical_structure ,Opioid ,Physical therapy ,medicine ,Neurology (clinical) ,medicine.symptom ,business ,Methadone ,medicine.drug ,Buprenorphine ,RC321-571 - Abstract
Opioid Use Disorder (OUD) is an impactful condition with only moderately effective treatments available and relapse especially common early in treatment. This project determined the feasibility of delivering an accelerated course of repetitive transcranial magnetic stimulation (rTMS) to participants with OUD during medically managed withdrawal. If feasible, delivering rTMS at this early stage of treatment may improve outcomes. Participants included those with moderate or severe OUD who were undergoing medically-managed withdrawal using either buprenorphine or methadone. During the taper, eighteen-sessions of rTMS were applied over three days (6-sessions/day separated by 30-minutes, 10Hz, figure-of-eight-coil, EEG coordinate F3, 3000 pulses each, 120% rMT, delivered during opioid image presentation). The first participant underwent open-label study-treatment, while the final six were treated in a double-blind sham-controlled fashion. The primary outcome measures included provoked craving following a standardized cue paradigm, as well as subjective pain measures. Four participants received active stimulation, three of which (27F, 27M, 31F) completed treatment at 120%rMT, and one (27M) withdrew due to symptoms of opioid withdrawal. Three participants received sham stimulation (30F, 27M, 51M) two of which completed treatment at 120%rMT and one other completing treatment at 100% rMT. The blind was effective and only one headache occurred as an adverse event. No statistics were run due to the small sample size, however the participants who received active stimulation reported that composite craving (want, resist, crave opioids) dropped numerically more in the active-group (mean decrease 10.3±8.1) then in the sham-group (mean decrease 7.0±4.6) following a standard opioid cue paradigm. Clinical pain was low at baseline and changed minimally following the intervention. No firm conclusions can be drawn from this pilot trial, which was stopped early due to the COVID19 pandemic, however accelerated treatment with rTMS appears to be well tolerated by those undergoing medically managed withdrawal. Keywords: opioid, craving, clinical trial, rTMS
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- 2021
21. Imaging the Alternatively Spliced D Domain of Tenascin C in Preclinical Models of Inflammatory Bowel Disease
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Christine M. Nelson, Heather Knight, Jamie Erickson, Bradford L. McRae, Victor Sun, Annette J. Schwartz Sterman, Stephanie M. Gaudette, Grace Lynch, Kristoff T. Homan, Calvin S. Pohl, Sahana Bose, Liang Zhang, and Soumya Mitra
- Subjects
biology ,business.industry ,Tenascin C ,medicine ,Cancer research ,biology.protein ,medicine.disease ,business ,Inflammatory bowel disease ,Domain (software engineering) - Abstract
Purpose To image colon-expressed alternatively spliced D domain of tenascin C in preclinical colitis models using near infrared (NIR) labeled targeted molecular imaging agents.Methods Human IgG and scFv fusion proteins specific to the alternatively spliced D domain of tenascin C were generated. Immunohistochemistry identified disease-specific expression of this extracellular matrix in mouse colitis models. Proteins were labeled with the NIR fluorophore IRDye 800CW via amine chemistry and intravenously dosed to evaluate targeting specificity in preclinical rodent and primate colitis models.Results The NIR labeled proteins successfully targeted colonic lesions in a murine model of colitis and appeared as distinct punctate spots. Co-administration of a blocking dose reduced the whole colon standardized uptake of the fluorescent dose >7-fold in mouse models. Estimates suggest local expression at >100 nM in diseased mouse colon. Macroscopic targeting specificity was not observed in diseased primate colon. Cellular level specificity was assessed via microscopy and immunohistochemistry.Conclusion Our imaging data suggest the alternatively spliced D domain of tenascin C is a promising target for delivery-based applications in inflammatory bowel diseases.
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- 2021
22. Distress tolerance and reactivity to negative affective cues in naturalistic environments of cannabis-using emerging adults
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Kathryn S, Gex, Kevin M, Gray, Aimee L, McRae-Clark, Michael E, Saladin, and Rachel L, Tomko
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Adult ,Cannabinoid Receptor Agonists ,Male ,Pharmacology ,Adolescent ,Environment ,Toxicology ,Article ,Young Adult ,Psychiatry and Mental health ,Hallucinogens ,Humans ,Female ,Pharmacology (medical) ,Cues ,Cannabis ,Craving - Abstract
BACKGROUND. Distress tolerance (DT) has been implicated as an important factor in the experience of negative affect (NA) and cannabis craving. However, previous research is limited by its use of laboratory paradigms that may not replicate in naturalistic settings. The current study examined how DT influenced reactivity to NA cues in daily life in a sample of frequent (≥3 times per week) cannabis-using emerging adults (age 18-21). METHODS. Using cue-reactivity ecological momentary assessment (CREMA), 63 (54% female; 85.7% white; M(age) = 19.62) participants reported on their cannabis craving and affect (sadness, relaxation) four semi-random times per day for two weeks (56 possible CREMA sessions/participant). We assessed affect and cannabis craving before and after exposure to neutral and NA cues. Multilevel modeling was used to examine within- and between-participant effects of cues, DT, and sex, as well as within- and between-participant average pre-cue affect and craving, on post-cue affect and craving. RESULTS. NA cues consistently predicted higher-than-normal post-cue sadness and lower relaxation, but not greater-than-normal post-cue craving. Cue type interacted with sex and DT to predict post-cue sadness, but not craving. Female participants and those reporting low DT reported higher sadness following NA cues compared to males and those with high DT, respectively. CONCLUSIONS. Frequent cannabis-using emerging adults differed in affect, but not cannabis craving, reactivity to NA cues as a function of sex and DT. Our results were partially consistent with prior human laboratory and CREMA research finding greater reactivity to NA cues among females and individuals with low DT.
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- 2022
23. Varenicline as a treatment for cannabis use disorder: A placebo-controlled pilot trial
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Gregory L Sahlem, Amanda Wagner, Aimee L. McRae-Clark, Kevin M. Gray, Brian J. Sherman, Nathaniel L. Baker, Lindsay M. Squeglia, and Rachel L. Tomko
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Marijuana Abuse ,medicine.medical_specialty ,media_common.quotation_subject ,Pilot Projects ,Toxicology ,Placebo ,Article ,chemistry.chemical_compound ,Pharmacotherapy ,Double-Blind Method ,Internal medicine ,medicine ,Humans ,Pharmacology (medical) ,Adverse effect ,Varenicline ,media_common ,Pharmacology ,biology ,business.industry ,Motivational enhancement therapy ,Abstinence ,biology.organism_classification ,Clinical trial ,Psychiatry and Mental health ,chemistry ,Smoking Cessation ,Cannabis ,business - Abstract
Background An efficacious pharmacotherapy for cannabis use disorder (CUD) has yet to be established. This study preliminarily evaluated the safety and efficacy of varenicline for CUD in a proof-of-concept clinical trial. Methods Participants in this 6-week randomized, placebo-controlled pilot trial received either varenicline (n = 35) or placebo (n = 37), added to a brief motivational enhancement therapy intervention. Outcomes included cannabis withdrawal, cannabis abstinence, urine cannabinoid levels, percent cannabis use days, and cannabis sessions per day. Results Both treatment groups noted significant decreases in self-reported cannabis withdrawal, percentage of days used, and use sessions per day during treatment compared to baseline. While this pilot trial was not powered to detect statistically significant between-group differences, participants randomized to varenicline evidenced numerically greater rates of self-reported abstinence at the final study visit [Week 6 intent-to-treat (ITT): Varenicline: 17.1% vs. Placebo: 5.4%; RR = 3.2 (95% CI: 0.7,14.7)]. End-of-treatment urine creatinine corrected cannabinoid levels were numerically lower in the varenicline group and higher in the placebo group compared to baseline [Change from baseline: Varenicline -1.7 ng/mg (95% CI: -4.1,0.8) vs. Placebo: 1.9 ng/mg (95% CI: -0.4,4.3); Δ = 3.5 (95% CI: 0.1,6.9)]. Adverse events related to study treatment did not reveal new safety signals. Conclusions Findings support the feasibility of conducting clinical trials of varenicline as a candidate pharmacotherapy for CUD, and indicate that a full-scale efficacy trial, powered based on effect sizes and variability yielded in this study, is warranted.
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- 2021
24. Consideration of sex as a biological variable in the translation of pharmacotherapy for stress-associated drug seeking
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Elizabeth M. Doncheck, Erin L. Martin, Aimee L. McRae-Clark, and Carmela M. Reichel
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Neurophysiology and neuropsychology ,Drug ,Translation ,Neuroactive steroid ,Physiology ,media_common.quotation_subject ,Addiction ,Neurosciences. Biological psychiatry. Neuropsychiatry ,Stress ,Bioinformatics ,Biochemistry ,Cellular and Molecular Neuroscience ,Review article ,Endocrinology ,Pharmacotherapy ,Medicine ,RC346-429 ,Molecular Biology ,Endogenous opioid ,media_common ,biology ,Endocrine and Autonomic Systems ,business.industry ,QP351-495 ,biology.organism_classification ,Treatment ,Clinical trial ,Drug development ,Sex ,Neurology. Diseases of the nervous system ,Cannabis ,business ,RC321-571 - Abstract
Stress is a frequent precipitant of relapse to drug use. Pharmacotherapies targeting a diverse array of neural systems have been assayed for efficacy in attenuating stress-induced drug-seeking in both rodents and in humans, but none have shown enough evidence of utility to warrant routine use in the clinic. We posit that a critical barrier in effective translation is inattention to sex as a biological variable at all phases of the research process. In this review, we detail the neurobiological systems implicated in stress-induced relapse to cocaine, opioids, methamphetamine, and cannabis, as well as the pharmacotherapies that have been used to target these systems in rodent models, the human laboratory, and in clinical trials. In each of these areas we additionally describe the potential influences of biological sex on outcomes, and how inattention to fundamental sex differences can lead to biases during drug development that contribute to the limited success of large clinical trials. Based on these observations, we determine that of the pharmacotherapies discussed only α2-adrenergic receptor agonists and oxytocin have a body of research with sufficient consideration of biological sex to warrant further clinical evaluation. Pharmacotherapies that target β-adrenergic receptors, other neuroactive peptides, the hypothalamic-pituitary-adrenal axis, neuroactive steroids, and the endogenous opioid and cannabinoid systems require further assessment in females at the preclinical and human laboratory levels before progression to clinical trials can be recommended.
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- 2021
25. A potent truncated form of human soluble CR1 is protective in a mouse model of renal ischemia–reperfusion injury
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Anjan K. Bongoni, Ingela B. Vikstrom, Jennifer L. McRae, Evelyn J. Salvaris, Nella Fisicaro, Martin J. Pearse, Sandra Wymann, Tony Rowe, Adriana Baz Morelli, Matthew P. Hardy, and Peter J. Cowan
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Medicine ,Science - Abstract
Abstract The complement system is a potent mediator of ischemia–reperfusion injury (IRI), which detrimentally affects the function and survival of transplanted kidneys. Human complement receptor 1 (HuCR1) is an integral membrane protein that inhibits complement activation by blocking the convertases that activate C3 and C5. We have previously reported that CSL040, a truncated form of recombinant soluble HuCR1 (sHuCR1), has enhanced complement inhibitory activity and improved pharmacokinetic properties compared to the parent molecule. Here, we compared the capacity of CSL040 and full-length sHuCR1 to suppress complement-mediated organ damage in a mouse model of warm renal IRI. Mice were treated with two doses of CSL040 or sHuCR1, given 1 h prior to 22 min unilateral renal ischemia and again 3 h later. 24 h after reperfusion, mice treated with CSL040 were protected against warm renal IRI in a dose-dependent manner, with the highest dose of 60 mg/kg significantly reducing renal dysfunction, tubular injury, complement activation, endothelial damage, and leukocyte infiltration. In contrast, treatment with sHuCR1 at a molar equivalent dose to 60 mg/kg CSL040 did not confer significant protection. Our results identify CSL040 as a promising therapeutic candidate to attenuate renal IRI and demonstrate its superior efficacy over full-length sHuCR1 in vivo.
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- 2021
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26. A pilot trial applying 18-sessions of repetitive transcranial magnetic stimulation to the dorsolateral prefrontal cortex of participants undergoing acute medically-managed withdrawal from opioids over three-days
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Gregory L. Sahlem, Lauren A. Campbell, Chanda D. Funcell, Mark S. George, and Aimee L. McRae-Clark
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Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 - Published
- 2021
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27. Consideration of sex as a biological variable in the translation of pharmacotherapy for stress-associated drug seeking
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Erin L. Martin, Elizabeth M. Doncheck, Carmela M. Reichel, and Aimee L. McRae-Clark
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Stress ,Addiction ,Translation ,Sex ,Treatment ,Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 ,Neurology. Diseases of the nervous system ,RC346-429 ,Neurophysiology and neuropsychology ,QP351-495 - Abstract
Stress is a frequent precipitant of relapse to drug use. Pharmacotherapies targeting a diverse array of neural systems have been assayed for efficacy in attenuating stress-induced drug-seeking in both rodents and in humans, but none have shown enough evidence of utility to warrant routine use in the clinic. We posit that a critical barrier in effective translation is inattention to sex as a biological variable at all phases of the research process. In this review, we detail the neurobiological systems implicated in stress-induced relapse to cocaine, opioids, methamphetamine, and cannabis, as well as the pharmacotherapies that have been used to target these systems in rodent models, the human laboratory, and in clinical trials. In each of these areas we additionally describe the potential influences of biological sex on outcomes, and how inattention to fundamental sex differences can lead to biases during drug development that contribute to the limited success of large clinical trials. Based on these observations, we determine that of the pharmacotherapies discussed only α2-adrenergic receptor agonists and oxytocin have a body of research with sufficient consideration of biological sex to warrant further clinical evaluation. Pharmacotherapies that target β-adrenergic receptors, other neuroactive peptides, the hypothalamic-pituitary-adrenal axis, neuroactive steroids, and the endogenous opioid and cannabinoid systems require further assessment in females at the preclinical and human laboratory levels before progression to clinical trials can be recommended.
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- 2021
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28. Mode Conversion Trimming in Asymmetric Directional Couplers Enabled by Silicon Ion Implantation.
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Xu R, Taheriniya S, Varri A, Ulanov M, Konyshev I, Krämer L, McRae L, Ebert FL, Bankwitz JR, Ma X, Ferrari S, Bhaskaran H, and Pernice WHP
- Abstract
An on-chip asymmetric directional coupler (DC) can convert fundamental modes to higher-order modes and is one of the core components of mode-division multiplexing (MDM) technology. In this study, we propose that waveguides of the asymmetric DC can be trimmed by silicon ion implantation to tune the effective refractive index and facilitate mode conversion into higher-order modes. Through this method of tuning, transmission changes of up to 18 dB have been realized with one ion implantation step. In addition, adjusting the position of the ion implantation on the waveguide can provide a further degree of control over the transmission into the resulting mode. The results of this work present a promising new route for the development of high-efficiency, low-loss mode converters for integrated photonic platforms, and aim to facilitate the application of MDM technology in emerging photonic neuromorphic computing.
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- 2024
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29. Add-On Deep Brain Stimulation versus Continued Vagus Nerve Stimulation for Childhood Epilepsy (ADVANCE): A Partially Randomized Patient Preference Trial.
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Suresh H, Mithani K, Warsi N, Ochi A, Otsubo H, Drake JM, Rutka JT, Kerr E, Smith ML, Breitbart S, Yau I, McRae L, Chau V, Weiss S, Jain P, Donner E, Fasano A, Gorodetsky C, and Ibrahim GM
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- Humans, Child, Adolescent, Male, Female, Treatment Outcome, Prospective Studies, Quality of Life, Vagus Nerve Stimulation methods, Deep Brain Stimulation methods, Patient Preference, Drug Resistant Epilepsy therapy
- Abstract
Outcomes following vagus nerve stimulation (VNS) improve over years after implantation in children with drug-resistant epilepsy. The added value of deep brain stimulation (DBS) instead of continued VNS optimization is unknown. In a prospective, non-blinded, randomized patient preference trial of 18 children (aged 8-17 years) who did not respond to VNS after at least 1 year, add-on DBS resulted in greater seizure reduction compared with an additional year of VNS optimization (51.9% vs. 12.3%, p = 0.047). Add-on DBS also resulted in less bothersome seizures (p = 0.03), but no change in quality of life. DBS may be considered earlier for childhood epilepsy after non-response to VNS. ANN NEUROL 2024;96:405-411., (© 2024 The Authors. Annals of Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)
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- 2024
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30. Development and optimization of a systematic approach to identifying lead service lines: One community's success.
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Smart P, McRae L, Formal C, and Lytle DA
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- Water Supply, Lead analysis, Cities, Drinking Water, Water Pollutants, Chemical analysis
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Lead service lines (LSLs), when present, are the largest source of lead in drinking water, and their removal is necessary to reduce public exposure to lead from drinking water. Unfortunately, the composition of many service lines (SLs) is uncertain. The town of Bennington, Vermont, for example, has unreliable SL records, making it challenging to build an inventory and conduct an LSL replacement program. In 2017, Bennington commenced a project to identify SL materials and replace all LSLs. 159 control homes, consisting of 99 LSL and 60 non-LSL sites, were chosen for record reviews, visual SL observations, fully flushed (FF) and sequential profile water sampling, and test excavations to evaluate method accuracies. Of the 159 control homes, records for 90 % of the 99 known LSL homes were accurate. Whereas 3 % of the 60 non-lead SL homes' records accurately identified SL material. Fully flushed and sequential profile samples (SPSs) were 73 % and 95 % accurate for identifying LSLs and 95 % and 83 % accurate for identifying non-LSLs, respectively. Results were 100 % accurate when visual observations, FF samples, and test excavation were used in a stepwise approach. A stepwise approach consisting of visual SL observations, FF samples, and SPSs achieved a 98 % accuracy at identifying LSLs and a 67 % cost reduction compared to performing test excavations at each home. Findings from this control group study are critical for state, tribal, and local officials to inform their decisions about the selected approach to identify unknown SLs., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Patrick Smart, MSK Engineers reports financial support was provided by Vermont Drinking Water State Revolving Fund, (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)
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- 2023
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31. Protected areas slow declines unevenly across the tetrapod tree of life.
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Justin Nowakowski A, Watling JI, Murray A, Deichmann JL, Akre TS, Muñoz Brenes CL, Todd BD, McRae L, Freeman R, and Frishkoff LO
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- Animals, Birds classification, Amphibians classification, Reptiles classification, Global Warming statistics & numerical data, Biodiversity, Conservation of Natural Resources methods, Conservation of Natural Resources statistics & numerical data, Vertebrates classification, Phylogeny, Endangered Species statistics & numerical data, Endangered Species trends
- Abstract
Protected areas (PAs) are the primary strategy for slowing terrestrial biodiversity loss. Although expansion of PA coverage is prioritized under the Convention on Biological Diversity, it remains unknown whether PAs mitigate declines across the tetrapod tree of life and to what extent land cover and climate change modify PA effectiveness
1,2 . Here we analysed rates of change in abundance of 2,239 terrestrial vertebrate populations across the globe. On average, vertebrate populations declined five times more slowly within PAs (-0.4% per year) than at similar sites lacking protection (-1.8% per year). The mitigating effects of PAs varied both within and across vertebrate classes, with amphibians and birds experiencing the greatest benefits. The benefits of PAs were lower for amphibians in areas with converted land cover and lower for reptiles in areas with rapid climate warming. By contrast, the mitigating impacts of PAs were consistently augmented by effective national governance. This study provides evidence for the effectiveness of PAs as a strategy for slowing tetrapod declines. However, optimizing the growing PA network requires targeted protection of sensitive clades and mitigation of threats beyond PA boundaries. Provided the conditions of targeted protection, adequate governance and well-managed landscapes are met, PAs can serve a critical role in safeguarding tetrapod biodiversity., (© 2023. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)- Published
- 2023
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32. Evaluation of the feasibility, diagnostic yield, and clinical utility of rapid genome sequencing in infantile epilepsy (Gene-STEPS): an international, multicentre, pilot cohort study.
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D'Gama AM, Mulhern S, Sheidley BR, Boodhoo F, Buts S, Chandler NJ, Cobb J, Curtis M, Higginbotham EJ, Holland J, Khan T, Koh J, Liang NSY, McRae L, Nesbitt SE, Oby BT, Paternoster B, Patton A, Rose G, Scotchman E, Valentine R, Wiltrout KN, Hayeems RZ, Jain P, Lunke S, Marshall CR, Rockowitz S, Sebire NJ, Stark Z, White SM, Chitty LS, Cross JH, Scheffer IE, Chau V, Costain G, Poduri A, Howell KB, and McTague A
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- Male, Female, Infant, Newborn, Humans, Child, Pilot Projects, Cohort Studies, Feasibility Studies, Ontario, Seizures, Febrile, Epilepsy diagnosis, Epilepsy genetics
- Abstract
Background: Most neonatal and infantile-onset epilepsies have presumed genetic aetiologies, and early genetic diagnoses have the potential to inform clinical management and improve outcomes. We therefore aimed to determine the feasibility, diagnostic yield, and clinical utility of rapid genome sequencing in this population., Methods: We conducted an international, multicentre, cohort study (Gene-STEPS), which is a pilot study of the International Precision Child Health Partnership (IPCHiP). IPCHiP is a consortium of four paediatric centres with tertiary-level subspecialty services in Australia, Canada, the UK, and the USA. We recruited infants with new-onset epilepsy or complex febrile seizures from IPCHiP centres, who were younger than 12 months at seizure onset. We excluded infants with simple febrile seizures, acute provoked seizures, known acquired cause, or known genetic cause. Blood samples were collected from probands and available biological parents. Clinical data were collected from medical records, treating clinicians, and parents. Trio genome sequencing was done when both parents were available, and duo or singleton genome sequencing was done when one or neither parent was available. Site-specific protocols were used for DNA extraction and library preparation. Rapid genome sequencing and analysis was done at clinically accredited laboratories, and results were returned to families. We analysed summary statistics for cohort demographic and clinical characteristics and the timing, diagnostic yield, and clinical impact of rapid genome sequencing., Findings: Between Sept 1, 2021, and Aug 31, 2022, we enrolled 100 infants with new-onset epilepsy, of whom 41 (41%) were girls and 59 (59%) were boys. Median age of seizure onset was 128 days (IQR 46-192). For 43 (43% [binomial distribution 95% CI 33-53]) of 100 infants, we identified genetic diagnoses, with a median time from seizure onset to rapid genome sequencing result of 37 days (IQR 25-59). Genetic diagnosis was associated with neonatal seizure onset versus infantile seizure onset (14 [74%] of 19 vs 29 [36%] of 81; p=0·0027), referral setting (12 [71%] of 17 for intensive care, 19 [44%] of 43 non-intensive care inpatient, and 12 [28%] of 40 outpatient; p=0·0178), and epilepsy syndrome (13 [87%] of 15 for self-limited epilepsies, 18 [35%] of 51 for developmental and epileptic encephalopathies, 12 [35%] of 34 for other syndromes; p=0·001). Rapid genome sequencing revealed genetic heterogeneity, with 34 unique genes or genomic regions implicated. Genetic diagnoses had immediate clinical utility, informing treatment (24 [56%] of 43), additional evaluation (28 [65%]), prognosis (37 [86%]), and recurrence risk counselling (all cases)., Interpretation: Our findings support the feasibility of implementation of rapid genome sequencing in the clinical care of infants with new-onset epilepsy. Longitudinal follow-up is needed to further assess the role of rapid genetic diagnosis in improving clinical, quality-of-life, and economic outcomes., Funding: American Academy of Pediatrics, Boston Children's Hospital Children's Rare Disease Cohorts Initiative, Canadian Institutes of Health Research, Epilepsy Canada, Feiga Bresver Academic Foundation, Great Ormond Street Hospital Charity, Medical Research Council, Murdoch Children's Research Institute, National Institute of Child Health and Human Development, National Institute for Health and Care Research Great Ormond Street Hospital Biomedical Research Centre, One8 Foundation, Ontario Brain Institute, Robinson Family Initiative for Transformational Research, The Royal Children's Hospital Foundation, University of Toronto McLaughlin Centre., Competing Interests: Declaration of interests APa is a current member of the National Institute of Health and Clinical excellence (NICE) technology appraisal committee B and has a financial interest in Genedrive PLC. KW has consulted for Stoke Therapeutics. JHC has received renumeration for lectures by GW pharma/Jazz, UCB/Zogenix, Biocodex, and Biogen; is a member of the Data Monitoring and Safety Committee for Admiral Trial (Stroke Therapeutics); and is Chair of the Medical Advisory Board for Matthews Friends, Dravet UK, and Hope for Hypothalamic Hamartoma. IES has served on scientific advisory boards for BioMarin, Chiesi, Eisai, Encoded Therapeutics, GlaxoSmithKline, Knopp Biosciences, Nutricia, Rogcon, Takeda Pharmaceuticals, UCB, and Xenon Pharmaceuticals; has received speaker honoraria from GlaxoSmithKline, UCB, BioMarin, Biocodex, Chiesi, Liva Nova, Nutricia, Zuellig Pharma, and Eisai; has received funding for travel from UCB, Biocodex, GlaxoSmithKline, Biomarin, Encoded Therapeutics, and Eisai; has served as an investigator for Anavex Life Sciences, Cerecin, Cerevel Therapeutics, Eisai, Encoded Therapeutics, EpiMinder, Epygenyx, ES-Therapeutics, GW Pharma, Marinus, Neurocrine BioSciences, Ovid Therapeutics, Takeda Pharmaceuticals, UCB, Ultragenyx, Xenon Pharmaceuticals, Zogenix, and Zynerba; and has consulted for Care Beyond Diagnosis, Epilepsy Consortium, Atheneum Partners, Ovid Therapeutics, UCB, Zynerba Pharmaceuticals, BioMarin, Encoded Therapeutics, and Biohaven Pharmaceuticals; and is a Non-Executive Director of Bellberry and a Director of the Australian Academy of Health and Medical Sciences and the Australian Council of Learned Academies. IES might accrue future revenue on pending patent WO61/010176 (filed in 2008; therapeutic compound); has a patent for SCN1A testing held by Bionomics and licensed to various diagnostic companies; has a patent molecular diagnostic or theranostic target for benign familial infantile epilepsy (PRRT2; 2011904493, 2012900190, and PCT/AU2012/001321 [TECH ID:2012-009]). GC has received honorarium from CADTH and serves as the Co-Lead of the Can-GARD Initiative and on the SickKids Precision Child Health steering committee. APo serves on the scientific advisory boards for TevardBio and Syngap Research Fund, and on the American Epilepsy Society Board of Directors. KBH has received support from RogCon Biosciences and Praxis Precision Medicines. AM has received consulting fees from Rocket Pharmaceuticals; honorarium from Jazz Pharmaceuticals; support for attending conferences from Jazz Pharmaceuticals and European Paediatric Neurology Society; fees for participating on boards for Biogen and Biocodex; and serves unpaid roles on the ILAE Genetic Literacy Task Force, EPICARE, and Great Ormond Street Hospital National Institute for Health and Care Research Biomedical Research Centre Chair of Junior Faculty. All other authors declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)
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- 2023
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33. Quantifying reliability and data deficiency in global vertebrate population trends using the Living Planet Index.
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Dove S, Böhm M, Freeman R, McRae L, and Murrell DJ
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- Animals, Reproducibility of Results, Vertebrates, Biodiversity, Conservation of Natural Resources, Planets
- Abstract
Global biodiversity is facing a crisis, which must be solved through effective policies and on-the-ground conservation. But governments, NGOs, and scientists need reliable indicators to guide research, conservation actions, and policy decisions. Developing reliable indicators is challenging because the data underlying those tools is incomplete and biased. For example, the Living Planet Index tracks the changing status of global vertebrate biodiversity, but taxonomic, geographic and temporal gaps and biases are present in the aggregated data used to calculate trends. However, without a basis for real-world comparison, there is no way to directly assess an indicator's accuracy or reliability. Instead, a modelling approach can be used. We developed a model of trend reliability, using simulated datasets as stand-ins for the "real world", degraded samples as stand-ins for indicator datasets (e.g., the Living Planet Database), and a distance measure to quantify reliability by comparing partially sampled to fully sampled trends. The model revealed that the proportion of species represented in the database is not always indicative of trend reliability. Important factors are the number and length of time series, as well as their mean growth rates and variance in their growth rates, both within and between time series. We found that many trends in the Living Planet Index need more data to be considered reliable, particularly trends across the global south. In general, bird trends are the most reliable, while reptile and amphibian trends are most in need of additional data. We simulated three different solutions for reducing data deficiency, and found that collating existing data (where available) is the most efficient way to improve trend reliability, whereas revisiting previously studied populations is a quick and efficient way to improve trend reliability until new long-term studies can be completed and made available., (© 2023 The Authors. Global Change Biology published by John Wiley & Sons Ltd.)
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- 2023
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34. Past, present, and future of the Living Planet Index.
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Ledger SEH, Loh J, Almond R, Böhm M, Clements CF, Currie J, Deinet S, Galewski T, Grooten M, Jenkins M, Marconi V, Painter B, Scott-Gatty K, Young L, Hoffmann M, Freeman R, and McRae L
- Abstract
As we enter the next phase of international policy commitments to halt biodiversity loss (e.g., Kunming-Montreal Global Biodiversity Framework), biodiversity indicators will play an important role in forming the robust basis upon which targeted, and time sensitive conservation actions are developed. Population trend indicators are one of the most powerful tools in biodiversity monitoring due to their responsiveness to changes over short timescales and their ability to aggregate species trends from global down to sub-national or even local scale. We consider how the project behind one of the foremost population level indicators - the Living Planet Index - has evolved over the last 25 years, its value to the field of biodiversity monitoring, and how its components have portrayed a compelling account of the changing status of global biodiversity through its application at policy, research and practice levels. We explore ways the project can develop to enhance our understanding of the state of biodiversity and share lessons learned to inform indicator development and mobilise action., (© 2023. The Author(s).)
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- 2023
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35. Ongoing over-exploitation and delayed responses to environmental change highlight the urgency for action to promote vertebrate recoveries by 2030.
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Cornford R, Spooner F, McRae L, Purvis A, and Freeman R
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- Animals, Birds physiology, Mammals, Climate Change, Ecosystem, Conservation of Natural Resources, Vertebrates, Biodiversity
- Abstract
To safeguard nature, we must understand the drivers of biodiversity loss. Time-delayed biodiversity responses to environmental changes (ecological lags) are often absent from models of biodiversity change, despite their well-documented existence. We quantify how lagged responses to climate and land-use change have influenced mammal and bird populations around the world, while incorporating effects of direct exploitation and conservation interventions. Ecological lag duration varies between drivers, vertebrate classes and body size groupings-e.g. lags linked to climate-change impacts are 13 years for small birds, rising to 40 years for larger species. Past warming and land conversion generally combine to predict population declines; however, such conditions are associated with population increases for small mammals. Positive effects of management ( > +4% annually for large mammals) and protected areas ( > +6% annually for large birds) on population trends contrast with the negative impact of exploitation ( < -7% annually for birds), highlighting the need to promote sustainable use. Model projections suggest a future with winners (e.g. large birds) and losers (e.g. medium-sized birds), with current/recent environmental change substantially influencing abundance trends to 2050. Without urgent action, including effective conservation interventions and promoting sustainable use, ambitious targets to stop declines by 2030 may already be slipping out of reach.
- Published
- 2023
- Full Text
- View/download PDF
36. Hybridization order is not the driving factor behind biases in duplicate gene losses among the hexaploid Solanaceae.
- Author
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McRae L, Beric A, and Conant GC
- Subjects
- Genes, Duplicate, Polyploidy, Evolution, Molecular, Bias, Genome, Plant, Solanaceae genetics, Brassicaceae genetics
- Abstract
We model the post-hexaploidy evolution of four genomes from the Solanaceae, a group of flowering plants comprising tomatoes, potatoes and their relatives. The hexaploidy that these genomes descend from occurred through two sequential allopolyploidy events and was marked by the unequal losses of duplicated genes from the different progenitor subgenomes. In contrast with the hexaploid Brassiceae (broccoli and its relatives), where the subgenome with the most surviving genes arrived last in the hexaploidy, among the Solanaceae the most preserved subgenome descends from one of the original two tetraploid progenitors. In fact, the last-arriving subgenome in these plants actually has the fewest surviving genes in the modern genomes. We explore whether the distribution of repetitive elements (REs) in these genomes can explain the biases in gene losses, but while the signals we find are broadly consistent with a role for high RE density in driving gene losses, the REs turn over so quickly that little signal of the RE condition at the time of paleopolyploidy is extant in the modern genomes.
- Published
- 2022
- Full Text
- View/download PDF
37. A one-step, tunable method of selective reactive sputter deposition as a wrinkling approach for silver/polydimethylsiloxane for electrically conductive pliable surfaces.
- Author
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Loh JYY, Zeineddine A, Shayegannia M, McNeil R, McRae L, and Kherani NP
- Abstract
The wrinkle period and morphology of a metal thin film on an elastic substrate is typically controlled by modifying the substrate before carrying out additional metal deposition steps. Herein, we show that a simultaneously selective and reactive sputtering plasma that modifies the surface of a polydimethylsiloxane (PDMS) substrate while not reacting with the metal during the deposition process decreases the wrinkle wavelength and induces additional wrinkling components and features such as ripples or folds. The selective reaction of the nitrogen plasma with PDMS functionalizes the siloxane surface into silicon oxynitride. This hardens the immediate surface of PDMS, with a quadratic increase in the Young's modulus as a function of the sputtering flow ratio. The increase in the critical strain mismatch and the corresponding presence of folds in the nitrogen-modified wrinkled silver film form a suitable plasmonic platform for surface-enhanced Raman spectroscopy (SERS), yielding an enhancement factor of 4.8 × 10
5 for detecting lipids. This enhancement is linked to the emergence of electromagnetic hotspots from surface plasmon polariton coupling between the folds/wrinkles, which in turn enables the detection of low concentrations of organics using SERS. Furthermore, when strained, the nitrogen-modified wrinkles enhance electrical conductivity by a factor of 12 compared with unmodified films. Finally, the optical properties of the substrate can be tuned by altering the N2 content. The simple addition of nonreactive nitrogen to silver sputtering enables simultaneous PDMS hardening and growth of the silver film and together provide a new avenue for tuning wrinkling parameters and enhancing the electrical conductivity of pliable surfaces., Competing Interests: Competing interestsThe authors declare no competing interests., (© The Author(s) 2022.)- Published
- 2022
- Full Text
- View/download PDF
38. A quantitative global review of species population monitoring.
- Author
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Moussy C, Burfield IJ, Stephenson PJ, Newton AFE, Butchart SHM, Sutherland WJ, Gregory RD, McRae L, Bubb P, Roesler I, Ursino C, Wu Y, Retief EF, Udin JS, Urazaliyev R, Sánchez-Clavijo LM, Lartey E, and Donald PF
- Subjects
- Animals, Birds, Data Collection, Humans, Volunteers, Biodiversity, Conservation of Natural Resources
- Abstract
Species monitoring, defined here as the repeated, systematic collection of data to detect long-term changes in the populations of wild species, is a vital component of conservation practice and policy. We created a database of nearly 1200 schemes, ranging in start date from 1800 to 2018, to review spatial, temporal, taxonomic, and methodological patterns in global species monitoring. We identified monitoring schemes through standardized web searches, an online survey of stakeholders, in-depth national searches in a sample of countries, and a review of global biodiversity databases. We estimated the total global number of monitoring schemes operating at 3300-15,000. Since 2000, there has been a sharp increase in the number of new schemes being initiated in lower- and middle-income countries and in megadiverse countries, but a decrease in high-income countries. The total number of monitoring schemes in a country and its per capita gross domestic product were strongly, positively correlated. Schemes that were active in 2018 had been running for an average of 21 years in high-income countries, compared with 13 years in middle-income countries and 10 years in low-income countries. In high-income countries, over one-half of monitoring schemes received government funding, but this was less than one-quarter in low-income countries. Data collection was undertaken partly or wholly by volunteers in 37% of schemes, and such schemes covered significantly more sites and species than those undertaken by professionals alone. Birds were by far the most widely monitored taxonomic group, accounting for around half of all schemes, but this bias declined over time. Monitoring in most taxonomic groups remains sparse and uncoordinated, and most of the data generated are elusive and unlikely to feed into wider biodiversity conservation processes. These shortcomings could be addressed by, for example, creating an open global meta-database of biodiversity monitoring schemes and enhancing capacity for species monitoring in countries with high biodiversity. Article impact statement: Species population monitoring for conservation purposes remains strongly biased toward a few vertebrate taxa in wealthier countries., (© 2021 The Authors. Conservation Biology published by Wiley Periodicals LLC on behalf of Society for Conservation Biology.)
- Published
- 2022
- Full Text
- View/download PDF
39. Global patterns of resilience decline in vertebrate populations.
- Author
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Capdevila P, Noviello N, McRae L, Freeman R, and Clements CF
- Subjects
- Animals, Conservation of Natural Resources, Ecosystem, Biodiversity, Vertebrates
- Abstract
Maintaining the resilience of natural populations, their ability to resist and recover from disturbance, is crucial to prevent biodiversity loss. However, the lack of appropriate data and quantitative tools has hampered our understanding of the factors determining resilience on a global scale. Here, we quantified the temporal trends of two key components of resilience-resistance and recovery-in >2000 population time-series of >1000 vertebrate species globally. We show that the number of threats to which a population is exposed is the main driver of resilience decline in vertebrate populations. Such declines are driven by a non-uniform loss of different components of resilience (i.e. resistance and recovery). Increased anthropogenic threats accelerating resilience loss through a decline in the recovery ability-but not resistance-of vertebrate populations. These findings suggest we may be underestimating the impacts of global change, highlighting the need to account for the multiple components of resilience in global biodiversity assessments., (© 2021 The Authors. Ecology Letters published by John Wiley & Sons Ltd.)
- Published
- 2022
- Full Text
- View/download PDF
40. A counterfactual approach to measure the impact of wet grassland conservation on U.K. breeding bird populations.
- Author
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Jellesmark S, Ausden M, Blackburn TM, Gregory RD, Hoffmann M, Massimino D, McRae L, and Visconti P
- Subjects
- Breeding, United Kingdom, Conservation of Natural Resources, Grassland
- Abstract
Wet grassland populations of wading birds in the United Kingdom have declined severely since 1990. To help mitigate these declines, the Royal Society for the Protection of Birds has restored and managed lowland wet grassland nature reserves to benefit these and other species. However, the impact of these reserves on bird population trends has not been evaluated experimentally due to a lack of control populations. We compared population trends from 1994 to 2018 among 5 bird species of conservation concern that breed on these nature reserves with counterfactual trends created from matched breeding bird survey observations. We compared reserve trends with 3 different counterfactuals based on different scenarios of how reserve populations could have developed in the absence of conservation. Effects of conservation interventions were positive for all 4 targeted wading bird species: Lapwing (Vanellus vanellus), Redshank (Tringa totanus), Curlew (Numenius arquata), and Snipe (Gallinago gallinago). There was no positive effect of conservation interventions on reserves for the passerine, Yellow Wagtail (Motacilla flava). Our approach using monitoring data to produce valid counterfactual controls is a broadly applicable method allowing large-scale evaluation of conservation impact., (© 2021 The Authors. Conservation Biology published by Wiley Periodicals LLC on behalf of Society for Conservation Biology.)
- Published
- 2021
- Full Text
- View/download PDF
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