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Bridging the Gap between Translational and Outcome Research in Cardiovascular DiseaseView this Special Issue
Molecular Characterization of Reactive Oxygen Species in Myocardial Ischemia-Reperfusion Injury
Myocardial ischemia-reperfusion (I/R) injury is experienced by individuals suffering from cardiovascular diseases such as coronary heart diseases and subsequently undergoing reperfusion treatments in order to manage the conditions. The occlusion of blood flow to the tissue, termed ischemia, can be especially detrimental to the heart due to its high energy demand. Several cellular alterations have been observed upon the onset of ischemia. The danger created by cardiac ischemia is somewhat paradoxical in that a return of blood to the tissue can result in further damage. Reactive oxygen species (ROS) have been studied intensively to reveal their role in myocardial I/R injury. Under normal conditions, ROS function as a mediator in many cell signaling pathways. However, stressful environments significantly induce the generation of ROS which causes the level to exceed body’s antioxidant defense system. Such altered redox homeostasis is implicated in myocardial I/R injury. Despite the detrimental effects from ROS, low levels of ROS have been shown to exert a protective effect in the ischemic preconditioning. In this review, we will summarize the detrimental role of ROS in myocardial I/R injury, the protective mechanism induced by ROS, and potential treatments for ROS-related myocardial injury.
Myocardial ischemia-reperfusion (I/R) injury occurs when the blood flow to the myocardium is obstructed, followed by the restoration of blood to the ischemic heart [1, 2]. Ischemia to a specific region of the body can provoke tissue damage due to lack of oxygen and nutrients; heart is particularly vulnerable since it demands high energy to function [1, 3]. It is reasonable to consider that the rapid and early restoration of blood flow to the ischemic regions prevents further damage. However, numerous studies have observed the reduced cardiac function and even the acceleration of myocardial injury after reperfusion [1, 3, 4]. Ischemic injury is a recognizable consequence of cardiovascular diseases including myocardial infarction, stroke, and coronary heart diseases. Moreover, some patients who suffer from severe coronary heart disease choose to undergo a coronary artery bypass grafting to promote cardiac function, yet they experience myocardial injury postoperatively [3, 5].
In response to a sudden ischemia, coronary vessels dilate to compensate for the low oxygen supply, allowing for maximal oxygen return/recirculation . However, the continuous deficiency of oxygen during ischemia shifts cardiac metabolism toward anaerobic glycolysis, disrupts ATP generation in the mitochondrial oxidative phosphorylation (accounting for 95% of ATP production in the heart), and thus reduces overall ATP availability . The ATP-dependent ion pumps, such as sodium potassium (Na+/K+) ATPase and calcium (Ca2+) ATPase, are disturbed largely by the ATP depletion. Secondary channels, including Na+/H+ exchanger, and decreased intracellular pH, lead to intracellular Na+ and Ca2+ overload [3, 6, 7]. Subsequently, the altered ion homeostasis and metabolism reduce cardiac contractility and structural organization, and initiate cell death via necrosis and apoptosis [3, 6]. Replenishment of blood during reperfusion rapidly restores cellular balance in the myocardium and therefore prevents further ischemic injury.
Perhaps somewhat counterintuitively, such normalization concurrently causes injury . The molecular mechanisms regarding I/R injury are multifactorial, and various hypotheses have been proposed to describe the pathogenesis of myocardial I/R [7, 8]. Reperfusion treatments, including thrombolysis and percutaneous coronary interventions, serve to manage the ischemic conditions but unexpectedly induce additional damage [9, 10]. Indeed, the reestablishment of blood flow may trigger apoptosis and necrosis in the myocardium .
A growing number of studies have investigated how reactive oxygen species (ROS) play an intriguing role in I/R, ranging from beneficial to inimical [7, 11]. At the basal level, ROS function as a mediator for multiple cellular signaling cascades including cell growth and stress adaptation . Conversely, excess ROS can damage tissues by oxidizing important cellular components such as proteins, lipids, and DNA, as well as activating proteolytic enzymes such as matrix metalloproteinases [7, 12]. Furthermore, the induction of protective mechanisms during ischemic preconditioning (IPC) can be associated with low level of ROS [7, 11]. The production of ROS has been implicated in both myocardial ischemia and reperfusion injury. During the past decade, studies continued to explore the mechanisms as well as develop clinical applications centered on ROS-related therapies to alleviate I/R injuries. More recently, novel concepts and treatments such as postconditioning and mesenchymal stem cells-based interventions have been thoroughly updated focusing on ROS-centered interventions in myocardial I/R diseases [13–16]. By highlighting these innovative findings, the current paper provides a timely review of the latest understanding of I/R and associated protective mechanisms linked to the unique role of ROS.
2. Involvement of ROS during Myocardial Ischemia
2.1. Physiological Relevance of ROS in the Cardiovascular System
ROS are essential in mediating physiological responses [12, 17]. Upon the exposure to environmental stresses such as hypoxia, ROS production can be significantly elevated to a level that overwhelms the endogenous antioxidant system and engenders tissue damage [7, 12, 17]. Typically, a small amount of superoxide (, a type of ROS) is generated through electron leakage in mitochondrial electron transport chain, which can further lead to the formation of other ROS such as hydrogen peroxide (H2O2) and hydroxyl radical () [3, 9, 18]. These byproducts of respiration may exert beneficial effects on cardiovascular functions and can be safely metabolized by the antioxidants under normal conditions [19, 20]. Cardiac mitochondria have been recognized as an important source of ROS in the myocardium, considering that a large number of mitochondria reside in the cardiomyocytes to meet a high energy demand [3, 20]. NADPH oxidases (Nox) also contribute to the major production of and H2O2 in cardiovascular cell types. Particularly, highly expressed Nox2 and Nox4 isoforms in the heart play an essential role in regulating the development of cardiomyocytes [21–23]. Other generating systems include lipoxygenase and xanthine oxidase (XO) [9, 18]. Moreover, the predominant expression of XO under stress has been shown to contribute to ROS generation in the perfused ischemic tissue .
2.2. ROS Formation during Ischemia
Although reperfusion is responsible for generating a ROS burst during reintroduction of molecular oxygen (O2) to the ischemic environment, accumulating evidence has suggested that oxidant stress commences before reperfusion [11, 17]. Indeed, Zhu and Zuo observed a rapid increase in production within three minutes of ischemia . Interestingly, the study identified oxymyoglobin as a novel source of generation in the rodent heart model during early ischemia, through an interaction between the iron ion in the heme group and reduced oxygen tension . Myoglobin can also serve to reservoir O2 but is quickly exhausted .
Studies have noted that the presence of residual O2 is a critical element for ROS generation during ischemia, in which an impaired mitochondrial electron transport chain is believed to facilitate the conversion of residual O2 to due to increased electron leakage (Figure 1) [11, 20]. Levraut et al. detected an irreversible decline in mitochondrial membrane potential in ischemic chicken cardiomyocytes. ROS-induced mitochondrial depolarization during ischemia is associated with myocyte death in I/R; specifically, the severity of depolarization is related to the extent of cell death in perfused tissues [11, 24]. The decline in membrane potential may be attributed to the opening of mitochondrial permeability transition pore (mPTP). However, the inhibition of mPTP activation does not significantly prevent depolarization, whereas the application of antioxidants restores membrane potential and prevents subsequent cell death . In fact, mPTP opening is limited during ischemia due to low pH environment, but mPTP does play a crucial role in reperfusion injury . At reperfusion, mPTP is activated, which exacerbates injury via ROS-induced ROS release cycle and initiates cell death signaling pathways . Collectively, Levraut et al. proposed a putative scheme of ischemic injury involving the disruption of mitochondrial inner membrane by ROS-induced lipid peroxidation that contributes to the repolarization failure in mitochondria later during reperfusion . Moreover, the impediment of mitochondrial depolarization and Ca2+ dysregulation by sarcolemma stabilizer suppress apoptotic and necrotic pathways, despite the presence of oxidative stress (OS) and an altered redox state .
In an attempt to detoxify the oxidative insult, a significant rise in the antioxidant defense system, such as glutathione increment, has been observed during ischemia . In addition, the formation of at the early period of ischemia is likely to be involved in facilitating protections towards ischemic tissues, which is the so-called IPC [15, 17]. A detailed discussion of this will be provided later in the review.
3. ROS Mechanism in Myocardial I/R
3.1. A Burst of Oxidants during Reperfusion
It is true that a timely reperfusion is essential to ease ischemic injury and salvage viable myocardium, yet it can promote cardiomyocyte damage . During reperfusion, the reactivation of aerobic metabolism induces an increase in ROS, particularly , which exceeds the endogenous antioxidant capacity [3, 6]. The shift towards a more reduced redox state during ischemia may also contribute to the production of ROS upon reoxygenation . The reduced form of iron ion mediates the Fenton chemistry to generate highly reactive hydroxyl ions . Of various cellular alterations in the perfused ischemic myocardium, distorted redox state is widely recognized in the initiation of I/R cellular damage, although the precise role of ROS in I/R remains elusive .
The overproduction of derives further ROS generation in the mitochondria, forming a vicious cycle of OS [20, 27]. For instance, the reaction between aconitase (a mitochondrial protein) and leads to the formation of ∙OH . The aconitase inactivation can be therefore regarded as an indicator for toxicity . An activation of XO during reperfusion is attributed not only to oxygen influx, but also to excess hypoxanthine (a substrate of XO) that is produced during ischemia as a result of ATP degradation [3, 10, 17]. In addition, ROS mediate the infiltration of neutrophils, which contribute to further generation via Nox activation (Figure 1) . Increased OS during I/R results in the uncoupling of nitric oxide synthase (NOS), which reduces NO production and enhances NOS-derived level . Those studies attributing the myocardial injuries to the decreased NO production during reperfusion are primarily based on the fact that, by applying NO or NO donors prior to I/R, the related injuries can be remarkably attenuated [29–33]. For instance, Liu et al. have proposed that the reperfusion-induced endothelial dysfunction can be caused by the decrease of NO formation, resulting in the diapedesis and neutrophil adherence in the ischemic region, thereby exacerbating I/R injuries . Moreover, NO can react with excessive to form peroxynitrite (ONOO−), an oxidant that suppresses the mitochondrial respiration by modulating the nitration of complexes I and IV [4, 35]. Since the respiratory oxygen consumption is interfered, additional ROS may be generated due to tissue hyperoxygenation (Figure 1) [4, 36].
3.2. Detrimental Effects Induced by ROS
As discussed earlier, overexuberant ROS that overwhelm the antioxidant defenses can induce protein denaturation and cause oxidative damage directly to DNA, especially mitochondrial DNA due to its proximity to the dysfunctional electron transport chain [26, 37]. The destabilization of mitochondrial and sarcolemmal membranes caused by lipid peroxidation enables the influx of nonspecific, small molecules across the membrane, resulting in mitochondrial matrix swelling and apoptosis [6, 11, 24]. ROS trigger inflammatory cascades and expressions of adhesive molecules, leading to leukocyte/capillary plugging and endothelial swelling that interfere with capillary flow. Matrix metalloproteinases and other proteases are also activated by ROS, further deteriorating the functions of multiple proteins such as glycolytic and antioxidant enzymes [7, 38]. Impaired ROS and Ca2+ regulation can propagate to spread the injury through gap junctions . Furthermore, the molecular alterations at the onset of reperfusion, such as ROS burst, recovery of pH, and Ca2+ overload, all facilitate the abrupt opening of mPTP, which is critical to reperfusion injury [7, 25, 39]. Although transient mPTP opening is involved in cardioprotection, prolonged opening results in irreversible changes within cellular bioenergetics and cell death due to the release of proapoptotic factors (e.g., cytochrome ) [7, 25]. Mitochondrial cardiolipin peroxidation also liberates cytochrome and enhances electron leakage at complexes I–III [3, 7]. The administration of mPTP inhibitor has been reported to reduce myocardial infarct size in animal models, serving as promising therapeutic to avoid lethal myocardial reperfusion injury . Despite the numerous detrimental outcomes related to ROS, repair processes including vascular remodeling and angiogenesis may occur at the later stage of reperfusion when ROS production returns to lower levels and resumes their roles as signaling molecules [7, 40].
3.3. Clinical Outcomes of Reperfusion Injury
Myocardial stunning is one of the clinical consequences associated with reperfusion injury. Although cellular homeostasis has been reestablished after reperfusion, the reversible contractile dysfunction may remain persistent and it is likely attributed to multiple mechanisms such as decreased ATP resynthesis [10, 26]. The sudden changes in ion concentration after reperfusion in the effort to restore balances induce reperfusion arrhythmias, a condition frequently experienced by patients undergoing surgical revascularization . Reperfusion arrhythmia, such as ventricular fibrillation and ventricular tachycardia, is primarily responsible for the sudden cause of death after blood flow restoration [10, 41]. Moreover, microvascular obstruction is observed after reperfusion in which the blood cannot completely reperfuse to the ischemic region after the release of occlusion [10, 41]. Based on the prior discussions, it is likely that ROS play an important role in these events and further investigation is necessary.
4. Protective Role of ROS in IPC
Although excessive ROS production has been indicated as a primary contributor of I/R injury, ROS-targeted therapies including antioxidant treatments have yielded mixed results in attenuating I/R-induced damage . The accumulation of such evidence suggests the potential role of ROS in the protection of cardiomyocytes. Indeed, studies have shown that the application of antioxidants impedes preconditioning protection. ROS formation during both ischemia and reperfusion is likely to participate in the protective mechanisms induced by preconditioning. Particularly, mitochondrial ROS are paramount in signaling IPC as detailed below .
4.1. Myocardial Preconditioning
Murry et al. first described the protective effect of preconditioning on myocardium in 1986 and observed a slower ATP depletion rate and a smaller infarct size in the heart treated with brief episodes of I/R cycles before prolonged occlusion followed by reperfusion [42, 43]. Later research recognized several types of preconditioning protocols including IPC, exercise preconditioning, and pharmacological preconditioning [2, 44, 45]. Preconditioning provides a beneficial “warm-up” that primes the tissue to subsequent injuries when it is subjected to prolonged stresses such as ischemia and hypoxia [2, 46]. Specifically, IPC is marked by transient exposures of sublethal I/R that induces myocardial protection against later I/R injury. Small amounts of ROS generated during short periods/cycles of I/R are indeed highly associated with the protective effect exerted by preconditioning . In particular, ROS originating from the mitochondria play a pivotal role in mediating cardioprotection via mechanisms involving the activation of survival programs [2, 7]. Moreover, lower OS has been observed in I/R preconditioned cardiac muscle during prolonged I/R, which is attributed to the reduced ROS generation in mitochondria . One of the well-established IPC mechanisms involves the opening of mitochondrial ATP-sensitive K+ () channel (Figure 1). channel is activated upon the exposure to preconditioning stimuli while the subsequent influx of K+ leads to depolarization and matrix alkalization, which consequently induces a moderate increase in ROS and the activation of downstream survival signaling events [7, 47]. Notably, these preconditioning-induced ROS may mediate protein kinase C (PKC) activity and, via multiple steps, inhibit the opening of mPTP (Figure 1) [2, 7]. As discussed earlier, mPTP is a major regulator of necrosis and apoptosis ; such inhibition of mPTP opening is therefore essential to the cardioprotection . In addition, the opening of the channel can generate mild matrix swelling which can improve ATP synthesis and fatty acid oxidation, leading to cardioprotective effects . The application of openers mimics IPC whereas blockers, such as 5-hydroxydecanoate, attenuate cardioprotection, further suggesting the importance of in IPC protection . Besides the exclusive role of mitochondrial ROS in signaling IPC , the initial burst of ROS is correlated with IPC efficacy, and it serves as essential preconditioning stimulus to the activation of as well as sarcolemmal () [2, 49].
Cardioprotection can also be provided by preconditioning of regular or mild exercise . Exercise has long been known for its potential to prevent cardiovascular diseases by modulating related risk factors such as obesity and hypertension . Termed exercise preconditioning, exercise-induced protection involves the interplay of several protective mediators including endogenous antioxidants that eventually leads to myocardial-specific biochemical adaptations [45, 50]. For instance, exercise stimulates the upregulation of heat shock proteins (HSPs), a group of proteins that is overexpressed spontaneously under stressful events (Figure 1) . HSPs are equipped by the cell as a defense mechanism in order to maintain cellular homeostasis. Specifically, HSPs are responsible for assisting proper folding of proteins and facilitating degradation of damaged proteins . The increased HSP activity may certainly be beneficial in the protection against I/R injury . Despite the cardioprotection exerted by HSPs, studies have shown that the application of antioxidants on exercised animal can suppress HSP72 expression, yet the cardioprotective effects remain unaffected . However, several studies have reported that the cardioprotective effect exerted by exercise against reperfusion injuries can be abolished when antioxidants are administrated during exercise, indicating the crucial role of ROS signaling in exercise-induced preconditioning pathways [53–55]. Similar to IPC, the activation of and channels in the exercised heart, where elevated PKC level is evidenced, also contributes significantly to cardioprotection (Figure 1). However, the exact role of channels in exercise preconditioning remains ambiguous [45, 56]. Most importantly, exercise enhances endogenous antioxidant systems and improves ATP synthesis and mitochondria functions, which all serve to strengthen and increase tolerance of heart .
Ischemic postconditioning, first put up by Zhao et al. in 2003, demonstrates a cardioprotection that is tantamount to IPC in a nonpretreated heart after I/R . It is later defined as “brief periods of ischemia alternating with brief periods of reflow applied at the onset of reperfusion following sustained ischemia” [13, 57]. Since reperfusion injuries occur within several minutes of blood reflow, postconditioning must be introduced as soon as the reperfusion is initiated . Basically, postconditioning and preconditioning follow similar protocol in which the myocardium is exposed to cycles of ischemia and reperfusion; however, the timing of the treatment varies. In a rat I/R model established by Kin et al., three postconditioning cycles were performed at the onset of reperfusion. Each cycle consisted of 10 s reperfusion followed by 10 s reocclusion. This postconditioning protocol decreased I/R-induced damage but demonstrated less cardioprotection as compared to preconditioning, which consisted of 5 min ischemia/10 min reperfusion cycles before the initiation of occlusion . Although the extent of postconditioning in attenuating reperfusion injury remains elusive , it is clear that the duration of reperfusion-ischemia cycles and the number of cycles greatly influence the degree of the protective effect . For instance, in a 30 min occlusion model, rats that were treated with three cycles of 30 s reperfusion and ischemia had less infarct size. However, detrimental effects occurred when the duration of treatment in each cycle was lowered to 5 or 15 s . The protective effect of postconditioning has demonstrated a similar mechanism to preconditioning, in which ROS are readily involved. By applying channel blockers, PKC inhibitors, or ROS scavengers during reperfusion, Penna et al. discovered a unique PKC-oriented redox pathway involved in postconditioning protections . ROS generation during early reperfusion was found to play an essential role in initiating the protective cascade, possibly via the activation of . The opening raises the level of H2O2, which ultimately leads to mPTP inhibition and thus prevents cell apoptosis (Figure 1) . It has also been revealed by Hausenloy et al. that the /ROS/PKC pathways involved in IPC are required to be activated during early reperfusion in order to achieve the protective effect . This is consistent with Downey’s finding that IPC exerts protection by triggering the ROS signaling pathway during the initial stage of reperfusion . The emphasis of the redox signaling that occurred at the onset of reperfusion implies a potentially parallel mechanism underlying both IPC and postconditioning. Currently, the effect of postconditioning against I/R has yielded variable results and further research is necessary to evaluate its protection on the heart.
5. Pharmacological Strategies in Myocardial I/R Injury
5.1. Antioxidants Treatment
Despite the beneficial role of ROS in preconditioning , excess ROS have been implicated in the pathogenesis of I/R injury and studies have presented substantial interests in developing therapies to prevent ROS accumulation . In particular, site-targeted treatments such as inhibiting ROS generation at mitochondrial or Nox source may improve the protective effect on the stressed myocardium [19, 64]. Furthermore, the combination of different antioxidants has been found effective in resisting I/R injuries (Figure 1) . Gao et al. have reported that glutathione provides better cardioprotection than ascorbic acid when treated at the beginning of reperfusion in a rat heart model. Moreover, the coadministration of both antioxidants enhances the protective effect as compared to individual treatment . One study examined the effect of VitaePro, a mixed antioxidant compound, and vitamin E in a 21-day oral treatment on rats before the induction of I/R. The results showed that both VitaePro and vitamin E exert cardioprotective effects during I/R, while VitaePro demonstrated a much stronger effect. The work suggests potential prospects of antioxidant drugs in resisting I/R injury . However, other studies on the effectiveness of antioxidant treatments in attenuating I/R-induced damage have yielded varied results . For instance, Flaherty et al. administrated human superoxide dismutase (h-SOD) intravenously to 61 patients prior to coronary angioplasty surgery. Such treatments have failed to demonstrate any improvement on heart function as compared to control group . In fact, several clinical studies have been performed to investigate the role of antioxidant in ROS-mediated reperfusion injuries by administrating antioxidant drugs either before percutaneous coronary intervention or after thrombolysis. Unfortunately, results are not optimistic from the antioxidant interventions in terms of reducing infarct size or enhancing heart function .
Apart from antioxidant treatments that scavenge excess ROS, targeting inhibition of ROS production at their own sources may be more favorable. With the sole function of generating ROS in both physiology and disease states , Nox has been considered as a therapeutic target in ROS-related injury. Discussed earlier, Nox contributes to a portion of ROS production during reperfusion . In response to I/R injury, both Nox2 and Nox4 isoforms are upregulated in the heart . Although it is reasonable to inhibit Nox activities in order to lessen the ROS activation during I/R injury, a complete inhibition of Nox family is not favorable since Nox is also responsible for the physiological production of ROS. Indeed, a minimal amount of ROS is essential to prevent I/R injury via metabolic adaptations involving hypoxia-inducible factor-1α (HIF-1α) and peroxisome proliferator-activated receptor-α- (PPARα-) dependent mechanisms . Therefore, selective blockage of Nox is highly desirable [23, 40]. Unfortunately, commonly known Nox inhibitors such as apocynin (a Nox2 inhibitor) and diphenyleneiodonium have failed to achieve sufficient specificity . In addition to Nox, accumulated evidence also suggests the involvement of XO in myocardial I/R oxidative injury . Studies evaluating allopurinol, a potent XO inhibitor, have generated positive results on reducing ROS generation and inhibiting cardiomyocyte apoptosis in myocardial infarction models (Figure 1) [70, 71].
Other pharmacologic agents can be used to stimulate conditioning pathways, in order to be as effective as preconditioning treatment. For instance, adenosine reduces myocardial infarct size by activating cardiomyocyte receptors and subsequent PKC pathways that are involved in preconditioning-induced cardioprotection . Cyclosporin administration before or at the onset of reperfusion also significantly ameliorates I/R injury by inhibiting mPTP opening and reserving mitochondrial function [26, 72]. Furthermore, drugs targeting the activation of channels, such as nicorandil and pioglitazone, have been shown to demonstrate prominent cardioprotection against I/R-induced injuries (Figure 1) . Therefore, activating specific conditioning cascade sites by corresponding drugs highlighted potential treatments to achieve similar protective effect as preconditioning.
5.2. Mesenchymal Stem Cell- (MSC-) Based Treatment
Recently, studies have attempted to excavate novel possibilities for treating I/R injuries. Arslan et al. identified that I/R-induced cellular damage may be attributed to the damage of functional proteins, which are essential for fatty acid oxidation, tricarboxylic acid (TCA) cycles, and glycolysis . MSC-derived exosomes can function as reservoirs of functional proteins and alter key biomedical markers of reperfusion injury via paracrine signaling, such as OS, ATP/NADH, and cell death in a positive manner. MSC engraftment also provides reparative effects on tissues that are irreversibly damaged by I/R [38, 74]. Indeed, the injection of MSCs into infarcted myocardium of rats one week after I/R has demonstrated significant improvement in heart conditions including decreased infarct size, indicating the potential therapeutic approach for I/R-induced injury via tissue regeneration . Other research has noticed the potential role of MSCs in suppressing OS and inflammation (Figure 1). Chen et al. have found that I/R-induced ROS production can be limited by injecting adipose-derived MSCs into the rats prior to I/R treatment, which is accompanied by a lower expression of inflammatory and apoptotic biomarkers . All those findings suggest the multiple potentials of MSCs in developing therapeutic interventions to reduce myocardial I/R injuries.
The current review updated the positive and negative role of ROS in myocardial I/R injury. ROS are responsible for the myocardial damage during both ischemia and reperfusion. On the other hand, a small amount of ROS is essential for exerting cardioprotective effects in preconditioning. Besides IPC, potential treatments such as postconditioning and exercise preconditioning have shown promising results in reducing I/R injury. In addition, specific pharmacological strategies including antioxidants, Nox and XO inhibitors, and MSCs-based treatments are encouraging therapeutics targeting ROS-related I/R injury. Although various therapies have been proposed to prevent or reduce I/R injuries, further research is required to determine their applications in the clinical setting.
Conflict of Interests
The authors declare that there is no conflict of interests regarding the publication of this paper.
Tingyang Zhou and Chia-Chen Chuang contributed to the work equally.
The authors thank Andrew Graef and Michael Motherwell for their assistance during the paper preparation.
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They say the best things in life are free! India’s favourite music channels 9XM, 9X Jalwa, 9X Jhakaas & 9X Tashan are available Free-To-Air. Make a request for these channels from your Cable, DTH or HITS operator.


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A 55-year-old man, Garba Ali, was on Monday arraigned in an Ikeja Chief Magistrates’ Court for allegedly raping a teenager.
The accused, a trader, who resides at 6, Adeniyi Kayode St., Ilupeju, a suburb of Lagos, was docked on a three-count charge of rape, sexual assault and breach of peace.
The prosecutor, Insp. Clifford Ogu, told the court that the offences were committed on Feb. 11 at the residence of the accused.
Ogu said that the victim, a 13-year-old girl, was hawking cheese cake after school hours when the accused called her.
“The accused bought N50 cheese cake from her and told her to come back for her money.
“On her return, the accused lured her to his room and sexually molested her,” he said.
Ogu added that the victim cried all the way back to her house and told her mother what the accused did.
The prosecutor said that the offences contravened Sections 166(b), 244 and 259 of the Criminal Law of Lagos State, 2011.
The accused, however, pleaded not guilty to the charges.
The Chief Magistrate, Mrs Taiwo Akanni, granted the accused bail in the sum of N500, 000 with two sureties in like sum.
She adjourned the case till March 13, pending issuance of legal advice by the Director of Public Prosecutions.

domain: news


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Cedarburg has a long and vivid history lovingly preserved in its limestone buildings, meandering creek and more than 200 buildings of historical significance. It was founded in the early 1840s by Irish and German immigrants who were lured to the potential of power from Cedar Creek. One of the first well-known buildings - the Cedarburg Grist Mill - remains a prominent reminder of the city’s dedication and care that it devotes to preservation. Another iconic building located in the center of town is the Wittenburg Mill. When it was built in 1864, it was the only woolen mill west of Philadelphia to produce worsted yarns. Today, the mill continues to thrive as the Cedar Creek Settlement, a collection of shops, artist studios, antique stores and restaurants.
Post-World War II suburbanization changed Cedarburg significantly. While the mills had all closed by the 1960s, the city experienced rapid population growth and the development of new commercial properties and housing subdivisions. In spite of the changes, more than 200 of Cedarburg's historic buildings have been preserved, and the city is home to eight listings on the National Register of Historic Places, including the Cedar Creek Settlement and the Columbia Road Historic District. The community profits from a vibrant tourist industry and hosts festivals and events throughout the year that attract visitors from other areas.
To view historic pictures of Cedarburg as captured by Harold C. Dobberpuhl, click here.
For more information regarding the history of Cedarburg, click here.

domain: geography


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Hamersley Range, mountains in the Pilbara region, northwestern Western Australia, extending east-southeast for 160 miles (260 km) south of the Fortescue River. Part of an ancient tableland broken by faults and gorges, the range terminates in rocky headlands and coral islets at the Indian Ocean. It includes the highest peak in Western Australia, Mount Meharry (4,111 feet [1,253 m]), which lies southeast of Wittenoom Gorge.
The range is important for its minerals, particularly iron ore. After 1960 large iron mines were developed at Mount Tom Price, Mount Newman, Paraburdoo, Pannawonica, and other sites; by the early 1990s the range accounted for more than 90 percent of Australia’s iron ore production. Railroads carry the ore to Dampier and Port Hedland on the coast, where it is processed and shipped abroad, principally to Japan. Blue asbestos, discovered at Wittenoom in 1917, was mined intermittently during the 1930s and methodically after 1943; a plant for the extraction of the mineral fibre was built there in 1950, but asbestos mining was discontinued in 1966 because of high production costs. Gold is found in small quantities. Part of the area, other than the mining sites, forms Hamersley Range National Park, where the wildlife includes red kangaroos, wallaroos, and dingoes. The range was visited in 1861 by Francis T. Gregory, an explorer and mineral surveyor, and was named for Edward Hamersley, one of the backers of Gregory’s expedition.


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We’re inviting you to tuck in to a seriously satisfying serve of ‘Crumble’, the new single from Melbourne pop darling Genes.
Released late last week, ‘Crumble’ is the perfect example of home-grown pop done right; a track that would sit right up there among the best sent from beyond our shores.
And it’s another step in the right direction for Genes, who continues to sparkle and shine among the brightest pop acts emerging from down under.
‘Crumble’ is super sweet, bristling with up-to-the-minute production, sweet vocals and, with a story about falling in love, serious commercial appeal.
“It’s about that overwhelming feeling right before the fall, before you crumble into someone for the first time,” Genes explains. “Do I catch myself in it, or do I let myself tip completely over the edge? It’s exciting and exhilarating and completely terrifying all at the same time. But, to Crumble is the best part.”
It’s hard not to ‘Crumble’ for Genes and her powers for pop when the serve is so sweet and satisfying.

domain: artistic


text: I am looking to build up a TT bike. I will be equipping it with Campy Record and ZIpp 404's. I bought my girlfriend a complete 2007 Felt B2 and it's a great bike, but I currently have an orange 2008 Orbea Orca http://gallery.mac.com/phototravel#100016 and need a TT bike for myself. I haven't ridden either bike as my GF's B2 is too big for me and there are no LBS's that have the Ordu. Anyone have any experience with either or both of these bikes? I can get the B2 Frame for $1500 (retail is $2000) or the Ordu frame for $2500 (retail was $3000), ...any advice?

domain: sports


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In the coming days, the United States Senate will vote on whether or not Ben Bernanke will go on to serve as Chairman of the Federal Reserve for another term. Some legislators are skeptical.
Senator Jim Bunning of Kentucky said Tuesday on CNBC that Bernanke’s own staff recommended against bailing out insurer AIG in September 2008 and that he subsequently tried to cover that up. Treasury Secretary Timothy F. Geithner quickly came to Bernanke’s defense, stating that AIG had to be saved in order to prevent a “catastrophic” blow to the American economy. According to Geithner, the goverment’s intervention in the financial market has created a system that is stabler and in a better position to provide the credit needed for a recovery. Evidently, we are to assume that were it not for Washington, even more businesses would be craving loans right now.
House Republican Darrell Issa of California, who has been investigating the AIG bailout, claimed that a whistleblower informed him of “troubling details” of the Fed Chairman’s role in the process. Chris Dodd of Connecticut, a Democrat and Chairman of the Senate Committee on Banking, is having none of it. Bernanke has done “a very good job,” said Dodd on Monday. “And but for his work, we would be in a very different position in this country today.” The senator admitted that it’s “hard to prove a negative,” but didn’t hesitate from warning that “our entire financial system might have collapsed but for [Bernanke’s] leadership.”
Senators from both parties set to confirm Bernanke for a second term credit him with averting a Second Great Depression. His actions, they argue, outweigh what blame he deserves for causing the financial meltdown in the first place. The Fed was in part responsible for the crisis but Bernanke refuses to admit it. According to his supporters however, the American people should be thankful for he could have done much worse.
Senator Bunning has asked Dodd to subpoena emails and other documents that prove him right. Bunning and other committee members have been allowed to review the documents in question at the Federal Reserve already but are bound by confidentiality from revealing their contents. Whether Dodd will oblige before the vote, if at all, remains to be seen.
With about forty senators lined up already to confirm Bernanke, it seems likely that the man will remain in place for another four years to come, in spite of his shared responsibility for today’s recession and regardless of whether or not bailing out AIG and banks was necessary to begin with.


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Verse and Poetics in George Herbert and John Donne
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Innovative and highly readable, this study traces George Herbert's and John Donne's development of a distinct poetics through close readings of their poems, references to their letters, sermons, and prose treatises, and to other contemporary poets and theorists. In demonstrating a relationship between poetics and religious consciousness in Donne's and Herbert's verse, Frances Cruickshank explores their attitudes to the cultural, theological, and aesthetic enterprise of writing and reading verse. Cruickshank shows that Donne and Herbert regarded poetry as a mode not determined by its social and political contexts, but as operating in and on them with its own distinct set of aesthetic and intellectual values, and that ultimately, verse mattered as a privileged mode of religious discourse. This book is an important contribution to the ongoing scholarly dialogue about the nature of literary and cultural study of early modern England, and about the relationship between the writer and the world. Cruickshank confirms Donne's reputation as a fascinating and brilliant poetic figure while simultaneously rousing interest in Herbert by noting his unique merging of rusticity and urbanity and tranquility and uncertainty, allowing the reader to enter into these poets' imaginative worlds and to understand the literary genre they embraced and then transformed.
- Taylor and Francis, February 2016
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You can see for miles and miles from the top of the hill at the centre of End of the Road. The wondrous sense of freedom is what hits you the minute you set foot on the grounds of Larmer Tree Gardens. It’s hard to resist the tangible feeling of anticipation that runs through the crowd. The weather may be looking precarious but everyone is smiling. It’s Thursday night and Teleman open The Woods stage soundtracking our first night in Dorset with beautiful renditions of ‘Düsseldorf’ and ‘Glory Hallelujah’. Then come The Shins, whose first UK performance in three years predictably attracts a huge crowd charmed by the sweet melancholy sound that captures the mood perfectly. But more lies ahead and we make a late diversion to the distant Tipi tent that rewards us with a fierce show from YAK, who fully live up to their reputation for energetic, eyeballs-out stage theatrics. Mosh pits and crowd surfing on the first night – result!
“We’re the fucking jukebox,” shouts Ezra Furman a few minutes later, inviting audience requests for his secret set. Bang – this is how you set the party spirit free! From Clash to Madonna and The Beatles it’s an explosive selection of genres and styles from one of today’s most charismatic and intense performers. The man clearly has a lot of secrets, so the following day he returns with another secret show at the tiny and exquisitely decorated Piano stage in the woods. “I’ve got so many bad ideas”, he muses with a caustic note in his voice; and then promptly launches into stripped down solo renditions of what he describes as “soul-crushingly depressing songs”. Everyone leaves startled and elated.
For an extra helping of flamboyant brilliance and subtle subversion we head off to see EOTR alumnus Meilyr Jones. Heavy rain descends just as he delivers the first swaggering Motown punch of ‘How to recognise a work of art’. Never mind the downpour. Everyone is transfixed by this softly-spoken Welsh musical shaman. “I’ve heard it’s the most popular ladies’ name in the UK. Incredible.” Pause. “Probably in England”, adds Jones with a faux coy demeanour and dives straight into the pastoral psychedelia of ‘Olivia’ that within seconds bursts into a rowdy brassy fury. “Fucking beautiful!” shouts someone in the crowd as Meilyr and his band prepare to leave the stage. Spot on dude! Fucking beautiful!
The focus on female talent is arguably one of the most notable elements of End of The Road’s identity. It’s not a new thing but something that lies at the heart of its ethos and has been reflected in the line-ups for a good few years now. This year’s headliners Bat for Lashes and Joanna Newsom have not just elevated the line up from the grim homogeny of many UK bills but reinforced the festival’s progressive commitment. But it’s not all about the headliners. What counts today is the undercard. Jenny Hvals’ startlingly intelligent theatricality, the invigorating Canadian indie folk of the festival debutant Basia Bulat, Eleanor Friedberger’s retro vignettes from New York and Serafina Steer’s latest experimental pop venture Bas Jan introduce both sonic and geographic diversity to an already smart and elegant mix. And it is a female artist, Anna Meredith, who delivers the ultimate End of The Road 2016 performance. Her full band orchestra show is nothing short of revolutionary. Like a sudden awakening, its vast brassy scope accelerates into a different dimension of sound revealing a majestic display of contemporary music that breaks through established genre barriers.
More surprising is a discernible psychedelic hue of the line up that features both new and familiar names (FEWS, GOAT, Flamingods), reflecting a broad spectrum of this thriving scene. Younghusband’s melodic psychedelia in the darkened Big Top tent proves a big hit with a psych-minded Friday morning congregation. The mesmerisingly beautiful Bat For Lashes Bride performance understandably draws the biggest crowd on Saturday night, but it’s FEWS – blasting through the far outreaches of the Tipi tent – that blow our minds and ears off. The following night, presided over by the psychedelic nomads Flamingods, the very same location becomes a climax of the most joyful and surreal carnival. “This is our last song. It’s about coming together!” scream the band as a wassailing mob led by glittery Rhain (adorned with flowers and tropical fruit) and Shopping’s very own Andrew Milk take over the stage in a jamboree of cacophonous technicolor euphoria. What a way to end a festival!
Despite the unusually soggy weather, by the end of our four days at Larmer Tree Gardens we are starting to get a sense of why for many people End of the Road is the highlight of their festival calendar. The fact that next year’s Early Bird tickets were gone within hours of going on sale is a testimony to the loyalty and trust of the growing pool of committed EOTRers. With smaller capacity than other established festivals, this little gem punches above its weight, resisting industry trends whilst delivering consistently brilliant line-ups. Like many of the best festivals it’s grown organically – out of hard work and love of music – rather than being thrust into existence by an established promoter with a big budget. It has an equally unblemished reputation amongst artists and volunteers alike. It’s organisation is faultless and there isn’t even a hint of the commercial expediency so obvious at many larger festivals.
It may not present the most musically diverse or daring of line-ups but it fully understands its remit. Yes, it is very middle class and at times painfully polite but this can also be seen as a virtue. Although some food and drink prices are a little excessive, there is plenty of variety. More importantly, and unlike most festivals EOTR allows punters to bring drinks into the arena, yet there is no sign of any serious alcohol casualties and the mood generally swings between mellow and excitable. There’s a very long list of excellent things to be said about End of the Road. The secret sets alone are worth the price of the ticket. In short, there’s every reason to treat yourself to a Dorset adventure in 2017.
For more photographs from End of the Road 2016 visit GIITTV’s gallery HERE.
Photo credit: Mike Hughes


A group of amateur radio operators from the Philippine Amateur Radio Association (PARA) worked with the engineers of STAMINA4SPACE Program (formerly named as the PHL-MicroSat Program) to test the full capabilities of DIWATA2’s Amateur Radio Unit. The task involves testing the receiving (RX) and transmitting (TX) capabilities of the satellite both for voice mode and data mode. It also includes determining the kinds of antennas, the clarity of voice communication, and how much power is actually needed to access the satellite. The testing effort lasted for two months, usually requiring operators to stay up until 1 am just to track the satellite at it passes over the Philippines, using a number of radio equipment and satellite antenna. DU1EV Eduardo Valdez, president of PARA and president of AMSAT Philippines, coordinated the frequency assignment of the satellite and its call sign DW4TA. The first successful contact made through the DIWATA2 microsatellite was on March 01, 2019, 1:27 AM, local time, between DV2JB Jharwin Barozzo (Dagupan, Pangasinan) and STAMINA4SPACE engineers 4I1DIT JP Almonte and Lorenzo Sabug operating as 4I1BBE (UP Diliman, Quezon City).
Plaques of appreciation from STAMINA4SPACE were awarded to the first 10 stations to access DIWATA 2, and certificates issued to those involved in the testing efforts. The AMSAT-PH club call sign DX1O was used as the event’s official call sign.
First 10 Stations to make a successful QSO via DIWATA2 Satellite
- Jharwin Barozzo, DV2JB (Phillippines, AMSAT), formerly DV2JHA
- Anthony Guiller Urbano, DU1AU (Philippines, AMSAT), formerly 4I1AWN
- Joseph Petruff, 7J1ADJ/JR6 (Japan)
- Afer Shi, BG5UTE (China)
- JS6DRQ (Japan)
- Iji Yoshitomo, JA6PL (Japan)
- Brian Santos, DU1MS (Philippines, PARL Inc.)
- JR6DI (Japan)
- Hong Liu, BH4ESB (China)
- Stanley Sumping Anak Albert Bejie, 9W8DNX (Malaysia)
For assisting with the testing efforts and achieving one of the firsts QSOs via DIWATA2, special awards were given to
- Percival Padilla, DV1XWK (Philippines, ARCOTP Inc.)
- Lee Castor Canono, D8BVK (Philippines)
- Veronica Catherine Anak Nohan (9W8VWW, Malaysia)
- Leo Madrid Almazan (WA6LOS/DU3ZX, a DOST Balik-Scientist)
The awards were given on April 26, 2019, at the Electrical and Electronics Engineering Institute Bldg., University of the Philippines, Diliman, Quezon City, through AMSAT Philippines and PARA president Atty. Eduardo Victor Valdez, PHL-50 project leader Dr. Marc Caesar Talampas, and STAMINA4SPACE program leader Dr. Joel Joseph Marciano Jr.
The testing team will continue to assist the STAMINA4SPACE program in monitoring the status of DIWATA2’s Amateur Radio Unit.
To learn how to access the DIWATA2 satellite, head directly to Satellite Communications.
Night Sky in Focus
Astronomy and Amateur Radio
© Anthony Urbano (Manila, Philippines)


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Bleach’s Ichigo, Rukia, and Aizen Coming to Jump Force
Bandai Namco announced today that Ichigo Kurosaki, Rukia Kuchiki, and Sosuke Aizen from the anime and manga series Bleach will come to Jump Force.
To go alongside this news, the development team announced that a new Hong Kong stage has been added to the mix. This stage includes elements from the One Piece world.
Jump Force takes characters from Dragon Ball, One Piece, Naruto, and more, and puts them in the real world. It will come out for the PlayStation 4, Xbox One, and PC.
Ubisoft has announced the release of a new Assassin’s Creed Odyssey Spartan skill for Amazon Alexa
A number of new things are coming to Rockstar Games’ GTA Online this week, including Double GTA$ & RP opportunities, Running Back (Remix), and more


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LONDON LG.Philips LCD has developed a TFT-LCD panel measuring only 1.3mm in thickness including the module for use in super-slim mobile phones.
The company says it is the thinnest panel of its type under development, 32 percent slimmer than the TFT-LCD panels currently in use for mobile phones. However, the display maker did not outline any timescales for manufacturing the part.
It added the development would enable mobile phone manufacturers to produce mobile phones even slimmer than the 6.9 mm thick phones available today. The panel would also make it possible to create slide-up phones that break the 10 mm barrier.
L.G.Philips also said in a statement Thursday (Sept. 28) the display is even slimmer than OLEDs, which are typically between 1.5 and 1.8mm. "This refutes the myth that LCDs are thicker than OLEDs," the company noted.
The 1.3mm LCD panel will be demonstrated for the first time at the SID Mobile Displays 2006 exhibition and conference being held in San Diego, California on October 3rd, 2006.
Ultra-thin LED backlight technology can raise the brightness of the panel to 400 nits. The company used internally developed light guide plate and glass substrate technologies to further reduce the panel’s thickness, so that brightness is between 200 and 300 nits.
The LCD panel uses L.G.Philips’ patent pending structural modification technology to provide greater durability without the need for a stainless steel plate to protect the LCD's components.

domain: design


First-class monarch and the Ooni of Ife, Oba Adeyeye Ogunwusi, has urged the Federal Government to intensify its patronage of local manufacturers as a deliberate means of growing the economy.
Ooni decried the government’s usage of the dollar as a means of benchmarking the economy, saying it was time for the government to be serious about building a productive economy.
The naira exchanged at N1195/$1 at the parallel market, on Friday, according to Bureau de Change operators.
A statement said while speaking with journalists at his palace in Ile-Ife in commemoration of his eighth anniversary of ascending the Ooni throne, he said the country’s political leaders must begin to patronise local industry in every sector, to generate employment for the populace.
According to him, it was time the leaders ensured that 70 per cent of products they used or consumed were made locally.
He said, “Their fleet of cars should be made up of the likes of Innoson vehicles. Our leaders should lead by example. They should make it a policy for foreign companies to produce 70 per cent of their products in Nigeria or they cannot get contracts in the country.
“Lawmakers and the executive should start using local products. I am a good example of a local content user; my attire is 75 per cent made in Nigeria. How many of our leaders wear made-in-Nigeria products?
“How many of their cars are made or assembled in Nigeria? My cap is made in Ife, Osun State; my overall was made in Iseyin, Oyo State; my beads are made in Edo and Ife; my shoes are made in Aba, Abia State; and my clothing is made in Kano State.”
He added, “Our lawmakers should start wearing clothes made in Nigeria to build the economy and stop using the dollar as the benchmark for everything; that is the best way to reduce the dollar pressure on our economy; that is the way to provide jobs for the youths and make our economy very productive and vibrant.”


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Hall stops Bell in second round
Former light-heavyweight contender Richard Hall knocked out former cruiserweight champion O’Neil Bell in the second round Saturday night.
Hall pressed the action quickly in the cruiserweight bout between native Jamaicans at the Hard Rock Live Arena. He sent Bell to a corner, connecting with lefts to the head early on.
In the second, Hall (30-8, 28 KOs) staggered the 36-year-old Bell with a punishing left to the head near the ropes. Bell’s knees buckled, Hall followed with two additional shots to the head and referee Sam Burgos stopped the bout at 1:58 of the round.
Bell (24-4-1) won the vacant IBF cruiserweight belt with a unanimous decision over Dale Brown in 2005. After one successful defense, Bell won a decision over WBA and WBC champion Jean Marc Mormeck in a unification bout in January 2007.


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Katherine O’Reilly, CNM
OB/GYN & Midwifery Services
SCL Health Medical Group
Katherine O’Reilly has worked at both ends of the life spectrum. Currently a midwife for SCL Health Medical Group for OB/GYN & Midwifery, she’s had the distinct privilege of welcoming hundreds of babies into the world over the last three and a half years. Prior to this, Katherine worked in home health and hospice, serving families who were saying their final goodbyes. “People often think that birth and death are so different but they’re really not. In both cases, people are at their most vulnerable. It’s about allowing people to maintain their dignity, whether they’re bringing in life or coming to life’s end.” In both cases, Katherine has been able to offer anticipatory guidance helping patients understand what to expect, and feels it’s an immense privilege people would choose her to come alongside and help them.
Katherine started training for massage therapy right out of high school, working at a spa and then owning her own massage practice. This work allowed her further her education as she commuted from Moab to Price, Utah for nursing school. Little did she know at the time that her training and skills in massage would someday be a useful asset alongside midwifery, and she acknowledges: “Massage is a huge comfort to both pregnant and laboring mothers. They love it!”
After nursing school, Katherine continued to build her career, managing a community nursing service in Moab while working on her master’s degree. Once she was accepted into the didactic portion of her master’s program she began work at HopeWest Hospice in Grand Junction while living in Moab. She traveled to Ohio for five months to complete her midwifery clinicals and then began work at Mesa County Health Department, providing services such as well-women’s care, family planning and STD treatment.
What was once Monument Women’s Health has undergone a transition over the past few years. Katherine comments, “Seeing SCL buy it and how much we’ve been able to grow this practice since, has been so phenomenal!” SCL Health Medical Group for OB/GYN & Midwifery, currently employs five OB/GYN physicians and five CNMs. Certified nurse midwifes are dual-certified as registered nurses with an emphasis in midwifery. Focusing on the normal physiological aspects of pregnancy, the midwives at SCL Health Medical Group for OB/GYN see the majority of the practice’s OB patients. Their training enables them to recognize when risks come up so they can collaborate care with the team of in-house OB/GYNs, consulting outside maternal fetal medicine when more specialized care is needed. “We have such fabulous relationships where we really work well together to co-manage patients as needed,” says Katherine.
Part of the growth the practice has seen over the past few years includes an increasing number of babies delivered. While the doctors and midwives collectively performed 405 deliveries in 2019, just last year they saw that number jump up to over 550 deliveries. “We try to individualize women’s care throughout their obstetrical and then labor and delivery experience,” explains Katherine.
“We try to make a nice, calm, relaxing environment and always educate women on all of the comfort care measures available to them: the bathtub, birthing ball, squat bar, different bed positions, massage, heat, ice, physical movement, and of course the pharmacological medications such as IV meds or an epidural. I think it’s important for women to know what tools are in their toolbox. And then let them guide their care because this is their journey.”
Katherine shares some of the team values when it comes to labor and delivery, such as the practice of delayed cord clamping which allows baby to get all the blood back from the placenta, delaying the first bath to help with baby’s family bonding and the importance of skin-to-skin contact. Breastfeeding is encouraged and St. Mary’s Hospital, the sole delivery site for SCL Health’s Medical Group for OB/GYN, houses a great team of lactation consultants who offer breastfeeding support, available even after moms go home from the hospital.
Katherine cares deeply about educating families about the very real perinatal mood disorders, which include depression, anxiety, OCD tendencies and psychoses, citing that women are at risk for several years after giving birth, not just immediately following delivery, and that men are often affected as well. She explains that issues surrounding bonding with baby, mood disorders, and the stigma surrounding these issues “are much more common than people realize, and one of my desires is to take away the stigma and to normalize them by holding that space so it’s safe to talk.”
Training received by both physicians and midwives prepares them to walk women through all stages of life. Katherine expresses the joy her work brings her: “It is seriously such an honor to help these women from preconception all the way through menopause. Our job is to guide them through each phase.”
The OB/GYN & Midwifery providers at SCL Health Medical Group are accepting new patients. To learn more, call their office directly at 970.298.9600 or visit their website at sclhealth.org to schedule an appointment.


Hmad Hammad, M. Dadash, D. Nissembaum y A. Biay
Writing and editing: Diario La Realidad Saharaui/DLRS 05/17/2019
The Sahrawi Committee CODAPSO meets with the US newspaper, The Wall Street Journal.
The Committee for the Defense of Self-Determination of the People of Western Sahara, CODAPSO, met on May 13 in the occupied city of El Aaiun, Western Sahara with the American newspaper The Wall Street Journal and has reported on the situation of human rights violations that the Saharawi suffer in the occupied territories .
As DLRS has been able to gather, the Committee for the Defense of the Right to Self-Determination of the People of Western Sahara met in El Aaiun on May 13 with the distinguished American journalist Dion Nissenbaum. The meeting was attended by Mr. Sidi Mohamed Dadash, Norwegian Rafto Human Rights Prize, the Vice Chair of the Committee, Mr. Hmad Hammad and Abdelaziz Biay member of the Committee “. Read more
Woman Who Filmed Police Faces 2 Years in Prison
(New York) HWR – Moroccan authorities are using a law designed to keep people from falsely claiming professional credentials to bring criminal charges against people trying to expose abuses, Human Rights Watch said today.
In the latest case, Nezha Khalidi, who is affiliated with the activist group Equipe Media in El-Ayoun, Western Sahara, will go on trial on May 20, 2019, accused of not meeting the requirements to call herself a journalist. Police arrested her on December 4, 2018, as she was livestreaming on Facebook a street scene in Western Sahara and denouncing Moroccan “repression.” She faces two years in prison if convicted.
“People who speak out peacefully should never have to fear prison for ‘pretending’ to be journalists,” said Eric Goldstein, deputy Middle East and North Africa director at Human Rights Watch. “The authorities shouldn’t be using a law designed to keep an unqualified person from claiming to be a doctor, for example, to punish people whose commentary displeases them.” Read more


Mumbai, Jul 7 (UNI) BJP general secretary Gopinath Munde today alleged that the Congress-NCP government in the state was unable to protect the Dalits, as the maximum number of Dalit atrocity incidents have occurred during its tenure.
Speaking at a meeting of Maharashtra BJP's Scheduled Caste (SC) front here, Mr Munde also cited incidents of dalit atrocity that took place at Khairlanji and Sindhudurg.
Speaking on the occasion, former BJP president Bangaroo Laxman criticised the UPA government for giving priority to Muslims ahead of SC and ST.
He alleged that the UPA government is involved in minority pampering and said that the government has reduced the allotment of funds to SC and ST ministry by Rs 2500 crore and Rs 1700 crore respectively, while it has granted funds amounting to Rs 1400 crore to the minority welfare ministry.
UNI JM SR RL KN1821


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Game Questions & Answers (Q&A) service lets you ask questions about video games for game consoles or PC games. So ask your Rescue Safari question for iPhone - iPad and get answers from real gamers or answer questions and share your insights and experience with the rest of the gaming community.
Question & Answers
Chopped Down All Trees
I was wondering if there was something that could be done to advance when all the trees have been chopped down and the game wants you to chop down more to go to the next level. My request has been ignored for 11 days now by Mike.

domain: hobby


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DOMAINE ROYET COTES DU COUCHOIS MIXED CASE
Those of you who have been to Domaine de Cromey know that we are in the heart of the Cotes du Couchois, vineyards that are the continuation of the Santenay-Maranges hooked tip of the southern Cotes de Beaune.
And like Santenay and Maranges before it, the Couchois appellation has come of age.
This is due to the dedication of a handful of producers who have bucked tradition and seen the potential of these vineyards that, until now, were always deemed too high up in the hills to produce ripe Pinot Noir.
Welcome to Burgundy in the throes of climate change. As they say these days, 'quality is climbing the hill'.
And while we see similar results coming out of the Hautes Cotes, nothing is quite so exciting to see as the Couchois coming to be. And we live right in the midst of it! In fact, the vineyard at Cromey is classified appellation Cotes du Couchois So we have our fingers on the pulse even more so than usual!
Meet the Domaine Royet.
The locomotive of the Couchois appellation.
Here is a 12 bottle mixed case of 2 different Cotes du Couchois reds with GROUND SHIPPING INCLUDED:
Domaine Royet Bourgogne Cotes de Couchois 2019
Bright Ruby color, fresh and intense black fruits, blackberry, cassis. A light toasty wood with the good acid base makes it mouth-watering. Fine, smooth tannins, good length. Aging potential: 5 years
Domaine Royet Bourgogne Cote de Couchois 'Expression' 2018
Intense ruby color. Aromas of black fruits, cassis and blackberry. After aeration, licorice and vanilla, clean woody notes. Full fruit with spices enveloped in velvety tannins. Aging potential: 5 years


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The Mississippi Republican Congressional delegation continues to blow past the diminished expectations set for it by Mississippi’s media.
Today, Rep. Gregg Harper’s office announced the appointment.
From the release . . .
U.S. Representative Gregg Harper (R–Miss.) has been named chairman of the Subcommittee on Elections for the Committee on House Administration by Chairman Dan Lungren of California.
“I am honored that Chairman Lungren has selected me to lead the Republican efforts for fair and principled elections,” said Harper. “I am eager to work on legislation that will modernize the voting process, safeguard against election fraud, and protect Americans’ right to vote.”
The Subcommittee on Elections, which has jurisdiction over all federal elections, is responsible for monitoring Congressional races across the United States and considering proposals to amend federal election law.
Harper is serving his second term in the U.S. House of Representatives and sits on the House Energy and Commerce Committee. Speaker John Boehner has also selected Mississippi lawmaker to serve on the Committee on Ethics.
Congrats to Congressman Harper.

domain: politics


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Grey Pleated Skirts - Summer Female Pleated Skirt - Japanese School Uniform - Harajuku Women Skirts
4.3 out of 5 (3 votes)
- Kingmoongarden Store
- Highest price
- Lowest price
- 1 piece
- Latest update
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15% OFF of highest recorded price
as of 2024-03-02T23:09:33+00:00Buy from AliExpress
The Grey Pleated Skirts Summer Female Pleated Skirt Japan School Uniform Harajuku Women Skirts are a stylish and comfortable option for women looking for a casual outfit.
Made from high-quality polyester material, these skirts are designed to provide a flattering fit and durability.
The skirts feature a solid pattern type and have an above knee, mini length, making them perfect for summer wear.
The casual style of these skirts makes them suitable for various occasions, including school, work, or everyday outings.
With the brand name WXCTEAM, you can trust the quality and design of these skirts.
The silhouette of the skirts is pleated, adding a touch of elegance and movement to your outfit.
The empire waistline adds a flattering shape to the skirt, making it suitable for different body types.
These skirts come with no decoration, allowing you to accessorize them according to your personal style.
The model number for these skirts is S, ensuring that you are getting the right size for your body.
Whether you are a student or simply love a fashionable look, these skirts are the perfect choice for school skirts.
Designed with the female body in mind, these skirts are tailored to provide a flattering and comfortable fit.
The grey pleated design of these skirts adds a trendy and chic touch to your outfit.
The Japan school uniform style combined with the Harajuku fashion influence makes these skirts unique and fashionable.
These skirts, also known as Women Saias or Faldas, are a versatile piece that can be styled in various ways.
Elevate your wardrobe with these Grey Pleated Skirts Summer Female Pleated Skirt Japan School Uniform Harajuku Women Skirts.
|Above Knee, Mini
|Grey Pleated Skirts


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Designer’s envy. We’ve all had it. Even non-designers get it. It’s that feeling you get when you see something so brilliant or so simple that it is just plain genius that you wish you had thought of it. Or maybe it’s just a beautiful design that is completely out of your comfort zone, and you’re so jealous that you can’t do that.
As a designer, seeing another designer’s excellent work is both good and bad – but either way, it’s motivating.


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This mid-length dress has flirty ruffle sleeves, handkerchief hem, and a front v-neckline. Self-fabric sash helps bring in the waist. Finished with out antique white buttons down the front. Shown here in Pink Geranium. Made from our soft cotton.
- 100% Cotton
- Breathable and meant for summer time light layers
- All Trovata fabrics are handmade in California.
- Machine wash cold, separately. Tumble dry low, medium iron as needed
- Wrinkle Resistant
- Side Pockets


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Budget Airlines Operating in China
The major budget airlines operating in Asia are opening more and more routes into mainland China. This page gives an overview of the budget airlines operating in China and the routes they service. For more specific information about prices, see the transport pages for the individual cities in China.
The Malaysia-based Air Asia is the budget airline servicing the most destinations in China. Currently they have flights to Tianjin (for Beijing), Hangzhou (for Shanghai), Chengdu, Guangzhou, Shenzhen, Guilin and Haikou. Comparatively speaking, flights to China aren’t as cheap as other routes on Air Asia, but are still good value. Some destinations in China have convenient transfers in Kuala Lumpur to final destinations including Australia and France. However, unless you manage to get a ‘promo’ fare, this is usually no cheaper than flying on a full-service airline.
Tianjin: To/From Kuala Lumpur only. Flights five times per week. Convenient “fly-thru” connection to Paris.
Hangzhou: Daily flights to/from Kuala Lumpur. Convenient “fly-thru” connections to Paris, the Gold Coast, Phuket, Jakarta and Singapore.
Guangzhou: Daily flights to/from Kuala Lumpur and Bangkok.
Shenzhen: Daily flights to/from Kuala Lumpur, Kota Kinbalu and Bangkok.
Chengdu: Five flights per week to/from Kuala Lumpur. Convenient “fly-thru” connections to Paris, the Gold Coast, Perth and Phuket.
Guilin: Four flights per week to/from Kuala Lumpur.
Haikou: Three flights per week to/from Kuala Lumpur.
Chongqing: Daily flights to/from Bangkok.
Jetstar Pacific services just a few destinations in China: Guilin, Haikou and Shantou. Prices are generally around $150 one-way including taxes.
Tiger Airways also has flights between Singapore and Guangzhou, Shenzhen and Haikou. Prices aren’t a whole lot cheaper than what you pay on full-service airlines.

domain: travel


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Bilson: Homefront can compete with Call of Duty, Battlefield
THQ's core games boss, Danny Bilson has been talking up their expectations for Kaos' new FPS title Homefront.
He explained in a recent interview with Eurogamer that he believes that Homefront is eminently good enough to be in the mix alongside the likes of Call of Duty, Battlefield and the recently re-invigorated Medal of Honor series.
Bilson began: "Yes, absolutely. When we started Homefront, I said 'guys, if you want to build a first person shooter that deals with modern combat you're competing with Call of Duty'. The mission is - we just want to be in the conversation. With Battlefield, with Call of Duty, with Medal of Honor. And I like to think we're in the conversation."
He continued: "Can we beat them? Those are insane numbers for fantastic games, over many years," he conceded. "This is a franchise launch but so far so good. I think we have a really good game. And I think in particular in the multiplayer battlefield is as much fun as anybody's. We're a more nimble company, so a moderate hit will mean a lot to us. And a blockbuster hit would be ridiculously huge for us. All we can do is make the best game we can, sell it as well as we can and hope for the best."
Homefront is out on March the 18th in the UK on PS3, Xbox 360 and PC, with the PC version being handled by the eminently capable Digital Extremes.
- Possible dates for the Steam Summer Sale appear online
- Rise Of The Tomb Raider on Xbox 360 doesn't appear in Square Enix's financials for this year
- The Iron Banner returns to Destiny next week with new gear and rewards
- Titanfall developers Respawn won't be at E3 this year
- Destiny: Xur's location and stock for May 28th
- Destiny's Trials Of Osiris declared a success, Bungie bans cheaters
- FIFA 16 will throw women's teams into the mix
- New The Elder Scrolls Online trailer shows off the expansive world of Tamriel
- Batman: Arkham Knight gets a new 7-minute gameplay trailer

domain: game


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Hiring activity or vacancy – which affects the employment rate in various industries, fell 2% in March 2021, compared to February this year, even as the fourth and final quarter of the 2020-21 financial year saw a 4% increase in professional activity. According to a recent report titled “Monster Employment Index – March 2021” from leading job portal moster.com. The Monster Employment Index or MEI fell to 266 last month from 296 in the corresponding month last year.
According to the report’s findings, demand for online hiring in March 2021 exceeded levels seen in March 2020, in four of the 27 industries tracked by the employment index. On a year-over-year basis, Agribusiness saw online recruitment growth of 12%, Courier/Freight/Transportation grew 9%, Computer Hardware and Software 5%, and teelcom/ISP eight percent.
Industries that saw a decline in annual growth included travel and tourism by 59%, education by 37%, and oil/gas/petroleum by 33%. The report adds that annual online demand for professionals saw growth in two of the 13 functional areas monitored by the index.
Online demand for professionals in occupations such as software, hardware, telecommunications and arts or creative has seen an increase in online hiring activity between the period of March 2020 and 2021. In the in the telecommunications sector, demand increased by 12%, while in the arts/creative fields, demand increased by 3% throughout the year.
Additionally, online hiring demand tracked by the employment index showed an upward trend in three of the 13 cities, compared to the year-ago period. Bengaluru, Hyderabad and Pune showed an upward trend in online recruitment activity. Watched by the employment index between March 2020 and 2021, Bengaluru showed an upward trend of 14%, Hyderabad 6% and Pune 2%.

domain: economics


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I love pickles. I really love all kinds of pickles, but one of my faves are the Tony Packo’s Sweet Hots, as seen here. They don’t have them in many stores by me, so my father-in-law brings them to me from Wisconsin. It doesn’t take me long to empty a jar and now I have a whole new way to enjoy them. Of course, you can use any pickles you like, this was just an interesting twist on the recipe for me. If you use regular pickle chips, of course they won’t be “sweet and spicy”, but you get the idea.
When D.Jones and I go out on the town for a cold beer, we like to order deep fried pickles. We both like them and they are a nice complement to an ice cold beer. That said, it’s not like I’d eat them all the time. This little version that I found here allows me to enjoy the crunchy, salty snack without the deep frying, which is a bonus.
It was super easy, too.
Baked Sweet & Spicy Pickle Chips
Approximately 16 pickle “chips”
1 c. panko bread crumbs
Preheat oven to 400*. Cover a baking sheet with tin foil. In a small bowl, whisk the egg. On a small plate, dump your cup of Panko bread crumbs.
Remove the pickle slices from the jar and lay them in a single layer on a paper towel. Use another paper towel to dab the liquid off of the top of the slices.
Dip each slice in the egg and then in the Panko, being sure to coat the whole slice.
Lay the panko breaded chips in a single layer on your baking sheet. Bake 15 minutes, flip them over and bake another 5. If they are still not as brown as you’d like them, turn the oven to broil for a couple of minutes.
Serve with ranch dressing.

domain: food


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The Canadian government has announced that it has no intention to resurrect the unpopular Internet surveillance bill and won’t implement any new snooping legislation that was initially thought likely come to pass.
Officially known as Bill C-30, it contained such disliked legal allowances, as giving the government the ability for warrantless mandatory disclosure of basic subscriber information and would have required ISPs to build systems that would allow for the interception and monitoring of their customer’s traffic. Fortunately none of this is now coming to pass, as was announced by justice minister Rob Nicholson, who said that his party had listened to the concerns of all Canadians.
However, one caveat to this announcement was that a very small part of the bill will be preserved in a new form, allowing for warrantless wiretapping of telephones in instances where an “emergency,” is taking place.
“We are immensely relieved,” said Chantal Bernier, the federal assistant privacy commissioner, when discussing the shutdown of the original bill. She described it as, “the result of the recognition of the fundamental right to privacy of Canadians, and also of their attachment to it.”
Initially announced in early 2012, the C-30 bill led to a huge backlash by average Canadian citizens, many of whom felt the legislation was too sweeping in its language and potentially allowed for the justified spying on innocent civilians – much in the same way as the more international SOPA and PIPA bills that were shot down in 2011/2012.
At the time, the government said that they would reassess the bill and make modifications before going ahead with it. However after a year of languishing, it appears that the C-30 will be scrapped for good, with only a minute element of its lawmaking powers retained.
“This is a great day,” said Ontario Privacy Commissioner Ann Cavoukian (via TheGlobeandMail) “This is a victory for privacy and for freedom.”


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(US, GoM) - Horizon Offshore, Inc. announced that its subsidiary, Horizon Vessels, Inc., has agreed to acquire theSea Wrangler, a dynamically positioned diving support and deepwater reel pipelay vessel.
The company expects to complete the purchase later this month and to finance a portion of the purchase price. Horizon intends to rename the vessel,Texas Horizon and place it into service as soon as possible following routine maintenance due to the vessel's current laid up status. The company plans to use the vessel to support its GoM operations in both the US and Mexican market areas.
David Sharp, president and CEO of Horizon Offshore commented, "With the purchase of theTexas Horizon, we hope to capitalize on the improved marine construction market by expanding the scope of our services. This dynamically positioned vessel should add profitability to our pipelay operations by allowing us to provide services we've historically subcontracted, and also gives us additional flexibility to install small diameter deepwater flowlines and umbilicals. Given our recent Pemex award, we believe this vessel will provide immediate utilization.''


Shelley King and Robert Cline Jr. in Laporte, CO!
Sounds Like: Steve Earle, Townes Van Zandt (Townes Van Zandt Central), Randy Rogers Band, Ryan Adams, Guy Clark
Robert Cline Jr.
Born into a deep rooted Texan family, Robert Cline Jr. is no stranger to the musical spirit and passion of the Lone Star State. His first guitar was a college graduation present, and he immediately immersed himself in learning to play. Robert began his music ...See Full Bio


£100m regeneration of Blackpool town centre confirmed
The sequence of headline projects that will catalyse the £100m regeneration of Blackpool town centre has been confirmed.
With the traditional retail offer under serious threat on high streets throughout the UK, Blackpool Council said it is committed to focusing large-scale investment in a series of major schemes that will breathe new life into the town centre over the next three years.
These projects include:
A £26m investment in a new, state-of-the-art conference centre next to the Winter Gardens which will open for busi... You can carry on reading TheBusinessDesk.com for free, but you have reached the maximum number of pages an unregistered user can view. To register for an account, click here or login below...


Bahrain to recognize Israel as UAE deal set to be signed
President Donald Trump speaks to the press before boarding Air Force One for a trip to a campaign rally in Freeland, Mich., Thursday, Sept. 10, 2020, in Andrews Air Force Base, Md. (AP Photo/Evan Vucci)WASHINGTON – Bahrain has become the latest Arab nation to agree to normalize ties with Israel as part of a broader diplomatic push by President Donald Trump and his administration to fully integrate the Jewish state into the Middle East. Trump announced the agreement on Friday, following a three-way phone call he had with Israeli Prime Minister Benjamin Netanyahu and Bahrain's King Hamad bin Isa Al Khalifa. The three leaders also issued a brief six-paragraph joint statement, attesting to the deal. Bahrain’s foreign minister will attend the event.
President Donald Trump campaigns first time in Michigan since pandemic
FREELAND, Mich. – Thousands of people turned out Thursday night in mid-Michigan at the MBS Airport to hear President Donald Trump speak. “Michigan will decide whether we return to prosperity,” President Trump said. “...Tell your governor to open your state.”The president had a lot of criticism for Gov. He also mentioned Biden visiting Michigan Wednesday in Metro Detroit. Polling released by Local 4 has Biden plus five over Trump in Michigan, which is a one-point above the margin of error.
New York Times correspondent Kathy Gray says Trump campaign removed her from Michigan rally
FREELAND, Mich. – A New York Times correspondent attending a rally held by President Donald Trump in Freeland said she was tracked down by the Trump campaign and removed from the rally. READ: President Trump to visit mid-Michigan todayTweets are embedded below:First for me: Trump campaign tracked me down from pics i tweeted and escorted me out. — Kathy Gray (@michpoligal) September 10, 2020I’ve just been kicked out of the trump rally. — Kathy Gray (@michpoligal) September 10, 2020And so it begins pic.twitter.com/fuLY4oasjP — Kathy Gray (@michpoligal) September 10, 2020Air force one just landed — Kathy Gray (@michpoligal) September 10, 2020Crammed in crowd in the rain for trump rally in michigan. Not many masks pic.twitter.com/5DZ6JBVNK8 — Kathy Gray (@michpoligal) September 10, 2020
Watch: President Donald Trump speaks at campaign rally in Michigan
FREELAND, Mich. – President Donald Trump spoke at a campaign rally in Freeland on Thursday. His campaign stop comes just one day after Democratic candidate Joe Biden made a stop in the state. Before departing the White House Trump highlighted a surge in virus cases in Europe to contend that the United States is faring well. Trump has characterized the rallies as “peaceful protests” and White House Press Secretary Kayleigh McEnany said attendees were exercising their First Amendment rights. It was a similar situation in North Carolina, where Trump held a rally this week that drew a mostly mask-less crowd of thousands.
President Trump to visit mid-Michigan Thursday
U.S. President Donald Trump is scheduled to deliver remarks in mid-Michigan on Thursday -- one day after former Vice President Joe Biden plans to visit the state. President Trump will speak in Freeland at 7 p.m. on Thursday at airport hangar Avflight Saginaw. The news of Trumps visit comes just after it was announced that former Vice President Joe Biden will also be visiting Michigan on Wednesday. He is the Democratic partys presidential nominee for the 2020 General Election. More: 2020 General Election coverage
Police: Man, 62, froze to death inside his mid-Michigan home
FREELAND, Mich. – A man found dead last week inside his mid-Michigan home froze to death inside the unheated mobile home, police said. Arnoul Jaros, 62, was emaciated but his cause of death was determined to be accidental hypothermia, Tittabawassee Township police said Monday. Officers and firefighters found Jaros' body “in a frozen state” when they forced their way into his home on Feb. 15, police said. Police said it had been at least two months since Jaros had been in contact with relatives, The Bay City Times reported. There was no electricity to the house and the temperature inside was at 25 degrees (minus 3.9 Celsius), police said in a news release.


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India is now the 6th largest economy in the world, according to the International Monetary Fund’s (IMF) World Economic Outlook (WEO) for April 2018.
India is at $2.6 trillion in terms of GDP, displacing France. The five economies ahead are United States, China, Japan, Germany and United Kingdom.
India is believed to grow at 7.4% in 2018 and 7.8% in 2019, making it fastest growing economy in the world.
India has made progress on structural reforms in recent past, including through implementation of Goods and Services Tax (GST), which will help reduce internal barriers to trade, increase efficiency and improve tax compliance.
According to IMF’ WEO, the medium-term growth outlook for India is a strong but important challenge is to increase its inclusiveness.
Apart, India & high public debt and recent failure to achieve budget & deficit target need fiscal consolidation into e medium term to further strengthen fiscal policy credibility. The main priorities for India are upgrading constraints on job creation and ensuring that demographic dividend is not wasted.
For this India needs to ease labor market rigidities, reduce infrastructure bottlenecks, and improve educational outcomes.