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Lapierre X-Control W je cenově dostupné dámské celoodpružené kolo na 27,5 palcových kolech, se zdvihy / mm a s osvědčeným systémem odpružení FPS+. Univerzální kolo vhodné jak pro pohodové vyjížďky s přáteli, tak i pro celodenní ježdění po horách. X-Control W je osazen vidlicí Rock Shox 30 Silver a komponenty Shimano s 3×9 převody%(26). Home // Mountain (MTB) // ” // Lapierre // LAPIERRE EDGE W HARDTAIL MTB BIKE LAPIERRE EDGE W HARDTAIL MTB BIKE Back to previous page Back. This is partly why new bikes come with a first free service. If your brakes start feeling a little spongy after a few weeks, you can adjust them at the barrel or the clamp or ask a. LAPIERRE X-Control W. Lapierre X-Control W je cenově dostupné dámské celoodpružené kolo na 27,5 palcových kolech, se zdvihy / mm a s osvědčeným systémem odpružení FPS+. Univerzální kolo vhodné jak pro pohodové vyjížďky s přáteli, tak i pro celodenní ježdění po h.

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Risk Factors and Pathophysiology T2DM risk factors include a complex combination of genetic, metabolic and environmental factors that interact with one another contributing to its prevalence.

Pathophysiology Regarding the pathophysiology of the disease, a malfunctioning of the feedback loops between insulin action and insulin secretion results in abnormally high glucose levels in blood [ 2 ]. Open in a separate window. Figure 1. Physical Activity Reduced physical activity and exercise training, and increased sedentary behaviors constitute a link between obesity and T2DM and are associated with increased markers of chronic low-grade systemic inflammation [ 60 , 61 ].

Gut Dysbiosis Gut microbiota is composed of many microbial species that impact human physiology and participate in different biological processes [ 71 ]. Metabolic Memory Metabolic memory refers to the persistence of diabetic complications even after maintained glycemic control.

Figure 2. Figure 3. Adipose Tissue Adipose tissue is a metabolically dynamic tissue capable of synthesizing a wide range of biologically active compounds that regulate metabolic homeostasis at a systemic level [ ]. Figure 4. Figure 5. Figure 6. Diabetic Dyslipidaemia and Atherosclerosis Development Dyslipidaemia is a common feature of T2DM, and increases the incidence of atherosclerosis and mortality of diabetic patients [ ].

Figure 7. Impaired Endothelial Function and Atherosclerosis Development Endothelium plays an important role in the regulation of vascular tone and structure through a balanced release of endothelial-derived relaxing and contracting factors. Mechanisms Leading to Endothelial Dysfunction in T2DM Vascular endothelial cells are particularly susceptible to developing intracellular hyperglycemia because glucose diffuses passively through their plasma membrane.

Endothelial Dysfunction in T2DM and Atherosclerosis Development Hyperglycemia-associated vascular injury, oxidative stress, inflammation and altered hemodynamic balance may initiate atherosclerosis development and formation of arterial thrombus [ ].

Conclusions The importance of research in the fields of glucose homeostasis, insulin and diabetes has not faded. Author Contributions U. Conflicts of Interest The authors declare no conflict of interest. References 1. Roden M. The integrative biology of type 2 diabetes. Stumvoll M. Type 2 diabetes: Principles of pathogenesis and therapy. Weyer C. The natural history of insulin secretory dysfunction and insulin resistance in the pathogenesis of type 2 diabetes mellitus.

Chatterjee S. Type 2 diabetes. Defronzo R. From the triumvirate to the ominous octet: A new paradigm for the treatment of type 2 diabetes mellitus. Schwartz S. Diabetes Care. Gaede P. Multifactorial intervention and cardiovascular disease in patients with type 2 diabetes.

Sarwar N. Diabetes mellitus, fasting blood glucose concentration, and risk of vascular disease: A collaborative meta-analysis of prospective studies. Grarup N. Genetic susceptibility to type 2 diabetes and obesity: From genome-wide association studies to rare variants and beyond. Wong N. Diet, lifestyle, and the risk of type 2 diabetes mellitus in women.

Schellenberg E. Lifestyle interventions for patients with and at risk for type 2 diabetes: A systematic review and meta-analysis. Chan J. Dabelea D. Liu L. Karter A. Sattar N. Type 2 diabetes in migrant south Asians: Mechanisms, mitigation, and management.

Lancet Diabetes Endocrinol. McKeigue P. Relation of central obesity and insulin resistance with high diabetes prevalence and cardiovascular risk in South Asians. Haines L. Rising incidence of type 2 diabetes in children in the U. Fuchsberger C. The genetic architecture of type 2 diabetes.

McCarthy M. Genomics, type 2 diabetes, and obesity. Dimas A. Impact of type 2 diabetes susceptibility variants on quantitative glycemic traits reveals mechanistic heterogeneity. Flannick J. Type 2 diabetes: Genetic data sharing to advance complex disease research. Franks P. Gene-environment and gene-treatment interactions in type 2 diabetes: Progress, pitfalls, and prospects.

Bellou V. Risk factors for type 2 diabetes mellitus: An exposure-wide umbrella review of meta-analyses. Carey V.

Body fat distribution and risk of non-insulin-dependent diabetes mellitus in women. Sinha R. Assessment of skeletal muscle triglyceride content by 1 H nuclear magnetic resonance spectroscopy in lean and obese adolescents: Relationships to insulin sensitivity, total body fat, and central adiposity. Hillier T. Complications in young adults with early-onset type 2 diabetes: Losing the relative protection of youth.

Weinstein A. Relationship of physical activity vs body mass index with type 2 diabetes in women. Lynch J. Moderately intense physical activities and high levels of cardiorespiratory fitness reduce the risk of non-insulin-dependent diabetes mellitus in middle-aged men. Venkatasamy V. Strasser B. Physical activity in obesity and metabolic syndrome.

Ross R. Does exercise without weight loss improve insulin sensitivity? Cerf M. Beta cell dysfunction and insulin resistance. Lausanne ; 4 Zheng Y. Global aetiology and epidemiology of type 2 diabetes mellitus and its complications. Bunney P. Orexin activation counteracts decreases in nonexercise activity thermogenesis NEAT caused by high-fat diet.

Regulation of insulin synthesis and secretion and pancreatic Beta-cell dysfunction in diabetes. Diabetes Rev. Halban P. Proinsulin processing in the regulated and the constitutive secretory pathway. Boland B. The dynamic plasticity of insulin production in beta-cells. Rorsman P. Seino S. Dynamics of insulin secretion and the clinical implications for obesity and diabetes. Islam M. The ryanodine receptor calcium channel of beta-cells: Molecular regulation and physiological significance.

Cuinas A. Activation of PKA and Epac proteins by cyclic AMP depletes intracellular calcium stores and reduces calcium availability for vasoconstriction. Life Sci. Lustig K. Expression cloning of an ATP receptor from mouse neuroblastoma cells. Simon J. Characterisation of a recombinant P2Y purinoceptor. Valera S. A new class of ligand-gated ion channel defined by P2x receptor for extracellular ATP. Blachier F. Effect of exogenous ATP upon inositol phosphate production, cationic fluxes and insulin release in pancreatic islet cells.

Christensen A. The Beta Cell in Type 2 Diabetes. Diabetes Rep. Yamamoto W. Endoplasmic reticulum stress alters ryanodine receptor function in the murine pancreatic beta cell. Hoang Do O. Insulin secretion from beta cells within intact islets: Location matters.

Liu M. Biosynthesis, structure, and folding of the insulin precursor protein. Diabetes Obes. Dali-Youcef N. Metabolic inflammation: Connecting obesity and insulin resistance.

Hummasti S. Endoplasmic reticulum stress and inflammation in obesity and diabetes. Roca-Rivada A. Giacco F. Oxidative stress and diabetic complications. Graciano M. Regulation of insulin secretion and reactive oxygen species production by free fatty acids in pancreatic islets.

Esser N. Inflammation as a link between obesity, metabolic syndrome and type 2 diabetes. Diabetes Res. Pradhan A. C-reactive protein, interleukin 6, and risk of developing type 2 diabetes mellitus. Vandanmagsar B. The NLRP3 inflammasome instigates obesity-induced inflammation and insulin resistance. Association A. Shamsuzzaman A. Independent association between plasma leptin and C-reactive protein in healthy humans. Leeuwenburgh C. Aging and exercise training in skeletal muscle: Responses of glutathione and antioxidant enzyme systems.

Polak K. New markers of insulin resistance in polycystic ovary syndrome. Bostrom P. A PGC1-alpha-dependent myokine that drives brown-fat-like development of white fat and thermogenesis.

Handschin C. The role of exercise and PGC1alpha in inflammation and chronic disease. Park K. Circulating irisin in relation to insulin resistance and the metabolic syndrome. El-Lebedy D. Novel adipokines vaspin and irisin as risk biomarkers for cardiovascular diseases in type 2 diabetes mellitus. Diabetes Metab. Lynch S. Ochoa-Reparaz J. Gut microbiome and the risk factors in central nervous system autoimmunity. FEBS Lett. Scarpellini E. Obesity and metabolic syndrome: An inflammatory condition.

Biagi E. Aging of the human metaorganism: The microbial counterpart. Age Dordrecht ; 34 — Sircana A. Cani P. Metabolic endotoxemia initiates obesity and insulin resistance. Tan J. The role of short-chain fatty acids in health and disease.

Tang C. Neis E. The role of microbial amino acid metabolism in host metabolism. Shan Z. Association between microbiota-dependent metabolite trimethylamine-N-oxide and type 2 diabetes. Turner R. Glycemic control with diet, sulfonylurea, metformin, or insulin in patients with type 2 diabetes mellitus: Progressive requirement for multiple therapies UKPDS The Steno-2 study.

Intensive multifactorial intervention reduces the occurrence of cardiovascular disease in patients with type 2 diabetes. Holman R. Ihnat M. Ceriello A. Engerman R. Pathogenesis of diabetic retinopathy. Olsen A. Heritable transmission of diabetic metabolic memory in zebrafish correlates with DNA hypomethylation and aberrant gene expression. Simmons D. Epigenetic Influences and Disease.

Rosen E. Epigenetics and Epigenomics: Implications for Diabetes and Obesity. Wahid F. MicroRNAs: Synthesis, mechanism, function, and recent clinical trials. LaPierre M. MicroRNAs as stress regulators in pancreatic beta cells and diabetes. Esguerra J. MicroRNAs in islet hormone secretion. Ofori J. Latreille M. MicroRNA-7a regulates pancreatic beta cell function.

Poy M. Reddy M. Epigenetic mechanisms in diabetic complications and metabolic memory. Blomen V. Stable transmission of reversible modifications: Maintenance of epigenetic information through the cell cycle.

Bogdanovic O. Mosammaparast N. Reversal of histone methylation: Biochemical and molecular mechanisms of histone demethylases. Breving K. The complexities of microRNA regulation: Mirandering around the rules. Brasacchio D.

Hyperglycemia induces a dynamic cooperativity of histone methylase and demethylase enzymes associated with gene-activating epigenetic marks that coexist on the lysine tail. Miao F. In vivo chromatin remodeling events leading to inflammatory gene transcription under diabetic conditions. Epigenetic mechanisms in diabetic vascular complications. Al-Haddad R. Epigenetic changes in diabetes. Nishikawa T. Normalizing mitochondrial superoxide production blocks three pathways of hyperglycaemic damage.

Kowluru R. Metabolic memory phenomenon and accumulation of peroxynitrite in retinal capillaries. Reversal of hyperglycemia and diabetic nephropathy: Effect of reinstitution of good metabolic control on oxidative stress in the kidney of diabetic rats.

Diabetes Complicat. Thompson J. Potential role of Toll-like receptors in programming of vascular dysfunction. Guarner V. Low-grade systemic inflammation connects aging, metabolic syndrome and cardiovascular disease. Top Gerontol. Kim J. Role of mitochondrial dysfunction in insulin resistance. Stump C. Petersen K. Mitochondrial dysfunction in the elderly: Possible role in insulin resistance.

Sazanov L. A giant molecular proton pump: Structure and mechanism of respiratory complex I. Anonymous Focusing on mitochondrial form and function. Spinelli J. The multifaceted contributions of mitochondria to cellular metabolism. Shigenaga M. Oxidative damage and mitochondrial decay in aging. Sergi D. Kelley D. Skeletal muscle fatty acid metabolism in association with insulin resistance, obesity, and weight loss. Simoneau J. Markers of capacity to utilize fatty acids in human skeletal muscle: Relation to insulin resistance and obesity and effects of weight loss.

Lipid oxidation is reduced in obese human skeletal muscle. Mootha V. PGC-1alpha-responsive genes involved in oxidative phosphorylation are coordinately downregulated in human diabetes. Patti M. Coordinated reduction of genes of oxidative metabolism in humans with insulin resistance and diabetes: Potential role of PGC1 and NRF1. Schrauwen-Hinderling V. Impaired in vivo mitochondrial function but similar intramyocellular lipid content in patients with type 2 diabetes mellitus and BMI-matched control subjects.

Phielix E. Lower intrinsic ADP-stimulated mitochondrial respiration underlies in vivo mitochondrial dysfunction in muscle of male type 2 diabetic patients. Schieber M. ROS function in redox signaling and oxidative stress. Ezraty B. Oxidative stress, protein damage and repair in bacteria. Johnson A. The inflammation highway: Metabolism accelerates inflammatory traffic in obesity. Schofield J. Montgomery M. Mitochondrial dysfunction and insulin resistance: An update.

Chavez J. A ceramide-centric view of insulin resistance. Liang H. PGC-1alpha: A key regulator of energy metabolism.

Bach D. Expression of Mfn2, the Charcot-Marie-Tooth neuropathy type 2A gene, in human skeletal muscle: Effects of type 2 diabetes, obesity, weight loss, and the regulatory role of tumor necrosis factor alpha and interleukin Novak I. Mitophagy: A complex mechanism of mitochondrial removal. Wei H. Selective removal of mitochondria via mitophagy: Distinct pathways for different mitochondrial stresses. Ding W.

Mitophagy: Mechanisms, pathophysiological roles, and analysis. Westermann B. Mitochondrial fusion and fission in cell life and death.

Yang L. Defective hepatic autophagy in obesity promotes ER stress and causes insulin resistance. Quiros P. EMBO J. Sebastian D. Mitofusin 2 Mfn2 links mitochondrial and endoplasmic reticulum function with insulin signaling and is essential for normal glucose homeostasis.

Whether it is macrovascular arteriosclerotic diseases or microvascular diseases, inflammation pathways play an important role in the pathogenesis of atherosclerosis caused by abnormal LDL-C level. On the other hand, methotrexate MTX exerts anti-inflammatory effects through its intracellular metabolite polyglutamate methotrexate and may help in preventing atherosclerotic events. However, low-doses of MTX do not reduce inflammatory factor levels e. These results suggest that it is necessary to screen appropriate populations high inflammation risk for receiving anti-inflammatory treatment besides the differences in anti-inflammatory drugs used.

Previous studies have indicated that the HsCRP levels are not only related to cardiovascular disease independent of traditional risk factors, but also can independently predict the occurrence and recurrence of adverse cardiovascular events [ 37 , 38 ].

Indeed, Wan et al. CMD, as a new microvascular paradigm, has been widespread before obstructive CAD is present in the epicardial coronary arteries, and plays the leading role in the pathophysiology of AMI. Imbalance in lipid metabolism is one of the initiating factors of CMD. Although the mechanism underlying CMD caused by dyslipidemia e.

KATP is not only involved in the metabolic regulation of coronary vascular tone e. ASCVD e. Although environmental factors e. ASCVD results in complex pathologies that develop over time due to genetic and environmental factors. To adapt to ever-changing gene-environment interactions, posttranslational regulations e.

Hence, the mutation of the microRNA binding site in the target gene will affect the splicing efficiency and stability of mRNA e. Based on the aforementioned, elucidating the specific regulatory mechanism has proven to be indispensable.

This study was also hurdled by some limitations. Secondly, Bonferroni adjustment was used to adjust the significance thresholds, but there was still the possibility of potential false-positive results especially for future research building on this study.

Therefore, results must be interpreted carefully. Cholesterol and atherosclerotic cardiovascular disease: a lifelong problem. J Am Heart Assoc. Eur Heart J. PubMed Article Google Scholar. Residual atherosclerotic cardiovascular disease risk in statin-treated adults: the multi-ethnic study of atherosclerosis. J Clin Lipidol. Evidence-based goals in LDL-C reduction. Clin Res Cardiol. ACE2 polymorphisms associated with cardiovascular risk in Uygurs with type 2 diabetes mellitus.

Cardiovasc Diabetol. The role of KATP channels in cerebral ischemic stroke and diabetes. Acta Pharmacol Sin. KATP channels in the cardiovascular system. Physiol Rev. Br J Pharmacol. A fatty acid-dependent hypothalamic-DVC neurocircuitry that regulates hepatic secretion of triglyceride-rich lipoproteins.

Nat Commun. Schmitz G, Buechler C. ABCA1: regulation, trafficking and association with heteromeric proteins. Ann Med. Effects of high-density lipoproteins on pancreatic beta-cell insulin secretion. Arterioscler Thromb Vasc Biol. Up-regulated ATP-sensitive potassium channels play a role in increased inflammation and plaque vulnerability in macrophages. Adiponectin may be a biomarker of early atherosclerosis of smokers and decreased by nicotine through KATP channel in adipocytes.

Cardiovasc Drugs Ther. Group IS. Effect of nicorandil on coronary events in patients with stable angina: the impact of Nicorandil in angina IONA randomised trial. Article Google Scholar. Astrocyte-specific deletion of Kir6. Exp Neurol. BMC Med Genet. ABCC8 polymorphisms are associated with triglyceride concentration in type 2 diabetics on sulfonylurea therapy.

Genet Test Mol Biomarkers. Prediabetes is associated with genetic variations in the gene encoding the Kir6. J Diabetes. J Hum Genet. Int J Cardiol. The common CT polymorphism in the sulfonylurea receptor gene ABCC8 , pancreatic beta cell function and long-term diabetic complications in obese patients with long-lasting type 2 diabetes mellitus. Exp Clin Endocrinol Diabetes. Pleiotropic genetic effects contribute to the correlation between HDL cholesterol, triglycerides, and LDL particle size in hypertensive sibships.

Am J Hypertens. Dolci, E. Concia, D. Invernizzi, S. Pasini, C. Selmi, M. Gershwin, M. Podda, Female predominance tible individuals, Lancet Lond. Huppertz, U. Treichel, A. Gassel, R. Jeschke, K. Meyer zum Buschenfelde, 12— Autoimmune hepatitis following hepatitis A virus infection, J. Weiler-Normann, C. Schramm, Drug induced liver injury and its relationship to — Hilzenrat, D. Zilberman, T. Klein, B. Zur, E. Sikuler, Autoimmune hepatitis in a [] A. Castiella, E.

Zapata, M. Lucena, R. Andrade, Drug-induced autoimmune liver genetically susceptible patient: is it triggered by acute viral hepatitis A? Skoog, R. Rivard, K. Batts, C. Smith, Autoimmune hepatitis preceded by [] Y. Kosinski, T. Urban, Z. Zhao, N. Long, N. Chalasani, et al. Features of autoimmune hepatitis in patients with drug-induced liver injury, Clin. Grunhage, U. Spengler, H. Fischer, T. Sauerbruch, Autoimmune hepatitis— Gastroenterol. Foureau, C.

Jacobs, W. Ahrens, M. Russo, H. Bonkovsky, [72] H. Tanaka, H. Tujioka, H. Ueda, H. Hamagami, Y. Kida, M. Ichinose, Autoimmune Drug-induced liver injury with autoimmune features, Semin.

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Kim, W. Rou, J. Lee, T. Song, W. Bae, et al. Vukotic, G. Vitale, A. D’Errico-Grigioni, L. Muratori, P. Andreone, De novo autoimmune hepatitis following acute hepatitis A, Kor.

Sohwagi Hakhoe chi 57 — Hussain, G. Aniruddha, W. Mahendra, Q. Umar, S. Rahul, D. Shreyas, [] C. Edmunds, U. Ekong, Autoimmune liver disease post-liver transplantation: a Autoimmune hepatitis triggered by hepatitis A viral infection A case report , IOSR summary and proposed areas for future research, Transplantation J.

Terziroli Beretta-Piccoli, P. Ripellino, C. Gobbi, A. Cerny, A. Baserga, C. Di [] K. Yoshizawa, H. Shirakawa, T. Ichijo, T. Tanaka, K. Kiyosawa, et al. Paiardini, S. Faisal, E. Renner, Recurrence of autoimmune liver diseases after liver trans- surface antigens as a driver of autoimmune hepatitis: insights from an in silico plantation, World J.

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Animal models for autoimmune hepatitis by Urs Christen.


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Browse other Mountain Bikes Free standard shipping on all bikes continental U. Flat rate shipping to Hawaii and Alaska. Browse other Mountain Bikes. Review This Product. The Latest. Bike of the Day: Crossworx Dash 29 1. Sven and the Squids vs. La Thuile EWS 1. For your first mountain bike pedal strokes, in helping you relish the local trails and Sunday outings, our line of semi-rigid EDGE mountain bikes, offering unbeatable value for money, is an ideal way to start out under the best conditions.

All EDGE models now contain a The only difference: a selection of components perfectly adapted to the female body shape, so as to optimize both well-being and ergonomics.

Our Cytech qualified mechanics will first make sure that your bike is fully checked and ready to ride. Then we will deliver it completely assembled direct to your home or place of work where we will set up your bike for your personal needs and answer any questions you may have.

Our delivery map indicates a general area, however, if you do not see your location on the map please call us on to discuss a special delivery.

After the first few weeks of use, the whole bike will settle down. As a result, the gears may need tweaking, some nuts and bolts may need tightening and you may well need to check the adjustment of the saddle and handlebars. A front derailleur may no longer want to shift all the way onto the big ring or will require a much firmer push to get it there.

It is advisable to get the cable tension adjusted as soon as this happens either by your local bike shop. This tune up is considered a necessary part of any bicycles maintenance schedule and as such should not be ignored. Brakes Your brakes will also be affected by cable stretch provided of course that they are NOT hydraulic in which case this does not apply. The symptom here is that they usually start to feel quite loose.

This is partly why new bikes come with a first free service. If your brakes start feeling a little spongy after a few weeks, you can adjust them at the barrel or the clamp or ask a mechanic at your local bike shop to do it for you. Repeat this process 20 times. Then accelerate the bike to a faster speed and apply the brakes until you are at walking speed. Repeat this process ten times. CRANKS Check the cranks and crank bolts or nut for tightness; grab a crank arm in each hand and try to wiggle them to check for looseness.

If there is play in the cranks, the nuts or bolts may need to be tightened. Cranks should be checked after every ride for the first week.

HEADSET A loose headset can be diagnosed by turning the front wheel to point left or right, holding the front brake on, and then rocking the bike backwards and forwards. Hold your fingers between the stem and the frame. Any movement indicates that you need to tighten the headset. Once you have checked these, use an allen key to tighten the seat post clamp. Check the seat is secure by giving it another check once you have finished. STEM Check that your front wheel and stem do not move independently, and that your handlebar clamp bolts are tight.

Perform this check by standing in front of the bike, holding the front wheel between your knees, and twisting the handlebars. You can prevent any movement by tightening the stem bolts and the handlebar clamp with an allen key.

Plus, giving your fork and shock a few seconds of attention here and there can prevent costly repairs or even replacements. Dirt is the number one enemy of suspension. After every ride make sure to wipe the seal area and stanchions of your fork and shock. Every few rides double check that your suspension sag is correct, as well as your rebound and compression adjustments. Working on your bike at home can seem daunting, and we’d always recommend you take your bike to a qualified mechanic if possible.

One of our Cytech qualified mechanics will hand build your bike leaving only a few minor adjustments for you to do once your new bike arrives. Our mechanic will also complete a rigorous Pre-Delivery Inspection PDI before carefully re-packing for shipping to you; but in order to fit the bike back into its box for delivery, some disassembly has to be done.

Re-assembly of these parts should be straightforward and should not take very long. Tools You’ll Need Not Provided A multi-tool or a 4mm or 5mm Allen key, a pedal wrench or 15mm Allen key, depending on your pedals and a pair of scissors to open the box and cut the zip-ties with. Open the Box and Remove Your Bike Carefully remove your bike from the box and remove all of the packaging and zip ties with your scissors or snips.

Never use a sharp knife as this can easily result in damage to paintwork and tyre sidewalls. Pedals and quick release if supplied will be in a small box at the bottom of your package as well as an instruction manual for your specific bike. Make sure you keep hold of this as it contains your bike’s serial number. Secure Your Front Wheel Bikes will be delivered with the rear wheel already fitted so all you have to do is slide in the front wheel. First, remove the plastic fork spacer, along with any other packing material.

Set the frame upright on the ground and attach the wheel. Make sure that the brake is properly aligned and that the wheel is sitting straight. Next, tighten the quick release skewer if supplied and make sure that the brake quick release is tightened.