Introduction {#s1}
============

The bladder functions to store and excrete urine, which is required to remove waste from the body. Normal urine storage occurs over a broad range of volumes that empties in a controlled and efficient manner at an appropriate time and location. This not only requires accurate sensation of bladder fullness, but also coordinated actions of the parasympathetic and sympathetic nervous systems to contract and relax the urinary bladder wall and urethral sphincters ([@B1]). Dysregulation of the urinary bladder results in lower urinary tract symptoms (LUTS) such as nocturia, urgency, frequency, incontinence, etc. ([@B2]), which if left untreated, can lead to systemic inflammatory response syndrome and sepsis, and even possibly death ([@B3], [@B4]). LUTS have a significant negative impact on quality of life and are strongly associated with depression ([@B5]--[@B7]). These symptoms also impact United States health care costs; overactive bladder alone is estimated to cost \$82.6 billion by 2020 ([@B8]). LUTS are frequent in the general population, affecting 62.5% of men and 66.6% of women ([@B9]). The incidence of LUTS also increases with age ([@B10]) and with an aging population ([@B11]), we expect the number of patients experiencing LUTS to be on the rise.

LUTS are not only associated with age, they are also comorbid with stroke, brain tumors, cerebral palsy, dementia, sexual dysfunction, spinal cord injury, multiple sclerosis, and diabetes ([@B12]--[@B20]). Diabetes is characterized by defects in the secretion or signaling of insulin that results in the impairment of glucose uptake and ensuing high plasma glucose levels ([@B21]). Initially, hyperglycemia results in an elevated concentration of glucose in the urine, exceeding the amount reabsorbed by the kidney, leading to osmotic diuresis and polyuria. During this early compensated state, patients may present with symptoms of overactive bladder, including urgency, frequency, and nocturia. Over time, the early compensated state progresses into a late decompensated state that research suggests is due to chronically high levels of glucose and oxidative stress (Figure [1](#F1){ref-type="fig"}; 22; 13). Patients within the late decompensated state present with symptoms of underactive bladder, including decreased bladder contraction, increased post-void residual volume, difficulty initiating and maintaining voiding, and enhanced capacity.

![Temporal progression of diabetic bladder dysfunction. Adapted from Daneshgari et al. ([@B13]).](fsurg-05-00072-g0001){#F1}

LUTS affect up to 50% of all diabetic patients and are referred to as diabetic bladder dysfunction (DBD) ([@B13], [@B22]). Despite recent advances in understanding DBD, underlying mechanisms are unclear and to complicate things further, there are few studies that parcel out pure age-dependent changes from dysfunction due to underlying pathology or disease ([@B10], [@B23]). Here, we discuss the current theories underlying DBD and a novel hypothesis that increased cellular senescence within the bladder is the initiating factor in tissue dysfunction, which culminates in symptoms of DBD.

Theories and Hypotheses on the Etiology of Diabetic Bladder Dysfunction {#s2}
=======================================================================

There are multiple suggested mechanisms underlying DBD symptoms that are generalized to the whole bladder although the majority are focused on the smooth muscle layer. Literature reports alterations within the components of muscle contraction (calcium handling, receptors, channels, protein isoforms, thin, and thick filaments) ([@B24]--[@B29]), oxidative stress ([@B30], [@B31]), inflammation ([@B32]--[@B34]), neuropathy ([@B35]--[@B37]), and age-related changes ([@B38]). Possibly the most consistently reported change is an increase in whole bladder weight (Figure [2](#F2){ref-type="fig"}; original data). Interestingly, diabetic animals and control aged animals have similar increases in bladder weight compared to young controls; these changes parallel the increased presence of LUTS with diabetes and age in human populations.

![Increased bladder weight in diabetic and aged animals. Bladder wet weight was measured in female and male control and diabetic animals (18--20 w of age; 1 month post-STZ injections) and in aged male animals (53 w of age). Diabetes was induced using the combination of a high fat diet and one streptozotocin injection (30 mg/kg) in Wistar animals.](fsurg-05-00072-g0002){#F2}

DBD encompasses both storage and voiding symptoms and has been hypothesized, by Daneshgari\'s group in 2009, to progress temporally from an early compensated state, where the bladder adapts to increased polyuria, to a late decompensated state due to chronically high levels of glucose and oxidative stress ([@B13], [@B39], [@B40]). This temporal hypothesis is the most current hypothesis detailing disease progression. In 2014, Chancellor further hypothesized that the early compensated state leads to the late decompensated state through tissue fatigue and changes in the structure and function of the bladder leading to ischemia, inflammation, oxidative stress, and this induces impaired contractility in the decompensated state ([@B38]).

This section highlights reported changes within the different layers of the urinary bladder. Scientific studies mentioned within this section rarely parcel out voiding behavior as an output measurement when investigating mechanisms of bladder dysfunction; therefore, classification into overactive or underactive bladder pathophysiology is unclear.

Urinary Bladder
---------------

### Urothelium

The urothelial layer is the inner most layer of the bladder that functions as a permeability barrier to urine, protecting the underlying tissue. It has sensory functions that respond to chemical, mechanical, and thermal stimuli by releasing factors such as ATP, acetylcholine, and nitric oxide to modulate afferent transmission, relaying the extent of bladder fullness ([@B41]--[@B44]). The urothelium is made up of three layers of cells: basal, intermediate, and apical or superficial cells ([@B45]). The superficial cells are the main component in barrier function and exhibit specialized tight junctions, which facilitate the prevention of unregulated chemical diffusion ([@B45]). Barrier dysfunction results in symptoms such as urgency and frequency and this layer has been shown to be altered by diabetes ([@B46]). For example, Hanna-Mitchell et al. in a streptozotocin (STZ; 65 mg/kg)---induced model of diabetes, through preferential toxicity to the insulin producing β-cells of the pancreas, reported that exposure to chronic hyperglycemia induces desquamation of the superficial cells, subsequently contributing to breaches in the barrier function of the urothelium ([@B47]). At a later time point, the urothelium exhibited barrier repair and vast changes both in cell morphology and gene expression (glucose metabolism, cell survival and proliferation, parasympathetic receptors, and cell stress/death), which are also factors that are altered in senescence ([@B47]). Further, Wang et al. reported increased urothelial inflammation in overactive bladder, which they noted did not differ between overactive patients with or without diabetes; however, overactive bladder was diagnosed solely based on urgency and urgency incontinence ([@B48]). Initial diabetes-induced damage to the urothelial layer could contribute to symptoms of overactive bladder, whereas repair accompanied with cellular changes may indicate the transition between the compensated and decompensated states of DBD.

### Lamina Propria

The lamina propria is a loose areolar connective tissue that is located deep to the urothelial layer. The lamina propria connects the urothelial layer to the underlying smooth muscle layer and is both blood perfused and innervated, supporting the urothelial layer with nutrients and neuromediators. This layer contains collagen as well as several cell types, including interstitial cells (IC), fibroblasts, and adipocytes ([@B41]). Studies have reported changes in collagen composition (both increased and decreased) possibly contributing to altered strength and stiffness of the tissue ([@B40]). Increased collagen levels within the lamina propria could lead to increased tissue stiffness and strength as well as decreased nutrient diffusion to the urothelial layer and initially contribute to symptoms of overactive bladder. Decreased collagen levels would result in decreased tissue and contribute to symptoms of underactive bladder. The function of resident cells of the lamina propria could also be affected by diabetes. Recent identification of IC seem to serve similar roles as IC of Cajal (ICC) in the gastrointestinal (GI) tract by regulating smooth muscle excitability and mediating responses to neurotransmitters ([@B49]--[@B51]). ICC have spontaneous pacemaker activity which is conducted to the smooth muscle layer through gap junctions resulting in electrical slow waves and phasic contractions. Neural inputs, from motor neurons in close proximity to ICC, can also induce contraction by electrically coupling with smooth muscle cells. This complex operates below the level of neural and hormonal smooth muscle regulation and a loss of any component or connectivity of the complex has been associated with GI motor disorders ([@B52]). For example, a decrease in the number of GI ICC is believed to contribute to disturbed GI motility in human patients with type 2 diabetes ([@B53]) and diabetic db/db mice ([@B54]). IC within the urinary bladder has gained much interest due to evidence of its association with bladder pathophysiology where the number of IC have been shown to be both increased ([@B55], [@B56]) and decreased in overactive bladder and bladder outlet obstruction ([@B57]). Further, alterations or disruptions of these IC have been proposed to disrupt homeostatic tissue function within the urinary bladder ([@B55], [@B58], [@B59]). Increases in the number of IC could in theory increase the amount of spontaneous smooth muscle activity; therefore contribute to symptoms of urgency within overactive bladder. In contrast, a decrease in the number of IC could lead to decreased contractility and symptoms present within underactive bladder.

### Smooth Muscle

The smooth muscle layer of the urinary bladder functions to contract (parasympathetic nervous system) and relax (sympathetic nervous system) the bladder during micturition and urine storage, respectively. There are a variety of DBD studies focused at the layer of the smooth muscle that depict modifications within contractility, neurotransmitter release, receptor and channel expression, thick and thin filament and contractile protein expression, and protein phosphorylation; however, results are varied showing both increased and decreased expression of components mentioned ([@B13], [@B25], [@B27]--[@B29], [@B31], [@B60]).

Urethra
-------

The urethra is a duct that transfers urine from the urinary bladder to the exterior of the body. The urethra is held closed by two sphincters, the internal urethral sphincter, and the external urethral sphincter, which are made up of smooth and skeletal muscle, respectively. Alterations with urethral function have been reported, showing both smooth and skeletal muscle dysfunction of urethral relaxation during the voiding reflex ([@B61], [@B62]). This could contribute to increased bladder pressure, increased void volume, and trouble initiating and maintaining voiding, altering normal bladder function and causing further damage to the urinary bladder. Consequences of these alterations include increased intravesicle pressure, as well as increased detrusor muscle contraction as a compensatory mechanism, contributing to underactive bladder symptoms.

Diabetes Is Associated With Increased Cellular Senescence {#s3}
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Cellular senescence is a physiologic process in which replication-competent cells undergo irreversible cell cycle arrest induced essentially by any insult that produces DNA damage (replicative exhaustion and telomere shortening, excessive/ prolonged cellular stress) that can be grouped into three different subtypes: replicative senescence, stress-induced premature senescence, and oncogene-induced senescence ([@B63], [@B64]). This DNA damage results in the downstream activation of p53 and convergence on the inhibition of cyclin-dependent kinases (CDK), a family of protein kinases that are involved with cell cycle regulation ([@B63]). The inhibition of CDK--cyclin complexes results in proliferative arrest and the crucial component responsible for the implementation of senescence is the hypo-phosphorylated form of retinoblastoma protein ([@B64]). Senescence is generally considered a physiologic process and a protective mechanism to prevent morbidity by reducing the transmission of genomic defects to the next generation ([@B63]). In fact, studies suggest that controlled senescence promotes tissue regeneration via the recruitment of phagocytic immune cells to sites of injury after which senescent cells are then cleared ([@B65], [@B66]). Recruitment of immune cells depend on senescent secretory activity known as the senescence-associated secretory phenotype (SASP), allowing the secretion of pro-inflammatory cytokines and chemokines, reactive oxygen species (ROS), growth factors, and proteases into the local tissue microenvironment through autocrine and paracrine signaling ([@B64], [@B67]). An accumulation of senescent cells occurs with aging and is associated with tissue dysfunction, as well as numerous pathologies. Interestingly, we have evidence that urothelial senescence also increases with age (Figure [3](#F3){ref-type="fig"}; original data). Mechanistically, senescence-induced tissue dysfunction and pathology is thought to occur through the chronic release of SASP mediators and a heightened inflammatory state ([@B64], [@B68]--[@B72]).

![Senescence associated-β-galactosidase staining is increased in aged Wistar urothelium compared to young control counterparts. Senescence associated-β-galactosidase staining (blue) and nuclear fast red counterstain in young (20 w of age) animals and old (53 w of age) animals (left and right panels, respectively). Representative images of bladder SA-β-galactosidase at 200X. SM, smooth muscle. UR, urothelium.](fsurg-05-00072-g0003){#F3}

Recent evidence suggests that cellular senescence is an important developmental contributor and/or consequence of type 2 diabetes ([@B70]). For example, several studies describe augmented inflammation and increased number of senescent cells within pancreatic β-cells of type 2 diabetic patients ([@B73], [@B74]). Monocytes from type 2 diabetic patients exhibit telomere shortening and increased oxidative DNA damage compared to healthy individuals ([@B75]). Fibroblasts isolated from diabetic wounds exhibit disturbed proliferation ([@B76]). Senescent cells are increased in adipose tissue of both type 2 diabetic animal models and patients ([@B77], [@B78]). Further, high glucose induces cellular senescence in multiple cell types *in vitro* including endothelial cells, mesothelial cells, vascular smooth muscle cells, mesenchymal stem cells, and skin fibroblasts ([@B79]--[@B83]). We also have evidence that high glucose increases cellular senescence in primary bladder smooth muscle cells (Figure [4](#F4){ref-type="fig"}; original data). Overall, evidence suggests an association between type 2 diabetes and increased cellular senescence, possibly via heightened (mitochondrial) oxidative stress ([@B77], [@B78]). In fact, targeting senescent cells in type 2 diabetes has been suggested as a therapeutic option ([@B70]). Low-grade systemic inflammation is a common manifestation of diabetes; however, the exact mechanisms that initiate this pathophysiological response, thereby contributing to diabetic complications, including DBD and LUTS is not known.

![High glucose increases senescence associated-β-galactosidase staining in primary bladder smooth muscle cells. Senescence associated-β-galactosidase (blue) and nuclear fast red counterstain in high mannitol osmotic control (22 mM; left panel) and high glucose (22 mM; right panel) after a 4 day incubation. Representative images of primary bladder smooth muscle cell senescence associated-β-galactosidase at 100X.](fsurg-05-00072-g0004){#F4}

The Immune Response and Inflammation in Diabetic Bladders {#s4}
=========================================================

The urinary tract has several lines of defense that protect against infection. The first line of defense are superficial urothelial cells that not only act as a physical barrier, but also secrete pro-inflammatory mediators and antibacterial agents. Urothelial cells are connected by tight junctions, made up of 4--6 intracellular protein strands containing claudin, occludin, junction adhesion molecules, and zonula occludens that link these strands to the intracellular cytoskeleton ([@B84], [@B85]). This robust architecture is essential, and it contributes to the sterility of the bladder by preventing passive movement of particles between the blood and the urine. Further, these cells contain thick scallop-shaped plaques along the apical membrane that are covered with a sulfated polysaccharide glycosaminoglycan layer to further maintain the physical barrier of the bladder by deterring microbial colonization ([@B84], [@B86], [@B87]). In addition, urothelial cells also secrete factors that inhibit bacterial growth by interfering with the structure of the bacterial cell membrane or preventing protein synthesis within the cell ([@B88]--[@B92]).

Urothelial cells possess an abundance of pattern recognition receptors (PRRs) of the innate immune system including Toll-like receptors (TLRs), which recognize early indications of infection and release pro-inflammatory mediators ([@B93]). TLR4 is perhaps the best understood and most prevalent TLR in the urothelium; stimulation of which has been shown to result in expulsion of bacteria containing vacuoles from urothelial cells ([@B94]). Activation of TLR4 leads to interaction of its intracellular binding domain with an adaptor protein complex that includes MyD88 ultimately promoting the NF-κB pathway and transcription of cytokines such as interleukin 6 (IL-6) and interleukin 8 (IL-8) ([@B94]). TLR4 and its downstream mediators have been shown to be increased in DBD suggesting increased inflammation may play a role in DBD pathogenesis ([@B34]).

Bacterial infection can also activate caspase induced apoptosis of infected urothelial cells, effectively releasing contents into the lumen of the bladder. This not only removes bacteria, but it also attenuates excessive release of pro-inflammatory molecules. However, excessive removal of urothelial cells can expose underlying cell layers to toxins that are present within urine. As a protective measure, the urothelium secretes sonic hedgehog (SHH) to activate the WNT pathway, initiating urothelial cell proliferation to restore the epithelial barrier ([@B95]). This mechanism is reinforced by studies that show higher levels of apoptotic cells, antiproliferative factor, ATP, and vascular endothelial growth factor in the urine or tissue of patients with bladder infection ([@B96]--[@B100]). While the WNT pathway has not been studied in DBD, bladder thickness of the urothelium are increased in DBD and could be the result of this signaling process ([@B32], [@B101]).

Neutrophils are the first immune cells recruited to the urothelium from the blood vessels to the lumen of the bladder where they can act upon bacteria ([@B102]). The number of neutrophils recruited is congruent with the relative amount of bacteria present, and peaks approximately 6 h after activation ([@B103]). While neutrophils are highly effective at eliminating bacteria, they are also toxic to bladder tissue because they release ROS, increase expression of cyclooxygenase 2 (COX2), and induce expression of other cytotoxic products that cause inflammatory damage to the bladder. Neutrophil byproducts have been shown to cause hyperplasia and also predispose the bladder to persistent infections ([@B104]).

Bladder mast cells reside beneath the epithelium and are triggered via secretions of damaged or stressed epithelial cells in response to ATP, IL-33, and β-defensin ([@B105]--[@B107]). Mast cells regulate the immune response by releasing pro-inflammatory molecules such as histamine and TNF-α, which further contributes to the recruitment of neutrophils ([@B108]). Diabetic patients have significantly higher levels of mast cells in the bladder than patients without diabetes ([@B48]). Interestingly, TNF-α is not only elevated in bladder smooth muscle cells and serum isolated from diabetic mice, it also plays a critically important role in DBD by activating Rho kinase and ultimately causing bladder smooth muscle cell hypercontractility; neutralizing TNF-α improved bladder function ([@B33]).

Oxidative Stress in Diabetic Bladders {#s5}
=====================================

Oxidative stress due to elevated levels of ROS has also been implicated in the pathogenesis of DBD. Diabetic hyperglycemia is capable of causing oxidative stress through several key mechanisms: upregulation of the polyol pathway, increased production of advanced glycation end-products, increased activity of protein kinase C, increased activation of the hexosamine pathway, and ultimately the overproduction of superoxide by the electron transport chain ([@B109]--[@B115]). As oxidative stress ensues, cellular functions are impaired due to damaged DNA, mitochondrial enzyme dysfunction, and phospholipid bilayer destruction. These damaging effects contribute to morphological and functional changes associated with DBD.

Multiple studies show the presence of oxidative stress and subsequent structural and functional modifications in diabetic bladders. For example, bladders from type 2 diabetic female Sprague-Dawley rats exhibit significant increases in nitrotyrosine and manganese superoxide dismutase protein expression compared to both age-matched control and diuresis ([@B40]). Diabetes and diuresis both resulted in significant increases in bladder weight; however, the increase in oxidative stress was specific only to the diabetic model. In another study, diabetic Sprague Dawley rats exhibited a reduction in catalase-like activity, a measure of antioxidant scavenging capability in aerobic cells compared to age-matched control and diuresis ([@B30]). Further, these diabetic bladders presented higher levels of apoptotic cells, an increase in lipid peroxidation, and an increase in inducible nitric oxide synthase expression and concluded that oxidative damage to the smooth muscle layer may contribute to DBD symptoms ([@B30]). In addition, diabetic bladders from 2 month old rats exhibited increased expression of genes involved in the production or regulation of ROS, higher levels of lipid peroxidation, reduced glutathione S-transferase activity, an increase in protein oxidation and nitrosylation, and increased apoptosis markers ([@B116]). Results from this study suggest that increased oxidative stress and apoptosis are associated with impaired bladder contractile capacity. Likewise, bladders from diabetic New Zealand rabbits, exhibited significantly increased lipid peroxides, aldose reductase, and sorbitol compared to both age-matched control and a diuresis model ([@B31]).

ROS can also lead to the breakdown of proteins via autophagy, which is a compensatory mechanism for an organism under oxidative stress to preserve cell organelles and proteins. ROS can induce autophagy by oxidizing a cysteine residue in Atg4, which acts to convert microtubule-associated protein light chain 3 to its active form, leading to autophagy ([@B117], [@B118]). A study involving both diabetic human and animal studies showed increased levels of autophagy in β-cells, and further proposed that autophagy serves a protective role against apoptosis by preserving cells and preventing further oxidative damage ([@B119]--[@B121]). However, persistent autophagy is detrimental as it leads to autophagic cell death ([@B120], [@B122]--[@B124]). Consequently, ROS-induced autophagy caused by diabetes can lead to further oxidative stress that damages or destroys smooth muscle cells, contributing to hypocontractility and bladder dysfunction ([@B116]).

We have observed increased senescence in DBD from type 2 diabetic female Wistar rats (high fat diet and 30 mg/kg i.p. STZ) at 1 month post-STZ injections (Figure [5](#F5){ref-type="fig"}; original data). At this time point, senescence was localized mainly to the urothelium layer of the bladder, which corresponds with Hanna-Mitchell\'s findings that the urothelial layer changes both in cell morphology and gene expression ([@B47]). Further, gene expression alterations in the diabetic urothelium reported by Hanna-Mitchell et al. are also factors that are altered in senescence ([@B125]--[@B127]). While inappropriate immune system activation has been well established in diabetes and DBD, it is not known whether the presence of senescent cells can exacerbate the pro-inflammatory/pro-oxidative milieu, thereby worsening LUTS.

![Senescence associated-β-galactosidase staining is increased in diabetic urothelium compared to control counterparts. Senescence associated-β-galactosidase (blue) staining and nuclear fast red counterstain in control (Left) and diabetic (Right) bladders. Diabetes was induced using the combination of a high fat diet and one streptozotocin injection (30 mg/kg) in Wistar animals. Representative images of bladder senescence associated-β-galactosidase staining at 100X, inserts at 400X magnification. SM, smooth muscle. UR, urothelium.](fsurg-05-00072-g0005){#F5}

Hypothesis {#s6}
==========

We hypothesize that uncontrolled urothelial senescence contributes to increased inflammation and oxidative stress within the bladder wall and contributes to symptoms of DBD (Figure [6](#F6){ref-type="fig"}). The SASP of senescent bladder cells, through uncontrolled and excessive pro-inflammatory mediators (e.g., cytokines, chemokines) and ROS generation, could further impair the function of healthy bladder cells, as well as mediate additional transition to the senescent state.

![Chronic hyperglycemia contributes to cellular stress and an accumulation of senescent cells. The presence of senescent cells further contributes to increased inflammation in the bladder wall, which leads to symptoms of diabetic bladder dysfunction.](fsurg-05-00072-g0006){#F6}

Mechanisms driving initial senescence induction on the apical side of urothelial cells may include chronic increases in urine volume and therefore increased workload and bladder stretch, and exposure to an altered urine content (increased protein, glucose, damaged tubule cell contents). Diabetic kidney disease is a prominent complication of diabetes that is characterized by glomerular hyperfiltration ([@B128]). The ultra-filtrate (urine), containing proteins, growth factors, and cytokines, causes apical tubular cell injury and interstitial fibrogenesis within the kidney ([@B128]). This ultra-filtrate is transferred from the kidney to the urinary bladder via ureters ([@B128]). Therefore, these same factors, which mediated kidney damage, are now exposed to the urothelial layer of the bladder. Increased exposure to chronic high blood glucose concentrations may also affect urothelial cells from the basal side. High and chronic levels of glucose is known to cause mitochondrial dysfunction and increases the expression of advanced glycation end products and ROS, both of which have been shown to induce senescence ([@B129]--[@B134]).

As mentioned previously, senescent cells release multiple factors (cytokines, ROS, etc.), which may induce DBD symptoms and further drive the accumulation of senescent cells. Oxidative stress, which has been shown in numerous *in vitro* and *in vivo* studies to be remarkably high in diabetic patients, is also a major factor in the activation of cellular senescence ([@B80]). The major source of senescence-inducing ROS appears to occur through mitochondrial dysfunction ([@B132]), although other enzymatic sources of ROS are also known to contribute ([@B134]). Furthermore, increased advanced glycation end products and chronic inflammation, both linked to diabetes, have also been shown to induce senescence ([@B130], [@B131], [@B133]). Whether accumulating senescent cells could be responsible for or the result of increased inflammation and ROS reported in diabetic bladders is not explicitly known; however, this process could be complementary in that high glucose results in a heightened inflammatory state that increases the accumulation of senescent cells. The SASP could enhance development and accumulation of senescence leading to a positive feedback loop (Figure [3](#F3){ref-type="fig"}).

The authors believe that the hypothesis presented is testable within the framework of current knowledge. While we have shown increased senescence associated-β-galactosidase staining within the urothelial layer of diabetic bladders, other markers indicative of cellular senescence at different and longer time points and within different models of diabetes should be measured. Multiple standard measurements have been established to indicate senescence. Senescent cells exhibit increased expression of senescence associated-β-galactosidase and p16^INK4A^ as well as secreted inflammatory factors (IL-1, IL-6, IL-8, VEGFA, MMPs) as part of their SASP, measureable by senescence associated-β-galactosidase assays, western blotting, and ELISA ([@B135]). Further, increased DNA damage and telomere shortening are also indicators of cellular senescence. The effect and presence of senescence during each state of DBD needs to be investigated coinciding with voiding behavior and cytometric measurements. For example, senescent cells may increase initially after initial insult of DBD due to increased volume of urine and subside with the recruitment of immune cells to the site of injury. One would expect that senescent cells may accumulate again within the later stages of DBD due to increased ROS after prolonged hyperglycemia and chronic increased voiding volume; this would concur with current literature showing the presence of cellular senescence with age as well as enhanced inflammation. One may further postulate if increased urothelial senescence could then lead to increased cellular senescence within the smooth muscle layer of the bladder. There are multiple models of diabetes and all could be used to test this hypothesis. A limitation to the use of diabetic animal models is that these models develop overt disease in short time frames whereas the human condition may develop over longer periods of time and are then managed with various therapeutics and lifestyle interventions; therefore, timing of disease progression and corresponding mechanistic alterations may not be identical. An important control group to consider would be cases of bladder dysfunction, both overactive and underactive bladder, that are not associated with increased blood glucose levels such as diabetes insipidus and bladder dysfunction associated with old age and other disease states. This would determine whether increased cellular senescence was the direct consequence of oxidative stress due to increased and chronic levels of blood glucose. Once evidence of senescence in animal models is established, it would be imperative to show increased urothelial senescence in human DBD patients within both overactive and underactive bladder symptoms possibly through urothelial biopsies.

Some potential limitations to this hypothesis include understanding whether senescent cells are the cause or the effect of DBD *in vivo*. Therefore, although therapeutic targeting of senescent cells may offer symptomatic relief to LUTS, it may not reveal the underlying pathogenic mechanism of bladder dysfunction. Furthermore, parsing out the contribution of senescent urothelial cells to the omnipresent oxidative and inflammatory burden in diabetes could prove challenging. This is especially pertinent given that the specific enzymatic and pattern recognition receptor specific sources of ROS and cytokines, respectively, have not been determined in senescent urothelial cells and will require careful experimental design and potentially novel models of DBD.

Clinical Perspectives {#s7}
=====================

Due to the insidious onset of DBD, patients may not notice changes in voiding habits until later stages ([@B86]). Additionally, patients may not voice their concerns to their healthcare providers unless questioned specifically on symptoms due to the stigma associated with LUTS, particularly with urinary incontinence ([@B136], [@B137]). In one study of women ages 20--45, only 10.8% with overactive bladder and 12.7% with urge incontinence have seen their physicians for those symptoms ([@B136], [@B138]).

Patients with suspected DBD should be evaluated with detailed history and physical exam. Once more serious causes of LUTS are ruled out, patients may undergo urodynamic testing to assess lower urinary tract function ([@B139], [@B140]). Urodynamic testing may not be necessary if diagnosis is clear ([@B139], [@B140]).

Current treatment for DBD include behavioral changes (i.e., weight loss, timed voids, pelvic floor exercises), pharmacological, and surgical interventions ([@B86], [@B139]). For overactive bladder, medications target bladder specific muscarinic receptors (anticholinergics) or ß~3~-adrenergic receptor agonists to reduce detrusor contractions ([@B86], [@B139]). Muscarinic antagonism improves some lower urinary symptoms; however, efficacy is questionable and tolerability is poor due to side effects, the major one being "dry mouth." In a study of patients with overactive bladder, oxybutynin and tolterodine treatment only resulted in one fewer leakage episode or micturition event per 48 h compared to placebo ([@B141]). Similarly, in a study where women took anti-muscarinic agents reported an average of three leaks a day after 6 months of treatment compared to an average of five a day at the start of treatment. Not only is efficacy of these drugs in question, there are significant side effects of these medications such as dry mouth, constipation, difficulty in urination, blurred vision, dry eyes, drowsiness, dizziness, and cognitive decline, which makes long term treatment a challenge for patients ([@B141]). The most bothersome side effect for patients is dry mouth; 25% of patients will cease taking this medication because of this side effect. Increased duration of dry mouth will cause dental caries and difficulty in speech; in order to alleviate the dry mouth symptoms, patients will drink more water and therefore exacerbate lower urinary tract symptoms. Patients that fail behavioral modification and pharmacological therapy may benefit from more invasive methods such as intradetrusor botulinum toxin A injections or neuromodulation ([@B86], [@B139]). For underactive bladder, behavior modifications are encouraged but pharmacologic options are limited; current treatment options include methods such as asking patients to "double-void," placement of an indwelling catheter, and intermittent self-catheterization ([@B86]). Long-term use of indwelling catheters are associated with high risk of complications such as urinary tract infections and urethral lesions ([@B142], [@B143]). Ultimately, other surgical intervention may be explored for both overactive and underactive bladder if the patient does not respond to less invasive treatment options ([@B86], [@B139]).

Senescence as a Novel Target for Diabetic Bladder Dysfunction Treatment {#s8}
=======================================================================

Aged or diseased tissues are not able to efficiently clear senescent cells, thereby resulting in their accumulation ([@B64]). Therefore, it is not surprising that recent studies support the therapeutic approach of targeting senescence for the treatment ([@B144]--[@B146]). Agents that prevent the activation of specific mechanisms of senescence, such as those involving telomerase, DNA-damage repair machinery, cell-cycle checkpoint kinases, and tumor suppressors, are all known to reduce indices of disease ([@B69], [@B147]). Similarly, the removal of senescent cells was recently shown to delay the onset of several age-related disease processes ([@B72], [@B144]).

As mentioned previously, LUTS is seen in up to half of diabetic patients and is associated with a significant negative impact on quality of life. With the increasing prevalence of diabetes, it is expected that complication of diabetes, such as DBD, is also on the rise. Further investigation into the association between urothelial senescence and DBD may lead to new therapeutic pathways. Senolytic therapy during the early stages of DBD may prevent further oxidative stress and possibly prevent progression of early stages of DBD to a later stage.

Agents that specifically target senescent cells for apoptosis represents a promising field of pharmacology and could be a more selective option for the treatment of DBD. To illustrate the impact of senescent cells on its surrounding tissue, one study showed that transplanting senescent ear chondrocytes into the knee joint region caused osteoarthritis-like condition in mice, while transplanting non-senescent cells did not ([@B148], [@B149]). A recent study reported that administration of two senolytics, dasatinib, and quercetin, reduced physical dysfunction induced by senescent cell transplantation and increased lifespan in old mice ([@B149]). Currently, senolytic therapy is used in some cancer treatments. For example, dasatinib is a senolytic used to treat certain forms of acute lymphoblastic leukemia and chronic myeloid leukemia ([@B150]). Other senolytics, such as navitoclax and UBX0101, are under clinical trials for the treatment of solid tumors and osteoarthritis, respectively. A recent article highlights the use of FOXO4-p53 interfering peptide, causing p53 nuclear exclusion in senescent cells and apoptosis, and resulting in protection against chemotoxicity and restoring the effects of age ([@B151]). Apoptosis of bladder senescent cells could decrease hypertrophy and prevent increased ROS and inflammation, both of which are characteristic of DBD. Interestingly, metformin is being evaluated as a SASP regulator for its effects on inhibiting the NF-κB pathway, ROS production, and inflammation ([@B152], [@B153]). The effects of metformin on urothelial senescence would be hard to elucidate; not only would metformin decrease plasma and urine glucose levels, it also acts as a SASP regulator. Further, treatment with sodium-glucose co-transporter-2 inhibitors would be an interesting positive control if increased urine glucose levels are responsible for increased urothelial senescence ([@B154]).

Conclusion {#s9}
==========

Despite recent advances in understanding DBD, the underlying pathways are poorly understood and therapeutic options are limited and not always effective, highlighting the need for novel interventions ([@B13], [@B22]). While cellular senescence is a normal physiological response to stress, uncontrolled senescence can be detrimental to human health in high accumulating numbers as evidenced in multiple age-related disease states, including diabetes. Numerous studies suggest that the increased presence of senescent cells leads to tissue dysfunction. In addition, urothelial barrier dysfunction is associated with symptoms of urgency and frequency. Therefore, we put forward the hypothesis that increased senescent urothelial cells in diabetic bladders contribute to symptoms of DBD. Because the urothelium plays an important role not only as a barrier to urine, but also as a sensor, identifying molecular mechanisms leading to senescence is essential. Additional work is needed to link the clinical symptoms of each state of DBD with the presence of cellular senescence within urinary bladder layers. Normal aging induced senescence and possible bladder dysfunctions associated with the aging process, as well as sex, hormonal status, diabetes duration, and reversal with treatment/exercise need to be investigated in coordination with bladder cellular senescence and DBD.

Ethics Statement {#s10}
================

All animal procedures were performed in accordance with the Guide for the Care and Use of Laboratory Animals from the National Institutes of Health and were reviewed and approved by the Institutional Animal Care and Use Committee of Augusta University.

Author Contributions {#s11}
====================

NK designed the hypothesis, conducted experiments, and wrote the paper. CM contributed to and edited the paper. JV contributed to the initial research into the inflammation and oxidative stress section. SL researched, edited, and rewrote the section. JM wrote the clinical perspectives section, contributed to the section senescence as a novel target for diabetic bladder dysfunction treatment, and edited the paper. RW designed the hypothesis and edited the paper.

Conflict of Interest Statement
------------------------------

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

**Funding.** National Institutes of Health (HL134604) and Bridge-funding program, Augusta University. AHA Post-doctoral fellowship (18POST34060003).

ATP

:   adenosine triphosphate

DBD

:   diabetic bladder dysfunction

CDK

:   cyclin-dependent kinase

COX

:   cyclooxygenase

GI

:   gastrointestinal

IC

:   interstitial cells

ICC

:   interstitial cells of Cajal

IL

:   interleukin

LUTS

:   lower urinary tract symptoms

M

:   muscarinic receptor

MMP

:   matrix metalloproteinases

MYD88

:   myeloid differentiation primary response 88

NF-κB

:   nuclear factor-kappa B

ROS

:   reactive oxygen species

SASP

:   senescence-associated secretory phenotype

SHH

:   sonic hedgehog

STZ

:   streptozotocin

TLR

:   toll-like receptors

TNF

:   tumor necrosis factor

VEGFA

:   vascular endothelial growth factor A

WNT

:   wingless-related integration site.

[^1]: Edited by: Clemens Mathias Rosenbaum, University Medical Center Hamburg-Eppendorf, Germany

[^2]: Reviewed by: Riccardo Campi, Università degli Studi di Firenze, Italy; Marco Roscigno, Azienda Socio-Sanitaria Territoriale Papa Giovanni XXIII, Italy

[^3]: This article was submitted to Genitourinary Surgery, a section of the journal Frontiers in Surgery


Your Right to Know

WASHINGTON — A secretive U.S. spy court has ruled again that the National Security Agency can
keep collecting every American’s telephone records every day, in the midst of dueling decisions in
two civilian federal courts about whether the surveillance program is constitutional.

The Foreign Intelligence Surveillance Court renewed the NSA phone-collection program yesterday,
said Shawn Turner, a spokesman for the Office of the Director of National Intelligence. Such
periodic requests are somewhat formulaic but required since the program started in 2006.

The latest approval was the first since two conflicting court decisions about whether the
program is lawful and since a presidential advisory panel recommended that the NSA no longer be
allowed to collect and store the phone records and search them without obtaining separate court
approval for each search.

In a statement, Turner said that 15 judges on the U.S. Foreign Intelligence Surveillance Court
on 36 occasions over the past seven years have approved the NSA’s collection of U.S. phone records
as lawful.

Also yesterday, government lawyers turned to the U.S. Court of Appeals for the District of
Columbia Circuit to block a federal judge’s decision that threatens the NSA phone-records
program.

The Justice Department filed a notice asking the appeals court to overturn U.S. District Judge
Richard Leon’s ruling last month that the program was likely unconstitutional. The government’s
move had been expected.

Larry Klayman, who filed the class-action suit against President Barack Obama and top
administration national-security officials, said he intends to petition the federal appeals court
next week to send the case to the Supreme Court.

Turner said U.S. intelligence agencies would be willing to modify the phone-records surveillance
program to provide additional privacy and civil-liberties protections as long as it was still
operationally beneficial. He said the Obama administration was carefully evaluating the advisory
panel’s recent recommendations.

In a separate case involving the program, a district judge in New York last month upheld the
data collection as lawful.


1. Field of the Invention
The present invention relates to a guanidine compound and a heat sensitive recording material and particularly, to a novel guanidine compound, and a novel heat sensitive recording material which can develop color at high image density by the inclusion of a diazonium salt compound and a coupler as color developing components and of the above-described guanidine compound as a base.
2. Description of the Related Art
Diazonium salt compounds form an azo dye by reacting with a compound called a coupler such as a phenolic derivative and the like, and at the same time, have photo-sensitivity and are decomposed by irradiation with light to lose the activity thereof. Therefore, diazonium salt compounds have been used for a long time as light recording materials typified by diazo copy (cf. xe2x80x9cBasics of Photographic Technology (shashin kogaku no kiso)xe2x80x94the chapter on non-silver salt photography (higinen shashin hen)xe2x80x94xe2x80x9d published by Japan Photographic Society (nippon shashin gakkai), corona corp., (1982) pp 89 to 117 and 182 to 201).
Further, diazonium salt compounds have recently been used for recording materials for which require fixation of an image by utilizing the fact that they are decomposed by light to lose their activity. Typical examples include light fixation type heat sensitive recording materials in which a diazonium salt compound and a coupler are heated according to image signals and allowed to react to form an image which is then fixed by irradiation with light (Koji Sato et al., Image Electron Society Bulletin (gazo denshi gakkai shi), vol. 11, No 4 (1982), pp 290 to 296, and the like).
In these heat sensitive recording materials, it is necessary for the diazonium salt and coupler to react immediately to develop color when heated, and conventionally organic salts such as tertiary amines, piperidines, piperazines, amidines, formamidines, pyridines, guanidines, morpholines and the like are added for the purpose of promoting the coupling reaction of the diazonium salt compound with the coupler. Among these, triphenylguanidine whose conjugated acid has a pKa of 7 has been mainly used for the guanidines.
However, when the reactivity of a diazonium salt compound with a coupler is low, a stronger base is required.
On the other hand, a multicolor heat sensitive recording material can be obtained by laminating heat sensitive recording layers developing different hues. The layer structure is not particularly restricted, and one example is a multicolor heat sensitive recording material in which a double heat sensitive recording layer comprising a combination of two kinds of diazonium salt compounds having different photo-sensitive wavelengths and couplers which develop different hues by reacting when heated with the respective diazonium salt compounds is laminated with a heat sensitive recording layer comprising a combination of an electron donative colorless dye with an electron receptive compound.
When a strong base as described above is used in the diazo heat sensitive recording layer of this type of multicolor heat sensitive recording material, it is necessary for the strong base to be superior in diffusion resistance so as not to influence other layers.
In view of the above circumstances, an object of the present invention is to provide a novel guanidine compound which is strongly basic and superior in diffusion resistance, and a novel diazo heat sensitive recording material which can develop color at high image density by the inclusion of a diazonium salt compound and a coupler as color developing components and of the guanidine compound as a base.
After intensive research into the structure of a guanidine compound in order to attain the above-described objective, the present inventors discovered the following facts (1) and (2), thus completing the present invention.
(1): Basicity increases by the substitution of an alkyl group for at least one of the three phenyl groups in triphenylguanidine owing to the substituent effect of the alkyl group.
(2): By forming bis type structure, the diffusion of a base into other layers can be prevented, and when a multi-layer structure is adopted, the color developing density in the layer which includes the base does not decrease and a deleterious influence is not exerted on other layers.
Namely, the first guanidine compound of the present invention is represented by the following general formula (1):
(in general formula (1), R1 and R2 represent an alkyl group or aryl group. R1 and R2 may be the same or different. R3 and R4 represent a hydrogen atom, alkyl group or halogen atom. R3 and R4 may be the same or different. X represents a divalent connecting group.).
The second guanidine compound of the present invention is represented by the following general formula (2):
(in general formula (2), R1 and R2 represent an alkyl group or aryl group. R1 and R2 may be the same or different. R3 represents a hydrogen atom, alkyl group or halogen atom.).
The third guanidine compound of the present invention is represented by the following general formula (3):
(in general formula (3), R5 and R6 represent a hydrogen atom, alkyl group or halogen atom. R5 and R6 may be the same or different. X represents an alkylene group.).
The first heat sensitive recording material of the present invention is a material comprising a substrate supporting thereon a heat sensitive recording layer comprising a diazonium salt compound, a coupler which reacts with the diazonium salt compound and develops color when heated, and a base, wherein the heat sensitive recording layer includes as the base at least one guanidine compound represented by general formula (1) according to the above-described first invention.
The second heat sensitive recording material of the present invention is a material comprising a substrate supporting thereon a heat sensitive recording layer comprising a diazonium salt compound, a coupler which reacts with the diazonium salt compound and develops color when heated, and a base, wherein the heat sensitive recording layer includes as the base at least one guanidine compound represented by general formula (2) according to the above-described second invention.
The third heat sensitive recording material of the present invention is a material comprising a substrate supporting thereon a heat sensitive recording layer comprising a diazonium salt compound, a coupler which reacts with the diazonium salt compound and develops color when heated, and a base, wherein the heat sensitive recording layer includes as the base at least one guanidine compound represented by general formula (3) according to the above-described third invention.
The fourth heat sensitive recording material of the present invention is a material comprising a substrate supporting thereon a heat sensitive recording layer comprising a diazonium salt compound, a coupler which reacts with the diazonium salt compound and develops color when heated, and a base, wherein the heat sensitive recording layer includes as the base at least one guanidine compound represented by general formula (4):
(in general formula (4), R7 and R8 represent an alkyl group. R7 and R8 may be the same or different. X represents a divalent connecting group.).
It is preferable that a heat sensitive recording material of the present invention comprises as the above-described coupler at least one pyrrolo [1,2-a] pyrimidine compound represented by the following general formula (5):
(in general formula (5), R9 to R12 represents a hydrogen atom, halogen atom, aryl group, alkyl group, cyano group, acyl group, substituted carbamoyl group, alkoxycarbonyl group, aryloxycarbonyl group, acyloxy group, alkoxy group, aryloxy group, alkylthio group, arylthio group, substituted sulfamoyl group, alkylsulfonyl group, arylsulfonyl group, alkylphosphoryl group, arylphosphoryl group or substituted amino group.).
In a heat sensitive recording material of the present invention, it is preferable to use a diazonium salt compound having a maximum absorption wavelength xcexmax of 450 nm or less in view of the hue and light fixation properties thereof, and it is more preferable to use at least one diazonium salt compound selected from compounds represented by the following general formula (6), compounds represented by the following general formula (7) and compounds represented by the following general formula (8):
(in general formula (6), Ar represents a substituted or unsubstituted aryl group. Each of R13 to R14 represents a substituted or unsubstituted alkyl group, or a substituted or unsubstituted aryl group. R13 to R14 maybe the same or different. Xxe2x88x92 represents an acid anion.),
(in general formula (7), each of R16, R17 and R18 represents a substituted or unsubstituted alkyl group, or a substituted or unsubstituted aryl group. R16, R17 and R18 may be the same or different. Y represents a hydrogen atom or xe2x80x94OR15 group. R15 represents a substituted or unsubstituted alkyl group, or a substituted or unsubstituted aryl group. Xxe2x88x92 represents an acid anion.),
(in general formula (8), each of R19 and R20 represents a substituted or unsubstituted alkyl group, or a substituted or unsubstituted aryl group. Xxe2x88x92 represents an acid anion.)


Nevada players bristled at the thought.

UCLA is a 20-point favorite in Saturday’s season opener. That had Wolf Pack players scoffing this week as they prepared to drop by the Rose Bowl.

“That seems a little high,” offensive lineman Joel Bitonio said. “They’re picked to win the Pac-12 [South]. We’re going to come down and show what Nevada is made of.”

Even Nevada’s first-year coach had a little indignation about the 20-point spread.

“It means zero … zero,” Brian Polian said. “It means absolutely nothing.”

Polian, an assistant at Texas A&M; last season, made his case.

“What was the line for the California game last year?” Polian said.

California was favored by 11. Nevada won, 31-24.

“What was the line when we went into Tuscaloosa?” Polian said.

Alabama was favored by 14. Texas A&M; won, 29-24.

Polian’s assessment of point spreads? Well, he was running short on ways to say he didn’t care, so he fell back on: “It means absolutely nothing.”

Oh, but they can mean something.

The line seemed a little low when Oregon, a 27-point favorite, beat Nevada, 69-20, in Oregon’s 2011 opener. The Wolf Pack has a 4-15 record against teams from Bowl Championship Series conferences since 2002.

Still, Nevada quarterback Cody Fajardo reminded people, “We walked in and beat Cal in their brand new stadium last season.”

The Bears finished 3-9 and fired Coach Jeff Tedford.

Upon further review

Fajardo, who attended Anaheim Servite High, danced around the fact that UCLA did not recruit him in 2009, saying, “I’m a hometown kid. I loved UCLA and would have loved to go there.” But, he said, “I love my decision picking here.”

Fajardo was in a less loving mood last spring during a Q&A; with Takingbadschotz.com.

Asked what team he was most looking forward to playing, he said, “It’d have to be UCLA. I can’t overlook that game. It’ll be tremendous, especially because I’m from that area. You know, maybe I’m a little bitter about them not offering me or taking any time for me because I’m right there in their backyard.”

Game time, finally

Eddie Vanderdoes has taken a long road to get to Saturday’s game.

He signed a letter of intent with Notre Dame, then asked out of his commitment so he could transfer to UCLA. Fighting Irish Coach Brian Kelly refused and Vanderdoes had to win an appeal.

His first week of practice, he injured his back and missed more than a week. Now he gets to play.

“I can’t wait, my first college football game,” the 6-foot-4, 305-pound freshman said. “It’s nice that it’s finally here. I don’t have any expectations. I just want to do what I can to help the team.

As for the journey to get there, Vanderdoes said, “I have a short memory.”

Ankou update

UCLA received good news on the injury front, as nose tackle Eli Ankou is expected to miss only four weeks because of a knee injury.

Ankou was injured during practice Monday. But an MRI revealed only minor damage. He was scheduled to undergo a surgery Thursday and should be back by October.

chris.foster@latimes.com

Twitter: @cfosterlatimes


Q:

Why does xxd add chars?

I am trying to reverse an od command from a system where I have no hexdump or base64 tools.
I do this like that (of course, in reality, the encoding takes place at the "small" system, the decoding is done on my workstation, but to test it, I try the whole way in one line first):
echo TEST | od -tx1 | xxd -r

Of course, echo TEST is just a placeholder here for eg. cat test.bmp or anything else.
> echo TEST
TEST

> echo TEST | od -tx1
0000000 54 45 53 54 0a
0000005

> echo TEST | od -tx1 | xxd -r
TEST

That looks right, but it is different, as we can see here if we give it to od again:
> echo TEST | od -tx1 | xxd -r | od -tx1
0000000 54 45 53 54 0a 00 00 00
0000010

Why does xxd -r add those 00s?

A:

It seems to work if I remove the offsets at all:
> echo TEST | od -tx1 -An
 54 45 53 54 0a
> echo TEST | od -tx1 -An | xxd -r -p
TEST
> echo TEST | od -tx1 -An | xxd -r -p | od -tx1 -An
 54 45 53 54 0a

Bingo! Note the extra " " in front of the bytes. It seems to have no effect.


Barring an unexpected, last-second change of heart that would stun his family, coaches and even himself, Booker T. Washington All-American defensive end Chad Thomas said he plans on signing a National Letter of Intent with the University of Miami on Wednesday morning.

“There’s no suspense,” said Thomas, days before taking his final official visit to Alabama this past weekend. “I’ve been throwing up ‘The U’ [with my hands] since the first game of the season. I’m not really trying to build suspense or get anybody fired up or rowdy.”

If Thomas, the only five-star recruit in UM’s recruiting class, doesn’t flip his commitment to Alabama or Florida State, he’ll be one of the few elite players in Miami-Dade County to stay with the first school he committed to. Of the top 10 players in Dade, according to 247Sports’ composite rankings, six have pulled back from a college commitment at least once during their recruitment.

Booker T. quarterback Treon Harris (Florida State commitment with interest in UM, Florida and Auburn) and Northwestern receiver Jojo Robinson (FSU commitment with interest in TCU, South Florida and Arkansas) could increase that number to eight if they sign elsewhere Wednesday.

There’s strong reason to believe Thomas won’t make it nine. That’s because he has been in love with the University of Miami’s Frost School of Music since well before UM’s coaching staff fell in love him.

“I thought he was full of it when he told me he played all these instruments and was a musician,” Booker T. Washington coach Tim “Ice” Harris said.

“Then he started playing them in front of me, showing me his beats, breaking it down. I was impressed.”

Thomas, who helped lead the Tornadoes to back-to-back state championships and a national title this season, said he fell in love with music at the age of 3 while listening to his late grandmother’s gospel CDs. Thomas said that as a toddler his grandmother bought him a toy guitar, and signed him up for piano lessons. By the time he was 5, Thomas said he was performing songs such as I’ll Take You There by the Staple Sisters on the piano and playing various instruments from the tuba and trumpet to the drums and bass.

After his grandmother passed away when he was 7, Thomas, an only child, said he would often care for himself because his parents were too busy working. On the bus ride and walk home from school, Thomas said he would usually entertain himself by creating his own beats. By the time he was in middle school, Thomas said he convinced his father, Chad Sr., a computer technician, to buy him an MC-808 sound generator.

“I remember when he took me to Sam Ash to go get it,” said Thomas, who attended classes at the New World School of the Arts until coaches were finally able to convince him to attend classes at Booker T. his senior year. “It was over $1,000. I told my dad there had to have been something in his brain saying this is going to make him and me money in the future.”

Thomas, a fan of beatmakers Timbaland, Louis V and J.U.S.T.I.C.E. League, said he has been trying to sell his own beats to musicians now for the last couple years. This past year, he finally found someone who was interested. It was local artist Lil Dred, the 20-year-old rapper and son of former UM cornerback Nate Brooks. Since its release in October, their song No Shone Remix has been played more than 245,000 times on SoundCloud.

Thomas, who has produced other popular tracks titled Thottie, She Weak and Overtime, said he has performed on some of his own tracks in clubs, parties and other places dozens of times. He said he has split the money he makes off what he produces and performs “50-50’’ with his mother, Stefanie Jones, a school director of a local day care.

“As a singer he’s more like a Drake type — singing but with a rap feel,” Booker T. Washington offensive coordinator Tim Harris Jr. said. “When it comes to instruments and music engineering, I think UM is ranked No. 1 and No. 2 in those fields. With his contacts in the music industry here in the city of Miami, that’s why it’s always been UM for Chad. ... Football-wise, Chad knows he can play at any school he wants to. But music is so important to him.”

Said Thomas: “It’s always been in my mind to go to school there. Football is not for long. I can go down with a knee injury tomorrow, but I know I’ll always be able to move my fingers and play an instrument, click a mouse.”

Thomas, who maintains a 3.3 grade-point average and scored an 18 on the ACT exam (well within the guidelines to qualify for UM), said he didn’t begin playing football until he was 12 at Gwen Cherry Park because when he was young he had asthma and a heart murmur. Thomas said he had to convince his parents to let him play.

Now an Under-Armour All-American and tabbed as the third-best defensive end in the country by 247Sports, Thomas says he has so much passion for football he usually cries before games.

With the Hurricanes in dire need of help along the defensive line, Booker T.’s coaches — who saw Thomas rack up 71 tackles and eight sacks this past season — believe Thomas has the size and maturity to help UM as soon as he walks through the doors in Coral Gables come June.

“People around the country talk about the pride we have here in high school and optimist [football],” said Thomas, who said he has had a green 1998 Ford Mustang parked in his mother’s driveway waiting to take him to college since last year.

“I know there’s a lot players who have that same pride at UM, but they’ve just got to put it all together and play like a team like back in the ’80s. We’ve got to bring that love, that passion for the game, and fight to make each other better every day. And I believe we will.”


1. Field of the Invention
The present invention in one embodiment relates to an improved foil, such as a fin or wing, having a stabilizing element that increases stability by reducing the effect of turbulence in air or water on mobile devices and which increases maneuverability of such devices.
2. Description of the Related Art
Many mobile devices have a foil, frequently a wing or a fin to stabilize their motion and provide lift. Nearly all types of watercraft use a vertical foil or fin to provide horizontal stability. Sailboats and other large watercraft frequently have a fin that is a direct extension of the hull. Surfboards and wind surfing boards often utilize one or more xe2x80x9cshark-likexe2x80x9d fins which may extend vertically up to 16 inches in a downward direction below the bottom surface of the surfboard or wind surfing board. This type of fin generally only stabilizes a boat, surfboard, or windsurfing board in a horizontal plane while riding through the water or on a wave under either smooth or rough water conditions. It offers little or no resistance to the vertical rise experienced during various watercraft maneuvers. Any maneuver that moves the weight forward and causes the rear of the watercraft or board to rise vertically may result in loss of control due to the fin losing contact with the wave or the water and result in a wipe out. Additionally as a wave becomes steeper and prepares to break, this type of fin, having only vertical design, will tend to lose contact with the face of the wave causing the loss of horizontal control and, in the case of a surfboard, allowing the board to slide sideways and cause a wipe out. Waves and turbulent water can also jar speedboats and sailboats or cause them to lose control.
The wings of airplanes or other aircraft have horizontal wings or stabilizers that provide lift and/or vertical stability, but the aircraft is still vulnerable to instability caused by turbulent air. Automobiles may also use a foil or blade appendage, commonly attached at the rear. This rear foil, sometimes known as a spoiler, provides downward force to help the tires maintain contact with the road. Like an airplane wing, however, the spoiler mostly provides stability in only one direction and is subject to the destabilizing effect of turbulent air. In short, most mobile devices have some type of airfoil, wing, or blade-like device that is designed to achieve stability, lift, and/or maneuverability, but there remain several disadvantages associated with these designs.
In one embodiment, the present invention advantageously reduces the effect of turbulent air or water upon a moving object, increases stability in a variety of directions and increases lift beyond foils currently in use. In another embodiment, the present invention also advantageously increases maneuverability of moving object in air, water or on land.
In one embodiment, a stabilizing element attaches to a water planing device or watercraft. It will be appreciated, however, that the stabilizing element can also be attached to other mobile devices, such as an automobile or an airplane, as described below. The stabilizing element which is preferably a stabilizing fin includes an upper vertical stabilizer element, a hollow tubular element, and a lower vertical stabilizer element. The upper vertical stabilizer element has an upper end for attachment to a bottom surface of a water planing device or watercraft. The hollow tubular element has an upper portion depending from a lower end of the upper vertical stabilizer element. The tubular element has an open front end and an open rear end. The lower vertical stabilizer element has an upper end depending from a lower portion of the hollow tubular element. During use thereof the upper and lower vertical stabilizer elements provide lateral stability and the hollow tubular element provides increased lateral stability and vertical stability for enhanced control by a user. The water planing device may be, for example, a surfboard or a wind surfing board. The watercraft may also be a sailboat or speedboat.
The stabilizing element stabilizes the water planing device or boat in a variety of directions under a variety of conditions. For example, this element gives the surfboard or wind surfing board rider longer, more controlled rides while the rider performs on the nose area of the board by holding the tail section down in the water. This element also gives the rider of the surfboard or a wind surfing board more control while riding through, in, or over the white water sections of waves while performing a variety of maneuvers. It gives the rider more control while riding on water or up or down a face of a steep wave on either a surfboard or a wind surfing board during either rough or smooth conditions. The stabilizing element stabilizes other watercraft in waves or turbulent water.
In accordance with one embodiment of the present invention, an increase in maneuverability is attained by the leading edge of the hollow element tapering to a defined edge. It is believed that this defined edge improves the maneuverability of the mobile device to which it is attached by biting into the fluid in which the mobile devices moves at the start of a turn.
In another embodiment, the hollow element, as it extends through the entire foil, maintains the foil shape of the entire fin or wing. This foil shape of the hollow element provides greater lift on the mobile device to which it is attached by creating more surface area against which the water or air may flow.
In another embodiment, the stabilizing element is attached to an aircraft. The wing of the aircraft has a hollow stabilizing element that helps provide additional lift and stability beyond wings currently in use.
In another embodiment, the stabilizing element attaches to the rear of an automobile, as a spoiler. Automobile spoilers are generally arranged to provide downward force to the rear tires, helping the tires remain in contact with the ground. The hollow element increases the surface area beyond commonly used spoilers, thereby allowing the spoiler to create more downward force without requiring greater length. In addition, the hollow element provides horizontal stability by channeling air through the body of the hollow element. It is also believed that the tapered front edges of the hollow tubular element increase maneuverability of the mobile device to which it is attached.
In another embodiment, the present invention comprises a stabilizer for a mobile device. The stabilizer has a first element that has a center-plane and an upper end for attachment to a bottom surface of the mobile device. The stabilizer also has a hollow tubular element that has a center-plane. The hollow tubular element is connected to the first element such that the center-plane of the hollow tubular element and the center-plane of the first element are not aligned.
In another embodiment, the present invention comprises a stabilizing system that includes a mobile device and a stabilizer. The stabilizer has a first element is connected to the mobile device and has a center-plane. The stabilizer also has a hollow tubular element that has a center-plane. The hollow tubular element is connected to the first element such that the center-plane of the hollow tubular element and the center-plane of the first element are offset. The hollow tubular element provides increased stability in at least two directions for enhanced control by a user of the mobile device and/or the stabilizing system.
In another embodiment, the present invention comprises a stabilizing fin for a water planing device that has an upper vertical stabilizer element, an arcuate element, and a lower vertical stabilizer element. The upper vertical stabilizer element has an upper end for attachment to a bottom surface of the water planing device. The arcuate element has an upper portion depending from a lower end of the upper vertical stabilizer element. The lower vertical stabilizer element has an upper end depending from a lower portion of the arcuate element.
In another embodiment, the present invention comprises a stabilizing system that includes a mobile device, and a stabilizer. The stabilizer comprises an upper vertical stabilizer element, an arcuate element, and a lower vertical stabilizer element. The upper vertical stabilizer element has an upper end for attachment to a bottom surface of the mobile device. The arcuate element has an upper portion depending from a lower end of the upper vertical stabilizer element. The lower vertical stabilizer element has an upper end depending from a lower portion of the arcuate element.


MINNEAPOLIS (AP) - Four University of Minnesota football players being investigated in a sexual assault were kicked off the team Wednesday.

Dominic Jones, a cornerback charged Monday with third-degree criminal sexual conduct in connection with the alleged rape of an 18-year-old woman in April, and three teammates - running back E.J. Jones, defensive end Alex Daniels and defensive back Keith Massey were dismissed from the team Wednesday, coach Tim Brewster said.

"It is an honor and a privilege to wear the uniform of the University of Minnesota and we have exceedingly high expectations for each of our student-athletes," Brewster said in a statement issued by the university. "We spend a considerable amount of time addressing our players regarding their personal conduct and we will not compromise our values. We are establishing a culture of integrity and we will demand that our players are held accountable for their actions."

Dominic Jones, a junior and one of the team's best defensive players, is accused of having sex with a woman who was "physically helpless" after a night of binge drinking at a campus apartment in early April.

Investigators estimated the woman's blood-alcohol content was more than 0.30 percent when they say Daniels used his cell phone to film Jones having sex with the woman. Forensic scientists later recovered a portion of the deleted film from the phone and say they have DNA evidence linking Jones to the woman.

Hennepin County Attorney Mike Freeman said Daniels, E.J. Jones and Massey also had sex with the woman earlier in the night. Freeman has not filed charges against those three but said they remain suspects in the case.

Minnesota athletic director Joel Maturi said he supported the dismissals.

"I am in full support of the decision of coach Brewster and I appreciate how he has handled this very difficult situation," Maturi said in the statement. "While this issue is deeply disappointing, the Athletics Department is sending a clear and unmistakable message that it will never compromise its code of conduct."

The school said the dismissals do not immediately affect the four players' scholarship status or standing as students at the university, but both are subject to review by the NCAA and the school.

Jeff DeGree, an attorney for E.J. Jones, said his client did not blame Brewster for the move.

"When the county attorney chose to characterize these guys as suspects, we were very disappointed," DeGree said. "That left Coach Brewster with little alternative. E.J. is very, very disappointed. He loves the University of Minnesota and he loves playing football there."

DeGree said that Jones did nothing criminal that night and is at best a witness to the events.

"They have had two to three months to review the case," DeGree said. "They decided not to charge them at the time and I don't know what at this point could change their minds."

Phone messages left with attorneys for the other players weren't immediately returned.

The players were going to be counted on heavily this season by a Gophers team already expected to struggle in Brewster's first season.

Despite being just 5-foot-8, Dominic Jones had started 20 straight games and emerged as a vocal leader on the defense. He also led the Big Ten last season with a 23.0-yard average on kick returns.

Daniels, who was teammates with Dominic Jones and Massey in high school in Columbus, Ohio, was a highly touted recruit by Glen Mason who was expected to be a key contributor on an improving defense.

E.J. Jones was the only true freshman on the Gophers' offense to start a game last season and was expected to team with Amir Pinnix and Jay Thomas in another loaded Minnesota backfield.

Massey, Dominic Jones' half brother, played in nine games as a redshirt freshman last season.