Endothelial dysfunction is the hallmark of hypertension, which is a multifactorial disorder. In the cardiovascular system reactive oxygen species play a pivotal role in controlling the endothelial function and vascular tone. Physiologically, the endothelium-derived relaxing factors (EDRFs) and endothelium-derived contractile factors (EDCFs) that have functions on the vascular smooth muscle cells. The relaxation induced by the EDRFs nitric oxide (NO), prostacyclin, and the endothelium-derived hyperpolarization factor (EDHF) could be impaired in hypertension. The impaired ability of endothelial cells to release NO along with enhanced EDCFs production has been described to contribute to the endothelium dysfunction, which appears to lead to several cardiovascular diseases. The present review discusses the role of oxidative stress, vascular endothelium, and vascular tone control by EDRFs, mainly NO, and EDCFs in different models of experimental hypertension. Hypertension is a multifactorial disorder that involves many mechanisms leading to risk factors for cardiovascular diseases. Endothelial dysfunction is defined as the imbalance between the production and bioavailability of endothelium-derived relaxing factors (EDRFs) and endothelium-derived contractile factors (EDCFs), associated with increased bioavailability of oxygen reactive species (ROS) and decreased antioxidant capacity characterized as oxidative stress. In this review we will discuss the involvement of oxidative stress and vascular endothelium as well as the importance of vascular tone control, relaxation, and contraction in hypertension.4), flavin-adenine-dinucleotide, flavin-mononucleotide, and nicotinamide-adenine-dinucleotide-phosphate  and hydrogen peroxide (H2O2) increase arginase activity/expression in the endothelial cells. This should lead to NOS uncoupling with reduced NO production and augmented superoxide anion (O−2) production. As shown by Romero et al. , which convert L-arginine and molecular oxygen to L-citrulline and NO, using such co-factors as tetrahydrobiopterin  or Ser1179 (bovine) activates eNOS  or Thr497 (bovine) decreases its activation  revealed higher baseline NO and H2O2 concentrations than normotensive rats  -mediated activation of NADPH oxidase (Heitzer et al., 495 residue in the Ca2+/CaM binding domain by PKC (Mount et al., 495 dephosphorylation results in eNOS uncoupling and O−2 production rather than NO generation (Lin et al., 495 eNOS phosphorylation site is more phosphorylated in hypertension or contains uncoupled eNOS remains unknown.Increased ROS bioavailability, decreased antioxidant capacity, or both occur in many models of hypertension such as SHR (Suzuki et al., 4 supplementation reverses the effect of uncoupled NOS induced by TERPY (Bonaventura et al., We have investigated the vascular mechanisms involved in the vasorelaxation induced by NO donors that present potential capacity to replenish vascular NO upon reduced NO bioavailability. Most of the studies using NO donors are performed on endothelium-denuded arteries to avoid interference of endogenously produced NO (Bonaventura et al., A and ETB receptors. ETA receptors are expressed on smooth muscle cells and promote contraction. ETB receptors are located on endothelial and smooth muscle cells, with opposite effects. Smooth muscle ETB activation evokes contraction, whereas endothelial ETB activation induces relaxation (Taddei et al., The altered function of endothelial cells leads to enhanced contraction (Endemann and Schiffrin, The SHR aorta exhibits a characteristic endothelial dysfunction that is not due to decreased EDRF release, but it is the result of simultaneous EDCF release. Indomethacin, a non-selective COX inhibitor, restores the blunted relaxation in SHR aorta to the level of normotensive (Lüscher and Vanhoutte, 2, TXA2, and ROS are proposed as COX-derived EDCFs. Increased endothelial [Ca2+]i is required to evoke EDCF-mediated responses. Dysfunction in Ca2+ handling within the endothelium is important for the exacerbation of endothelium-dependent contractions in SHR aorta (Tang et al., Endoperoxides, PGI2O2 modify the vascular activity of NOS and COX in concentration-dependent way (Cai et al., 2 evokes vasorelaxation, whereas in aging animals or SHR it induces contraction (Vanhoutte, Independent of the genesis of hypertension, specific ROS such as HInhibitors of COX (Taddei et al., In conclusion, the data presented in this work suggest that decreased NO availability along with enhanced EDCFs production contribute to the endothelium dysfunction and impaired vascular relaxation in hypertension Figure . ConsideThe 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.


Our article reports a meta-analysis of available evidence on high-dose chemotherapy followed by autologous stem cell transplantation for primary breast cancer. A previous publication by Berry et al. reported a closely related meta-analysis and the authors regret not citing this article:Berry DA, Ueno NT, Johnson MM, et al. High-dose chemotherapy with autologous stem cell support as adjuvant therapy in breast cancer: Overview of 15 randomized trials. J Clin Oncol 2011;29:3214-3223Berry et al. provide evidence that high-dose chemotherapy followed by autologous stem cell transplantation (HDCT) support prolongs relapse-free survival but does not improve overall survival in patients with high-risk primary breast cancer. In our subgroup analysis, age and hormone receptor status had a significant interaction with OS. In the study by Berry et al., OS was statistically different by treatment arm in the subgroup for women with both hormone receptor-negative and HER2-negative tumor, for whom there was a 33% reduction in the risk of death. The hypothesis suggest that this breast cancer category presents increased sensitivity to dose intensification of alkylating agents and should remain the subject of clinical HDCT studies.While our meta-analysis evaluated publication bias and heterogeneity in the included studies, our analysis did not include an analysis of individual patient data, which Berry et al. did carry out. The lack of an analysis on individual patient data can be considered as a limitation of our meta-analysis.


Physiotherapy is concerned with identifying and maximizing movement potential, within the spheres of promotion, prevention, treatment and rehabilitation. Physical therapists practice in a broad range of inpatient, outpatient, and community-based settings such as hospice and palliative care centers where as part of a multidisciplinary team of care, they address the physical and functional dimensions of the patients’ suffering. Physiotherapy treatment methods like therapeutic exercise, electrical modalities, thermal modalities, actinotherapy, mechanical modalities, manual physical therapy and assistive devices are useful for a range of life-threatening and life-limiting conditions like cancer and cancer-associated conditions; HIV; neurodegenerative disorders like amyotrophic lateral sclerosis, multiple sclerosis; respiratory disorders like idiopathic pulmonary fibrosis; and altered mental states. The professional armamentarium is still expanding with inclusion of other miscellaneous techniques which were also proven to be effective in improving quality of life in these patients. Considering the scope of physiotherapy in India, and in palliative care, professionals in a multidisciplinary palliative care team need to understand and mutually involve toward policy changes to successfully implement physical therapeutic palliative care delivery. World Confederation for Physical Therapy (WCPT) defines Physical Therapy as; “… providing services to people and populations to develop, maintain and restore maximum movement and functional ability throughout the life-span. Physiotherapy includes the provision of services in circumstances where movement and function are threatened by the process of ageing or that of injury or disease. Full and functional movement are at the heart of what it means to be healthy. Physiotherapy is concerned with identifying and maximizing movement potential, within the spheres of promotion, prevention, treatment and rehabilitation. Physiotherapy involves the interaction between physiotherapist, patients or clients, families and care givers, in a process of assessing movement potential and in establishing agreed upon goals and objectives using knowledge and skills unique to physiotherapists”.Physical therapists practice in a broad range of inpatient, outpatient, and community-based settings, including the following:Hospitals Outpatient clinics or officesRehabilitation facilitiesSkilled nursing, extended care, or subacute facilitiesHomesEducation or research centersSchools and playgrounds Hospices or palliative care centersCorporate or industrial health centersIndustrial, workplace, or other occupational environmentsAthletic facilities Fitness centers and sports training facilities.Physiotherapists play an inherent role in the multidisciplinary palliative care team emphasizing on improving function and quality of life in patients who are deemed to require physical and functional dimensions of care. PhysicalFunctional dimension is defined as one’s perceived ability to perform accustomed functions and activities of daily living, experienced in relation to expectations and adaptations to declining functionality. Functionet al.[Inspite of most of population being rural, the current status of medical personnel and facilities in our country is scarce; with only 34% of physicians and 25% of all hospital beds are available in rural areas. Nursing is considered as a low-status job and is not a much-sought-after profession for young people. Hence the need for an efficient allied health professional to fill in the current needs of palliative care team sees the emergence of physical therapists, with their thorough professional background and clinical expertise, as invaluable members in the team of care.Physicians address the physical dimension to their extent and nurses in functional dimension. Addressing both the aspects simultaneously can be more beneficial for the patient. Considering the current healthcare scenario in India as reported by Seamark et al. Inspite The objective of this paper is to update the palliative care clinicians, physical therapists and other team members on the role of a physical therapist in a palliative care team by detailed view of physical therapy treatment methods and their evidence for application into conditions requiring palliative care.It comprises passive movement, assisted active movement, active movement, assisted-resisted active movement, and resisted movement techniques. The techniques can be applied in anatomical planes or as functional movement direction. The techniques can be performed on land or in water. The latter is termed as “hydrotherapy”. Best examples of therapeutic exercise techniques are relaxation, massage, suspension therapy, muscle- re-education, progressive resisted exercise, floor aerobics, active mobility exercises, mobilization and stabilization exercise, proprioceptive neuromuscular facilitation (facilitation and inhibition techniques); breathing exercise; postural training; work simulation, work conditioning and work hardening; graded activity program and cognitive-behavioral training. ExerciseLow-frequency modalities like neuromuscular electrical stimulation  and functional electrical stimulation, iontophoresis, high-voltage pulsed galvanic current, transcutaneous electrical nerve stimulation (TENS) and diadynamic currents; medium frequency modalities like Russian currents and Interferential therapy. High frequency modalities are usually grouped under deep-heating modalities under thermal modalities. Electrical modalities are very useful adjuncts in pain management.Cryotherapy ; superficial heating agents ; hydrotherapy (whirlpool and contrast bath). Thermal modalities are effective adjuncts to exercise and/or electrical modalities.Traction therapy, compression therapy, therapeutic taping and continuous passive motion. Compression therapy can be very useful in managing lymphedema.Ultraviolet, LASER, Extracorporeal Shock Wave therapy are useful in selected situations.Biofeedback is useful in patients with limited cognitive abilities and neuromuscular dyscontrol.Massage, deep transverse frictions, myofascial release, trigger point therapy, muscle energy techniques, motor control retraining.Joint mobilization using passive physiological and passive accessory (joint play) movements, combined movements, mobilization with movements, manipulation (high-velocity low amplitude thrust techniques).Neurodynamic techniques of neural tissue loading and nerve massage.Manual physical therapy techniques are used in a variety of settings ranging from hospital-based to home-based. The effects of the techniques depend upon the skills of the handling therapist.Orthosis- splints/ braces: supportive devices for the body parts.Prosthesis: artificial limbs.Mobility aids: locomotor training devices like wheelchair, prone crawlers.Walking aids: canes, crutches and walkers.Assistive devices are useful for training functional activities for patients with limited function.et al,[et al,[Pate et al, and Bryal,[et al, reportedl,[et al,Toot in additet al,[Laakso emphasizet al, said, inOxford Textbook of Palliative Medicine, as follows;The importance of physical therapy is widely stated in the most-read textbook- Physiotherapy aims to “optimise the patient’s level of physical function and takes into consideration the interplay between the physical, psychological, social and vocational domains of function…… The physiotherapist understands the patients underlying pathological condition, but this is not the focus of treatment. The focus of physiotherapy intervention is, instead, the physical and functional sequelae of the disease and/or its treatment, on the patient.”[patient.”Physiotherapy aims to: maintain optimum respiratory function; maintain optimum circulatory function; prevent muscle atrophy; prevent muscle shortening; prevent joint contractures; influence pain control; optimize independence and function; and, education and participation of the carer.The following section describes the role of physical therapy in common conditions that require palliative care.Physical therapists have a very important role to play in holistic care of patients diagnosed with cancer as stated by Flomenhoft and RashPhysical therapy treatment techniques have also been reported in cancer-related fatigue by Watson and Mock, breast c2023et al,[et al,[Narayanan and Koshy emphasizet al, said thal,[et al, performeThe Chartered Society of Physiotherapy (CSP)’s evidence summary emphasizes the effectiveness of physical therapy in the palliative care of older people. Physicalet al,[Multiple sclerosis (MS) is the met al, also fouet al,et al,[Weih et al, performeet al,[et al.[et al,[et al,[The use of motor imagery (MI)—presumed to be a visual and kinesthetic neural representation of the overt behavior—has relied on two major assumptions. The first assumption is that the internally generated movement patterns involve the same neuronal correlates as the overt behaviors . Second, it assumes that using MI will lead to cortical and subcortical neuronal modification that is of benefit to a person who has experienced a stroke. Mental practice as an effective technique for locomotor training and rehabilitation was also employed in most neurological conditions as found in their comprehensive review by Malouin and Richards.[Ginis et al, reportedl,[et al. Katz et l.[et al, earlier l,[et al, in theirl,[et al, mentioneRichards.The role of physical therapy in palliative care of patients with respiratory disorders ranges from home-based care such as training symptom control for cough and breathlessness to providing interventions such as airway clearance techniques in the intensive and critical care units in hospital-based rehabilitation. The renowned professional body for respiratory and cardiac conditions, the American Thoracic Society emphasisPulmonary rehabilitation is a multidisciplinary program of care for patients with chronic respiratory impairment that is individually tailored and designed to optimize physical and social performance and autonomy. ATS has listed four essential components of pulmonary rehabilitation as; (1) exercise training , (2) education , (3) psychosocial and behavioral intervention , and (4) outcome assessment. This was also mentioned by Lanken et al,[en et al, that pulThe therapeutic efficacy of pulmonary rehabilitation was demonstrated convincingly in many systematic reviews and randomized controlled trials and hence physical therapy in the form of exercise training in globally accepted and widely practised position statements and treatment guidelines.et al,[Nici et al, mentioneet al,[Of the respiratory disorders requiring palliative care, the most life-limiting condition is idiopathic pulmonary fibrosis. Raghu et al, stated tet al, reportedet al, physicalKeenleyside and Vora recommenLeGrand stated tSachs and Weinberg explaineet al,[Emery et al, found exCiesla elaboratThe reported benefits of formalized exercise training to an informal recreational physical activity in chest physical therapy also extended to include systemic conditions like chronic renal failure to have positive effects on quality of life by Eng and Ginis. Also selet al,[et al,[et al,[et al,[Palliative care improved outcomes in patients living with HIV or AIDS. Home palliative care and in-patient hospice care improved a number of patient outcomes, particularly in terms of pain and symptom control, anxiety, insight and spiritual well-being. Harding et al, also stal,[et al, and hencl,[et al, 2005, O’l,[et al, found aeet al,[et al,[et al,[et al,[Earlier proponents like O’Brien et al, and O’Brl,[et al, advocatel,[et al, in anothl,[et al, found cosound mind and a sound body” and authors like Wilfey and Kunce[et al,[Exercises as a treatment for altered psychological states have been through over the years grounded on the principle, “and Kunce and Tuckand Kunce found eace[et al, also fouThough exercise had been a part of behavioral medicine for treating altered physiological states like obesity, diabetes, cardiovascular risk modification and smoking according to Martin and Dubbert, through et al,[et al,[et al,[et al,[Exercise therapy programs such as aerobic exercise training was shown by McCann and Holmes to positet al, confirmeet al, for anxiet al, who founl,[et al, found chl,[et al, found exl,[et al, found adSteptoe and Cox found thTkachuk and Martin in their84Though theoretically not part of physical therapy, physical therapists are trained in the following techniques and they do perform these in their regular practice.Tarler-Benlolo emphasizet al,[EMG Biofeedback, exercise91et al, and exeret al, was showet al, and, Qiget al,Other complementary therapies which are often included in physical therapist’s treatment armamentarium are acupuncture, aromatherapy, reflexology, relaxation and massage.Massage therapy as a complementary therapy technique for feet and handPhysical therapy was shown to have positive influence on quality of life and perceived well-being in a wide range of patient populations requiring palliative care such as cancer, HIV, neurological disorders, cardiopulmonary conditions and mental illnesses.The scope of physiotherapy practice is influenced by the ratio of qualified physiotherapists to the population. The number of physiotherapists per head of population in India is 1:212,000. This oftet al,[Meier et al, suggesteFuture studies are warranted on the following aspects;Assessment of knowledge, attitudes, beliefs and experiences toward palliative care among physical therapistsEvolution of a palliative care training program for physical therapists.Qualitative research on experiences of palliative care team members with physical therapistsInfluence of physical therapy on patient and caregiver perceptions and quality of life in other palliative care conditions.The authors wish to recommend three approaches to improve physical therapy in palliative care.Improving professional knowledge and skillsChanging professional attitudes toward care at end-of-lifeRecognizing the palliative care healthcare system in India.Coming together is the beginning, keeping together is progress, working together is success”“- Henry Ford.


Mitochondrial outer membrane permeabilization (MOMP) is the ultimate step in dozens of lethal apoptotic signal transduction pathways which converge on mitochondria. One of the representative systems proposed to be responsible for the MOMP is the mitochondrial permeability transition pore (MPTP). Although the molecular composition of the MPTP is not clearly understood, the MPTP attracts much interest as a promising target for resolving two conundrums regarding cancer treatment: tumor selectivity and resistance to treatment. The regulation of the MPTP is closely related to metabolic reprogramming in cancer cells including mitochondrial alterations. Restoration of deregulated apoptotic machinery in cancer cells by tumor-specific modulation of the MPTP could therefore be a promising anti-cancer strategy. Currently, a number of MPTP-targeting agents are under pre-clinical and clinical studies. Here, we reviewed the structure and regulation of the MPTP as well as the current status of the development of promising MPTP-targeting drugs. Traditionally, MPTP has been regarded as a multimeric complex, which putatively consists of the voltage dependent anion channel (VDAC) in the OMM, the adenine nucleotide translocase (ANT) in the IMM, cyclophilin D (CyP-D)—a mitochondrial matrix protein that exhibits peptidylprolyl cis-trans-isomerase activity, and some other proteins such as hexokinase (HK) ; pro-apoptotic multidomain proteins (Bax and Bak); pro-apoptotic BH3-only proteins  , promotes binding of Bcl-XL to VDAC, leaving Bax free from Bcl-XL. Free Bax interacts with Bak and/or Bax to form pore structures for the release of cytochrome c  -4-hydroxyphenyl]-2-naphthalene carboxylic acid) are well known to induce clinical remission in patients with APL  is an expanded porphyrin which displays an elevated oxidizing potential, thereby triggering excess generation of ROS  and dithiodipyridine (DTDP) can cause thiol oxidation of a critical cysteine residue (Cys 56) of ANT, through which BMH and DTDP may induce MOMP and cell death irrespective of the expression level of Bcl-2 (Costantini et al., Resveratrol, a polyphenolic compound from grapes and wine, can inhibit mitochondrial ATP synthesis and trigger MOMP (Fulda et al., Curcumin is a major constituent of turmeric powder from the plant Curcuma longa. Among several anti-cancer mechanisms of curcumin are the modulation of Bcl-2 family proteins and cellular ROS, inhibition of the NF-κ B survival pathway, and inhibition of cyclooxygenase-2 (Divya and Pillai, Betulinic acid, a natural pentacyclic triterpenoid of the lupane class, is known to trigger mitochondrial apoptosis in cancer cells (Fulda et al., Berberine, an alkaloid derived from plants of the Berberidaceae family, has been shown to exert direct effects on mitochondria, including the interaction with ANT (Pereira et al., L on the OMM to prevent them trapping Bax, allowing free Bax to form OMM channels (Neuzil et al., in vitro data, which warrant further clinical trials with α-TOS (Neuzil et al., α-TOS, a vitamin E analogue, competes with ubiquinone in binding to Q sites of respiratory complex II, which results in the displacement of ubiquinone from complex II, disrupts the electron flux, and consequently generating ROS (Dong et al., Honokiol is a small molecule polyphenol isolated from the genus Magnolia (Fried and Arbiser, Again, GSK3 plays a role in the opening of the MPTP through the phosphorylation of CyP-D. In 206 osteosarcoma ρ° cells with an extreme Warburg phenotype, constitutively active ERK was shown to oppose this signaling by phosphorylating and inhibiting GSK3 (Masgras et al., Mitochondria have pivotal opposing roles in energy generation for cell survival and cytochrome c release for apoptotic cell death. Although the concept of the MPTP is still evolving, mounting evidence indicates that the MPTP is directly responsible for cytochrome c release, leading to apoptotic cell death. Targeting the MPTP for cancer treatment has two advantages: tumor specificity and bypass of the resistance mechanisms. Metabolic reprogramming and mitochondrial alterations in cancer cells could provide important clues for developing tumor-specific anti-cancer agents. MOMP finally occurs as a consequence of upstream pro-apoptotic signaling events, which are frequently deregulated in many cancers and which become resistant to most classical anti-cancer agents that target upstream regulators of MOMP (Fulda et al., 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.


Understanding the role of different proteins in controlling synapses formation and stabilization may help elucidating, at the network level, the mechanisms by which inhibitory transmission controls network excitability and oscillatory behavior, crucial for information processing in the brain.Aim of this e-book is to highlight recent advances in these processes, bringing together leading experts in the field, who have made major contributions to our understanding of the cellular and molecular mechanisms regulating the appropriate assembly, location, and function of pre and postsynaptic specializations at inhibitory synapses.This e-book comprises nine reviews, one perspective and three research articles organized in a logic way following the information flow from the pre to the postsynaptic site.via protein–protein interactions across the synaptic cleft.In the first article, Jovanovic and Thomson  (School via postsynaptic calcium signals, triggered by the depolarizing action of GABA and activation of voltage-dependent calcium channels.Grantyn et al.  (Instituvia transcriptional and post-translational modifications.Early in postnatal life, the depolarizing action of GABA is crucial for the construction of neuronal circuits. This process depends on intracellular chloride homeostasis which is under control of the cation-chloride co-transporter KCC2. In addition, by interacting with actin cytoskeleton, KCC2 exerts, independently of its role on chloride homeostasis, a crucial role on spines morphogenesis. Chamma et al.  (INSERM In the following research paper, Bhumbra et al.  (DepartmA receptor antagonists or gating modifiers. GABA transient may limit the activation of postsynaptic receptors and their binding reaction to mono-ligand state, promoting low probability channel opening and fast deactivation kinetics.Once released from presynaptic terminals, GABA diffuses in the synaptic cleft and binds to postsynaptic receptors. This process is very fast and occurs in non-equilibrium conditions. Barberis et al.  (Departmtransporters may exert a homeostatic control on GABA release is put forward in a perspective article by Conti et al. (The intriguing hypothesis that GABA i et al.  (DepartmA receptor isoforms, physiologically relevant to phasic and tonic inhibition. The highest potency would be compatible with extrasynaptic receptors, containing the α 6 subunit and exposed, during spillover of GABA from synapses, to low agonist concentrations, while the lowest potency would be compatible with synaptic GABAA receptors containing the α2/α3βγ subunits, exposed, during vesicular release, to high agonist concentrations.In the following review, Mortensen et al.  (DepartmA-mediated conductance. They suggest that the β 3 subunit may be an important pharmacological target for the treatment of striatal disorders.Using a genetic approach, Janssen et al.  (DepartmA receptors and other ligand-gated ionic channels or G-protein coupled receptors co-localized on the postsynaptic membrane. The interaction may occur via a direct coupling between two receptors or via the activation of intracellular signaling pathways. Usually the interaction results in a reduced GABAergic inhibition with consequent disinhibition. A similar receptor–receptor interaction may occur also at extrasynaptic sites to regulate tonic GABAA-mediated inhibition.Next, Shrivastava et al.  (DepartmSassoè-Pognetto et al.  (DepartmA receptors in front of presynaptic releasing sites, by directly interacting with several types of α-containing subunits. Its heterogeneity, obtained through alternative splicing and post-translational modifications, associated with complex biophysical properties of its domains leads to the construction of diverse structural scaffolds that can accommodate different GABAA receptor subtypes. Gephyrin is also recognized as a crucial hub for multiple signal transduction pathways and trans-synaptic signaling that ultimately impact on synaptic dynamics and synaptic plasticity.The complex and still “enigmatic” role of the scaffolding molecule gephyrin at GABAergic synapses is exquisitely reviewed by Tretter et al.  (DepartmPapadopoulos and Soykan  (Max-PlaA receptors subunits mRNA in the hippocampus and cortex of post mortem brains of individual suffering from alcohol dependence. Interestingly, the observed changes refer mainly to extrasynaptic GABAA receptors, which mediate tonic inhibition responsible for regulating basic neuronal excitability.Finally, Jin et al.  (Departm


Actin is a protein abundant in many cell types. Decades of investigations have provided evidence that it has many functions in living cells. The diverse morphology and dynamics of actin structures adapted to versatile cellular functions is established by a large repertoire of actin-binding proteins. The proper interactions with these proteins assume effective molecular adaptations from actin, in which its conformational transitions play essential role. This review attempts to summarise our current knowledge regarding the coupling between the conformational states of actin and its biological function. Proteins are essential building blocks of the living systems. They are involved in all the biological functions playing structural and/or regulatory roles. In most of the cases proteins are required to be adaptive, i.e., to change their structure and function under certain cellular conditions. A frequent example of this adaptation is the up and down regulation of their activity, which occurs in many cases through interactions with other proteins and/or small regulatory molecules. The conformational elasticity of the proteins is essential for their adaptive properties. In many cases the details of the relationship between the various conformational states and the functions of proteins are well established. In some cases the characterisation of the coupling between the structural transitions and the modifications in the biological function is not complete. As proteins are often central components of cellular machineries, the detailed description of their conformational dynamics is desirable.The interest in actin has extensively increased since its discovery by Straub  . In theiAfter some debate since the first report on actin as an intranuclear entity dated back to the 60s Lane,  actin alActin is not restricted to metazoans but can also be found in plants. Since the discovery of the actomyosin complex in plants [Vorobeva and Poglazov, Actin has a large repertoire of interacting partners including metal ions, nucleotides and actin-binding proteins, which attribute versatile functions to actin [Sheterline et al., It is essential to understand how actin can adapt and modify its conformation for the various biological processes, what cellular components are effective to regulate these conformational transitions and how these different structural states are coupled to the complex and tightly regulated mechanisms through which actin fulfils its manifold biological activity. Here we review the present knowledge on the conformational dynamics of actin from structural, spectroscopic and cellular biology studies of complexes that actin forms with its interacting partners. We will also attempt to discuss how these conformational differences contribute to the functional segregation of actin structures in living cells.Since its discovery in 1942 Straub,  from aceActin exists in both monomeric (globular or G-actin) and polymeric (filamentous or F-actin) form .. The fiUnder physiological ionic conditions actin monomers assemble into filaments. Actin polymerisation proceeds through kinetically distinct steps. It is initiated by the slow formation of actin nuclei (dimers/trimers), which serve as seeds for the subsequent filament elongation. During elongation more actin monomers associate to than dissociate from either of the two ends, which results in the net growth of both filament ends. The steady-state phase is characterised by a dynamic equilibrium where the length of the actin filaments remains constant, while actin monomers continually associate to and dissociate from the ends. In this dynamic equilibrium a stationery population of free actin monomers is established, called critical concentration, whose value lies between the critical concentration of the barbed and pointed end. Besides structural polarity, determined by the arrangement of actin protomers within the filament, actin filaments also exhibit a kinetic polarity, which is defined by the different monomer association and dissociation rates at the two ends. The barbed or plus end binds actin monomers faster than the pointed or minus end. Although its ATPase activity is not crucial for actin polymerisation, actin self-assembly is associated with the ATPase cycle, which powers treadmilling process Wegner, .The first high-resolution structural model of the actin filament at a resolution of 8 Å was proposed by [Holmes et al., fs range reflect the rearrangements of atoms/molecules, and these structural changes can be resolved by X-ray crystallography, electron microscopy (EM), cryo-EM and femtobiological approaches [Egelman, ns correlation times are related to the change in the restricted segmental motion of a monomer/protomer or a few neighbouring protomers and can be determined by time-dependent fluorescence anisotropy [Ikkai et al., Rather than being rigid structures, both monomeric and filamentous actin have remarkable conformational flexibility and adopt many various structural states in response to interaction with their partner molecules [Orlova and Egelman, Egelman, . The ns KD = 10−10 M) than ADP (KD = 10−8 M) [Neidl and Engel, KD ∼10−9 M) is thought to be occupied by magnesium in cells [Estes et al., −1) [Schuler, Pi). This results in the appearance of an ATP/ADP-Pi cap at the barbed end, while the rest of the filament contains ADP-bound actin protomers [Brenner and Korn, Pi almost simultaneously, which results in homogeneous ADP-bound actin protomers along the whole filament [Yao et al., The main ligands that bind to the central cleft of the actin monomers are an adenosine nucleotide and a divalent cation  inset a Schuler, , which iSchuler, . In the The Holmes model postulated the importance of an interstrand hydrophobic plug-pocket interaction in filament integrity [Holmes et al., The importance of this cross-strand hydrophobic interaction and loop mobility in actin filament integrity was supported by disulfide cross-linking studies. These experiments showed that mutant G-actin—in which the loop is locked to the protein backbone—could not polymerise [Shvetsov et al., 2+-ADP actin monomers had lower steady-state phosphorescence emission anisotropy, and thus greater torsional flexibility than filaments polymerised from Mg2+-ATP actin monomers [Rebello and Ludescher, Cys374 in S1 and substantially greater intermonomer flexibility of filaments that were assembled from ADP-actin monomers than those assembled from ATP-actin monomers. These data suggest that more tenuous interprotomer connections are formed when the filament is polymerized from ADP-bound monomers [Nyitrai et al., The influence of the different nucleotides on the conformational dynamics of actin filaments was first demonstrated by the analysis of EM images of negatively stained actin filaments, and by dynamic elasticity and viscosity measurements of solutions of F-actin. These measurements suggested that actin filaments formed from ATP-actin monomers were more rigid than actin filaments assembled from ADP-actin monomers [Janmey et al., Lp = 9 μm), which suggests similar bending flexibilities [Isambert et al., 3—which mimics the γ-phosphate [Combeau and Carlier, Pi-state resulted in higher flexural rigidity of F-ADP-Pi-actin (Lp = 13.5 μm) compared to F-ATP, or -ADP-actin [Isambert et al., A detailed light microscopy analysis of the thermal fluctuations of fluorescently labelled F-actin showed that there was no difference in the persistence length of actin filaments assembled from either ATP-actin or ADP-actin monomers  [Hild et al., Gln137 close to the γ-phosphate of the bound ATP. As Gln137 is implicated in the ATPase mechanism these structural rearrangements may be related to the regulation of ATPase activity of actin [Oda et al., Consistently, FRET measurements showed that the replacement of ATP by ADP in the nucleotide-binding cleft resulted in conformational changes that bring 3-F-actin and ADP-F-actin showed that the structure of S2 is more disordered in the ADP-state which results in breaking one of the longitudinal bonds and destabilization of the filament [Orlova and Egelman, Actin self-assembly and ATPase activity were also shown to alter the conformation of the DNase I binding loop (or D-loop)  inset c 2+-F-actin were shown to be higher compared to Ca2+-actin filaments using spectroscopic and EM approaches [Orlova and Egelman, 2+-F-actin than for Mg2+-F-actin [Nyitrai et al., Tightly bound cations can modify the conformational state of actin as well. Both the torsional and bending flexibilities of Mg2+-G-actin and Mg2+-G-actin in the range of 6–26 °C, while above 26 °C a conformational transition was detected in Ca2+-actin monomers [Nyitrai et al., 2+-F-actin was found to be lower than that of Ca2+-F-actin in the range between pH 6.5 and pH 7.4 [Hild et al., 2+-F-actin. The interprotomer connections were more rigid at both pH 6.5 and 7.4 in Mg2+-F-actin than in Ca2+-F-actin [Hild et al., Temperature-dependent FRET measurements revealed no difference between the flexibility of the outer domain (S1 and S2) of Ca2+-actin filaments was proved to be unaffected (Lp ∼8 μm) when the filaments were polymerized at different pH values (between pH 5 and 9) [Arii and Hatori, 2+-F-actin increased from ∼4.5 μm to ∼9 μm as the pH increased from 5 to 9, suggesting higher mobility of actin protomers within Ca2+-F-actin at lower pH values [Arii and Hatori, 2+-actin and Mg2+-actin filaments as the pH decreased [Kron and Spudich, The persistence length of MgThe polymerisation of actin filaments was accelerated and the helical pitch between the protomers was increased by lowering the pH [Zimmerle and Frieden, The observations described above demonstrate that small ligands—such as nucleotides and cations—and also external conditions—such as the pH—modify the conformation of actin. Despite the large amount of accumulated data the biological function of these structural modifications remained somewhat ambiguous. Some observations indicated that ATP hydrolysis altered the thermodynamic and mechanical properties of actin filaments and their interactions with actin-binding proteins. These results led to the hypothesis that ATP hydrolysis may serve as a biological clock in living cells. The maturation of the filaments is sensed and reflected by the change in the nucleotide state, and thus in the conformation of actin filaments [Allen et al., In many cases, when the conformation of actin filaments is changed upon ligand-binding, the effects propagate along the filaments through the interaction of neighbouring actin protomers, i.e., through long-range allosteric interactions. Such allosteric interactions were reported for many actin-binding compounds Oosawa,  and are Amanita phalloides, is the best characterised so far. Phalloidin binds tightly to actin filaments, reduces the rate of Pi release [Dancker and Hess, Pi-actin , which suggests different interprotomer interactions in F-actin in the ADP-Pi state compared to the ATP-, or ADP state [Orban et al., Several actin-binding natural products that have cytotoxic activity exhibits cooperativity [Wieland and Faulstich, Jaspis johnstoni)—also binds to actin filaments competitively with phalloidin [Bubb et al., Another cyclic peptide, jasplakinolide—that can be found in a marine sponge  can alter the regulation of the cytoskeleton and/or bind directly to actin [Richard et al., Apart from these examples many other poisonous chemicals (such as for example jararhagin) [Costa and Santos, D. discoideum has 17 [Romans and Firtel, D. melanogaster and mammals have 6 genes [Fyrberg et al., The tuning of the conformation and thus cellular function of actin can be achieved by the various actin isoforms which coexist in living cells. Actin is expressed as a variety of isoforms generated by gene duplications. Yeasts have 1 actin gene [Gallwitz and Seidel, S. cerevisiae and D. discoideum actin filaments based on 3D helical reconstruction from EM images show that these actin filaments are similar in terms of the overall three-dimensional morphology, which confirms that these parameters were conserved through the evolution [Orlova et al., S. cerevisiae actin filaments than in muscle actin [Orlova and Egelman, S. cerevisiae actin protomers than in muscle actin [Orlova et al., S. cerevisiae actin filaments by time-dependent phosphorescence anisotropy decay measurements indicated higher torsional flexibility for yeast F-actin than for muscle F-actin [Prochniewicz and Thomas, S. cerevisiae G-actin compared to muscle actin in the barbed end, in the region of S1 and S2 and in protomer-protomer contact areas within the actin filaments as well [Stokasimov and Rubenstein, S. cerevisiae F-actin [Orlova et al., D. discoideum F-actin in the Ca2+-bound form displays less extensive interstrand contacts between the two long pitch helix than muscle actin, while these contacts are more massive in D. discoideum F-actin in its physiologically relevant Mg2+-bound form [Steinmetz et al., D. discoideum Mg2+-F-actin is longer (Lp = 4.2 μm) than that of the D. discoideum Ca2+-F-actin (Lp = 1.6 μm) or the muscle Mg2+-F-actin (Lp = 2.3 μm). Therefore, the enhanced interstrand connectivity seems to provide the structural basis for the altered bending flexibilities of the actin filaments.Available structural analyses of rabbit muscle, 2+-actin filaments were thermodynamically more stable than the α-skeletal Mg2+actin filaments. On the other hand, α-cardiac Mg2+-actin filaments are more stable than the α-cardiac Ca2+-actin filaments [Orban et al., The muscle specific α-skeletal and α-cardiac actin isoforms differ only in four amino acids [Vandekerckhove and Weber, Although the experiments of recent years have shed light on many aspects of the isoform specific functional variations of actin, the understanding of how these conformational dynamics differences of polymers assembled from different actin isoforms contribute to the isoform specific functions demands further investigations.Apart from small ligands and peptides described above actin interacts with a large number of partner proteins. These proteins can change the conformation of actin when regulating its biological functions. Although the coupling between these structural-functional changes is not completely understood yet, there are indications that the actin-binding protein induced structural modifications are established for certain biological functions. In the next session we attempt to provide examples for these conformational changes.2+-F-actin [Orlova and Egelman, Pi is bound to myosin) the binding of myosin subframent-1 was not cooperative and was accompanied by a smaller change in the microsecond rotational dynamics of F-actin than in the rigor state [Prochniewicz et al., Myosins interact with actin in all of their known biological activities. As a classic example, myosins play special and central role in the manifestation of muscle contraction [Geeves et al., A recent study has found evidence that the effect of the myosin on the conformation of actin depends on the myosin isoform as well [Prochniewicz et al., The field focusing on the functions of various myosins is large and growing. It is well established that the specialised forms of myosins play essential roles in many biological functions in synergic interactions with actin. Despite the decades of investigations the information regarding the conformational effects of myosins on the structural and dynamic properties of actin filaments is limited, indicating that further investigations will be needed to properly describe and understand the biological functions of these interactions.2+-ATP actin monomers in a nucleotide dependent manner (KD(Mg-ATP) = 2 μM, KD(Mg-ADP) = 80 μM) [ is a small (5kDa) WH2-domain (Wiskott-Aldrich syndrome protein-homology 2) containing protein. It sequesters actin monomers by forming a 1:1 nonpolymerisable complex with them, which does not participate in actin assembly at either end of the filament [Cassimeris et al., 2+-ATP-G-actin at intermediate rates (100–400 s), which suggests that the conformational dynamics of G-actin is restricted upon Tβ4-binding [De La Cruz et al., Trp and the Tyr band of the near-UV CD spectrum of Mg2+-ATP-G-actin [De La Cruz et al., Tyr residues around the nucleotide binding cleft led to the proposal that the nucleotide binding cleft is narrower in the Tβ4-G-actin complex. In support of this, FRET measurements showed that Tβ4-binding decreased the distance between probes attached to Lys61 (S2) and Cys374 (S1) and to Lys61 (S2) and ɛ-ATP, while increased the distance between Gln41 (S2) and Cys374 (S1). This indicates that Tβ4 rotates the D-loop towards the bound nucleotide away from S1 enclosing the nucleotide binding cleft [Dedova et al., Extensive spectroscopic and biochemical analysis revealed that Tβ4-binding was accompanied by significant changes in the conformation of actin monomers [De La Cruz et al., KD = 0.1 − 1 μM [Pantaloni and Carlier, Profilin is an essential actin binding protein that plays important role in controlling actin dynamics and actin-based motile processes. The structure of different profilin isoforms in complex with actin isoforms were solved by X-ray crystallography [Schutt et al., The high-resolution crystal structure of the profilin-actin complex shows that binding of profilin to G-actin results in the rotation of the two major domains by 4.7° relative to each other in a ‘clamp’-like fashion, closing around the profilin and opening up the nucleotide-binding cleft [Schutt et al., ADF/cofilin (actin-depolymerising-factor) (AC) family of proteins can be grouped into five functionally distinct classes of actin-binding proteins  which are characterized by the presence of the ADF homology (ADF-H) actin-binding module [Lappalainen et al., An extensively studied member of the AC protein family is ADF/cofilin that contains a single ADF-H domain. ADF/cofilin binds both G-, and F-actin, preferentially their ADP-bound form in a 1:1 and 2:1 stoichiometry, respectively [Hayden et al., Gln41 (S2) and Cys374 (S1) [Dedova et al., Lys61 (S2) and Cys374 (S1) [Blondin et al., The recently solved crystal structure of twinfilin's ADF-H domain in complex with a G-actin molecule reveals that the binding interfaces are located in the groove between S1 and S3 of actin [Paavilainen et al., Pi release from ADP-Pi-F-actin [Blanchoin and Pollard, The binding of ADF/cofilin to actin filaments exhibits a high degree of kinetic cooperativity [Hawkins et al., Gln41 (S2) and Cys374 (S1) in neighbouring protomers and an increase in their mobility, which suggests a more flexible protein matrix around the probes and loosening of the intermonomer contacts within the long-pitch strand of F-actin [Scoville et al., The atomic model of ADF/cofilin-decorated F-actin revealed extensive contacts of the bound ADF/cofilin molecule with the outer domain of actin protomer [McGough et al., The analysis of the thermally driven fluctuations of fluorescently labelled actin filaments revealed that ADF/cofilin increased the bending flexibility and decreased the persistence length of actin filaments by 5-fold [McCullough et al., 2+-dependent severing activity, with gelsolin remaining bound to the barbed end of the severed filament [Hesterkamp et al., The gelsolin family consists of seven different proteins characterized by repeats of gelsolin-like (G) domains, including gelsolin, adseverin, villin, capG, advillin, supervillin and flightless I, which are involved in the regulation of actin dynamics [Silacci et al., Cys374. Further cross-linking and fluorescence measurements showed that the nucleation by gelsolin was promoted by conformational changes between the D-loop and the C-terminal of protomers, which propagate along the filament from the gelsolin capped barbed ends [Khaitlina and Hinssen, Helical reconstruction of cryo-EM images showed that by binding to the side of F-actin gelsolin bridges two neighbouring actin protomers within the short pitch helix, and induces distortions within the actin filament which may sufficiently weaken the noncovalent interactions to break and sever the filaments Bearer, . EM recoBoth in vitro and in vivo, the rate of the spontaneous polymerisation of actin is limited by the instability of the initial actin dimers/trimers. In cells, to overcome this kinetic barrier and regulate precisely the spatiotemporal initiation of actin structures, membrane-associated stimuli-dependent nucleation factors catalyze the de novo formation of actin filaments by unique mechanisms. The first identified nucleation machinery includes the WASP/WAVE/Scar proteins (Wiskott-Aldrich syndrome protein/WASP family verprolin homologous/suppressor of c-AMP response) which activate the Arp2/3 complex to generate a branched daughter filament from a pre-existing mother filament Pollard, . RecentlS. cerevisiae was also proposed to induce conformational changes within yeast actin filaments, which was indicated by the increase of the pyrene excimer fluorescence in formin-nucleated actin filaments [Wen and Rubenstein, The mechanisms by which nucleation factors catalyze filament assembly and regulate barbed end dynamics has been extensively studied over the past few years. For detailed information we direct the readers to recent reviews [Kerkhoff, Minor changes in the highly conservative amino-acid composition of actin can have deep impact on the structure of actin, its function and interactions with its partner molecules  [Bookwalter and Trybus, Mutations in actin are frequently manifested in the form of skeletal [Sparrow et al., Under in vitro conditions, the M132V nemaline actin mutant obtained from human biopsies was demonstrated to have lower polymerization capability and increased velocity in the actomyosin motility assay [Marston et al., The T278I mutation of the ACTG1 gene coded cytoskeletal γ-actin can also cause autosomal dominant hearing loss [van Wijk et al., In the case of the familial hypertrophic cardiomyopathy some mutant actin  presented slower folding in vitro. The incorporation of the monomers into the filamental structure affected adversely as well [Vang et al., Besides mutations in actin itself, mutations in genes encoding actin-associated proteins also lead to genetic conditions. Dystrophin and its homologous utrophin are members of the spectrin-superfamily. These proteins are associated with the costameric cytoskeleton in striated muscle that circumferentially locates around the myofibrils in register with the Z-disk and physically couples the force-generating myofibrils to the sarcolemma Ervasti, . The mutThe effects of dystrophin and utrophin on the structural dynamics of actin filaments were studied with transient phosphorescence anisotropy. The results showed that both of these proteins altered the rotational dynamics of actin filaments [Prochniewicz et al., It is difficult to pinpoint in a simple model the biological function related to the conformational changes in actin monomers or filaments. The difficulty comes from two sources. Actin has various and complex biological functions and apparently it can effectively and relatively quickly adapt to many intracellular situations and binding partners. On the other hand there are a large number of molecules from small cations to proteins which contribute to the broad conformational landscape of actin. While these conformational changes are extensively studied in vitro, very little is known about the conformational dynamics of actin in the cellular environment. One of the aims of the previous sections of this review was to provide examples of these specific interactions and environments, and to give an overview regarding the role of the conformational state of actin.Although the described interactions were specific some of them could provide bases for a more general model regarding the regulatory function of actin conformation. Recent observations suggested that formins, a group of actin nucleation factors, could substantially change the conformation of actin filaments by making them more flexible [Bugyi et al., So far, the conformational dynamics of actin, and the effects of different factors were investigated in depth under in vitro conditions. Considering the rich variety of actin functions and the large amount of data accumulated in these studies some of the couplings between the structural changes and biological functions were revealed. In many other cases the complete understanding of the roles of intramolecular mechanisms in actin demands further studies. Cellular actin networks interact simultaneously with more proteins that can induce different changes in the conformational dynamics of individual actin monomers or filaments. How are these changes superimposed—enhanced or dampened—and determine the overall conformational dynamics of actin networks? How does the conformational dynamics of actin filaments play a role in the establishment of the functional properties of relevant actin networks? Recent advances in the development of novel technologies (such as fluorescence lifetime imaging microscopy (FLIM) or fluorescence anisotropy decay imaging microscopy (FADIM) [Suhling et al., fs to ms and can be measured by different approaches  of the rotation. The rotational correlation times describing the rotational motion of G-, or F-actin are distributed to a broad time scale; from ches see .mechanical property of actin filaments, it measures the resistance of the filament to an external twisting torque.mechanical property of actin filaments, it measures the resistance of the filament to bending forces.K) of F-actin by the following equation:describes the flexural rigidity of actin filaments. It equals the arc length of the filament over which the tangent angle at every point along the arc length correlates in three-dimensional motion. The persistence length is the distance over which the filament bends due to thermal fluctuations. The persistence length is related to the flexural rigidity (kB is the Boltzmann-constant and T is the absolute temperature. Actin filaments belong to the semiflexible polymers with typical persistence length of 0.1 – 20 μm.where


The human genome harbors an impressive number of genes encoding enzymes that primarily metabolize or transport drugs or other xenobiotics (XMEs). Genetic and functional variation in these genes is tremendous and has complex consequences, depending, for example, on whether enzyme structure or expression is affected, or whether the produced metabolite is pharmacologically or toxicologically active or not. Despite numerous impressive examples of the impact of genetic variation on pharmacokinetics and drug response, today's knowledge is incomplete regarding most XME genes and fragmentary even for many well-investigated XMEs. This is one of the reasons why clinical pharmacogenetic studies are often controversial and clinical application in personalized medicine is presently limited. Advanced technology and ongoing large-scale projects are rapidly uncovering the existing genetic variation in all populations on earth, ultimately enabling the personal genome in the very near future. A wealth of mostly rare novel variants is awaiting functional characterization either by high-throughput expression/phenotyping techniques or by prediction using improved algorithms to estimate functional relevance.With this Research Topic we would like to give an up-to-date overview about the current knowledge in this field by covering both, known hard facts as well as cutting-edge advancement in novel genetic and genomic variation of XMEs and their functional consequences. Five major subtopics which include 20 research or review papers are included in this E-book. These are the following:Clinical application of CYP2C19 pharmacogenetics toward more personalized medicine Lee, , review.Pharmacogenetics of cytochrome P450 2B6 (CYP2B6): advances on polymorphisms, mechanisms, and clinical relevance : resolving the puzzle (Stephens et al., MDMA, methamphetamine, and CYP2D6 pharmacogenetics: what is clinically relevant? (de la Torre et al., Molecular interactions between NAFLD and xenobiotic metabolism (Naik et al., Toward a clinical practice guide in pharmacogenomics testing for functional polymorphisms of drug-metabolizing enzymes. Gene/drug pairs and barriers perceived in Spain (Agúndez et al., Clinical implications of XME gene variantsCYP3A4 in three South African populations (Drögemöller et al., Characterization of the genetic variation present in Frequencies of 23 functionally significant variant alleles related with metabolism of antineoplastic drugs in the Chilean population: comparison with Caucasian and Asian populations (Roco et al., Pharmacogenomic diversity among Brazilians: influence of ancestry, self-reported color, and geographical origin (Suarez-Kurtz et al., Inter/intraethnic variability of XME gene variantsImpact of the interaction between 3′-UTR SNPs and microRNA on the expression of human xenobiotic metabolism enzyme and transporter genes (Wei et al., CYP2C19 (Helsby and Burns, Molecular mechanisms of genetic variation and transcriptional regulation of Regulation of XME gene expressionImpact of genetic polymorphisms on chemotherapy toxicity in childhood acute lymphoblastic leukemia (Gervasini and Vagace, Multilocus genotypes of relevance for drug metabolizing enzymes and therapy with thiopurines in patients with acute lymphoblastic leukemia (Stocco et al., Functional polymorphisms in xenobiotic metabolizing enzymes and their impact on the therapy of breast cancer (Vianna-Jorge et al., High-resolution melting analysis of the common c.1905+1G>A mutation causing dihydropyrimidine dehydrogenase deficiency and lethal 5-fluorouracil toxicity (Borràs et al., Polymorphisms of phase I and phase II enzymes and breast cancer risk (Justenhoven, CYP2C8 gene rs11572080 with regard to colorectal cancer risk (Ladero et al., Analysis of the functional polymorphism in the cytochrome P450 Pharmacogenetics in cancer therapy


Easton (In speech-related fields, researchers had begun formulating ideas for modularizing speech movements even prior to Bernstein's influence. Cooper et al. , for ins. Easton  had firs. Easton  shifted . Easton , with liMeanwhile, researchers in other areas have built a substantial volume of experimental and modeling research around the neuromuscular organization and biomechanics of non-speech movement, including work on complex fine motor systems such as the fingers (e.g., Overduin et al., The great majority of evidence for modularization derives from experiments on non-human spinal structures (see Tresch et al., In our view, neuromuscular modules are built specifically to drive body structures that are biomechanically efficacious, enabling them to operate feed-forward, i.e., with little or no central feedback control. This has often been assumed as a premise underlying modularization (e.g., Loeb et al., While there remains some controversy around whether these modules are best defined in terms of their neural (e.g., d'Avella and Bizzi, Developing a theory of speech production that accords with current work on neuromuscular modularization, we believe, has the potential to link a number of fields and methodologies surrounding a central question in cognitive science, with implications for all aspects of speech research, from phonetics and phonology to the phylogenetic and ontogenetic development of speech. In addition to bringing another complex motor system into the broader discussion of neural modules, modularizing speech at the neuromuscular level promises a major advance for speech models, constituting a “missing link” between speech movement primitives (Ramanarayanan et al.,


The arbitrariness of the linguistic sign is a fundamental assumption in modern linguistic theory. In recent years, however, a growing amount of research has investigated the nature of non-arbitrary relations between linguistic sounds and semantics. This review aims at illustrating the amount of findings obtained so far and to organize and evaluate different lines of research dedicated to the issue of phonological iconicity. In particular, we summarize findings on the processing of onomatopoetic expressions, ideophones, and phonaesthemes, relations between syntactic classes and phonology, as well as sound-shape and sound-affect correspondences at the level of phonemic contrasts. Many of these findings have been obtained across a range of different languages suggesting an internal relation between sublexical units and attributes as a potentially universal pattern. Linguistic theory widely adopts Saussure's  essentiaEmpirical evidence for such phenomena primarily comes from signed languages  sometimes further imitating the emotional impression they have on us, e.g., the German “Uff” which transposes the ejected breath (ff) with which we instinctively express a reaction of relief into written German .According to Wundt , some onOrganon model, they also fulfill the conative/appealing function as in the calling (German “he”) or the request to keep silent (German “ssst”).Following Schrott and Jacobs , in inteTesting cross-cultural agreement in the understanding of phonological iconicity of interjections, Sauter et al.  asked nakyoro kyoro for “looking around” or “spinning”; Tamil thuru thuru for “eager” or “active”). Following Dingemanse, sensory imagery is perceptual knowledge that derives from sensory perception of the environment and the body. Although scarcely represented in Indo-European languages, Atoda and Hoshino  but lack the central feature of compositionality to qualify as morphemes. They even appear across language borders in non-cognate-words of remote languages  also seem to depict sensory imagery and therefore might qualify as iconic mappings.According to Bergen , availabSapir  initiateMore recently, Peña et al.  reportedShrum et al.  extendedmaluma with a curvy round shape and takete with a spiky angular shape. The effect was subsequently labeled as “kiki/bouba effect” and replicated across a wide range of unrelated languages such as Himba (Bremner et al., Substantial evidence for phonological iconicity as a cross-linguistic phenomenon was derived from a seminal experiment of Köhler . Within Maurer et al.  found thDevelopmental and cross-linguistic studies strongly suggest an innate origin of iconic mappings. However, dependent variables used are offline measures and especially adults' judgments might reflect metacognitive strategies.To overcome this problem, Westbury  implemenUsing an implicit learning categorization task combined with EEG, Kovic et al.  presenteLikewise, Ramachandran points to possible synkinetic mappings of hand and jaw movements, controlled in two adjacent areas in the Penfield motor homunculus (Ramachandran and Hubbard, Building on their research on sound-size correspondences, Taylor and Taylor  asked moFocusing on real text instead of artificial word material, Fónagy  contrastIn a more general approach, Heise  extendedAryani et al.'  softwareAnother account of systematic mappings of phonology to affective dimensions was proposed by Zajonc et al. , who conSystematic form-meaning mappings are abundant in many languages, although not always necessarily iconic in nature. Yet, these latter ones hold strong implications for the essence of human language and its origin.Given the relatively small inventory of phonemes and the potentially infinite number of concepts to be expressed, the Saussureian principle of arbitrariness certainly remains a general key feature of human language Gasser, , allowinFay et al.  point inStrictly arbitrary relations between levels of phonology and semantics as assumed by psycholinguistic models (e.g., Levelt et al., 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.


Schizosaccharomyces pombe. This simple model has contributed significantly to our understanding of how the cell cycle is regulated, and serves as an excellent model for studying aspects of cytokinesis. Here we will discuss the state of our knowledge of how the contractile ring is assembled and disassembled, how it contracts, and what we know of the regulatory mechanisms that control these events and assure their coordination with chromosome segregation. © 2011 Wiley-Liss, Inc.Cytokinesis is the final stage of the cell cycle, and ensures completion of both genome segregation and organelle distribution to the daughter cells. Cytokinesis requires the cell to solve a spatial problem  and a temporal problem (to coordinate cytokinesis with mitosis). Defects in the spatiotemporal control of cytokinesis may cause cell death, or increase the risk of tumor formation [ S. pombe model, giving references to reviews addressing aspects of fission yeast biology that are beyond the scope of this overview. As their common name implies, cells of the fission yeast Schizosaccharomyces pombe divide by medial fission, reminiscent of cell division of animal cells. The cells take the form of a cylinder capped by hemispherical ends. During interphase, cells grow mainly at their tips, with cell length being a measure of cell cycle progression. Upon commitment to mitosis, cells stop elongating and reorganize the actin and tubulin cytoskeletons in preparation for nuclear and cell division [McCully and Robinow,S. pombe. This has led to the use of this simple model system for studies addressing the regulatory and mechanistic aspects of cytokinesis, which have provided many insights into the regulation of this critical stage of the cell cycle. Cytokinesis is regulated by a group of protein kinases known as the septation initiation network (SIN). The SIN is essential for cytokinesis, and is coregulated with mitotic events, to ensure the coordination of mitosis and cytokinesis (see below). S. pombe. We will briefly introduce the S. pombe has a single, essential mitotic cyclin-dependent kinase (CDK), named cdc2p: its function is conserved in distantly related yeasts such as S. cerevisiae where it is named CDC28, and in human cells, where it is known as CDK1 [Beach et al.,Reorganization of the actin and tubulin cytoskeletons for mitosis and cytokinesis depends upon commitment mitosis and CDK activity [reviewed by Marks et al.,S. pombe [He et al.,S. pombe [reviewed by Martin,Unlike mammalian cells, fission yeast undergo a “closed” mitosis, in which the nuclear envelope does not break down, and the spindle forms inside the nucleus [Hagan and Hyamsmid1 and pom1 [Huang et al.,The PH-domain protein mid1p, is a key factor of positioning CR at the medial cell cortex [Chang et al.,The second is nuclear export of mid1p at the G2/M transition, which targets mid1p to the cortex proximal to the nucleus [Sohrmann et al.,An elegant study from the Pollard lab [Wu et al.,When cells enter metaphase, F-actin and myosin II (myo2p) independently appear on the medial cortex and then interact with each other to form the CR [Naqvi et al.,for3-null mutant [Nakano et al.,de novo polymerization of F-actin is the dominant pathways for CR assembly in S. pombe. Actin subunits depolymerized from actin patches in cell tips are bound to profilin cdc3p [Balasubramanian et al.,S. pombe differs from animal cells, where assembly of the CR is induced after inactivation of CDK1 and anaphase onset. Formation of the S. pombe CR early in mitosis is mediated by mid1p, which acts as an organizing scaffold for the actin polymerization machinery and myo2p to the future division site. Mid1p has a C-terminal PH domain with low similarity to the metazoan cytokinesis proteins of the anillin family, which directly bind to both F-actin and myosin II [reviewed by D'Avino,In addition to myo2p, an IQGAP-like actin-crosslinking protein rng2p, the formin cdc12p, and the F-BAR protein cdc15p are also incorporated into cortical mid1p nodes in early metaphase, independently of F-actin [Wu et al.,mid1 mutant cells, although CR formation is not initiated at metaphase, myo2p associates with a cable-like F-actin structure elongating from the cell cortex during anaphase, resulting in formation of an abnormally shaped CR, which is frequently displaced from the cell middle [Huang et al.,S. pombe division is symmetrical while another system, probably SIN-mediated, supports CR-assembly. Interestingly, at least two other species of the Schizosaccharomyces genus, S. japonicus and S. octosporus do not have a clear ortholog of mid1p and in these organisms CR assembly is initiated during anaphase [Alfa and HyamsS. pombe, which is required for formation of the septin ring and cell separation in S. pombe [Berlin et al.,In S. pombe ortholog of the conserved CDC14-family of phosphoprotein phosphatases; it is implicated in many cellular processes, and is regulated by phosphorylation and localization [Cueille et al.,S. pombe. The CR is assembled stepwise during mitosis [Wu et al.,Flp1p/clp1p is the Drosophila POLO [Ohkura et al.,plo1, cdc7, or spg1 promotes CR and septum formation from any stage of the cell cycle, uncoupling the usual dependency of cytokinesis upon entry into mitosis [Fankhauser and Simanis,The SIN is a group of protein kinases which are essential for cytokinesis. Signaling requires the activity of three protein kinases, each of which has a regulatory subunit (kinase-regulator); cdc7p-spg1p [Fankhauser and Simanis,The SIN has been implicated in assembly of contractile actin ring (CR) [Hachet and Simanis,S. pombe SPB is composed of cytoplasmic and nuclear components which are separated by the nuclear envelope and connected by fine striations [Ding et al.,Laser ablation of SPBs in fission yeast during mitosis suggests that at least one SPB must be intact during anaphase B for cytokinesis to occur [Magidson et al.,sid4 or cdc11 block association of SIN proteins with the SPB, and prevent SIN signaling. Ectopic activation of the SIN in a sid4 mutant fails to promote septum formation, indicating that SPB association of SIN proteins is important for signaling [Balasubramanian et al.,The SIN proteins associate with the SPB via a tripartite scaffold comprised of ppc89p, sid4p and cdc11p [Chang and Gould,in vitro [Furge et al.,During interphase, spg1p, byr4p, and cdc16p are all observed at the SPB; cdc16p and byr4p are interdependent for localization [Sohrmann et al.,Spg1p in its GTP-bound form interacts with cdc7p during mitosis [Sohrmann et al.,spg1 and cdc7 [Guertin et al.,cdc7 mutants and some alleles of spg1 [Sparks et al.,The protein kinase sid1p and its regulatory subunit cdc14p appear at the new SPB only after the inactivation of CDK and onset of anaphase B [Guertin et al.,Biochemical analysis has shown that cdc16p, spg1p, mob1p, and cdc13p (the mitotic cyclin for cdc2p) all bind to the N-terminal domain of cdc11p [Morrell et al.,par1, the B′ regulatory subunit of PP2A [Jiang and Hallberg,fin1 [Grallert et al.,The transition from the symmetric to the asymmetric configuration of the SIN and the initiation of septation requires inactivation of mitotic CDK [Yamano et al.,zfs1 and scw1 are RNA binding proteins [Beltraminelli et al.,cdc7 mutant at the permissive temperature [Mulvihill et al.,A number of putative regulators of the SIN have been identified genetically; S. pombe SIN in another yeast, Saccharomyces cerevisiae, is called the mitotic exit network (MEN). In addition to a role in cytokinesis, the MEN is required for the inactivation of CDK, and exit from the mitotic state into G1; for reviews, see [Burke,The biological counterpart of the ee Burke,. Many coee Burke,. Some coee Burke,. The kinee Burke,.As mentioned above, the SIN seems to be important for stabilizing the CR after onset of anaphase and to sustain assembly of CR components until cytokinesis is finished. The SIN and flp1p/clp1p, are both implicated in a cytokinesis checkpoint, which blocks the next round of mitosis in response to perturbed assembly of the CR [Le Goff et al.,Overexpression of C-terminal truncated cdc12p, probably corresponding to a dominant active form lacking the auto-inhibitory domain, induces cdc15p- and CR-dependent cytokinesis even in interphase cells [Yonetani and Chang,S. pombe, only a small subset of these can trigger reorganization of F-actin, CR formation and septation when their activity is altered [Matsuyama et al.,Though whole genome-based screening shows that more than 200 proteins are localized to the division site in After the completion of nuclear division, the CR constricts, which is followed by the primary septum synthesis. At present, it is unclear whether CR constriction is an active, motor-driven process, or whether it occurs passively, as the septum is deposited behind it. Previous studies have shown the following: Mutant cells that are unable to assemble a coherent CR deposit septum materials at the cell cortex [Streiblova et al.,S. pombe, the Arp2/3-complex is not required for CR assembly [Wu et al.,Araidopsis thaliana [Boutte et al.,Drosophila early embryo [Cao et al.,S. pombe cells the Rab11-homolog ypt3p localizes to the medial region during cytokinesis, dependent on an intact actin cytoskeleton [Cheng et al.,S. pombe.As the primary septum is synthesized, actin patches accumulate around the region of septation. In ace2 produces multicompartmented cells [Alonso-Nunez et al.,The primary septum is composed of linear chains of 1,3-β-glucan [Humbel et al.,S. pombe CR with those of mammalian cells, and speculate upon possible mechanisms for its assembly and constriction. We will begin with a brief review of the mechanics of cytokinesis in mammalian cells.In this section, we will discuss the assembly, constriction and disassembly of the CR, with particular emphasis on the mechanical and structural aspects of these processes. We will also compare the properties of the In animal cells, cytokinesis is brought about by membrane ingression, which has been named the cleavage furrow (CF). The CF is thought to be induced by geometrical asymmetry of the cortical tension in the cell. Several mechanisms for CF formation have been proposed [reviewed by Wang,Caenorhabditis elegans oocyte Centralspindlin also reduces Rac GTPase-activity, which inhibits the formation of an Arp2/3-complex-dependent branched actin network and thereby ensures formation of the formin-dependent CR, which is composed of straight F-actin [Canman et al.,C. elegans oocyte [reviewed by Werner and Glotzer,In animal cells, the central spindle and overlap region of astral microtubules (MTs), which extend from opposite spindle poles, promote CR assembly at telophase. Centralspindlin, a protein complex consisting of MKLP1, a kinesin-6 dimer, and Rho-family GTPase-activating protein (RhoGAP) subunits, plays the central role in this system [Mishima et al.,Sulfolobus acidocaldarius [Lindas et al.,Cytokinesis is accomplished by the scission of a “bridge” connecting the daughter cells. Dynamic reorganization of membranes including scrambling of outer and inner sides of plasma membrane, SNARE–mediated vesicle fusions, and membrane scission by ESCRT complex is required for this step [reviewed by Prekeris and Gould,de novo at mitosis (and does not arise from conversion of interphase actin cables or patches), but they are differ significantly with regard to how CR F-actin is formed: from dozens of cdc12p nodes or from a small number of cdc12p spots. Recent studies have shown that the cdc12p spot formation depends on its FH3 domain and the actin-bundling protein ain1p, and is dispensable for CR assembly [Yonetani et al.,In this section, we will address two questions: first, what is the origin of CR F-actin? Second, is the CR formed by a spot/leading cable mechanism, or from a band of nodes? Considerable effort has been devoted to analysis of CR assembly [Vavylonis et al.,de novo assembly. The cortical flow of preformed F-actin is supported by direct observations of flux of fluorescently labeled actin [Cao and Wang,de novo assembly of CR F-actin was observed as accumulation of actin at the equator of blebbistatin-treated mitotic cells where the cortical flow is abolished [Guha et al.,At least two nonexclusive mechanisms seem to be involved in recruitment of actin to the equatorial region during cytokinesis in animal cells: cortical flow and S. pombe cells. The CR actin filaments have mixed polarities, and interdigitating myosin-like thick filaments between them were also observed in animal cells [Sanger and Sanger,S. pombe is discussed below.It is generally accepted that the CR is comprised mainly of actin and myosin II. However, their precise configuration in the ring remains undetermined. EM observations in several dividing cells have revealed that CR F-actin generally aligns parallel with the equator beneath the plasma membrane at the division site [Schroeder,As mentioned above, cortical F-actin filaments oriented perpendicular to CR, which would not be involved in CR constriction according to the purse-string model, are often detectable. Filaments with this orientation have escaped detection by EM observation. Given the high turnover rates of actin and myosin II in CR, this perpendicular F-actin may also be dynamic, probably more than CR F-actin, and hence may be difficult to preserve during severe fixation. Functional dissection of these filaments might substantiate alternative mechanisms for cortical ingression during cytokinesis Wang,. Along sDrosophila and HeLa cells [Field and Alberts,Some actin-binding proteins (ABPs) localized selectively at CR are thought to characterize the special properties of CR F-actin bundles. The actin-bundling protein α-actinin localizes to the CF in dividing NRK cells and is involved in accumulation of CR F-actin [Mukhina et al.,It is noteworthy that the equatorial accumulation of F-actin is not always evident in dividing cells, whereas ABPs or myosin II are clearly detectable in most cases [e.g., Neujahr et al.,It also remains possible that myosin II contributes to organization of CR F-actin bundles. Myosin II is implicated in rearrangement of the actin cytoskeleton in protruding lamellae of fibroblast cells [Verkhovsky et al.,In the purse-string hypothesis, myosin II motors are presumed to generate a force driving CR constriction via interaction with CR F-actin. Inhibition of the ATPase activity of myosin II using blebbistatin blocks cytokinesis in mammalian cells without affecting CR F-actin assembly [Straight et al.,S. pombe has two myosin II isoforms, myo2p and myo3p , both of which localize to the CR [Bezanilla and Pollard,S. pombe cytokinesis remains unclear. F-actin accumulates at the division site in myo2-null cells but fails to form a ring [Kitayama et al.,myo2-E1 allele), significantly reduces the actin-binding and motor activity of myo2p [Lord and Pollard,myo2-E1 mutant cells, node condensation into a ring abolished at restrictive temperature and is delayed at the permissive temperature [Coffman et al.,myo2-E1 cells constrict twofold slower than those in wild-type cells [Stark et al.,myo3 exacerbates the phenotype of myo2-E1 cells, the two myosin-IIs seem to share overlapping functions in cytokinesis [Motegi et al.,C. elegans, UNC-45 colocalizes with myosin II during cytokinesis in the early embryos [Barral et al.,S. pombe rng3p belongs to the same UCS -family and associates with myo2 and other four myosin proteins cotranslationally [Amorim and Mata,myo2-E1 cells [Lord et al.,Folding of the myosin head domain requires a co-chaperone of the (UNC-45/CRO1/She4p) family of proteins. In Dictyostelium or Drosophila S2 cells, accumulation of individual myosin-II filaments at the equatorial region has been visualized as small rods less than 1 μm in length by fluorescence microscopy [Yumura and Fukui,One of the observable characteristics of myosin II molecules is to assemble into bipolar thick filaments through their tails [Kaminer and Bell,FRAP analysis has shown that CR F-actin and cortical F-actin turn over rapidly both in fission yeast and mammalian cells [Pelham and Chang,S. pombe cells, the sole ADF, named as adf1p, localizes to the CR and is essential for accumulation of F-actin at the division site during cytokinesis [Nakano and Mabuchi,Xenopus ADF/cofilin, XAC, localizes to the leading edge of the CF in a fertilized egg and also participates in its formation [Abe et al.,In S. cerevisiae, the CR is not essential for cytokinesis, and septation alone manages to carry out the closure of bud neck [Bi et al.,It is unequivocal that in dividing animal cells net inward forces are generated along the equator, whether by the CR or by other mechanisms, and they drive the constriction of the medial cortex [Rappaport,in vitro. Fine and time-resolved EM observation of CR and the medial region of dividing fission yeast cells may also help to address this issue. An attractive model for generation of the contractile force has been proposed, which posits that polymerization and depolymerization of CR F-actin can produce mechanical force for the ring contraction in the presence of end-tracking crosslinkers even without myosin II motors [Zumdieck et al.,Whatever the actual function of CR constriction is, its mechanism(s) is still an open question. As discussed above, the purse-string model should be challenged by examining whether myo2p assembles into minifilaments Schizosaccharomyces pombe has proved to be an informative model for the study of cytokinesis and its coordination with mitosis. Many of the structural components required for cytokinesis are well conserved through evolution, so the fission yeast provides an excellent background in which to test the in vivo effects of defined mutations; when proteins are involved in multiple processes, hypomorphic alleles may permit separation of these functions. Though we have learnt a great deal about how cytokinesis occurs in S. pombe through a judicious mixture of cell biology, genetics and biochemical analysis, it is clear from the foregoing discussion that much remains to be done. Scientifically speaking, the next few years should be very exciting!The fission yeast


Microorganisms transform inexpensive carbon sources into highly functionalized compounds without toxic by-product generation or significant energy consumption. By redesigning the natural biosynthetic pathways in an industrially suited host, microbial cell factories can produce complex compounds for a variety of industries. Isoprenoids include many medically important compounds such as antioxidants and anticancer and antimalarial drugs, all of which have been produced microbially. While a biosynthetic pathway could be simply transferred to the production host, the titers would become economically feasible when it is rationally designed, built, and optimized through synthetic biology tools. These tools have been implemented by a number of research groups, with new tools pledging further improvements in yields and expansion to new medically relevant compounds. This review focuses on the microbial production of isoprenoids for the health industry and the advancements though synthetic biology. Escherichia coli or Saccharomyces cerevisiae, which serves as a microbial cell factory  and recombined control elements  were screened to select the E. coli strain that produced sevenfold more mevalonate , human 5-phosphomevalonate kinase (hPMK), yeast 5-diphosphomevalonate decarboxylase (yPMD), and E. coli IPP/DMAPP isomerase , by introducing heterologous genes for IPP isomerase  from Nostoc punctiforme, which were inserted into the chromosome of E. coli. This plasmid-free strain created astaxanthin as its only carotenoid at 1.4 mg/g dcw  method” to put together multiple genes in a single step, Nishizaki et al.  improved lycopene production. “Multiplex automated genome engineering” (MAGE) was proposed by Wang et al. They modified 24 genetic components at once from a degenerate pool of synthetic DNA, achieving a fivefold increase in lycopene production in just 3 days , was achieved  was overexpressed to produce α-santalene, a skin cancer chemopreventative, at 0.21 mg/g dcw  and kaurene synthase-like (SmKSL) as well as GGPP synthase (BTS1) and FPP synthase (ERG20) in S. cerevisiae (Zhou et al., Biosynthetic pathways for various diterpenes and sesquiterpenes have also been engineered for improved production through synthetic biology. To maximize production of several sesquiterpenes, Asadollahi et al. replaced the nativeS. cerevisiae, but production levels of the Taxol intermediate, taxadiene, were low. Several changes to taxadiene synthesis in yeast were introduced, including an alternate geranylgeranyl diphosphate synthase from S. acidocaldarius and a codon-optimized taxadiene synthase from Taxus chinensis, ultimately resulting in a 40-fold titer increase to 8.7 mg/l (Engels et al., E. coli as a host, Ajikumar et al. (Application of synthetic biology tools to microbial production of the cancer chemotherapy drug paclitaxel will decrease its cost and increase its availability. Paclitaxel, known as Taxol, is a potent chemotherapy drug, which is very difficult to chemically synthesize (Chandran et al., r et al.  divided de novo design of biosynthetic pathways (Ajikumar et al., The past decade has witnessed the potential of synthetic biology to make the microbial isoprenoid production become industrially relevant. However, further improvements in yield and expansion to new medically important compounds can be attained through the development of additional tools. An incomplete understanding of the complexity of biosynthetic pathways limits the ability to fully forward engineer microbial production (Nielsen and Keasling, 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.


Lower limb injuries in sport are increasingly prevalent and responsible for large economic as well as personal burdens. In this review we seek to determine which easily implemented functional neuromuscular warm-up strategies are effective in preventing lower limb injuries during sports participation and in which sporting groups they are effective.Seven electronic databases were searched from inception to January 2012 for studies investigating neuromuscular warm-up strategies and injury prevention. The quality of each included study was evaluated using a modified version of the van Tulder scale. Data were extracted from each study and used to calculate the risk of injury following application of each evaluated strategy.Nine studies were identified including six randomized controlled trials (RCT) and three controlled clinical trials (CCT). Heterogeneity in study design and warm-up strategies prevented pooling of results. Two studies investigated male and female participants, while the remaining seven investigated women only. Risk Ratio (RR) statistics indicated 'The 11+' prevention strategy significantly reduces overall  0.54 to 0.84) and overuse  lower limb injuries as well as knee  injuries among young amateur female footballers. The 'Knee Injury Prevention Program' (KIPP) significantly reduced the risk of noncontact lower limb  and overuse  injuries in young amateur female football and basketball players. The 'Prevent Injury and Enhance Performance' (PEP) strategy reduces the incidence of anterior cruciate ligament (ACL) injuries . The 'HarmoKnee' programme reduces the risk of knee injuries  in teenage female footballers. The 'Anterior Knee Pain Prevention Training Programme' (AKP PTP) significantly reduces the incidence of anterior knee pain  in military recruits.Effective implementation of practical neuromuscular warm-up strategies can reduce lower extremity injury incidence in young, amateur, female athletes and male and female military recruits. This is typically a warm-up strategy that includes stretching, strengthening, balance exercises, sports-specific agility drills and landing techniques applied consistently for longer than three consecutive months. In order to optimize these strategies, the mechanisms for their effectiveness require further evaluation. Historically, stretching as part of a warm-up strategy before exercise has been strongly advocated to prevent injury . Howeveret al. [et al. [Neuromuscular training programmes are hypothesized to improve joint position sense, enhance joint stability and develop protective joint reflexes, ultimately preventing lower limb injuries. Hübscher et al.  recentlyet al. . However [et al.  systematThe aims of this systematic review were: (1) to evaluate the efficacy of functional neuromuscular warm-up strategies which do not require additional equipment in preventing lower limb injury in order to guide clinical and sporting practice; and (2) to identify the common elements of successful strategies in order to guide future research.Embase, SPORTDiscus, Google Scholar, PubMed, ISI Web of Knowledge, Scirus and PEDro were searched for articles from inception to June 2011 and updated in January 2012. Search terms included (movement training OR neuromuscular OR proprioceptive OR proprioception OR plyometric) AND (training OR program OR programme) AND prevent* AND (injury OR injuries). Limits included English language (due to the cost of translation) and human studies. The reference list of retrieved articles was manually checked for potentially relevant studies.Inclusion/exclusion criteria are shown in Table et al. [et al. [A modified version of the nine item van Tulder et al.  was used [et al.  criteria [et al. . Two indDetails of study design, participant characteristics, interventions, statistical analysis, results and study limitations were extracted and tabulated from each included study by one reviewer (KH). Additionally, two reviewers (KH and CB) extracted data related to participant numbers and injury incidence for the various types of lower limb injuries reported. Review Manager version 5.0 was used to calculate risk ratios (RR) and their 95% Confidence Intervals (CI) for all comparisons as well as to produce forest plots to represent this data visually. The number needed to treat (NNT) was calculated only for variables producing a statistically significant RR . Sensitivity analysis was completed to identify if the use of equipment improved injury prevention. To complete this, the effectiveness of a selection of eight studies, five randomized controlled trials (RCTs) -16 and tThe initial search identified 766 articles Figure . DuplicaTable Details of each study are summarized in Table RRs for the effectiveness of neuromuscular warm-up strategies in preventing undefined lower limb injuries are shown in Figure None of the strategies evaluated were able to produce significant reductions in hip or thigh injuries, with calculated risk ratios shown in Figure P = 0.046). The AKP PTP [RRs for the effectiveness of neuromuscular warm-up strategies in preventing knee injuries are shown in Figure  AKP PTP  was ableRRs for the effectiveness of neuromuscular warm-up strategies in preventing lower leg and ankle injuries are shown in Figure This systematic review investigated the effectiveness of neuromuscular warm-up strategies for injury prevention. Based on available data a number of strategies appear to be effective in preventing lower limb injuries. Specifically, 'The 11+'  strategyThe quality assessment criteria revealed that the studies had various methodological weaknesses affecting their internal validity. Firstly, sample sizes were often too low to evaluate specific injuries . If evaluating the effectiveness of neuromuscular warm-up programmes on more specific injuries, sample size calculations prior to commencement and recruitment of larger samples are recommended. Additionally, future studies should ensure blinding of assessors, concealment of treatment allocation, intention to treat analysis and more adequate randomization procedures to reduce the impact of issues relating to internal validity. External validity was also limited, in particular the applicability of the findings to age groups other than between 13 and 26 years.There is also a need to determine the mechanism of effectiveness of neuromuscular warm-up strategies and determine whether injury reduction is the result of each individual component or due to a combination of exercises. No studies were identified which compared two different components or combinations of neuromuscular warm-up strategies and, in general, programmes targeted varying risk factors associated with a variety of specific injuries. Addressing this through further research will enable more emphasis on effective components of injury-specific interventions and facilitate the development of more successful neuromuscular warm-up strategies for injury prevention, specifically in reference to specific lower limb injuries.et al. [et al. [et al. [et al. [et al. [There is limited homogeneity between the prevention strategies and the methods of recording injury incidence, making data pooling for meta-analysis inappropriate. Injury incidence was reported by a certified athletic trainer , a coachet al. , Gilchri [et al. , LaBella [et al. , Kiani e [et al.  and Brus [et al. . This poAdverse effects were only noted in four studies ,28,31,33The effectiveness of three neuromuscular warm-up strategies in preventing the total number of lower limb injuries was evaluated in studies included in this review. Of these, only 'The 11+'  and KIPPThe PTP  may haveHip and thigh injuries were recorded during the evaluation of two neuromuscular warm-up strategies, 'The 11+'  and 'TheKnee injury rates were recorded in all of the nine studies, with six of these recording ACL injuries. Based on available data, four neuromuscular warm-up strategies were found to be effective in preventing knee injuries. These included individual studies showing 'The 11+'  and 'HarSuccess of the AKP PTP  may relaet al. [et al. [et al. [et al. [et al. [et al. [et al. [Despite investigating the same warm-up strategy , Mandelbaum et al.  demonstr [et al.  showed o [et al.  was a CC [et al.  performe [et al.  there wa [et al.  informed [et al.  while th [et al. ,28-34.The PTP , and KLIThe 'HarmoKnee'  programmet al. [The effectiveness of four neuromuscular warm-up strategies which did not require additional equipment in preventing lower leg and ankle injuries were evaluated in studies from this review. Based on the results, no neuromuscular warm-up programme was able to reduce lower limb injury risk significantly. However, it should be considered that the KIPP  indicateet al.  which evet al.  results A previous systematic review comparing balance work  and neuromuscular exercises  revealed that ankle sprains were reduced by 36% and 50%, respectively . AdditioAccording to the present systematic review, several practical neuromuscular warm-up strategies which do not require additional equipment that is not readily available at the usual amateur competition or training venues are effective to varying degrees at preventing lower limb injuries. However, in some instances a large number of participants would need to undertake a strategy before one injury is prevented. This is the case with the PEP  strategyImportantly, this systematic review highlights several areas that may account for significantly better injury prevention when incorporating neuromuscular warm-up strategies. These include: (1) incorporation of stretching, strengthening and balance exercises, sports-specific agility drills and landing techniques; (2) completing the strategy for longer than three consecutive months; and (3) completing of the strategy at all training sessions. In addition to these programme specifics, further evaluation of the '11+'  programmFurther studies need to determine whether 'The 11+' , KIPP 3, 'HarmoKThe current systematic review identified five practical neuromuscular warm-up strategies which do not require additional equipment and which may effectively reduce the risk of lower limb injuries. Specifically 'The 11+' reduced overall and overuse lower limb injuries and knee injuries in young amateur female football players, the 'KIPP' reduced non-contact overall and overuse lower limb injuries in young amateur female football and basketball players, the 'HarmoKnee' programmThe authors declare that they have no competing interests.KH and CB were the primary initiators of the study while all authors made substantial contributions to data analysis and interpretation. All authors were involved in drafting and revising the manuscript and approved the penultimate version. The final version was approved and submitted by DM.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1741-7015/10/75/prepub


Cannabis sativa (cannabis) should be considered doping in sports. Results from a 2010 report in the United States  the main psychoactive constituent and responsible for the observed toxic effects after smoking, while other cannabinoids are responsible for minor effects, such as cannabinol (CBN), which is 10% as psychoactive as THC Huestis, . THC is The non-psychoactive cannabidiol (CBD) is anxiolytic in humans following a single dose (Zuardi et al.,