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BioMed Research International
Volume 2015, Article ID 917156, 10 pages
Inhibition of ACE Retards Tau Hyperphosphorylation and Signs of Neuronal Degeneration in Aged Rats Subjected to Chronic Mild Stress
1Molecular Pharmacology Unit, Department of Chemistry and Applied Biosciences, ETH Zurich, Winterthurerstrasse 190, 8057 Zurich, Switzerland
2International Neuroscience Institute (INI) Hannover, Rudolf-Pichlmayr-Strasse 4, 30625 Hannover, Germany
3Medical Research Centre (MRC), Ain Shams University Hospitals, Abassia, Cairo 11591, Egypt
4Institute of Pharmacology and Toxicology, Department of Medicine, University of Zurich, Winterthurerstrasse 190, 8057 Zurich, Switzerland
Received 20 August 2015; Accepted 12 November 2015
Academic Editor: Grazia D'Onofrio
Copyright © 2015 Said AbdAlla et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
With increasing life expectancy, Alzheimer's disease (AD) and other types of age-associated dementia are on the rise worldwide. Treatment approaches for dementia are insufficient and novel therapies are not readily available. In this context repurposing of established drugs appears attractive. A well-established class of cardiovascular drugs, which targets the angiotensin II system, is such a candidate, which currently undergoes a paradigm shift with regard to the potential benefit for treatment of neurodegenerative symptoms. In search for additional evidence, we subjected aged rats to chronic unpredictable mild stress, which is known to enhance the development of AD-related neuropathological features. We report here that four weeks of chronic mild stress induced a strong upregulation of the hippocampal angiotensin-converting enzyme (Ace) at gene expression and protein level. Concomitantly, tau protein hyperphosphorylation developed. Signs of neurodegeneration were detected by the significant downregulation of neuronal structure proteins such as microtubule-associated protein 2 (Map2) and synuclein-gamma (Sncg). Ace was involved in neurodegenerative symptoms because treatment with the brain-penetrating ACE inhibitor, captopril, retarded tau hyperphosphorylation and signs of neurodegeneration. Moreover, ACE inhibitor treatment could counteract glutamate neurotoxicity by preventing the downregulation of glutamate decarboxylase 2 (Gad2). Taken together, ACE inhibition targets neurodegeneration triggered by environmental stress.
1. Introduction
Alzheimer's disease (AD) is the most common form of dementia. While genetic factors are causally linked to familial AD, the pathogenesis of the predominant late-onset sporadic AD is diverse and less defined. Age is one of the best-documented risk factors for sporadic AD, which acts in concert with a wide array of brain insult-promoting vascular and metabolic factors such as hypertension, ischemia, diabetes, high cholesterol, and different forms of environmental stress and stress-related psychiatric symptoms, that is, depression and anxiety [1–3].
Experimental models of AD often reproduce genetic alterations whereas the impact of additional brain-damaging factors is more difficult to assess. The chronic unpredictable mild stress (CUMS) model imitates psychiatric risk factors such as psychological, psychosocial, and physical stress [4]. In agreement with the well-established impact of stress on neuronal viability, the model promotes signs of neuronal degeneration such as decreased synaptic transmission at hippocampal CA1-CA3 synapses, impaired neurogenesis, and cognitive dysfunction [5–7]. The sensitivity to stress in this model increases with age, a major factor of AD pathogenesis [8]. The relationship to AD is further supported by several studies, which show that the CUMS procedure worsens disease progression in genetic AD mouse models [9–11].
Moreover, the chronic mild stress protocol induces major neuropathological hallmarks of AD, that is, enhanced β-amyloid (Aβ) generation, tau hyperphosphorylation, and the appearance of various other AD markers [9, 11, 12]. In this respect, the chronic mild stress model could complement genetic AD models because the CUMS model solely relies on endogenously expressed proteins. In view of the recent failure of large clinical trials, which targeted β-amyloid plaques [13, 14], such alternative models, which imitate the disease process before the accumulation of Aβ plaques, could become of substantial value.
Inefficient Aβ plaque-targeting approaches also raise the necessity to identify players in AD pathogenesis, which could interrupt the disease process at an earlier stage [15]. For one player in AD pathogenesis a paradigm shift is currently on the way, which is the angiotensin system, notably the angiotensin-converting enzyme (ACE). While many studies considered ACE primarily as an enzyme that could promote proteolysis of β-amyloid in vitro [16–18], recent experimental and clinical studies provide strong evidence that inhibition of ACE-dependent angiotensin II generation in vivo could actually reduce signs of neurodegeneration in experimental AD models [19, 20] and slow the cognitive decline of patients with Alzheimer's disease [21–25].
In view of this emerging development, we aimed to further analyse the impact of ACE inhibition on early signs of neurodegeneration and applied the chronic unpredictable mild stress model in our study.
2. Materials and Methods
2.1. Chronic Unpredictable Mild Stress Model
Male Wistar rats (15 months of age) were subjected to the chronic unpredictable mild stress (CUMS) battery for four weeks. The CUMS protocol was performed essentially as described previously [8, 9]. After four weeks of stress, more than 90% of stressed rats showed signs of anhedonia as documented by a decrease in sucrose preference compared to nonstressed controls (i.e., <50% of sucrose consumption compared to nonstressed controls). The age-matched control group was housed under standard conditions and had free access to food and water. The captopril treatment group received captopril in drinking water (50 mg/kg/day, dissolved fresh every day) during the CUMS protocol. After 28 days of stress, at an age of 16 months, 4 h before the beginning of the dark phase, rats were anesthetized with ketamine and xylazine (100 mg/kg and 10 mg/kg, i.p.), and brains were removed and processed for immunohistology [9, 20]. For whole genome microarray gene expression profiling, biochemical analyses, and immunoblotting, the hippocampus was dissected out on ice and processed for further use as detailed below.
All animal experiments were performed in accordance with the NIH guidelines and were approved by the local committee on animal research (MRC, Ain Shams University Hospitals, Cairo, Egypt).
2.2. Whole Genome Microarray Gene Expression Profiling of Hippocampal Gene Expression
For whole genome microarray gene expression analysis, total hippocampal RNA was isolated from stressed rats and age-matched nonstressed control rats. Total RNA was processed for whole genome microarray gene expression profiling and hybridized to the GeneChip Rat Genome 230 2.0 Array (more than 31 000 probe sets, Affymetrix) as detailed previously [20]. The total RNA from 3 animals was pooled for one gene chip, and two gene chips are presented for each group. Microarrays were scanned with the Affymetrix GeneChip Scanner 7G, and signals were processed with a target value of 300 using GCOS (version 1.4, Affymetrix). Applied selection criteria for differently expressed genes (2-fold change requirement, just alpha, no false discovery correction, and ) were validated specifically for drug treatment effects [20] and follow the guidelines of the Microarray Quality Control (MAQC) project for the identification of reproducible gene lists [26, 27]. Probe sets with significant difference ( and ≥2-fold difference, with call present and/or signal intensity ≥100) between stressed rats and nonstressed, age-matched control rats were used for GO classification. Microarray data are available at the NCBI GEO repository (GSE72062).
Gene expression of Ace and Map2 in the hippocampus of stressed rats and nonstressed controls was determined by real-time quantitative (q) RT-PCR with a LightCycler 480 (Roche Diagnostics). Sequences of the forward and reverse primers were as follows: Ace forward 5′-GATTGCAGCCGGGCAACTTTTC-3′; Ace reverse 5′-CGGATCCGATGATCCTTCGC-3′; Map2 forward 5′-CACTGGAAGAAGCCTCGAAGA-3′; Map2 reverse 5′-CACGGGCATTTCGATGAACC-3′.
2.3. Immunoblotting, Immunohistology, and Biochemical Methods
Immunoblot detection of hippocampal proteins was performed with hippocampal tissue extracts as described [9, 20]. For immunohistology and immunofluorescence analysis, we used paraffin-embedded brain sections obtained from stressed and nonstressed rats (8 μm, taken at 50 μm intervals, 10–15 sections per set). The following antibodies were used for immunoblotting, immunofluorescence, and immunohistology: anti-Ace antibodies raised in rabbit against an antigen corresponding to amino acids 720–750 of mouse Ace [20]; anti-angiotensin II antibodies raised in rabbit against synthetic angiotensin II [20]; anti-APP/Aβ antibodies raised in rabbit against a peptide corresponding to amino acids 672–714 of human APP [20]; anti-AT1R antibodies raised in rabbit against an antigen corresponding to amino acids 306–359 of the mouse Agtr1a sequence [20]; anti-Gad65 antibody (clone N-GAD65, developed in mouse against a synthetic peptide corresponding to amino acids 4–22 of human GAD65); anti-Grin3a antibodies raised in rabbit against a synthetic peptide derived from the extracellular domain of rat Grin3a (Abcam); anti-MAP2 mouse monoclonal antibody generated against bovine microtubule-associated protein, MAP2 (Clone AP-20); anti-chondroitin sulfate proteoglycan NG2 mouse monoclonal antibody generated against a truncated form of NG2 (MAB5384); anti-PHF-tau pSer202 and pThr 205 antibody (mouse monoclonal antibody, clone AT8; Pierce); and anti-Sncg antibodies raised in goat against an internal region of human SNCG (Santa Cruz Biotechnology).
Hippocampal Ace activity was assessed with a fluorogenic substrate (Abz-FRK(Dnp)-P; Biomol) as described [20], and determination of hippocampal glutamic acid decarboxylase (Gad) enzyme activity was performed as detailed previously [8].
2.4. Statistical Analysis
The results are presented as means ± s.d. We used unpaired two-tailed Student's -test for comparisons between two groups. Statistical significance was set at a value of <0.05, unless otherwise specified.
3. Results
3.1. Chronic Unpredictable Mild Stress Induced Upregulation of Hippocampal Ace Protein and Gene Expression
Chronic stress worsens the progression of AD in patients and transgenic disease models [9–11] but underlying mechanisms are incompletely understood. Because the angiotensin-converting enzyme (ACE) is upregulated in brains of AD patients and mice [20], we asked for an interrelationship between Ace and stress. We used the chronic unpredictable mild stress model to investigate the role of Ace in stress-induced signs of neurodegeneration. Initially, we analysed the localization of Ace in stressed and nonstressed rat brain. Complementary to previous data with AD mice [20], endothelial cells lining a brain vessel of a stressed rat showed strong immunostaining for Ace (Figure 1(a)). Immunofluorescence localization of the pericyte marker, chondroitin sulfate proteoglycan Ng2, indicated that Ace was predominantly present in vascular endothelial cells whereas adjacent pericytes showed weaker staining for Ace (Figure 1(b)).
We further investigated the localization of Ace by immunohistology and focused on the hippocampal area because chronic mild stress induces profound changes at hippocampal CA3-CA1 synapses [7], that is, the brain area, which is highly susceptible to AD-related neuronal damage. In agreement with previous results [20], immunohistology analysis detected Ace immunoreactivity in cell bodies of hippocampal CA3 neurons (Figure 1(c)). Moreover, immunohistology revealed a strong increase in Ace immunoreactivity in hippocampal CA3 neurons of a stressed rat relative to that of a nonstressed control (Figure 1(c)).
In agreement with the increased Ace immunoreactivity, the gene expression level of hippocampal Ace was also significantly increased in stressed rats, that is, the hippocampal Ace gene expression level was -fold higher in stressed rats compared to that in nonstressed controls (; Figure 1(d)). Concomitantly, with Ace gene expression, the increased hippocampal Ace protein level of stressed rats was detected in immunoblot (Figure 1(e)). The increase in Ace protein was accompanied by a significantly elevated hippocampal Ace activity; that is, the hippocampal Ace activity was -fold higher () in stressed rats compared to that in nonstressed controls (Figure 1(f)). The elevated Ace activity was also reflected by an increased hippocampal angiotensin II content in stressed rats relative to nonstressed controls (Figure 1(g)). Taken together, chronic unpredictable mild stress led to a significant upregulation of the Ace protein in the hippocampal area of stressed rats. As a consequence of Ace upregulation, the hippocampal angiotensin II content in stressed rats was elevated compared to that in nonstressed controls.
3.2. Tau Hyperphosphorylation in the Hippocampus of Stressed Rats
The strong upregulation of Ace in the hippocampus of stressed rats prompted us to search for signs of hippocampal neurodegeneration because previous data showed a causal relationship between Ace upregulation and signs of neurodegeneration in a genetic model of AD [20]. In this context we determined the level of tau hyperphosphorylation as a hallmark of AD. Immunohistological analysis demonstrated that four weeks of chronic unpredictable mild stress induced a strong increase in the level of phosphorylated tau protein in the hippocampus of an aged rat, as detected in a hippocampal section with anti-PHF (AT8) antibody (Figure 2(a)). Immunohistology also revealed that the increased tau phosphorylation was predominant in neurons of the CA1-CA3 region (Figure 2(a)). In contrast, PHF antibody staining was negligible in hippocampal neurons of the nonstressed control (Figure 2(a)).
Immunoblot detection of phosphorylated tau in hippocampal tissue extracts confirmed the immunohistology data and showed an increased level of hyperphosphorylated tau protein in stressed rats compared to that in nonstressed controls (Figure 2(b)). As an additional control, the total level of hippocampal tau protein was not different between stressed and nonstressed rats (Figure 2(b), lower panel). Taken together, the upregulation of Ace and angiotensin II in hippocampal neurons of stressed rats was accompanied by tau hyperphosphorylation.
Ace-dependent angiotensin II generation promotes signs of hippocampal neurodegeneration by activation of the AT1 receptor (AT1R) in a genetic AD model [20]. Complementary to those data, immunofluorescence analysis of a stressed rat brain showed AT1R immunoreactivity in hippocampal CA1 neurons, which also displayed accumulation of hyperphosphorylated tau protein (Figure 2(c)). Concomitantly, neuronal loss of a highly PHF-positive CA1 neuron was detected (Figure 2(c)). Thus, stress promoted Ace-dependent release of the AT1R-stimulating angiotensin II peptide together with tau hyperphosphorylation in hippocampal AT1R-positive neurons.
3.3. Whole Genome Microarray Gene Expression Profiling Detected Stress-Induced Signs of Hippocampal Neurodegeneration
We further investigated the impact of stress on signs of neurodegeneration and performed whole genome microarray gene expression profiling of hippocampal gene expression. Gene ontology (GO) analysis searched for differently expressed neuron-specific genes by applying neuron-specific GO terms, that is, neuron, axon, dendrite, and synapse. Following established selection criteria for significantly different probe sets (≥2-fold difference and ), the GO analysis documented that stress triggered the significant downregulation of neuron-specific genes, which were categorized according to the cellular localization of the respective proteins, that is, cytoplasm and membrane (Figures 3(a) and 3(b)).
The list of significantly downregulated genes encompasses major neuronal structure proteins such as microtubule-associated protein 2 (Map2) and synuclein-gamma, Sncg (Figure 3(a)). Because the loss of neuronal Map2 is a characteristic feature of AD-related neurodegeneration, which is causally linked to stress-induced tau hyperphosphorylation [9, 28], we performed immunolocalization of the hippocampal Map2. Immunohistology analysis detected the decreased Map2 content in hippocampal CA1 neurons of a stressed rat compared to that of a nonstressed control (Figure 3(c)). The stress-induced downregulation of the hippocampal Map2 protein was further confirmed by qRT-PCR (Figure 3(d)). Together these data indicate that chronic unpredictable mild stress led to tau hyperphosphorylation and decreased the level of neuron-specific genes such as Map2. The decreased expression of neuronal structure proteins complements previous data, which show that chronic mild stress triggers alterations of hippocampal synapses and promotes a decrease in dendritic spine density [7].
The expression of glutamic acid decarboxylase 2 (Gad65/Gad2) was also downregulated by chronic unpredictable mild stress (Figure 3(a)). The decreased Gad65 expression could account for the significantly decreased hippocampal Gad enzyme activity, which was measured in hippocampal tissue extracts of stressed rats compared to that of nonstressed controls (Figure 3(e)). The ensuing decreased metabolism of the excitatory neurotransmitter, glutamate, could be partially responsible for the increased tau phosphorylation under chronic mild stress [8, 29]. In addition to the decreased glutamate degradation, the expression of the inhibitory and neuroprotective NMDA receptor subtype Grin3a (NR3A) [30, 31] was also downregulated by stress (Figure 3(b)). Immunohistology data complemented the microarray study and showed abundant membrane-localized Grin3a protein in hippocampal CA1 neurons of a nonstressed control whereas the neuronal Grin3a protein was barely detectable in the hippocampal neurons of a stressed rat (Figure 3(f)). As a consequence of stress-induced Grin3a (NR3A) downregulation, glutamate excitotoxicity, for example, triggered by decreased Gad enzyme activity, could be further augmented [30, 31]. Taken together, whole genome microarray gene expression profiling detected signs of neurodegeneration and markers of enhanced glutamate excitotoxicity in the hippocampus of stressed rats.
3.4. Treatment with the Brain-Penetrating ACE Inhibitor, Captopril, Retarded Signs of Neurodegeneration Induced by Chronic Mild Stress
In view of the strongly upregulated Ace protein, we asked whether treatment with the brain-penetrating ACE inhibitor, captopril, could affect the process of neurodegeneration triggered by stress. Aged rats were treated with captopril during the chronic unpredictable mild stress procedure. As a sign of neurodegeneration, we determined the hippocampal tau phosphorylation. Immunohistology analysis revealed a substantially decreased level of hyperphosphorylated tau protein in hippocampal CA3 neurons of a stressed rat with captopril treatment relative to that of a stressed control without ACE inhibitor treatment (Figure 4(a)). Immunoblot detection of hyperphosphorylated tau confirmed immunohistology data and demonstrated the decreased hyperphosphorylated tau protein content in the hippocampus of stressed rats with captopril treatment relative to that of stressed rats without treatment (Figure 4(b)). Concomitantly, with the decreased tau phosphorylation, the stress-induced loss of synuclein-gamma (Sncg) was also retarded by ACE inhibition with captopril (Figure 4(c), upper panel).
We next assessed the hippocampal Gad65 protein level and activity. Immunoblot analysis showed that captopril treatment counteracted the stress-induced decrease in hippocampal Gad65 protein (Figure 4(c), lower panel). The preserved Gad65 protein was accompanied by a significantly higher hippocampal Gad activity in stressed rats with captopril treatment compared to that in stressed rats without treatment (Figure 4(d)). Taken together, our data indicate that inhibition of ACE with a brain-permeable ACE inhibitor retarded the stress-induced tau hyperphosphorylation and counteracted the downregulation of Gad activity triggered by chronic mild stress.
Previous studies indicate that chronic mild stress enhances the generation of Aβ as a major neuropathological feature of AD [12] while ACE inhibition decreases the hippocampal Aβ level, as documented in a genetic AD model [20]. The increased Aβ generation could be a consequence of the stress-induced increase in the steady-state level of the amyloid beta (A4) precursor protein (App) [32]. Complementary to those data, immunoblot analysis detected the high hippocampal App load in stressed rats without treatment whereas the hippocampal App content was substantially decreased in stressed rats with ACE inhibitor treatment (Figure 4(e), upper panel). Concomitantly, immunoblot analysis revealed that the hippocampal Aβ level was also decreased in stressed rats with ACE inhibitor treatment compared to that in stressed rats without treatment (Figure 4(e), lower panel).
4. Discussion
4.1. Chronic Unpredictable Mild Stress Triggered Signs of Hippocampal Neurodegeneration
Our study applied the chronic unpredictable mild stress model, which imitates major features of sporadic AD such as tau hyperphosphorylation, enhanced Aβ generation, and other signs of dendritic and synaptic degeneration [7, 12]. In agreement with those previous studies, we also found that chronic mild stress triggered signs of hippocampal neurodegeneration, which was documented by hippocampal tau hyperphosphorylation, decreased levels of major neuronal proteins such as Map2 and Sncg, and an increased level of Aβ-generating App. Concomitantly, with AD-related signs of neurodegeneration, glutamate excitotoxicity-enhancing features appeared such as decreased Gad65 protein level and enzyme activity and decreased hippocampal expression of the glutamate-inhibitory NMDA receptor subtype, Grin3a (NR3A). The ensuing sensitization of glutamate excitotoxicity could contribute to stress-induced signs of neurodegeneration because glutamate excitotoxicity is a major factor, which contributes to neurodegeneration and tau hyperphosphorylation [29].
4.2. Chronic Mild Stress Induced Upregulation of Hippocampal Ace Protein and Activity
In search for additional stimuli, which could account for the development of stress-induced signs of neurodegeneration, our study detected a significantly increased hippocampal protein level of the angiotensin II-generating enzyme, Ace. Immunohistology analysis localized the upregulated Ace protein not only in brain vessels but also in neuronal cell bodies of the hippocampus. Concomitantly, an increased hippocampal Ace activity and angiotensin II peptide level were detected. The upregulation of neuronal Ace expression and protein level could be a direct consequence of the stress-induced activation of the hypothalamic pituitary adrenocortical (HPA) axis because several studies found that ACE expression was triggered by glucocorticoids and glucocorticoid receptor activation [33–35].
4.3. ACE Inhibition Retarded Signs of Neurodegeneration Induced by Chronic Mild Stress
The upregulated Ace protein could be causally involved in signs of neurodegeneration triggered by chronic mild stress because treatment with the brain-penetrating ACE inhibitor, captopril, retarded the development of signs of stress-induced neurodegeneration, that is, tau hyperphosphorylation, downregulation of neuronal proteins, decreased Gad enzyme activity, and increased hippocampal App level.
The mechanism underlying the neuroprotective activity of central ACE inhibition is not entirely understood. Several studies indicated that the neuroprotective effect of central ACE inhibition is largely due to a decrease in angiotensin II generation and subsequently blunted activation of the angiotensin II AT1 receptor, AT1R [20, 36–40]. Such conclusion is supported by data, which show the involvement of angiotensin II-AT1R in major neuropathological features such as tau hyperphosphorylation [37], enhanced glutamate release [38], and increased Aβ formation [20, 39, 40]. In addition to direct neuroprotection, inhibition of the ACE-AT1R axis could also counteract the stress response by blunting the release of ACTH [41]. In agreement with a role of the ACE-angiotensin II-AT1R axis in stress-induced neurodegeneration, we found that the hippocampal angiotensin II content was increased by stress, and hippocampal neurons with hyperphosphorylated tau protein and overt neurodegeneration were AT1R-positive.
In view of the stress-induced upregulation of the hippocampal Ace and the neuroprotective activity of ACE inhibition in the chronic mild stress model, our data support a causative role of ACE in stress-induced neurodegeneration. Because the model reproduces major features of sporadic AD (i.e., tau hyperphosphorylation, Aβ generation, and glutamate excitotoxicity), our study could provide a rationale for the documented efficacy of centrally active ACE inhibitors in several clinical studies, which showed retardation of AD-related cognitive decline as a major sign of neurodegeneration [21–25]. In this context, the suggested repurposing of ACE inhibitors for clinical conditions related to AD and other types of dementia [42] could be a potential option, which deserves further study.
5. Conclusion
Inhibition of ACE with the centrally acting captopril retarded the development of hippocampal tau phosphorylation, signs of neurodegeneration, and amyloid beta (A4) precursor protein (App) upregulation in rats subjected to chronic unpredictable mild stress, as a model, which reproduces major pathological features of sporadic AD.
Conflict of Interests
The authors have no conflict of interests.
This study was supported in part by ETH Research Grant ETH-18 14-2.
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- Y. Dasarathy, J. J. Lanzillo, and B. L. Fanburg, "Stimulation of bovine pulmonary artery endothelial cell ACE by dexamethasone: involvement of steroid receptors," American Journal of Physiology—Lung Cellular and Molecular Physiology, vol. 263, no. 6, pp. L645–L649, 1992. View at Google Scholar · View at Scopus
- R. S. Fishel, S. Eisenberg, S. Y. Shai, R. A. Redden, K. E. Bernstein, and B. C. Berk, "Glucocorticoids induce angiotensin-converting enzyme expression in vascular smoth muscle," Hypertension, vol. 25, no. 3, pp. 343–349, 1995. View at Publisher · View at Google Scholar
- S. Villapol and J. M. Saavedra, "Neuroprotective effects of angiotensin receptor blockers," American Journal of Hypertension, vol. 28, no. 3, pp. 289–299, 2015. View at Publisher · View at Google Scholar
- M. Tian, D. Zhu, W. Xie, and J. Shi, "Central angiotensin II-induced Alzheimer-like tau phosphorylation in normal rat brains," FEBS Letters, vol. 586, no. 20, pp. 3737–3745, 2012. View at Publisher · View at Google Scholar · View at Scopus
- Y.-M. Kang, D.-M. Zhang, X.-J. Yu et al., "Chronic infusion of enalaprilat into hypothalamic paraventricular nucleus attenuates angiotensin II-induced hypertension and cardiac hypertrophy by restoring neutrotransmitters and cytokines," Toxicology and Applied Pharmacology, vol. 274, no. 3, pp. 436–444, 2014. View at Publisher · View at Google Scholar · View at Scopus
- D. Zhu, J. Shi, Y. Zhang et al., "Central angiotensin II stimulation promotes β amyloid production in Sprague Dawley rats," PLoS ONE, vol. 6, no. 1, Article ID e16037, 2011. View at Publisher · View at Google Scholar · View at Scopus
- J. Liu, S. Liu, Y. Matsumoto et al., "Angiotensin type 1a receptor deficiency decreases amyloid β-protein generation and ameliorates brain amyloid pathology," Scientific Reports, vol. 5, article 12059, 2015. View at Publisher · View at Google Scholar
- N. Glorioso, P. Dessìfulgheri, S. Alagna et al., "Angiotensin converting enzyme inhibition reduces ACTH release due to hypoglycaemia," Clinical and Experimental Hypertension A, Theory and Practic, vol. 9, no. 2-3, pp. 665–670, 1987. View at Publisher · View at Google Scholar · View at Scopus
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LSVA and Combined Arms are Merging!
Last week we celebrated 10 years of building the veteran community here at Lone Star Veterans Association (LSVA). We began 10 years ago by focusing on veterans returning from combat in Iraq and Afghanistan. Since then we've expanded that focus to include other critical members of the veteran community where all are represented, veterans and families, connected together around a common vision of One Veteran Community. Now the LSVA membership exceeds 10,000 people.
We want to make sure that our community is defined by our strengths, not just our challenges. As Veterans, we aspire to be defined by our excellence, by our service, and by our ability to lead our communities through the many challenges and opportunities ahead. Together we can build One Veteran Community where we accelerate the impact of veterans on America.
Looking at the next 10 years we want this program model to extend beyond Houston. Better technology enables this achievement. Engaging and monitoring thousands of veterans each year ensures that the right services and support find the right needs much quicker than ever before.
That's why we are proud to announce that we are merging with Combined Arms, the best in class non-profit specifically focused on building the veteran community.Read more
VRG Forum Update
Last week we hosted another great lunch for the 60+ veteran employee resource groups at our VRG Forum event. Big thanks to the Tasting Room for hosting the lunch again. We were able to come together and hear from our committee leads on the progress made since December on our focus areas:
- Increasing Veteran Hiring
- Supporting Veteran Owned Businesses
- Organizing Group Volunteering
We'd like to share in this post some notes from the meeting as well as some helpful information and next steps before our next lunch.
See photos from our most recent lunch hereRead more
What Does LSVA Do?
Ever since I joined the board of LSVA back in 2013 the biggest question I was asked (and admittedly, we'd ask ourselves) is "What exactly does LSVA do?" It was like being in that scene in Office Space trying to explain what "everyone already knows". Over time we've been a mile wide and an inch deep, but I'm very proud that we've discovered what we can do better than anyone else serving veterans in Houston, get connected. We aren't a career placement agency, we don't do community service projects, or operate an emergency response team.... any more. At one time we did all of those things, simultaneously.Read more
Celebrate 10 Years with the Veteran Community
Here at Lone Star Veterans Association we're celebrating 10 years in 2019 of our mission to build One Veteran Community. We can't thank everyone that has been along this wild ride so far, and has signed up for the next 10 years. There have been delirious highs and depressing lows along the way, but throughout it all we've had YOU our community of veterans driving our mission to where we are today.... over 10,000 members!
2019 Community Leader Applications Open
Lone Star Veterans Association is recruiting passionate and driven leaders to build One Veteran Community. Only the best will become LSVA Community Leaders, those that connect veterans and their families to resources, opportunities, and one another. Community Leaders will be trained and deployed into their neighborhoods and workplaces to execute fun, positive, and inclusive activities that will inspire and connect.Read more
Community Leader Spotlight Carlis Miller
Lone Star Veterans Association has become what it is today by the dedication and sacrifice of our Community Leaders. These volunteers have taken time from their personal life to strengthen the community of our veterans by establishing an avenue for veterans to network. Our volunteers are paving the path towards One Veteran Community. We want to take time to thank our December Spotlight Board of Director and Volunteer Carlis Miller for his dedication to LSVA. Carlis is a pillar of our community. Thank you, Carlis!!!Read more
Community Leader Spotlight - Sharon Nitsche
Lone Star Veterans Association has become what it is today by the dedication and sacrifice of our Community Leaders. These volunteers have taken time from their personal life to strengthen the community of our veterans by establishing an avenue for veterans to network. Our volunteers are paving the path towards One Veteran Community. We want to take time to thank our November Spotlight Volunteer Sharon Nitsche for her dedication to LSVA. Sharon is a pillar of our community.Read more
Military veterans in Houston find support in faith-based organizations
We were recently spotlighted for our work in building the veteran community for our Christian members.Read more
One Veteran Community
We were excited to share our process of community building and our experience of doing so for the multi-faceted veteran community. We're proud to be working towards building One Veteran Community a foundation for the entire American community, one brick at a time.
Why Veterans and Civilians Should Share Their Faith Journey Together
When we were planning our Veteran Christian group in 2017 one of our Advisory Council members asked an obvious question, that I didn't at first understand. He asked, "Would it would be appropriate for me to attend since I did not serve in the military." I didn't understand because at Lone Star Veterans Association our motto for events is that they're fun, positive, and inclusive. We have focused on inclusivity recently because we were founded with a focus on Iraq and Afghanistan combat veterans but decided to expand our focus to all eras of service and to civilian supporters. It was at that point that we discussed how important it was for this group to focus on not just attracting Christian Veterans, but any Christian that wants to hear a veteran share his or her faith journey.Read more

subset: commoncrawl


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If you don't want to be swindled out of your money by the notorious dumpster rental service companies operating within the Woodbury, MN area, then try striking a deal with Ames Dumpster Rental instead by calling 888-416-8891 now. We are capable of meeting the dumpster demands of any individual, as we've amassed a very distinct selection of receptacle bins in Woodbury, MN, as well as an effective workforce to ensure the timely delivery of each bin going to the client's location of choice. We honestly do not mind if you ask for a small bin or a colossal construction dumpster – if it's in our storage place (it probably is!), we'll happily dispatch it to your location in Woodbury on the date and time you require it. To get a dumpster rental unit in Woodbury, MN, give us a call right away, at 888-416-8891.
Inexpensive Services You can Rely Upon
While other companies are proud of the profits they make from their customers, we take pride in being able to help out consumers with each need they approach us with. We've assisted a large number of people in Woodbury get their clean-up taken care of swiftly and easily, so you can be assured you'll be receiving the very best service we can provide. Workers at Ames Dumpster Rental correct the duties they're assigned to swiftly and independently, thereby enabling consumers to concentrate on the areas of their projects that really matter. If you need a dumpster for a week, or prefer to arrange a regular change out throughout the next six months, we can take care of you, and we won't wreck your spending budget doing it.
It took a while for a substantial portion of our clientele to understand that their plastic trash bins couldn't cut it for their larger-than-usual residential and commercial projects. Needless to say, it'd be time consuming and incredibly impractical to use a measly garbage can with a lid on top to collect the clutter left behind a powerful thunderstorm or a kitchen area remodeling project. Ames Dumpster Rental has the right size dumpster for you, just waiting to be delivered. And because you have much better things to do than wait all day for us, we'll schedule your drop off or pickup in the earliest time possible, and we'll make sure we're there on time. The success we've experienced in Woodbury and across the state of Minnesota isn't just attributed to our wide array of receptacle bins, but our enthusiasm to bend backwards in favor of our highly valued consumers.
Do not Delay: Call Today!
Your dumpster rental demands are made uncomplicated when you call Ames Dumpster Rental. You won't need to look any further, be troubled over any more details, or throw away any more of your priceless time, most especially when you undoubtedly have more serious things to do. If you need a functional roll off container or dumpster transported to your Woodbury, MN property in timely fashion, do not think twice to contact us at 888-416-8891 today. We are more than willing to serve you!
The Only Dumpster Rental Firm You Can Rely on within Woodbury
If you want to work with a corporation that recognizes your distinctive dumpster rental needs, then it'd be wise to work with Ames Dumpster Rental, so contact them at 888-416-8891 today. Your dumpster delivery will be dealt with by well-mannered specialists who will get there promptly, thereby letting you return to your busy day. People from the Woodbury, MN area may avail our one-of-a-kind, trusted, and cost-effective dumpster rental services by calling 888-416-8891 now.
Quality Service at Economical Rates
Regardless of what size roll off container you need, for any domestic or commercial job, you need a crew of professionals in your corner to help you identify the best size for you, get your delivery on the schedule, then make certain we get it there on time. Our unequaled consumer service is how we're building a name for ourselves in Woodbury. That means you'll get the best work we can offer, at the best possible cost.
So if you require a massive construction dumpster, and need us to replace it once a week, or if you have need of a modest, 10 yard roll off container for a few days, Ames Dumpster Rental will have the dumpster ready, deliver it right on time, and provide you top-notch client service at a rate you'll like. At Ames Dumpster Rental, we believe that satisfying clients will warrant our success in the long run, so we'll do everything possible to ensure your satisfaction. We won't ever skimp on the quality of our products, service and work ethics, as our outstanding reputation in Woodbury depends on it.
Pickup Your Phone and Ask for Your Dumpster Today
With Ames Dumpster Rental on your side, you truly don't need to look any further. We know we currently have the perfect dumpster to satisfy your needs, and we can get it to you right on time as well. And if you ask us to serve everyday for a month, or even just for a day, know that we'll gladly oblige you in any way that we can. The values of awesome service we stick to will ensure that you will be satisfied with our work each and every time.
Ames Dumpster Rental employs the finest dumpster rental experts in the industry, so you can always depend on us to get the task finished correctly. We are armed and prepared to supply dumpster rental solutions for anyone in Woodbury, MN, so be sure to phone us at 888-416-8891 whenever you need us.


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Each Thursday morning at 10:00 a.m., fellow democrats and progressives meet at the Democratic Resource Center for coffee and conversation. We discuss politics, current issues, community events, volunteer opportunities and more. Join us for coffee and see what it's all about.
Back to All Events
Earlier Event: August 6Summer Fest
Later Event: August 18Koffee Klatch


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The Legacy of Militancy in Punjab
Long Road to 'Normalcy'
- Inderjit Singh Jaijee - Civil Rights Activist
- Dona Suri - Former Newspaper Editor
No man ever steps in the same river twice, for it's not the same river and he's not the same man—Heraclitus
Militancy convulsed Punjab from roughly 1984 to 1994. Afterwards, politicians, government spokespersons and assorted intellectuals declared that 'Khalistan' was gone and the state was 'returning to normalcy' as though the state would suddenly find itself in some pleasant place of bygone era. But that is far from the truth.In reality, when the gunfire ceased, 10 years of turmoil left lasting scars and chronic afflictions. Reduced accountability warped administrative and executive 'culture' and threat perception coloured the attitude of the judiciary for years. Victimization at the hands of both police and insurgents created risk-averse citizens who prioritized personal safety above all, while policies pertaining to state debt and industry impacted economic development.This book recounts the no-holds-barred struggle to suppress militancy that morphed into an unrestricted abuse of power. It details how militancy affected the credibility of the judiciary, why trials dragged on for 25 years, how militancy influenced the popular culture and how the youth are still responding to conditions in today's Punjab.
'Exciting writing buttressed by new documentation and presentation make this an essential book for general as well as scholarly readers'.


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Campaign: "Virginia Is for Lovers"
Brand: Virginia Tourism Corporation
Agency: The Martin Agency
Update an iconic brand positioning to respond to a real, relevant cultural event
One Thought:
Virginia is for everyone.
In the wake of a tragic display of hatred and domestic terrorism, the state of Virginia needed to not only rebuke the actions in Charlottesville, but also reinforce the underlying values that Virginians hold dear. Their state has always been for lovers, and in the wake of Charlottesville, it was critical to reinforce the message of inclusion and diversity.
What The Martin Agency told Fast Company:
"We know that Charlottesville and the state of Virginia are places we know and love, and we know they're diverse, inclusive and welcoming," says The Martin Agency CEO Matt Williams. "We also know the violence we saw last weekend isn't what that city or the state is about. 'Virginia is for lovers' has always been true, and it's never been a more relevant message to send."
Lessons to be learned:
- Simple rallying cries — The message The Martin Agency developed was simple and memorable: a rallying cry for Virginians to internalize and project as they move forward. As folks continue to process the events in Charlottesville, the simplicity of "Virginia is for everyone" lends focus and clarity to an immensely complicated issue.
- Agility — The Martin Agency acted within hours of the events in Charlottesville, at first putting a sign in front of its offices in Richmond, which was picked up by the Virginia Tourism Corporation on Instagram to begin promoting positivity across the state as quickly as possible. #StandForLove has garnered more than 11,000 tags on Instagram since The Martin Agency installed the sign outside its offices.
- Creating value — In this particular example, the agency acted independently to create value. There was no brief from the client or kickoff call; it simply saw an opportunity to make an impact and executed. The work was eventually picked up by the Virginia Tourism Corporation, but The Martin Agency's work created value even before if became a branded message, demonstrating how agencies still can and should lead with creativity.


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1109 N. Hermitage, #2
2 Bedrooms
2 Bathrooms
Gorgeous new condo in Wicker Park. Built in 2009, this property features luxury appliances, beautiful crown molding, a fireplace, a large deck and one garage space. Dark hardwood floors throughout and an abundance of natural light.
As REP Group agents, we respect and appreciate our client's privacy. To inquire about pricing for similar properties in the area, please contact us directly at email@example.com.


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I am a professional web developer. I love building products for the web that serve people.
Professional Development Skills
Version Control
I use Git a lot. I am well versed at committing, pushing, pulling, merging, rebasing, squashing, forking, cherry-picking, diffing, tagging, and releasing. I love leaving a codebase with a well documented and informative version history.
Terminal Friendly
I live in the commandline. Primary unix-like, but I can do Windows when I need to.
Frontend Web Development
- Methods: Semantic, Accessible
- Processors: PostCSS, Sass, Less
- Methods: BEMIT, OOCSS, functional CSS
- Libraries: Tailwind, Tachyons
- Variants: ES2015+, Node
- Libraries: React, jQuery
- Package Managers: NPM, Yarn
Build Tools
- webpack (example)
- Gulp
Backend Web Development
- Frameworks: Laravel, Symfony
- Applications: WordPress (Roots)
- Package Managers: Composer
- Tools: PHP_Codesniffer, PHPUnit
- MySQL, MariaDB
Dev Ops
- Vagrant
- Ansible
- Docker
- CI/CD tools such as Travis and CircleCI
- Error tracking tools like Sentry
What I'm learning on the weekends…
- Rust
- GraphQL
- Vue
Work Experience
Freelance Web Developer (2016 - Present)
Select Projects:
- The Bible Project: landing pages for email campaigns
- The Art of Wayfaring: full website
- An undisclosed startup: a frontend (React) app prototype for pitching to investors.
- An undisclosed non-profit: an email/SMS reminder system with an user management interface (React frontend, Laravel backend).
Rentbridge – Interim CTO (October 2018 - February 2019)
United Youth Outreach – Creative/IT Coordinator (January 2018 - March 2019), Media/Tech Intern (Summer 2016; Summer 2015)
United Youth Outreach is a non-profit organization that empowers young leaders to do youth ministry. It functions as an umbrella for a multitude of different ministries. I have been working with United Youth Outreach for almost 4 years in a number of capacities. Over the years, I've built websites for the different ministries, provided graphic design, and have even built an app (Laravel).
True Market – Full Stack Web Developer (January - December 2018)
True Market is a full service digital agency in Calgary, Alberta. I was a full stack web developer for True Market, however, functionally, I was the lead developer. I was responsible for building the team's current web stack.
Open Source
I contribute to open source software. See my contributions on GitHub.
Roots – Team Member (July 2018 – Present)
Roots builds tools for building better WordPress websites. Yuck, WordPress — right?! Supposedly 30% of the web is built with WordPress — so it's here to stay. Roots builds tools to modernize WordPress development. After using the tools and contributing for a few years, I joined Roots as a team member in 2018. As a team member, I continue to provide support, help maintain and contribute to existing projects, and am leading a new project.
Eston College – Bachelor's of Biblical Studies (cand.) (September 2013 – Present)
Eston College is a small Bible college in Eston, Saskatchewan — the middle of nowhere!
- Certificate of Music and Discipleship (2014)
- Certificate of Discipleship in Techonology (2015)
- Associate Diploma of Biblical Studies (2016)
- Bachelor's of Biblical Studies (2019)
- Outstanding Student in Tech Discipleship (2015)


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Hornets acquire Dwight Howard
Follow us: @CapSportsReport on Twitter | The Capital Sports Report on Facebook
By Anthony Caruso III | Publisher
One year after joining his hometown team, Dwight Howard is on the move again. He was traded on Tuesday night to the Charlotte Hornets.
Also, the Hornets acquired the 31st overall pick.
The Atlanta Hawks acquired Miles Plumlee and Marco Belinelli. They also get the 41st overall pick in the second round in the deal.
More to come.
Any Corrections?. You can contact Anthony Caruso III, Publisher at firstname.lastname@example.com.
Follow us: @CapSportsReport on Twitter | The Capital Sports Report on Facebook
©2007-2019 The Capital Sports Report. Please honor copyright! Piracy hurts writers, devalues their works, and puts you and your employer at risk of lawsuits. All original materials contained on this website are protected by the United States copyright law and may not be reproduced, distributed, transmitted, displayed, published or broadcasted without the prior written permission.


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There aren't many people who can say they've had the opportunity to fly in a air force training plane, feel what its like pulling Gs.
Well, FOX40's Pedro Rivera can now say he has checked that off of his bucket list.
"I can easily say this was one of the most rewarding experiences I've ever had. I thought we were going to get inside one of the training planes go up in the air for a few minutes and make our way back down…but instead it far exceeded my expectations," Pedro explained.
Pedro and photographer Grant Hansen started their morning off in a briefing meeting at Beale Air Force Base to go over their mission. The objective: To see what its like to be an Air Force pilot for the day.
After more than 10 hours of training, they hit the equipment room to get in gear.
It wasn't exactly a scene out of "Top Gun."
Pedro is afraid of roller coasters so to say the least, he was certainly nervous about the flight but at least they were looking the part.
After getting the straps in, Grant and Pedro were up in the sky and quickly learned what pulling Gs or gravitational force was all about.
In total, they pulled 5 Gs.
Your body crunches up and you start seeing tunnel vision,
Most Air Force pilots Pedro spoke to do this on a regular basis, even pulling as much as 9 Gs.
Surprisingly the duo made it through without throwing up or passing out.
After that, it was smooth sailing, getting views only some have dreamed of. The mountains, pacific ocean and of course flying over the Golden Gate Bridge and Alcatraz Island.
From 20,000 feet in the sky to racing around on the ground in mobile chasers, there's never a dull moment on Beale Air Force Base.


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Pleasant Valley Conservancy State Natural Area is a 140 acre natural area in western Dane County near the town of Vermont. The property contains prairie remnants, wetlands, and extensive oak savannas and has been under intensive management for the past 20 years. The Brock family of Madison, WI took the initiative to restore the land to its natural state after purchasing it as a way to spend more time outdoors with their children. To better understand the history of the area, read this article that was written by the Journal Sentinel last week about the Brock family and their work at Pleasant Valley.
Hiking will be partly across steep bluffs, and long pants with sturdy hiking shoes are recommended. At the end of the three-hour trip, light refreshments will be served at the small cabin on site.
Park on Pleasant Valley Road fire number 4609 along the south side of the driveway.
Led by: Tom and Kathie Brock


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Greetings Fellow Alumni:
Happy 2004! As Chairman of Wharton's worldwide Alumni Association Board, I wish to welcome you to what I know will be an exciting year for Wharton and the Wharton alumni network. Vige Barrie, Board President and I, along with other members of the board, are working diligently to strengthen our alumni network and to continue to support and build alumni connections with each other throughout the world.
Specifically, Our Board's Mission Is To:
1) Encourage and improve the professional and volunteer relationships between the alumni and the School, including career placement, admissions, alumni affairs and development;
2) Encourage and assist in the formation, development and operation of both regional and affinity-based alumni clubs worldwide;
3) Represent the alumni in communication and interaction among the School, its alumni and the business community; and
4) Strengthen ties between alumni and students so that both prospective and actual Wharton students recognize the value of the alumni network.
Some of Our Goals for the Year Ahead Are As Follows:
Alumni Conference. Assist with the organization of a Global Alumni Forum within the United States to complement the extremely successful international forums.
New Clubs. Encourage new affinity-based clubs and groups. This will add to the Wharton Health Care Network, the Wharton Private Equity Network and the newly formed Wharton Women in Business and "Wharton Out For
Business" Club. Also, we plan to increase interaction among alumni club leaders through annual Alumni Leadership Conferences.
Reunions and 125th Anniversary. Help the School organize another year of successful alumni reunions. Also, begin planning alumni involvement in the School's 125th anniversary in 2006.
Career Management. Continue working with the career management office to improve benefits offered to alumni in career management and job search.
More Annual Fund Participation. Help to increase not only the total dollars raised, but the percentage of alumni participating in the Wharton Annual Fund.
Increase Campus Presence. Ensure that more alumni make speeches and appearances on campus in an effort to expand connections between students and alumni. Also, encourage student clubs to organize alumni advisory boards.
The one element that is essential to the success of our mission is YOU. All Wharton graduates are a vital part of Wharton's Alumni Association. Without your involvement, Wharton cannot maintain its level of excellence. We need you!
It is my belief that the network does not come to you – you must affirmatively access it. I also believe that, in our network, enthusiasm is meaningful currency.
If you are currently an active member of Wharton's alumni network, thank you for your dedication. If you are interested in getting involved and would like to find out more information on volunteer opportunities, please contact the Alumni Affairs office at firstname.lastname@example.com.
There are many ways in which you can make a difference. Start by going to wave.wharton.upenn.edu for a Wharton alumni club in your region or your area of interest.
I look forward to communicating our activities and achievements in upcoming issues of the Wharton Alumni Magazine. Please feel free to e-mail me directly with any questions.
Thank you for your support of the Wharton Alumni Association.
David N. Feldman, Esq., W'82, L'85
Chairman, Wharton Alumni Association
The Wharton Women's Task Force and Wharton Alumni Affairs are sponsoring an evening of animated discussion with four New Leaders – prominent women role models who will describe their unique leadership approach.
Featured leaders are Dorrit Bern, Chairman, CEO & President, Charming Shoppes, Inc.; Dina Dublon, EVP & CFO, J.P. Morgan Chase; Rosemarie Greco, Director of Health Care Reform, Office of the Governor, State of PA; and Carol Ammon, Chairman & CEO, Endo Pharmaceuticals, Inc. Roz Courtney, WG'76, will moderate.
Place: Huntsman Hall
Reception: 6:00 p.m.
Panel Discussion: 6:45 p.m.
Please join this provocative discussion. For more information contact Wharton Alumni Affairs at 215.898.8478 or email firstname.lastname@example.com.
Out For Business, the gay/lesbian Wharton alumni organization, was recently formed and already has more than 175 members. The group is geared to helping gay/lesbian Wharton alumni to network as well as to help current students. Out For Business has developed an alumni/student mentorship program, and has various social/networking events in New York City throughout the year, including an annual Fall Dinner. Among the group's goals for 2004 is to establish chapters in other parts of the country. If you are interested in joining, please go to www.outforbusiness.org and register online.


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Tell the EPA: Save the Clean Water Rule
Republicans in Washington may not care much about the environment, but you would think that anyone would want to protect their own drinking water. But apparently for Andrew Wheeler, Trump's EPA chief, helping polluters profit is a higher priority.
Wheeler wants to get rid of a rule that helps protect the drinking water for 117 million Americans.1 Under his leadership, the EPA published a proposal to replace the Obama-era Clean Water Rule with the aptly named Dirty Water Rule, a far weaker alternative.
But the proposed rule isn't law yet. The EPA is taking comments on the Dirty Water Rule until April 15. Sign the petition now and CREDO will file a comment on your behalf.
Tell the EPA: Abandon the Dirty Water Rule and protect our waterways and streams.
From the Great Lakes to Puget Sound to rivers across the South, America's waterways are at risk. Our rivers, lakes and bays depend on the streams that feed them and wetlands that filter out pollutants.
But the Trump EPA rule change would remove Clean Water Act protections for thousands of streams and wetlands.2 And it could get even worse: One part of the rule could rip protections from nearly 60% of our nation's streams.3
The EPA's reckless rule change is not supported by scientific evidence. It is being promoted and rushed through the rulemaking process with little public input. But polluters have been pushing this for years, and they are thrilled.
We need to stand up for clean water and make sure that the EPA hears loud and clear that getting rid of the Clean Water Rule is unacceptable.
Tell the EPA: Abandon the Dirty Water Rule and protect our waterways and streams.
- Environmental Protection Agency, "Geographic Information Systems Analysis of the Surface Drinking Water Provided by Intermittent, Ephemeral and Headwater Streams in the U.S." July 2009.
- Nathan Rott, "Trump EPA Proposes Major Rollback Of Federal Water Protections," NPR, Dec. 11, 2018.
- Ibid.


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From about May to early December, Southern Sudan has its rainy season. And sometimes when it rains, it just keeps raining. After weeks and weeks of soaking rain, the ground is saturated and the land becomes just one big mud bog. The sticky mud, called black cotton, will suck one's shoes right off his feet. And vehicles can be stuck for weeks - sometimes months.
This summer, PPF's own truck, Mercy, was stuck for weeks on the wrong side of a river because of flooding. All work that depended on the truck had to wait for the water levels to drop.
We've found at PPF if anything is worth doing, it's going to be hard work. This is especially the case with ministry work in Africa. There are weather problems, money problems, logistics problems, health problems, and last but not least... people problems!
Thankfully, we serve a God who is not intimidated by our problems. He is strong to save - and provide. And God provides for all our needs. He doesn't work on our timetable, but there is nothing wrong with that! It keeps us humble, and constantly "in touch" with Him.
Mission work can be like the weather - always changing. Sometimes we go through dry seasons, and sometimes there are rainy days. Thank you for standing with us during all "weather conditions." We pray we enjoy many opportunities in the future to serve God's people together.


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New designs for teachers & coaches platform.Actually it was a pilot made for Qikker Online. I was proud of the job, that's why I decided to show it :)
Worked as designer and art director for Qikker Online. Illustrations by Lauraine Meyer.Deliverables: UX/UI and visual design for actual design page.


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http://www.pinerypark.on.ca. Pinery will rent kayaks, canoes, bikes, skiis in winter. Just waiting for your family getaway, this home has 2 king size beds, master on main floor has a king and upstairs bedroom has a king. 1 queen upstairs bedroom and foyer area has a bedroom with 2 sets of bunk beds, 1 set has a double bed on the bottom. 2 pull out queen sofas in the upstairs common area, this area has dining table and a fridge. Large screen TV's, sunken living room with gas fireplace, plus a main living area. Spacious kitchen and elegant dining area, large deck off upper level, natural gas BBQ. Stroll the lovely subdivision and admire the upscale new homes or take a short drive, or bike down the bike trail to the Pinery Park to go canoeing, paddle boating, hiking or just relaxing and enjoying one of the 9 sandy beaches. A Pinery Park Pass is provided for your enjoyment. A perfect winter getaway for cross country skiing and snowshoeing at the Pinery Park.Located just a 7 minute drive south of Grand Bend and close to Pinery Park, is this lovely, spacious home located in a quiet wooded subdivision. May/Jun/Sept $600/N, 2 N min, $2000/wk; Victoria Weekend $2600 for any part of the weekend. Fall/winter/spring $500/N, $1800/wk; Xmas/New Year's $800/N, 3 night minimum. The owner suggests if you have a pet…use the services of a boarding kennel. You can get info about the Pinery at
Reservations for Pinery Bluffs Chalet is managed by Bluewater Cottage Rentals
$2600 / Week in July & August / $600 /night with week and month discounts available
10100 Pinery Bluff Road Lambton Shores ON N0M 1T0


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NaNoWriMo - Week Four
And, just like that, here we are, Week 4 of NaNoWriMo 2016.
I said before that I wasn't sure why November got picked for all the challenges. It already feels like a challenging month. It's fall, which, despite the very artistic climate, is still a somber time. It's getting towards Christmas, so you can feel the excitement, and anxiety, starting to build. And, of course, there's that, (for Americans at least), very large, busy, often stressful, holiday right at the end of it.
That seems the most frustrating thing of all. Right when you should be heading into the home stretch, you can't relax just yet. The last challenge is still ahead of you.
That's what it's felt like for too long in my life. Like the moment I get one question answered, I'm reminded of all the others still up in the air. I can't exult over even the smallest accomplishment because I remember the work still undone. All my progress feels like nothing because I haven't made progress in "that" area.
Of course, the reason Nano is in November is the same reason why I have a hard time letting myself relax. The challenge isn't about doing it when it's convenient, when your schedule is clear and there are no distractions or other things to worry about. It's about doing it when there's every other thing to worry about, when you have to scrape for minutes to make your word count, and a thousand voices are telling you it isn't worth it.
Nano is about writing a novel when it's hard. Because if you can figure out how to do that…
In the same way, I know life is never going to offer me what my brain wants: a completely free moment, where all my questions are answered and there's nothing asking anything of me. That's never going to happen. There will always be unanswered questions. There will always be something else to do. There will always be a voice telling me that I can't rest, that I haven't earned it yet.
But I have to move past that voice. Past that thought process entirely, the one that says I have to "earn" things. Because that will never happen. I will never be good enough for my anxiety and my self-doubt. You can't fill a bucket with no bottom, and that's what those thoughts are.
So, you learn to write when the world tells you there's no value in it. And you learn to lest yourself rest, let yourself celebrate, even when the world tells you there's no point in it. Because there is value, and there is a point.
But there's more to it than even that.
So often we treat things like self-care and, to an extent, things like creativity as interruptions, breaks from the "real" work. We might recognize their importance, but we see them as an intermission. A break, a breather, time to get things together, then right back to work, mister.
But I'm learning they aren't. We are seeing, from the consequences of ignoring it more than anything, how vital self-care is. Like regular maintenance for your car. A good idea, but still something apart from the purpose of the vehicle.
But it's not. It's as much a part of the process as anything else, and I'm seeing it through the writing. Because creativity is not an intermission, it's a part of the play.
I think most writers go in knowing what they're stories are about. I don't just mean the plot, but the themes, what the story is really about. The story I'm writing for Nano this year I've had in my head for a while, so I'm familiar with the premise, the big questions I want to answer through the story and the characters. But it wasn't until I started writing it that I discovered what it was actually about.
I don't know how often this happens for other writers, but it's happened pretty consistently for me every Nano so far. I'll start out with an idea, what I think the novel is about, and, through the process, discover it's about a lot more than I thought.
That happened this week. I was writing a scene that I didn't even have an idea for and didn't even know I needed until that day, and in writing that scene I realized it was a thesis statement for the book.
Like I said, this happens a lot, but it still surprises me. And, just like last week, I was reminded why I need to write this book. Not just for the story itself, but for myself.
This month isn't just about writing a book, it's about what I learn while writing a book. And it's why I know things like creativity and self-care and celebrating are not interruptions but steps in the process. Because they all contribute. They make you feel better, yes, but they also make you better.
Writing is how I process. Not just journaling, but fiction too. Nano is how I am figuring out the world, and, hopefully, putting something good back into it.
So I'm going to keep doing it. Because it's good for me, not only that I have a creative outlet but that I understand life better. Because that will help me understand people better and that will help me treat them better and that… Oh, that…
That will change the world.
And so I'm going to keep writing. Even and especially when it's hard. And I'm going to let myself rest and exult, even and especially when it's hard.
Because if I can figure out how to do that, I can write a novel. If I figure out how to do that, I can do anything.
We are in the home stretch, and whether you're still going strong or if you're wondering how you'll ever reach the end, know that I'm behind you all the way. You've made progress, you are making progress, and whether that means a whole novel or not, this has been worth it. Always.
Be good, Nanos.


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Orchids in Bloom at The Strong Museum March 31–May 14
March 6, 2018
For Immediate Release
Shane Rhinewald, 585-410-6365, email@example.com
Noelle McElrath-Hart, 585-410-6325, email@example.com
Orchids in Bloom
at The Strong® Museum
March 31–May 14
Marvel at more than 150 orchids in Dancing Wings Butterfly Garden during Orchids in Bloom at The Strong museum from Saturday, March 31 through Monday, May 14. Enjoy a rare opportunity to get up close to a variety of colorful orchids from all over the world—including Central and South America and Asia—and take pictures as butterflies rest on the flowers.
"We're excited to offer the second annual Orchids in Bloom program in Dancing Wings Butterfly Garden," says Craig Sherwood, manager of grounds and live collections at The Strong. "Last year, guests loved taking pictures of different orchid varieties, such as Dendrobium and Phalaenopsis orchids. Paired with the butterflies and animals, the orchids help create a unique, tropical atmosphere in the garden and serve as a great way to begin the spring season."
Dancing Wings Butterfly Garden is the only year-round, indoor butterfly garden in upstate New York and is home to hundreds of free-flying, tropical and native butterflies, as well as button quail, a chameleon, turtles, a tortoise, and a green aracari toucan.
Garden fees apply for Orchids in Bloom. Guests may purchase general museum admission plus butterfly garden tickets online or at the museum's admissions desk. Presented in memory of Carol D. Simmons. Programs underwritten in part by Delta Air Lines, the official airline of The Strong.
Museum Hours: Monday–Thursday, 10 a.m. to 5 p.m.; Friday and Saturday, 10 a.m. to 8 p.m.; Sunday, noon to 5 p.m.
General Admission Fees (does not include admission to Dancing Wings Butterfly Garden®): age 2 and older $15, under age 2 free, members free.
Admission to Dancing Wings Butterfly Garden: General Admission fee plus $4 for members, $5 for nonmembers, under age 2 free.
Parking: Free parking is available at the museum for all guests on a first-come, first-served basis during regular museum hours. Please note that, on high visitation days, the museum lot may reach capacity early in the day. If space is not available on site at the time of your visit, additional parking is available at neighboring municipal garages for a fee. The Strong is not responsible for fees incurred at off-site locations.


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Captain Phil Harris has passed away. He was 53 years old.
He was the captain of the fishing vessel Cornelia Marie which was featured on the discovery Channel program Deadliest Catch. He suffered a massive stroke at the end of January and died yesterday, February 9.
I did not know Phil Harris personally. He was just a person whose job was featured on a very well-filmed, well-run documentary program. But I am a great fan of that show and Phil Harris was a fascinating part of the story.
I found some personal resonance in his suffering of a blood clot and pulmonary embolism on the show recently. I had a similar event in 2005, though mine was not nearly as serious or scary as his. His lifestyle was much more unhealthy; he smoked, ate poorly, went long periods on little sleep, and had a ridiculously high stress level.
He was a character and fascinating to listen to as he tried to run a risky fishing business and teach that business to his sons. I can't say that I was surprised to read of his death, but I will miss watching him.
I am thinking this morning of his sons, the rest of his family, and his friends and crew.


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Beginner's Guide to Kickboxing Fitness Franchising Business
In the fitness industry, the kickboxing fitness franchise is increasing in popularity. You can always find specialized fitness centers that are dedicated and committed to serving clients who want to have fun, exclusive and proven workout that can guarantee results. Today, business owners are increasing their profits by expanding their fitness clubs in size and number and one area is through kickboxing fitness. Detailed market research is crucial to achieving a unique and competitive edge over the market, and the great approach for specialized and smaller facilities are obvious.
As compared to large-scale counterparts, kickboxing fitness franchise costs less in start-up cost, requiring fewer employees, and more simple and easier to manage. Because kickboxing involves techniques and moves, it does not really require too much investment in gym equipment. People are more fitness-inspired with real fitness goals, so many are not contented with the mere access of gym or workout equipment, but they want real fitness programs like what a kickboxing program can provide. People undergoing the kickboxing fitness program feel a sense of empowerment because it is a type of fitness program that is combative and primitive. The majority of the customer base is women. The kickboxing fitness program became so popular that most franchised kickboxing classes have outgrown other martial arts facilities. A lot of professional kick boxers have developed workout programs for members to get fit, and other business owners offer additional services such as blood pressure monitoring, blood sugar monitoring, and bone density monitoring.
There is an increasing popularity of business models offering members a 24-hour key card access with different fitness routines. Many Americans want to get fit and kickboxing fitness centers gain higher profits every year because of the demand. It is crucial for any fitness business such as a kickboxing facility to keep up with the new technology through digital marketing, new communication tools, automated security, and modern machines in order to reduce overhead cost. It is important to take into consideration the right timing and special promotions in the first few months of the year because this is the critical periods of knowing if your business will thrive. Excellent marketing is very important to having New Year promotions to allow higher membership rates. Kickboxing franchise is a sure way to have proven marketing strategies for higher success rate.
Are you interested to have a kickboxing business via franchising Allow us to help you find the right fitness franchising business for you, come and check our website or homepage now. You can take advantaged of the great benefits of having a fitness industry business through a kickboxing franchise.


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Miserable. I don't know how else to describe it. I woke up this morning with every muscle in my back screaming as a result of yesterday's shoveling. Unfortunately,all I did yesterday was to clear the 24″ of snow from my front walk. I didn't even tackle my car. I honestly wasn't sure I was going to be able to walk today. But I got out of bed, loaded up on some pain medicine and headed out to dig my car out.
As I was working on my car we had a little excitement. It appears some jerk on our street ordered a pizza! So the poor Papa John's pizza guy in his 4 wheel drive Jeep got stuck trying to make it up our hill to deliver the Pizza. He didn't make it but 50 feet! Our street has not been plowed so he was stuck. A bunch of the guys had to go help him dig out and shove him down the street. He had to walk the pizza up the hill to deliver it. And I am sure you all are as curious about the tip as we were…they gave him $1.00 A dollar!!!! How outrageous is that.
So back to shoveling! I worked on my car for an hour and a half and only got a small area cleared in front of the car. There is literally no where to put the snow. I was miserable and in pain! So I did what all smart people do…I hired one of the guys down the street to finish digging my car out. He was able to dig the other 3/4 of my car out in about 45 minutes! It was the best $20 I ever spent.
The Federal Government is closed tomorrow which means my office is closed. That is a good thing, because I am not going anywhere fast. Not really sure when I will be able to go somewhere. Even more upsetting is the weather forecast. We have more snow expected on Tuesday/Wednesday. They say it could even be another foot of snow. What am I going to do with another foot of snow! It is not like this stuff is melting.
I honestly cannot imagine how people live like this on a regular basis.
Utterly Miserable and Cooped Up Inside In D.C.
My progress after an hour and a half of digging
Pizza man stuck in the road
Carson trying to navigate a path in the backyard
Yes, there is suppose to be a street there.