Electronic Cigarette Vape Exposure Exacerbates Post-Ischemic Outcomes in Female but Not in Male Rats.

BACKGROUND: Nicotine-containing electronic cigarette (EC) vaping has become popular worldwide, and our understanding of the effects of vaping on stroke outcomes is elusive. Using a rat model of transient middle cerebral artery occlusion, the current exploratory study aims to evaluate the sex-dependent effects of EC exposure on brain energy metabolism and stroke outcomes. METHODS: Adult Sprague-Dawley rats of both sexes were randomly assigned to air/EC vapor (5% nicotine Juul pods) exposure for 16 nights, followed by randomization into 3 cohorts. The first cohort underwent exposure to air/EC preceding randomization to transient middle cerebral artery occlusion (90 minutes) or sham surgery, followed by survival for 21 days. During the survival period, rats underwent sensorimotor and Morris water maze testing. Subsequently, brains were collected for histopathology. A second cohort was exposed to air/EC after which brains were collected for unbiased metabolomics analysis. The third cohort of animals was exposed to air/EC and received transient middle cerebral artery occlusion/sham surgery, and brain tissue was collected 24 hours later for biochemical analysis. RESULTS: In females, EC significantly increased (P<0.05) infarct volumes by 94% as compared with air-exposed rats, 165±50 mm3 in EC-exposed rats, and 85±29 mm3 in air-exposed rats, respectively, while in males such a difference was not apparent. Morris water maze data showed significant deficits in spatial learning and working memory in the EC sham or transient middle cerebral artery occlusion groups compared with the respective air groups in rats of both sexes (P<0.05). Thirty-two metabolites of carbohydrate, glycolysis, tricarboxylic acid cycle, and lipid metabolism were significantly altered (P≤0.05) due to EC, 23 of which were specific for females. Steady-state protein levels of hexokinase significantly decreased (P<0.05) in EC-exposed females; however, these changes were not seen in males. CONCLUSIONS: Even brief EC exposure over 2 weeks impacts brain energy metabolism, exacerbates infarction, and worsens poststroke cognitive deficits in working memory more in female than male rats.

Do large-scale agricultural entities achieve higher livelihood levels and better environmental outcomes than small households? Evidence from rural China.

There is an ongoing debate about the type or scale of agriculture that should be most encouraged. This study explores the differences in livelihood levels and outcomes between new agricultural business entities (NABEs) and traditional small households. We applied the analytical tools of a sustainable livelihood framework and a multiple linear regression model to describe the determinants of livelihood outcomes of 105 NABEs and 119 traditional small households in two typical areas around the Sichuan Basin in China. The results show that the overall livelihood level of NABEs is 1.40 times higher than traditional small households. NABEs with a mixed livelihood strategy of both planting and breeding have the highest livelihood level, followed by planting NABEs and breeding NABEs. About 3.13% of all agricultural entities are at risk of falling into poverty; the greater risk levels are associated with the subsidized households (30.00%), pure farmers (12.50%), and part-time farming households (1.69%). NABEs in the study area are verified to use 2.06 times more pesticide and herbicide inputs compared to traditional small households. Education level, technical training, financial accessibility, and the connection with professional cooperatives are common factors influencing the livelihood levels of the two groups of agricultural entities. Livelihood levels of NABEs are also significantly influenced by the age of NABE leaders, planting area per capita, and agricultural insurance. Based on these results, the study proposes policy interventions that are most appropriate for achieving higher livelihood levels among both NABEs and small households. Although the mixed type of NABEs and non-farming households are recognized as being better agricultural entity types for poverty alleviation, we recommend a balance between fostering NABEs and maintaining traditional small households; guidance related to green agriculture production for NABEs is also urgently needed.

Total Syntheses of Rhodomollins A and B.

The first and asymmetric total syntheses of rhodomollins A and B, two rhodomollane type grayanoids featuring a d-homograyanane carbon skeleton and an oxa-bicyclo[3.2.1] core, were accomplished via a convergent strategy. A Stille coupling and a lithium-halogen exchange/intramolecular nucleophilic addition to the aldehyde sequence were employed to assemble two enantioenriched fragments. The oxa-bicyclo[3.2.1] core was achieved through an intramolecular SN2 substitution of cyclic sulfate of 1,2-diols (Williamson ether synthesis). The A ring oxidation states were adjusted by a Payne/Meinwald rearrangement sequence and subsequent redox transformations.

Moderate operation scales of agricultural land under the greenhouse and open-field production modes based on DEA model in mountainous areas of southwest China.

The identification of the moderate scale of agricultural land was recognized as one of the key measures promoting sustainable agriculture development. However, due to the research gap in mountainous areas, new agricultural business entities (NABE) in these areas usually either refer to the plain area or simply pursue large scale, resulting in low production efficiency and even posing a threat to their sustainable survival. In this study, the Data Envelopment Analysis (DEA) model and Tobit regression model tools were employed to quantitatively reveal the moderate scale and key driving factors of agricultural land under the scale operation modes of greenhouse and open-field types. It was based on 154 NABE questionnaires in the mountainous areas around the Sichuan Basin in China, where NABEs are flourishing. The findings show an approximately "inverted U-shaped" curve relationship between NABE's production efficiency and their planting scale. The primary reason for the failure of NABE to achieve an overall high level of production efficiency is scale inefficiency. The optimal scale intervals for the greenhouse and open-field types of scale operation modes are 3.0-4.3 ha and 3.3-5.0 ha, respectively. Business entities' age, land circulation scale, land rent, and agricultural insurance are common factors that influence the scale efficiencies of both the greenhouse and open-field types. Accordingly, policy interventions regarding the guidance of moderate-scale operation of agricultural land are proposed for achieving the dual goal of cultivating NABE and implementing the Rural Revitalization Strategy in mountainous areas of China. While contributing to the knowledge on scale efficiency of agricultural land, this research also enlightens the practice of policy-making targeted to the sustainable development of agricultural industry led by NABE worldwide.

Multimodal magnetic resonance imaging after experimental moderate and severe traumatic brain injury: A longitudinal correlative assessment of structural and cerebral blood flow changes.

Traumatic brain injury (TBI) is a worldwide problem that results in death or disability for millions of people every year. Progressive neurological complications and long-term impairment can significantly disrupt quality of life. We demonstrated the feasibility of multiple magnetic resonance imaging (MRI) modalities to investigate and predict aberrant changes and progressive atrophy of gray and white matter tissue at several acute and chronic time points after moderate and severe parasagittal fluid percussion TBI. T2-weighted imaging, diffusion tensor imaging (DTI), and perfusion weighted imaging (PWI) were performed. Adult Sprague-Dawley rats were imaged sequentially on days 3, 14, and 1, 4, 6, 8, and 12 months following surgery. TBI caused dynamic white and gray matter alterations with significant differences in DTI values and injury-induced alterations in cerebral blood flow (CBF) as measured by PWI. Regional abnormalities after TBI were observed in T2-weighted images that showed hyperintense cortical lesions and significant cerebral atrophy in these hyperintense areas 1 year after TBI. Temporal DTI values indicated significant injury-induced changes in anisotropy in major white matter tracts, the corpus callosum and external capsule, and in gray matter, the hippocampus and cortex, at both early and chronic time points. These alterations were primarily injury-severity dependent with severe TBI exhibiting a greater degree of change relative to uninjured controls. PWI evaluating CBF revealed sustained global reductions in the cortex and in the hippocampus at most time points in an injury-independent manner. We next sought to investigate prognostic correlations across MRI metrics, timepoints, and cerebral pathology, and found that diffusion abnormalities and reductions in CBF significantly correlated with specific vulnerable structures at multiple time points, as well as with the degree of cerebral atrophy observed 1 year after TBI. This study further supports using DTI and PWI as a means of prognostic imaging for progressive structural changes after TBI and emphasizes the progressive nature of TBI damage.

Post-stroke periodic estrogen receptor-beta agonist improves cognition in aged female rats.

Women have a higher risk of having an ischemic stroke and increased cognitive decline after stroke as compared to men. The female sex hormone 17ß-estradiol (E2) is a potent neuro- and cognitive-protective agent. Periodic E2 or estrogen receptor subtype-beta (ER-ß) agonist pre-treatments every 48 h before an ischemic episode ameliorated ischemic brain damage in young ovariectomized or reproductively senescent (RS) aged female rats. The current study aims to investigate the efficacy of post-stroke ER-ß agonist treatments in reducing ischemic brain damage and cognitive deficits in RS female rats. Retired breeder (9-10 months) Sprague-Dawley female rats were considered RS after remaining in constant diestrus phase for more than a month. The RS rats were exposed to transient middle cerebral artery occlusion (tMCAO) for 90 min and treated with either ER-ß agonist (beta 2, 3-bis(4-hydroxyphenyl) propionitrile; DPN; 1 mg/kg; s.c.) or DMSO vehicle at 4.5 h after induction of tMCAO. Subsequently, rats were treated with either ER-ß agonist or DMSO vehicle every 48 h for ten injections. Forty-eight hours after the last treatment, animals were tested for contextual fear conditioning to measure post-stroke cognitive outcome. Neurobehavioral testing, infarct volume quantification, and hippocampal neuronal survival were employed to determine severity of stroke. Periodic post-stroke ER-ß agonist treatment reduced infarct volume, improved recovery of cognitive capacity by increasing freezing in contextual fear conditioning, and decreased hippocampal neuronal death in RS female rats. These data suggest that periodic post-stroke ER-ß agonist treatment to reduce stroke severity and improve post-stroke cognitive outcome in menopausal women has potential for future clinical investigation.

Red Cell Microparticles Suppress Hematoma Growth Following Intracerebral Hemorrhage in Chronic Nicotine-Exposed Rats.

Spontaneous intracerebral hemorrhage (sICH) is a disabling stroke sub-type, and tobacco use is a prominent risk factor for sICH. We showed that chronic nicotine exposure enhances bleeding post-sICH. Reduction of hematoma growth is a promising effective therapy for sICH in smoking subjects. Red-blood-cell-derived microparticles (RMPs) are hemostatic agents that limit hematoma expansion following sICH in naïve rats. Considering the importance of testing the efficacy of experimental drugs in animal models with a risk factor for a disease, we tested RMP efficacy and the therapeutic time window in limiting hematoma growth post-sICH in rats exposed to nicotine. Young rats were chronically treated with nicotine using osmotic pumps. sICH was induced in rats using an injection of collagenase in the right striatum. Vehicle/RMPs were administered intravenously. Hematoma volume and neurological impairment were quantified ≈24 h after sICH. Hematoma volumes in male and female nicotine-exposed rats that were treated with RMPs at 2 h post-sICH were significantly lower by 26 and 31% when compared to their respective control groups. RMP therapy was able to limit hematoma volume when administered up to 4.5 h post-sICH in animals of both sexes. Therefore, RMPs may limit hematoma growth in sICH patients exposed to tobacco use.

A Deep Learning-Aided Automated Method for Calculating Metabolic Tumor Volume in Diffuse Large B-Cell Lymphoma.

Metabolic tumor volume (MTV) is a robust prognostic biomarker in diffuse large B-cell lymphoma (DLBCL). The available semiautomatic software for calculating MTV requires manual input limiting its routine application in clinical research. Our objective was to develop a fully automated method (AM) for calculating MTV and to validate the method by comparing its results with those from two nuclear medicine (NM) readers. The automated method designed for this study employed a deep convolutional neural network to segment normal physiologic structures from the computed tomography (CT) scans that demonstrate intense avidity on positron emission tomography (PET) scans. The study cohort consisted of 100 patients with newly diagnosed DLBCL who were randomly selected from the Alliance/CALGB 50,303 (NCT00118209) trial. We observed high concordance in MTV calculations between the AM and readers with Pearson's correlation coefficients and interclass correlations comparing reader 1 to AM of 0.9814 (p < 0.0001) and 0.98 (p < 0.001; 95%CI = 0.96 to 0.99), respectively; and comparing reader 2 to AM of 0.9818 (p < 0.0001) and 0.98 (p < 0.0001; 95%CI = 0.96 to 0.99), respectively. The Bland-Altman plots showed only relatively small systematic errors between the proposed method and readers for both MTV and maximum standardized uptake value (SUVmax). This approach may possess the potential to integrate PET-based biomarkers in clinical trials.

Red Blood Cell Microparticles Limit Hematoma Growth in Intracerebral Hemorrhage.

BACKGROUND: Spontaneous intracerebral hemorrhage (sICH) is the deadliest stroke subtype with no effective therapies. Limiting hematoma expansion is a promising therapeutic approach. Red blood cell-derived microparticles (RMPs) are novel hemostatic agents. Therefore, we studied the potential of RMPs in limiting hematoma growth and improving outcomes post-sICH. METHODS: sICH was induced in rats by intrastriatal injection of collagenase. RMPs were prepared from human RBCs by high-pressure extrusion. Behavioral and hematoma/lesion volume assessment were done post-sICH. The optimal dose, dosing regimen, and therapeutic time window of RMP therapy required to limit hematoma growth post-sICH were determined. We also evaluated the effect of RMPs on long-term behavioral and histopathologic outcomes post-sICH. RESULTS: RMP treatment limited hematoma growth following sICH. Hematoma volume (mm3) for vehicle- and RMP- (2.66×1010 particles/kg) treated group was 143±8 and 86±4, respectively. The optimal RMP dosing regimen that limits hematoma expansion was identified. RMPs limit hematoma volume when administered up to 4.5-hour post-sICH. Hematoma volume in the 4.5-hour post-sICH RMP treatment group was lower by 24% when compared with the control group. RMP treatment also improved long-term histopathologic and behavioral outcomes post-sICH. CONCLUSIONS: Our results demonstrate that RMP therapy limits hematoma growth and improves outcomes post-sICH in a rodent model. Therefore, RMPs have the potential to limit hematoma growth in sICH patients.

Chronic Nicotine Exposure Increases Hematoma Expansion following Collagenase-Induced Intracerebral Hemorrhage in Rats.

Spontaneous intracerebral hemorrhage (sICH) is a deadly stroke subtype, and tobacco use increases sICH risk. However epidemiological studies show that, there are no confirmatory studies showing the effect of tobacco use on sICH outcome. Therefore, we evaluated the effect of chronic nicotine exposure (as a surrogate for tobacco use) on outcomes following sICH. Young male and female rats were randomly assigned to either nicotine (4.5 mg/kg b.w. per day) or vehicle (saline) treatment (2-3 weeks) groups. sICH was induced by injecting collagenase into the right striatum. Neurological score and hematoma volume were determined 24 h post-sICH. The hematoma volumes in nicotine-treated male and female rats were significantly higher by 42% and 48% when compared to vehicle-treated male and female rats, respectively. Neurological deficits measured in terms of neurological score for the nicotine-treated male and female groups were significantly higher when compared to the respective vehicle-treated male and female groups. Our results show that chronic nicotine exposure increases hematoma volume post-sICH in rats of both sexes. Identifying the mechanism of nicotine-dependent increase in hematoma growth post-sICH will be crucial to understanding the detrimental effect of tobacco use on the severity of bleeding following intracerebral hemorrhage.

Nicotine Exposure Along with Oral Contraceptive Treatment in Female Rats Exacerbates Post-cerebral Ischemic Hypoperfusion Potentially via Altered Histamine Metabolism.

Smoking-derived nicotine (N) and oral contraceptives (OCs) synergistically exacerbate ischemic brain damage in the female, and the underlying mechanisms remain elusive. Our published study showed that N toxicity is exacerbated by OC via altered mitochondrial electron transport chain function. Because mitochondria play an important role in cellular metabolism, we investigated the global metabolomic profile of brains of adolescent and adult female Sprague-Dawley rats exposed to N with or without OC (N+/-OC). Rats were randomly exposed to saline or N+/-OC for 16-21 days followed by random allocation into two cohorts. The first cohort was used to characterize the cortical metabolome. Pathway enrichment analysis showed a significant increase in several histamine metabolites including 1-methylhistamine, 1-methyl-4-imidazoleacetate, and 1-ribosyl-imidazleacetate, along with carnosine and homocarnosine in adolescent and adult animals treated with N and N+OC in relation to respective saline controls, which may be reflective of altered histamine metabolism with nicotine treatment. We also observed reduced levels of the neurotransmitters N-acetyl-aspartyl-glutamate (NAAG), gamma-aminobutyrate (GABA), and N-methyl-GABA in N+OC treatment in adolescent animals. The second cohort underwent bilateral carotid artery occlusion and hypotension followed by cerebral blood flow (CBF) assessment a day later. Autoradiographic images of the brain 24 h after ischemic episodes showed severe reduction in cortical and hippocampal local CBF in N+/-OC-exposed rats compared with saline treated. Because GABA and histamine are critical for CBF maintenance, altered metabolism of these neurotransmitters may be responsible for observed severe post-ischemic hypoperfusion, which in turn exacerbates ischemic brain damage.

Mild Hyperthermia Aggravates Glucose Metabolic Consequences in Repetitive Concussion.

Traumatic brain injury (TBI) is one of the leading causes of mortality and disability around the world. Mild TBI (mTBI) makes up approximately 80% of reported cases and often results in transient psychological abnormalities and cognitive disruption. At-risk populations for mTBI include athletes and other active individuals who may sustain repetitive concussive injury during periods of exercise and exertion when core temperatures are elevated. Previous studies have emphasized the impact that increased brain temperature has on adverse neurological outcomes. A lack of diagnostic tools to assess concussive mTBI limits the ability to effectively identify the post-concussive period during which the brain is uniquely susceptible to damage upon sustaining additional injury. Studies have suggested that a temporal window of increased vulnerability that exists corresponds to a period of injury-induced depression of cerebral glucose metabolism. In the current study, we sought to evaluate the relationship between repetitive concussion, local cerebral glucose metabolism, and brain temperature using the Marmarou weight drop model to generate mTBI. Animals were injured three consecutive times over a period of 7 days while exposed to either normothermic or hyperthermic temperatures for 15 min prior to and 1 h post each injury. A 14C-2-deoxy-d-glucose (2DG) autoradiography was used to measure local cerebral metabolic rate of glucose (lCMRGlc) in 10 diverse brain regions across nine bregma levels 8 days after the initial insult. We found that repetitive mTBI significantly decreased glucose utilization bilaterally in several cortical areas, such as the cingulate, visual, motor, and retrosplenial cortices, as well as in subcortical areas, including the caudate putamen and striatum, compared to sham control animals. lCMRGlc was significant in both normothermic and hyperthermic repetitive mTBI animals relative to the sham group, but to a greater degree when exposed to hyperthermic conditions. Taken together, we report significant injury-induced glucose hypometabolism after repetitive concussion in the brain, and additionally highlight the importance of temperature management in the acute period after brain injury.

Automated Assessment of Hematoma Volume of Rodents Subjected to Experimental Intracerebral Hemorrhagic Stroke by Bayes Segmentation Approach.

Simulating a clinical condition of intracerebral hemorrhage (ICH) in animals is key to research on the development and testing of diagnostic or treatment strategies for this high-mortality disease. In order to study the mechanism, pathology, and treatment for hemorrhagic stroke, various animal models have been developed. Measurement of hematoma volume is an important assessment parameter to evaluate post-ICH outcomes. However, due to tissue preservation conditions and variables in digitization, quantification of hematoma volume is usually labor intensive and sometimes even subjective. The objective of this study is to develop an automated method that can accurately and efficiently obtain unbiased cerebral hematoma volume. We developed an application (MATLAB program) that can delineate the brain slice from the background and use the Hue information in the Hue/Saturation/Value (HSV) color space to segment the hematoma region. The segmentation threshold of Hue is calculated based on the Bayes classifier theorem so that the minimum error is mathematically ensured and automated processing is enabled. To validate the developed method, we compared the outcomes from the developed method with the hemoglobin content by the spectrophotometric assay method. The results were linearly correlated with statistical significance. The method was also validated by digital phantoms with an error less than 5% compared with the ground truth from the phantoms. Hematoma volumes yielded by the automated processing and those obtained by the operator's manual operation are highly correlated. This automated segmentation approach can be potentially used to quantify hemorrhagic outcomes in rodent stroke models in an unbiased and efficient way.

Sex-Dependent Differences in Physical Exercise-Mediated Cognitive Recovery Following Middle Cerebral Artery Occlusion in Aged Rats.

Stroke remains a leading cause of death and disability in the United States. No current treatments exist to promote cognitive recovery in survivors of stroke. A previous study from our laboratory determined that an acute bout of forced treadmill exercise was able to promote cognitive recovery in 3 month old male rats after middle cerebral artery occlusion (MCAo). In this study, we tested the hypothesis that 6 days of intense acute bout of forced treadmill exercise (physical exercise - PE) promotes cognitive recovery in 11-14 month old male rats. We determined that PE was able to ameliorate cognitive deficits as determined by contextual fear conditioning. Additionally, we also tested the hypothesis that PE promotes cognitive recovery in 11-13 month old reproductive senescent female rats. In contrast to males, the same intensity of exercise that decrease cognitive deficits in males was not able to promote cognitive recovery in female rats. Additionally, we determined that exercise did not lessen infarct volume in both male and female rats. There are many factors that contribute to higher stroke mortality and morbidities in women and thus, future studies will investigate the effects of PE in aged female rats to identify sex differences.

Dearomative Dual Functionalization of Aryl Iodanes.

Herein we describe the dearomatization of aryl iodanes through an unprecedented "rearrangement/addition" sequence. The process consists of two stages. First, a rapid [3,3] sigmatropic rearrangement of the aryl iodane with an α-stannyl nitrile affords a highly electrophilic dearomatized intermediate at -78 °C. A low-temperature rearrangement then enables the unstable dearomatized species to be trapped in situ with various nucleophiles. As a consequence, the reaction not only breaks the aromaticity of the aryl iodane but also sequentially installs two different functional groups, thus resulting in a polysubstituted alicyclic product.

Benzyne-mediated trichloromethylation of chiral oxazolines.

A three-component reaction between benzyne, oxazolines and chloroform was developed for the synthesis of trichloromethylated chiral oxazolidines. Benzyne not only serves as an electrophile towards oxazolines but also acts as a base for the deprotonation of chloroform. The dual functions of benzyne enable the trichloromethylation of chiral oxazolines and thus construct chiral N,O-quaternary stereocenters.

One-pot Fluorination and Organocatalytic Robinson Annulation for Asymmetric Synthesis of Mono- and Difluorinated Cyclohexenones.

A one-pot fluorination and organocatalytic Robinson annulation sequence has been developed for asymmetric synthesis of 6-fluoroyclohex-2-en-1-ones and 4,6-difluorocyclohex-2-en-1-ones. The reactions promoted by cinchona alkaloid amine afforded products bearing two or three stereocenters in good to excellent yields with up to 99% ee and 20:1 dr.

Plasmonic Optical Imaging of Gold Nanorods Localization in Small Animals.

Gold nanoparticles (GNP) have been intensively investigated for applications in cancer imaging and therapy. Most imaging studies focused on microscopic imaging. Their potential as optical imaging probes for whole body small animal imaging has rarely been explored. Taking advantage of their surface plasmon resonance (SPR) properties, we aim to develop a noninvasive diffuse optical imaging method to map the distribution of a special type of GNP, gold nanorods (GNR), in small animals. We developed an integrated dual-modality imaging system capable of both x-ray computed tomography (XCT) and diffuse optical tomography (DOT). XCT provides the animal anatomy and contour required for DOT; DOT maps the distribution of GNR in the animal. This SPR enhanced optical imaging (SPROI) technique was investigated using simulation, phantom and mouse experiments. The distribution of GNR at various concentrations (0.1-100 nM, or 3.5 ug/g-3.5 mg/g) was successfully reconstructed from centimeter-scaled volumes. SPROI detected GNR at 18 µg/g concentration in the mouse breast tumor, and is 3 orders more sensitive than x-ray imaging. This study demonstrated the high sensitivity of SPROI in mapping GNR distributions in small animals. It does not require additional imaging tags other than GNR themselves. SPROI can be used to detect tumors targeted by GNR via passive targeting based on enhanced permeability and retention or via active targeting using biologically conjugated ligands.

Mild synthesis of triarylsulfonium salts with arynes.

Reactions between arynes and alkyl sulfides have been extensively studied over the past few decades. These reactions commonly end with a dealkylation process and thus deliver thioethers as final products. In contrast, the transformation described furnishes valuable triarylsulfonium salts, in lieu of thioethers, from arynes and diarylsulfides. The reaction features mild conditions and a broad substrate scope. A suite of functional groups such as ketones, esters, nitriles, aryl ethers and aryl halides is tolerated, which can be issues faced by traditional synthetic methods. The practicality of the reaction and its extension to the synthesis of triphenyl selenonium salt are also exhibited herein.