The term “prion" was originally coined by Prusiner to explain the unusual infectious agent in transmissible spongiform encephalopathies  C) is α-helical rich, soluble in mild detergents, sensitive to protease digestion, and releasable from lipid membrane by phosphatidylinositol-specific phospholipase C (PI-PLC) digestion. During prion disease, a portion of PrP converts to an aberrant conformational isoform called PrPSc, which is mostly β-sheeted, highly aggregated, protease-resistant, and unable to be released from lipid membrane by PI-PLC digestion.Prions were defined as small proteinaceous infectious particles that cause TSEs Sc isoform seeds the conversion of normal PrPC to the pathogenic PrPSc and causes the disease. The self-propagating characteristic of disease-associated PrPSc has been demonstrated by cell-free conversion assay and serial protein misfolding cyclic amplification (sPMCA) Sc and prion infectivity in sPMCA provides strong evidence supporting the prion hypothesis Sc and prion disease.The prion hypothesis postulates that, because of its self-propagating property, PrPSc, an altered conformational PrP isoform, is the causative agent for prion disease has been a challenge for the prion field for decades, mainly because PrPSc is highly aggregated, preventing it from being purified to homogeneity using conventional biochemical methods. An alternative approach is to reconstitute prion infectivity in vitro with defined components. Amyloid fibers formed in vitro with bacterially expressed recombinant PrP (recPrP) have been shown to contain limited prion infectivity C purified from brains ScClearly establishing that PrPC to pathogenic PrPSc. This self-propagating property of PrP conformers is best demonstrated by in vitro assays. Recombinant PrP in amyloid fibers represents a self-propagating conformational state that is distinct from normal PrPC, but recPrP in amyloid fibers is generally without the biochemical hallmark of PrPSc, C-terminal proteinase K (PK)-resistance. The in vitro assays that propagate the classic PK-resistant PrPSc conformation include cell-free conversion assay and sPMCA Sc as seed and PrPC purified from cultured cells as substrate, which is far less efficient than sPMCA that employs crude brain homogenates. The difference between two assays suggests the presence of factors in the brain homogenates that promote efficient prion propagation. Polyanions, such as RNA molecules and proteoglycans, have been identified as one type of cofactors in the brain homogenate that enhance prion propagation A key concept of the prion hypothesis is that prion is a self-propagating PrP conformer, which elicits the conversion of host-encoded normal PrPPrion infectivity obviously depends on the seeding or self-propagating property of PrP conformers. However, a PrP conformer with seeding or self-propagating capability does not necessarily contain prion infectivity in vivo, that is, cause spongiform encephalopathy in animals. This notion is exemplified by PrP amyloid fiber, which clearly contains a strong seeding or self-propagating capability, but does not have a strong association with in vivo infectivity. The PrP amyloid fibers in the brain tissues of a familial prion disease patient induce a prominent PrP-amyloid accumulation in “humanized" knock-in mice carrying the same mutation, demonstrating in vivo seeding or self-propagating property of PrP amyloid fibers Collectively, the seeding or self-propagating property of a prion is essential for its infectivity, but not all PrP conformers with seeding or self-propagating capability are competent to cause prion disease in animals.C via sPMCA in the presence of lipid and RNA as cofactors, the newly formed prions contain high infectivity The role of cofactors in prion infectivity remains to be clarified, but comparing several in vitro reconstituted infectious prions indicates that they play an important role in prion infectivity. When infectious prions were formed with recPrP or purified PrPC conformation to increase β-sheet content and PrP aggregation, a conformational change similar to PrPC-to-PrPSc conversion C susceptible to conversion or simply facilitate PrPSc-steered PrPC conversion. Alternatively, cofactors may facilitate PrP conversion by concentrating both PrPSc and PrPC on the surface of a single lipid vesicle or a single polyanion molecule. Another possibility could be that the cofactors stabilize the infectious PrPSc conformation by forming a complex with PrPSc and being a part of the infectious particle.To date, two types of cofactors, lipids and polyanions, are identified as influencing prion propagation and infectivity, but the precise mechanism remains unclear. It can be envisioned that cofactors may act on several steps of PrP conversion. Both polyanion and lipid bindings alter the normal PrPBoth lipids and polyanions enhance prion propagation, yet polyanion does not appear to be critical for prion infectivity Most cofactor-related studies use mouse or hamster prions. It is well known that prions from different species or different prion strains have very different properties, which could be due to the different combinations of various lipid or polyanion molecules. It is also possible that other types of molecules could serve as cofactors, contributing to the diverse biological properties of prions. Further investigation of prion cofactors will help us to gain the insights of this enigmatic infectious agent, which is essential for us to combat these devastating diseases.


Seasonal shifts in host use by mosquitoes from birds to mammals drive the timing and intensity of annual epidemics of mosquito-borne viruses, such as West Nile virus, in North America. The biological mechanism underlying these shifts has been a matter of debate, with hypotheses falling into two camps: (1) the shift is driven by changes in host abundance, or (2) the shift is driven by seasonal changes in the foraging behavior of mosquitoes. Here we explored the idea that seasonal changes in host use by mosquitoes are driven by temporal patterns of host reproduction. We investigated the relationship between seasonal patterns of host use by mosquitoes and host reproductive phenology by examining a seven-year dataset of blood meal identifications from a site in Tuskegee National Forest, Alabama USA and data on reproduction from the most commonly utilized endothermic  and ectothermic (frogs) hosts. Our analysis revealed that feeding on each host peaked during periods of reproductive activity. Specifically, mosquitoes utilized herons in the spring and early summer, during periods of peak nest occupancy, whereas deer were fed upon most during the late summer and fall, the period corresponding to the peak in births for deer. For frogs, however, feeding on early- and late-season breeders paralleled peaks in male vocalization. We demonstrate for the first time that seasonal patterns of host use by mosquitoes track the reproductive phenology of the hosts. Peaks in relative mosquito feeding on each host during reproductive phases are likely the result of increased tolerance and decreased vigilance to attacking mosquitoes by nestlings and brooding adults (avian hosts), quiescent young , and mate-seeking males (frogs). Seasonal patterns of host selection by arthropods are a critical component in the amplification and spillover of arthropod-borne zoonoses Although several hypotheses regarding seasonal shifts in host use by mosquitoes have been proposed and tested, the mechanism underlying these shifts remains elusive. The hypothesis that host-feeding patterns are due to seasonal changes in the abundance of avian hosts was not supported by field data from Florida Many of the host species commonly preyed upon by mosquitoes undergo dramatic seasonal variation in behavior, often associated with reproduction. Specifically, animal parents are known to exhibit changes in habitat-use, time-budget, food choice, and detectability at various stages of their reproductive cycle. Therefore, we hypothesize that seasonal changes in host use by mosquitoes reflects the life history of their most commonly utilized hosts, rather than any trait shared by members of a taxonomic class. Furthermore, because of the changes in host behavior associated with reproduction, we predict that seasonal patterns of host use are driven by temporal peaks in the reproductive biology of a few key host species.c = 18.39) with very high likelihood (wi  =  1) of being the better model  bloodmeals were split among 43 other host species . While mer model . Relativt models .c (wi  =  0.7). Seasonal host use of early-season  and late-season breeding frogs  paralleled changes in the detectability  was better than the null, although by less than two ΔAICc . Supporttability  of thoseOur data suggest that seasonal changes in patterns of host use by mosquitoes reflect the breeding cycles of their host animals. For endothermic hosts—deer and herons—we found that peaks in host use by mosquitoes were remarkably synchronized with peaks in reproductive investment. Seasonal patterns of mosquito feeding on the ectothermic hosts—frogs—on the other hand, tracked temporal peaks of calling by advertising males. Although mate attraction and post-birth/hatching behavior are quite different components of reproductive investment, both activities likely increase the susceptibility of the respective hosts to being fed upon by mosquitoes.For animals that exhibit some form of parental care, periods of reproductive investment are likely to increase susceptibility to mosquito attack for both parents and offspring. Brooding mother birds, for example, must stay at the nest to transfer heat to young and protect them from predators As in birds, the reproductive behaviors and developmental stages of mammalian prey items are likely to influence the susceptibility of individuals to mosquito attacks. In deer, age-dependent predator avoidance tactics may expose fawns to increased levels of parasitism from mosquitoes, the incidence of which can be quite high For frogs, activities that increase predation risk also contribute to increased parasitism by blood-feeding dipterans. The rate of frog capture by bats is significantly higher when frogs are calling, suggesting that sexual advertisement increases predation risk Various behaviors associated with reproduction have undesirable side effects which expose animals to increased vulnerability to attacks by predators While the period of peak mosquito feeding on each host also corresponds to an increase in population size of each species (births/hatching of young), our data do not support the hypothesis that seasonal patterns of host use are driven by increases in host abundance alone. In white-tailed deer, the population increases by approximately two-fold during the period of birthing This work constitutes the first study to examine changes in species-specific host preference over time. Many other studies 2 circle, with a variety of habitat types, including beaver ponds, rush marsh, oxbow lakes, hardwood swamp, upland pine forest, mixed hardwood and coniferous forest, and hardwood bottomland Host use data was obtained by blood-meal identification of mosquitoes aspirated from resting sites Odocoileus virginianus) fawning dates were obtained from herds on managed lands within 65 km of the mosquito collection site . Alabama Division of Wildlife and Freshwater Fisheries personnel collected female deer using firearms and determined age (days) of fetuses, used to estimate date of parturition Ardea herodias) nesting was determined by semiweekly observations of a heron rookery within the study site (2008–2009). Adult, juvenile and nestling herons observed in the rookery were counted at each visit until the rookery was abandoned each year (late June). Counts were then used to calculate the number of individuals occupying the rookery per semimonthly period. Nesting data for yellow-crowned night-heron, (Nyctanassa violacea), were obtained from the Cornell Lab of Ornithology, North American Nest-Record Card Program. The predicted number of chicks per nest per semimonthly period was calculated from historic nesting records from six southeastern states (Florida (northern counties only), Georgia, Louisiana, South Carolina, Tennessee and Texas) from 1976 to 1995. No records from Alabama were available. The presence of calling male frogs  was determined from monthly visits (February – October) to five ponds within the study site in 2008 For the most commonly fed upon hosts, we collected data on various aspects of reproductive biology, including nesting phenology, birth dates, and male vocalizations for mate attraction. White-tailed deer (c) We used linear mixed-effects models fit using maximum likelihood to investigate the relationship between relative host use and host reproductive biology. Relative host use was calculated as the proportion of total blood meals originating from a given host in a given time period . Blood meal data for each host species were summed across years prior to calculation of relative host use. All proportions were arcsine square root transformed (angular transformation) prior to analysis. For each host we fit a model containing a fixed effect for the host reproduction variable and a null model which assumed constant host use across time. In all models, we included a random intercept for the time step of each observation to control for possible autocorrelation among the data points. Models were ranked and compared using Akaike's Information Criterion corrected for small sample sizes . Species of Anopheles, which took >90% of blood meals from a single host species (white-tailed deer), were not included in the analyses.For white-tailed deer, great blue heron, and yellow-crowned night heron, data were analyzed in semimonthly increments. Data from 1,378 blood meal identifications from six mosquito species  were incCulex territans and Culex peccator) were included in the analysis for anuran hosts. No other mosquito species commonly fed on frogs.For anuran hosts, relative host use was calculated as the proportion of total blood meals each month derived from early- or late-breeding frogs. Data from 164 frog-derived blood meal identifications  from twoTable S1Hosts of Aedes sticticus, Aedes vexans, Coquillettidia perturbans, Culex erraticus, Culex peccator, Culex quinquefasciatus and Culex territans from Tuskegee National Forest, AL, USA (2001–2004 and 2006–2008). Host use was determined by PCR-based assays identifying the vertebrate source of blood from field-collected mosquitoes.(DOC)Click here for additional data file.


Alcohol-related birth defects are collectively known as fetal alcohol spectrum disorders (FASDs), which are a leading cause of cognitive defects in North America. Studies using animal models have shown that alcohol induces global changes in gene expression in the developing brain. Using an FASD mouse model that they previously established, Shiva Singh and colleagues tested the hypothesis that long-term alterations in gene expression, mediated by epigenetic mechanisms, are a feature of FASDs. Developing mice were exposed to alcohol and, as adults, their epigenomes were assessed for changes in DNA methylation patterns and non-coding RNA (ncRNA) expression. The analysis unveiled long-lasting alterations in DNA methylation in response to fetal alcohol exposure. These changes mapped to the promoters of certain ncRNAs, implicating ncRNA deregulation in FASDs.


A possible role for sterols in the development of autism spectrum disorder (ASD) has not been proven, but studies in disorders of sterol biosynthesis, chiefly Smith-Lemli-Opitz syndrome (SLOS), enable hypotheses on a causal relationship to be discussed. Advances in genetic technology coupled with discoveries in membrane physiology have led to renewed interest for lipids in the nervous system. This paper hypothesizes on the role of sterol dysfunction in ASD through the framework of SLOS. Impaired sonic hedgehog patterning, alterations in membrane lipid rafts leading to abnormal synaptic plasticity, and impaired neurosteroid synthesis are discussed. Potential therapeutic agents include the development of neuroactive steroid-based agents and enzyme-specific drugs. Future investigations should reveal the specific mechanisms underlying sterol dysfunction in neurodevelopmental disorders by utilizing advanced imaging and molecular techniques. The autism spectrum describes a group of disorders with early childhood onset, characterized by persistent core deficits in socialization, language, and stereotypic and repetitive behavior . Over 50Cholesterol serves many essential roles in the developing nervous system. It is a structural component of myelin and membrane lipid rafts, serves as a substrate for neurosteroid formation, and facilitates hedgehog signaling , 10. ImpDHCR7) located on chromosome 11q12-13 [Smith-Lemli-Opitz syndrome (SLOS) is an autosomal recessive disorder of cholesterol biosynthesis caused by mutations in the gene encoding 7-dehydrocholesterol reductase  is a morphogen involved in the patterning of the nervous system and limbs, along with other transcription factors and secreted proteins [SHH is covalently modified with both palmitate and cholesterol and secreted as part of a lipoprotein complex that regulates brain morphogenesis through the patched/smoothened signaling system [SHH is secreted from the notochord and ventral floor plate cells and forms a concentration gradient along the entire dorsal-ventral axis [SHH after covalent modification by cholesterol is the establishment of a morphogenic SHH concentration gradient that moves from the ventral (high concentration) to dorsal regions (lower concentration). Variations in the SHH gradient affect intracellular cell signaling systems and ultimately determine the expression of future cell types by sequential induction of transcription factors in ventral progenitor cells [SHH morphogenic front is one determinant of the structural fate of the maturing brain [SHH signaling [SHH processing, as evidenced in holoprosencephaly [Sonic Hedgehog , SREBF chaperone, site-1 protease, fatty acid synthase, and squalene synthase [DHCR7 has also been shown to alter expression of key molecules for intracellular signaling and vesicular transport such as Egr1, Snx, and Adam19 [DHCR7 mutations that lead to behavioral manifestations in SLOS. More studies are needed to determine if these mechanisms are involved in the human pathophysiology of SLOS and other neurodevelopmental disorders. Rafts may represent one of the many biologic substrates that shape neuronal networks in the brain. Recent data has shown that reduction in cholesterol levels impair exocytosis of synaptic vesicles [A, and NMDA receptors are affected by abnormal sterol levels or whether these abnormalities are present either transiently or for longer periods in regions of the developing brain for individuals with autism. Therefore, we hypothesize that neuronal or glial expression of autism candidate genes and their resulting membrane proteins may be altered in disorders of abnormal cholesterol homeostasis.Studies on cholesterol and lipid organization in disease have led to progress in understanding the molecular basis of neurologic disorders . As a resynthase . Decreasd Adam19 . These svesicles . NumerouA and NMDA receptors, myelin formation, axonal guidance, and dendrite growth [Neurosteroids are steroid molecules produced by the central nervous system to rapidly augment neuronal excitability through membrane-bound, ion-gated neurotransmitter receptors , 56. Whie growth , 62, 63.A receptor [Because of their broad psychiatric characteristics, neurosteroids have been implicated in the behavioral profile of SLOS . Biochemreceptor . Interesreceptor , 68. Theα-reductase and 3α-hydroxysteroid dehydrogenase [Since cholesterol does not cross the blood-brain barrier, neurosteroids are synthesized with cholesterol de novo . For nearogenase . CurrentSHH patterning and lipid rafts are not likely to be achieved until future studies elucidate the specific mechanisms and biologic substrates underlying brain development. These studies may be aided by advances in functional neuroimaging and molecular imaging techniques. Furthermore, discussion on the ethics involving embryologic or childhood neuromodulatory therapy in patients with abnormal neural patterning should be considered if technology advances toward such a therapeutic option. In conclusion, we propose that ASD in SLOS, and perhaps other disorders of cholesterol homeostasis, occurs because of impairments in sonic hedgehog patterning, altered lipid raft structure resulting in aberrant synaptic plasticity, and impaired neuroactive steroid synthesis. Future investigations to explore these hypotheses are encouraged and may enhance our understanding of sterols in autism and other neurodevelopmental disorders.Current treatment of SLOS involves endogenous cholesterol supplementation in the form of crystallized purified cholesterol suspended in Ora-Plus, microencapsulated powdered purified cholesterol (brandname SLOesterol), or egg yolks. Several publications discuss the role of simvastatin therapy –73. Effi


Helicobacter hepaticus infection enhances access of bacterially-associated products to pattern-recognition receptors located on surfaces of macrophages and dendritic cells. Receptor ligation leads to activation of transcription factors, including NF-kappa B, that regulate production of chemo-attractants for macrophages and neutrophils, recruitment of which is a hallmark of inflammation. These acute inflammatory events are re-enforced by expression of powerful inflammatory mediators such as TNF-α and IL-2, which amplify acute inflammatory gene expression and enhance cell survival. If not properly extinguished, the innate inflammatory response is maintained and further amplified by activation of cell-mediated adaptive immunity.The importance of chronic inflammation as a risk factor for major cancers is well documented , and theThere is now strong evidence that biomolecular damage found in inflamed tissues is caused by a battery of highly reactive oxygen and nitrogen species capable of damaging all classes of biomolecules. Reactive species are generated mainly by activated macrophages and neutrophils, but can also be produced at functionally significant levels endogenously within epithelial cells themselves , 4. In aH. hepaticus) that cause DNA strand breaks, inhibit ATM-dependent response pathways, and suppress repair of DNA adducts [What we have also learned from recent studies is that cell death and genotoxicity in this environment are not induced solely by chemicals arising from immune cells or epithelial cells, but that these effects are augmented by bacterial toxins , which is known to be associated with increased cancer risk, is particularly relevant to our continuing efforts to elucidate mechanisms underlying these interactions. IBD results from intermittent and severe activation of the mucosal immune system in the gastrointestinal tract to promote chronic inflammation. Infiltration of gut tissue by lymphocytes, neutrophils, and macrophages results in prolonged exposure to pro-inflammatory cytokines and to highly reactive chemical species that induce oxidation, nitration and chlorination of DNA, RNA and proteins. Secondary effects also result from oxidation of unsaturated lipids, creating a cascade of highly reactive unsaturated carbonyls, which also damage DNA, RNA, and proteins. Chronic exposure to products of inflammation can thus result in chemical damage to all classes of cellular macromolecules, altered protein expression, and dysregulated cell proliferation.Hiccs, part of a 1.71-Mb interval on chromosome 3, as a major susceptibility locus for H. hepaticus-induced colitis and colon cancer in H. hepaticus-infected 129 Rag−/− mice also treated with azoxymethane [+ innate lymphoid cells. Analogous pathways may be operable in IBD and associated colorectal cancers in humans.Current theories cite the intestinal microbiome in IBC as a central driver of both inflammation and subsequent development of dysplasia in genetically-predisposed individuals, acting similarly in experimental models involving mice with immune dysregulation. These processes appear likely to be associated with the pathogenesis of cancer development. Interestingly, other investigators recently identified a genetic locus, ymethane . This loWhile alterations of the intestinal microbiome have been described in IBD patients, with suggestions that particular species may be associated with ileal Crohn's disease, no individual bacterial species or groups have been consistently associated with either colonic Crohn's disease or ulcerative colitis. Likewise, the role that microbial biomolecular activity may play in these diseases remains unknown. Metabolomic analysis of fecal water from patients with these diseases has identified microbial population shifts suggesting that functional capacity may be more critical than microbial membership . While c


Secondly, we note that motor learning often refers to deliberate practice and the resulting performance enhancement and adaptability. We discuss the close interplay between neural plasticity, motor learning and cognitive aging. Thirdly, we review research on motor skill acquisition in older adults with, and without, impairments relative to aging-related cognitive decline. Finally, to enhance future research and application, we highlight the implications of neural plasticity in skills learning and cognitive rehabilitation for the aging population.For more than two decades, there have been extensive studies of experience-based neural plasticity exploring effective applications of brain plasticity for cognitive and motor development. Research suggests that human brains continuously undergo structural reorganization and functional changes in response to stimulations or training. From a developmental point of view, the assumption of lifespan brain plasticity has been extended to older adults in terms of the benefits of cognitive training and physical therapy. To summarize recent developments,  Functional decline is evident in cognitive, motor, social, psychological, physical domains. Older adults often experience greater anxiety, poorer memory and attention, slower processing speeds; motor control and learning capabilities decreased; greater behavioral variability is usually observed. These areas of decline collectively cause neurodegenerative disorders like mild cognitive impairment (MCI), Alzheimer’s disease (AD), or AD-related dementia. The compromised functionality reduces the quality of life and causes great concerns in the geriatric and gerontological communities. However, functional deterioration is not inevitable. Behavioral improvements are likely to occur while having an active lifestyle that is a key to reduce the negative impact of cognitive-motor aging on daily functions and to enhance the quality of life. The development of effective diagnostic tools, better intervention strategies and technologies is of the utmost importance for geriatric researchers and practitioners  and motor abilities for coping with daily challenges. Actively engaging in physical, motor or intellectual exercises, or deliberately receiving multisensory stimulations, can prevent functional decline and preserve cognitive functions. In general, cognitive and motor performance deteriorates considerably as a result of an inactive lifestyle, biological aging and cognitive impairments  is an inherent characteristic or ability for lifelong skills learning and relearning. Specifically, neural plasticity refers to the capacity of the central nervous system (CNS) to alter its existing cortical structures  and functions  in response to experience, learning, training, or injury  , and developmental dyspraxia, a kind of motor learning difficulty in children) and aging-related dysfunctions . Instructors can teach developmentally appropriate skills to children  are a key for successful cognitive training and interventions  occurs when a learner practices a given skill or a set of skills. Upon completion of the task-specific practice, a learner continues to acquire or stabilize a given skill or a set of skills. In particular, motor learning would be more pronounced after an optimal post-practice interval during which a learner is sleeping or napping. This mode of motor learning refers to off-line learning . Nighttime sleeping or daytime napping is required for such a learning mode. In motor behavior literature, motor skill acquisition is said to be composed of these two closely related learning mechanisms , feedback about the outcome of a motor skill) for motor learning to an extent similar to that of younger adults  and small reductions in timing error . In retention tests, older adults with intact cognitive and motor functions outperformed those who had relatively poorer scores in an eye-hand-coordination test (finger tapping), the Mini Mental State Exam (MMSE), and the Trail Making Test (TMT-A and B). Cognitive, neural and motor deficiencies in older adults might explain their compromised on-line motor learning  strengthens memory and executive functions that are crucial for older learners suffering from functional decline . Individual differences in cognitive and motor functions in older adults should be considered when designing and implementing training programs. Future research to identify major barriers and facilitators to brain fitness and motor functionality in older adults is integral to cognitive-motor skill learning and rehabilitation. An apparent challenge now lies in the search for an optimal therapeutic approach to enhance skills learning in older adults.Furthermore, computer-based practice significantly enhances cognitive rehabilitation in healthy older adults; the beneficial effects of training can be sustained for 3 months. The results bear important implications about the “While discussing brain fitness or motor ability of older adults, we describe the developmental pattern and define “normal aging”, and “cognitive aging”. We will also answer the questions, “what is successful aging?” and, “how do older adults achieve successful aging through exercise or practice?” Importantly, we address the features of learning and relearning in older adults who are cognitively and motorically intact or impaired. Finally, the links between physical exercise and brain function in older adults will be highlighted. Figure normal aging or aging literally means that an individual may experience multiple aspects of expected change  during the passage of time, from conception to death. A functional increment or progression can be seen in early life , and even in older stages; regression takes place at later stages  be implemented in a meaningful and effective way to help older adults?” Some researchers classified research on exercise and brain health into four categories: (1) to determine frequency, intensity, type and level of physical activity for diverse aging populations; (2) to identify the major or realistic cognitive benefits by participating in physical activity; (3) to understand the psychological and physiological factors that influence physical activity participation both in healthy and unhealthy older adults; and (4) to promote appropriate interventions, establish practical evaluation criteria and develop policies to increase physical activity among those at risk of cognitive impairment , reaction time, cognitive tests, functional MRI (fMRI) measures. Very fit older adults outperformed those less fit in behavioral and neuroimaging parameters. Better cardiovascular fitness resulted in superior test performances on executive functions, suggesting exercise-dependent neural plasticity of the aging brain. By improving physical fitness, neural structure, synaptic plasticity and transmission can be strengthened.Regarding the effects of exercise on e et al.  tested oFinally, we discuss our two experiments exploring motor control and learning in MCI and AD patients. MCI usually refers to the transitional or intermediate phase between cognitive aging and AD. Older adults with MCI are increasingly at risk of developing dementia . We emphasize the benefits of motor practice or physical exercise for both cognitively normal and impaired older adults. We propose ideas to enhance future geriatric research or practice for older adults. We suggest using off-line sleep-based motor learning and mindfulness training for older adults who may suffer from cognitive or motor disorders.More attention should be paid to the contribution of sleep-based skills learning to cognitive and motor skills, and possibly to the physical and neural rehabilitation of older adults (Walker et al., Furthermore, mindfulness training or awareness meditation may also benefit cognitive and motor rehabilitation in older adults. Mindfulness training refers to the mind and body exercises that facilitate attention focus on the experience of current time. It helps participants reach internal peacefulness, mind-body integration or coupling, via meditation Siegel, . Importae.g., deliberate walking, mind games, or leisure activities; Willis and Nesselroade, Finally, we have three important points. The first is that participation in exercise is critical for preventing cognitive decline in older adults. Persistence maximizes the gains from physical activity . SecondlThe 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.


Dopamine dysregulation syndrome is a complication of the dopaminergic treatment in Parkinson's disease that may be very disabling due to the negative impact that compulsive medication use may have on patients' social, psychological, and physical functioning. The relationship between subthalamic nucleus deep brain stimulation and dopamine dysregulation syndrome in patients with Parkinson's disease remains unclear. Deep brain stimulation may improve, worsen, or have no effect on preoperative dopamine dysregulation syndrome. Moreover, dopamine dysregulation syndrome may appear for the first time after deep brain stimulation of the subthalamic nucleus. The outcome of postoperative dopamine dysregulation syndrome is poor despite stimulation and medication adjustments. Here we review the phenomenology and neurobiology of this disorder, discuss possible mechanisms that may underlie the diverse outcomes of dopamine dysregulation syndrome after subthalamic nucleus deep brain stimulation, and propose management strategies. Dopamine dysregulation syndrome (DDS), originally described as “hedonistic homeostatic dysregulation” by Giovannoni et al. , is a diDDS has been related to levodopa and potent short-acting dopamine agonists as subcutaneous apomorphine, but it also can occur with other dopamine agonists. The compulsive use of DRT may lead to negative social behaviours such as hoarding medication.DDS may encompass other psychomotor pathologies due to antiparkinsonian therapy as punding—complex meaningless stereotyped and repetitive motor behaviours—and impulse control disorders, such as pathological gambling, hypersexuality, compulsive shopping, and binge eating . DDS is probably underdiagnosed because patients may not complain of their behaviour and physicians may forget to ask about that. There are no large epidemiological studies about the prevalence of DDS in the general PD population. The prevalence of DDS in patients attending Parkinson's disease centers is 3-4% , 3. The DDS diagnostic criteria proposed by Giovannoni et al.  in his s Pezzella et al. used the following selection criteria for DDS : (a) PD Some factors may contribute or predispose to develop DDS in PD patients. Impulsivity and sensation and novelty-seeking personality traits have been found in patients with PD and DDS –6. It haGenetic factors may also be relevant . It has Many PD patients with DDS fulfil DSM-IV criteria for substance dependence because of the negative effect that the pathological use of medication has on their social, psychological, and physical functioning . The negative reinforcement model is one of the proposed theories to explain addiction . Based oThere is evidence of sensitization of the ventral striatum reward system by PET imaging with 11C]-raclopride in PD patients with DDS who had enhanced levodopa-induced ventral striatal dopamine release compared with levodopa-treated patients with no compulsive drug use C-raclopr.Deep brain stimulation of the subthalamic nucleus (STN-DBS) is an established therapy for advanced PD patients with motor complications . BilaterDespite the motor improvement of patients who underwent STN-DBS, its effect on nonmotor symptoms of Parkinson's disease, especially neurobehavioral disorders as impulse control disorders, punding, and DDS has not been widely studied.The relationship between STN-DBS and DDS in patients with Parkinson's disease remains unclear. While some authors described a complete resolution of the behaviour disorder after STN-DBS –19, otheTo our knowledge, there are 9 PD patients with DDS reported in the literature who improved or resolved after STN-DBS –19. WitjPostoperative DDS improvement may be related to the reduction of dopaminergic agents allowed by surgery , 19, 22.Subthalamic nucleus deep brain stimulation may not influence DDS evolution or even can worsen it. 71% of patients with preoperative DDS reported by Lim et al. (12 patients) remained unimproved or worsened after surgery .Interestingly, dopamine dysregulation syndrome can also appear for the first time after deep brain stimulation of the subthalamic nucleus. We reviewed the literature searching for reports of PD patients in whom DDS appeared within 12 months of STN-DBS. To our knowledge, at least, 7 cases have been reported , 19–21. The first patient with postoperative DDS was reported by Houeto et al. in 2002 , a 61-yeLim and colleagues reported in 2009 two patients with DDS which apparently appeared for the first time after bilateral STN-DBS . HoweverWe have recently reported three PD patients who developed DDS within a year after surgery . The firA definite causal relationship with STN-DBS cannot be made since the outcome of DDS after discontinuing DBS could not be assessed—our patients did not tolerate it for the rapid worsening of their motor performance. Besides, DDS could have appeared in the evolution of the patients' disease independently of the surgical treatment. However, the temporal relationship between STN-DBS surgery and the onset of DDS suggests that STN-DBS might have played a role in the appearance of DDS.One possible explanation for the appearance or worsening of DDS after STN-DBS could be misplacement of the electrodes in the medial zone of the STN, which corresponds to its limbic territory  and is rSeveral neuroimaging studies have found that STN-DBS induced metabolic modifications in cortical and subcortical structures related to limbic and associative circuits –28. ThusOn the other hand, the psychostimulant effect of STN-DBS , 34 seemThe seemingly paradoxical occurrence of either improvement or worsening of DDS after STN-DBS or, furthermore, the de novo appearance of this addictive behaviour may be related to individual differences in the extent of mesolimbic dopaminergic denervation , 35. PETReward-seeking behavior is mediated by the amygdala and nucleus accumbens, both of which receive dopaminergic projections from the ventral tegmental area . Thus, PThis might be the case of de novo DDS patients, in whom the combined effect of dopaminergic replacement therapy  and DBS on the limbic territory of the STN could have led to hyperstimulation of the mesolimbic system, thus precipitating the onset of DDS.The clinical management of DDS is challenging, particularly when appears after STN-DBS. Despite a good postoperative motor outcome, most patients overused dopaminergic drugs not because they felt pleasurable effects but to avoid anxiety, dysphoria, and other nonmotor symptoms , 21, 37.Preoperative recognition of DDS and other impulse control disorders is correlated with a better outcome of these behaviours after DBS, whereas lack of recognition, poor motor benefit, and higher dopaminergic medication doses after surgery were associated with persistence or even new cases of DDS .Changes in stimulation parameters, attempts to reduce the dose of dopaminergic drugs, and the addition of antipsychotics and/or antidepressants may not be helpful. The outcome of DDS after STN-DBS was poor in the majority of reported cases , 19–21.The issue of how to manage antiparkinsonian drugs after STN-DBS remains unsettled. A large and rapid reduction in dopamine replacement therapy with withdrawal of dopaminergic agonists may induce apathy and severe depression in many patients , whereasQUIP (Questionnaire for Impulsive and Compulsive Disorders in Parkinson's disease) [Identifying vulnerable patients to develop DDS seems of paramount relevance. Young-onset PD, male gender, previous history of substance abuse, impulsive sensation seeking personality, presence of depressive symptoms, and artistic professions have been considered risk factors for DDS –8 as weldisease)  or PET sdisease)  may be uThe adequate location of electrodes is another crucial factor. Contacts close to the ventromedial part of the STN should be avoided. Perhaps the use of computational modelling , 26, wheNevertheless, it seems advisable to avoid a hyperdopaminergic state during the postoperative period, since high doses of dopaminergic medication added to STN-DBS therapy may predispose to developing DDS in vulnerable patients. Further research should be undertaken in order to identify patients who are vulnerable to DDS and to define the most appropriate postoperative management.


Subsequent metabolic reactions (such as cyclization) generate enormous complexity and diversity from these basic starting materials. Isoprenoids are vital to all organismal classes, supporting core cellular functions such as aerobic respiration (ubiquinones) and membrane stability (cholesterol)  are the largest group of natural products, comprising over 25,000 known compounds esterol) . IsoprenThe basic isoprenoid building blocks (IPP and DMAPP) are generated in cells by one of two distinct biosynthetic routes. The classical mevalonate (MVA) pathway was first described in yeast and mammals in the 1950s By the early 1990s, however, the existence of an alternative route to IPP had become clear through metabolic labeling studies in bacteria and plants The two isoprenoid biosynthetic routes, the mevalonate (MVA) and non-mevalonate (MEP) pathways, have distinct evolutionary origins and are phylogenetically compartmentalized Toxoplasma gondii (which causes toxoplasmosis) and the malaria-causing Plasmodia species, including the agent of severe malaria, Plasmodium falciparum. While plants contain both the MVA and MEP pathways, the Apicomplexans do not contain the MVA pathway and exclusively generate isoprenoids via the MEP pathway.While most eukaryotes use the MVA pathway, phyla that have acquired a plastid organelle  possess the eubacteria-like MEP pathway. In microbes, this includes the Apicomplexan protozoan pathogens Isoprenoids are essential in all eubacteria in which they have been studied P. falciparumP. falciparum produces severely truncated N-glycosyl groups that may not be required for protein function The MEP pathway is also clearly essential in Apicoplexan eukaryotes, including the protozoan malaria parasite E. coli and P. falciparum, can treat malaria in field trials, and has been validated as an inhibitor of isoprenoid biosynthesis in vivo T. gondii and Mycobacterium tuberculosis) 50 is a remarkable >11,000 mg/kg—presumably since there is no mammalian homolog to be inhibited The MEP pathway has a number of characteristics that make it a favorable target for antimicrobial drug development. Much like bacterial cell wall biosynthesis, which has been so successfully targeted by antibacterial agents, the MEP pathway is essential for microbial growth, and none of the enzymes of this pathway are present in mammalian cells. Validation of many of the properties of a new isoprenoid-inhibitor class of antibiotic has come from studies of the small phosphonic acid compound fosmidomycin. Fosmidomycin inhibits DXR (the first dedicated step in the MEP pathway) in multiple organisms M. tuberculosis, and P. falciparum, which share the MEP pathway. New drugs that inhibit this pathway hold great promise as broad-spectrum agents, with potential appeal for commercially viable pharmaceutical development in the first-world as antibacterial agents  and use in developing nations in combination therapies for malaria and tuberculosis.Drug resistance has created an urgent need for new antimicrobial agents to combat Gram-negative bacteria,


Here we briefly review the 1H-MRS studies that have explored relationships between glutamatergic metabolites, symptoms, and cognitive function in clinical samples. While some of these studies suggest that more severe symptoms may be associated with elevated glutamatergic function in the anterior cingulate, studies in larger patient samples selected on the basis of symptom severity are required.The glutamate hypothesis of schizophrenia, proposed over two decades ago, originated following the observation that administration of drugs that block NMDA glutamate receptors, such as ketamine, could induce schizophrenia-like symptoms. Since then, this hypothesis has been extended to describe how glutamate abnormalities may disturb brain function and underpin psychotic symptoms and cognitive impairments. The glutamatergic system is now a major focus for the development of new compounds in schizophrenia. Relationships between regional brain glutamate function and symptom severity can be investigated using proton magnetic resonance spectroscopy (1H-MRS) to estimate levels of glutamatergic metabolites  Accumulating evidence suggests that glutamatergic dysfunction may contribute to the pathogenesis of schizophrenia, and the symptoms and cognitive deficits associated with the disorder . The gluN-methyl-d-aspartate glutamate receptor complex (NMDAR) such as phencyclidine (PCP) or ketamine to healthy volunteers induces effects which resemble aspects of schizophrenia symptomatology forms a cornerstone of the glutamate hypothesis of schizophrenia  to estimate the concentration of glutamatergic metabolites. MRI scanners with field strengths of 3 T or above can resolve glutamate, at least for the most part, from its metabolite glutamine . At loweIndividual 1H-MRS glutamate studies in schizophrenia have produced some inconsistent findings. In general, studies at higher field strengths suggest that frontal glutamine function is elevated in the early stages of psychosis , 19, wheIn order to better understand the possible relationships between 1H-MRS glutamate, glutamine, and Glx levels and symptom severity, we identified publications that have reported associations with severity along symptom domains. These included studies in individuals at risk of psychosis, and patients with first-episode psychosis or established schizophrenia , detected an association between positive symptom severity and mPFC Glx, although this did not survive correction for multiple comparisons : in schizophrenia, deficits on this task are associated with abnormal activation in the ACC and DLPFC . In a stOther tasks investigated include the Stroop, digit span distractibility test, auditory verbal learning test (AVLT), N-back task, Iowa gambling task and verbal fluency test Table . Of thesThe relationship between glutamate and cognition in schizophrenia has been further investigated by combining 1H-MRS with functional magnetic resonance imaging (fMRI) of the blood oxygen level dependent (BOLD) response to measure changes in regional brain activation as participants perform cognitive tasks. In subjects at clinical high risk of developing psychosis, reductions in thalamic glutamate were correlated with an elevated BOLD response in the prefrontal cortex during a verbal fluency task, whereas the converse association was observed in controls . In a stSeveral studies have also reported correlations between brain glutamate levels and overall level of social and occupational functioning Table . In gene1H-MRS studies relating regional glutamate measures to symptoms in schizophrenia have produced inconsistent findings. There may be several methodological reasons for this, including differences in the brain region investigated, and between samples such as medication, illness stage, and symptom severity. The use of sub-optimal technical approaches such as low field strengths together with small sample sizes may also underlie the conflicting findings. A recent study at 4 T indicates that elevations in the ratio of Gln/Glu are present in schizophrenia patients, consistent with elevated glutamatergic neurotransmission . Howeverpost hoc to the main study findings. A few studies have directly compared glutamatergic metabolite levels in patient groups on the basis of symptom severity, specifically those who were or were not currently experiencing symptom exacerbation (The majority of studies that have investigated relationships between glutamate levels and symptom severity have applied correlational analysis, usually erbation , were orerbation  or did oerbation . All fouThe field would benefit from further studies pre-selecting groups of patients who differ in severity of negative symptoms or cognitive impairment, or longitudinal studies comparing within-subjects glutamate levels during periods of illness stability compared to relapse. Studies of the relationships between cognitive dysfunction and glutamate in schizophrenia may benefit from combination with fMRI to determine the efficiency of glutamate in supporting networks that subserve cognitive function. To date there are only a handful of published studies of this type. Finally, relationships between glutamate levels and symptom severity may be indirect; for example Stone et al. showed that hippocampal glutamate may interact with striatal dopamine to determine risk of psychosis , and a pOne question is whether baseline levels of glutamate, glutamine, or Glx are predictive of subsequent outcome or response to treatment in schizophrenia. A recent study showed that elevated frontal Glx at baseline was associated with poor response after 4 weeks of antipsychotic treatment . This isd-serine and the glycine transporter type 1 inhibitor sarcosine reduce total and negative symptoms as an adjuvant to antipsychotic medication (a priori on the basis of symptom severity.The suggestion that symptoms that do not respond well to conventional antipsychotic treatment may have a glutamatergic basis , 49 warrdication , 64. Lamdication  and smaldication , 66. FurThe 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.


Intensive care unit-acquired weakness (ICUAW) has been recognized as an important and persistent complication in survivors of critical illness. The absence of a consistent nomenclature and diagnostic criteria for ICUAW has made research in this area challenging. Although many risk factors have been identified, the data supporting their direct association have been controversial. Presently, there is a growing body of literature supporting the utility and benefit of early mobility in reducing the morbidity from ICUAW, but few centers have adopted this into their ICU procedures. Ultimately, the implementation of such a strategy would require a shift in the knowledge and culture within the ICU, and may be facilitated by novel technology and patient care strategies. The purpose of this article is to briefly review the diagnosis, risk factors, and management of ICUAW, and to discuss some of the barriers and novel treatments to improve outcomes for our ICU survivors. Decreasing mortality following critical illness over the last few decades has shifted the focus from short-term to long-term outcomes in intensive care unit (ICU) survivors. Survivors are often left with profound neuromuscular weakness resulting in persistent functional disability and decreased quality of life for years after hospital discharge ,2. Reasoet al., in 1984 in patients unable to wean from mechanical ventilation [The first reported cases of flaccid paralysis from peripheral neuropathy following sepsis was documented by Bolton tilation . Since ttilation ,9,10. Hotilation ,12. As aIn the last decade, studies have identified a number of risk factors for ICUAW, but most are small, observational studies with important methodological limitations ,12. TherPost hoc analyses of two large randomized control trials looking at intensive insulin therapy in both surgical and medical ICUs reported a significant reduction in ICUAW with tight glycemic control [Hyperglycemia may be an important risk factor for the development of ICUAW.  control ,14. HoweThere remains substantial controversy regarding the association of ICUAW with two other commonly cited risk factors: corticosteroids and neuromuscular blocking agents (NMBA). Although three prospective observational studies have shown increased risk of ICUAW with corticosteroid exposure ,15,16, aIn recent years, a number of studies have documented the safety and feasibility of early mobility in the ICU -6. In adNovel rehabilitation technology, such as neuromuscular electrical stimulation (NMES) and cycle ergometry, may provide an opportunity for early rehabilitation even when the patient is unable to actively participate . In healthy volunteers, NMES can improve or preserve muscle strength by preventing disuse atrophy through stimulated muscle contraction , but theEnforced bedrest, oversedation, and delirium are common barriers to early rehabilitation in the ICU. Sedation and analgesia are commonly instituted (with or without neuromuscular blockade) in the ICU for management of patient discomfort, anxiety, and asynchrony during mechanical ventilation. Changes in sedation strategies, including novel sedative agents such as dexmedetomidine , use of Even more radical might be finding a viable alternative to mechanical ventilation in which sedation and analgesia use can truly be minimized. Extracorporeal membrane oxygenation (ECMO) has become an area of increasing interest following its successful use for H1N1-associated ARDS . By provICUAW is an important complication that contributes to functional disability and decreased quality of life in ICU survivors. Indeed, it is an important component of the post-intensive care syndrome (PCIS) representing any new or worsening impairment in physical, cognitive, or mental heath status following an acute care hospitalization . The lacThe authors declare that they have no competing interests.CML made a substantial contribution to the conception of the mini-review, drafting of the manuscript and revising it critically for important intellectual content. EF conceived the mini-review, and helped in drafting the manuscript and revising it critically for important intellectual content. Both authors read and approved the final manuscript.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1741-7015/10/115/prepub


Mesenchymal stem cells (MSC) have generated a great amount of enthusiasm over the past decade as a novel therapeutic paradigm for a variety of diseases. Currently, MSC based clinical trials have been conducted for at least 12 kinds of pathological conditions, with many completed trials demonstrating the safety and efficacy. This review provides an overview of the recent clinical findings related to MSC therapeutic effects. Roles of MSCs in clinical trials conducted to treat graft-versus-host-disease (GVHD) and cardiovascular diseases are highlighted. Clinical application of MSC are mainly attributed to their important four biological properties- the ability to home to sites of inflammation following tissue injury when injected intravenously; to differentiate into various cell types; to secrete multiple bioactive molecules capable of stimulating recovery of injured cells and inhibiting inflammation and to perform immunomodulatory functions. Here, we will discuss these four properties. Moreover, the issues surrounding clinical grade MSCs and principles for MSC therapeutic approaches are also addressed on the transition of MSCs therapy from bench side to bedside. Stem cells have the capacity to self-renew and to give rise to cells of various lineages. Thus, they represent an important paradigm of cell-based therapy for a variety of diseases. Broadly speaking, there are two main types of stem cells, embryonic and non-embryonic. Embryonic stem cells (ESCs) are derived from the inner cell mass of the blastocyst and can differentiate into cells of all three germ layers. However teratoma formation and ethical controversy hamper their research and clinical application. On the other hand, non-embryonic stem cells, mostly adult stem cells, are already somewhat specialized and have limited differentiation potential. They can be isolated from various tissues and are currently the most commonly used seed cells in regenerative medicine. Recently, another type of non-embryonic stem cells, known as induced pluripotent stem cell (iPSC) has emerged as a major breakthrough in regenerative biology. They are generated through enforced expression of defined transcription factors, which reset the fate of somatic cells to an embryonic stem-cell-like state.Cellular therapy has evolved quickly over the last decade both at the level of in vitro and in vivo preclinical research and in clinical trials. Embryonic stem cells and non-embryonic stem cells have all been explored as potential therapeutic strategies for a number of diseases. One type of adult stem cells, mesenchymal stem cells, has generated a great amount of interest in the field of regenerative medicine due to their unique biological properties. MSCs were first discovered in 1968 by Friedenstein as an adherent fibroblast-like population in the bone marrow capable of differentiating into bone . Differe(1) MSCs must be adherent to plastic under standard tissue culture conditions;(2) MSCs must express certain cell surface markers such as CD73, CD90, and CD105, and lack expression of other markers including CD45, CD34, CD14, or CD11b, CD79alpha or CD19 and HLA-DR surface molecules;(3) MSCs must have the capacity to differentiate into osteoblasts, adipocytes, and chondroblasts under in vitro conditions.This review will provide an overview of the recent clinical findings related to MSCs. Roles of MSCs in clinical trials conducted to treat GVHD and cardiovascular diseases are highlighted. The therapeutic effects of MSC are mainly attributed to their four important biological properties. Here, we will discuss these four properties and the issues surrounding use of MSCs that need to be addressed during the transition of MSCs therapy from bench side to bedside.http://clinicaltrials.gov has showed 206 clinical trials using MSCs for a very wide range of therapeutic applications Figure While accumulating data have shown the therapeutic effects of MSCs in animal models of various diseases, we only focus on the clinical application of MSCs in this review. The first clinical trial using culture-expanded MSCs was carried out in 1995 and 15 patients became the recipients of the autologous cells . Since tAcute graft-versus-host disease (aGVHD) occurs after allogeneic hematopoietic stem cell transplant and is associated with high morbidity and mortality -8. CurreAll these studies with varying numbers of patients and different degrees of GVHD severity suggest that complete and partial responses can be achieved in a majority of patients after MSCs infusion and that MSCs might represent a potential novel therapy for GVHD.Despite progression of treatment options, ischemic heart disease and congestive heart failure remain major causes of morbidity and mortality. Cellular therapy for cardiovascular disease heralds an exciting frontier of research. Among the used cell types, MSCs are an attractive candidate for cardiovascular repair due to their abovementioned biological properties. In preclinical studies using experimental animal models of cardiac injury, MSCs had been show to engraft after systemic or local administration and improve the repair of infarcted myocardium -21. In aClinical trials using MSCs to improve cardiac function have also demonstrated encouraging results. For instance, in a pilot study, sixty-nine patients who underwent primary percutaneous coronary intervention within 12 hours after onset of acute myocardial infarction were randomized to receive intracoronary injection of autologous bone marrow mesenchymal stem cell or standard saline. Several imagining techniques demonstrated that MSCs significantly improved left ventricular function . We condHere we summarized the currently completed clinical trials registered with clinicaltrials.gov that using MSC to treat cardiovascular diseases Table . While aIn regard to liver diseases, MSCs have been used to treat cirrhosis in a limited number of patients. In a phase I trial, four patients with decompensated liver cirrhosis were included. They received autologous MSC infusion through a peripheral vein. There were no side-effects in the patients during follow-up. The quality of life of all four patients improved by the end of follow-up . In anotThe use of MSCs in clinical applications requires understanding of their biological characteristics that contribute to the therapeutic effects. Currently, the following four properties are considered the most important Figure : (1) theMSCs have the capacity to migrate to, and engraft in, sites of inflammation after systematic administration and exert local, functional effects in the resident tissue. Various studies have demonstrated that under a variety of pathologic conditions, MSC selectively home to sites of injury, irrespective of the tissue. Ortiz LA et al showed that murine MSCs could home to lung in response to injury, adopt an epithelium-like phenotype, and reduce inflammation in lung tissue of mice challenged with bleomycin . We founCell migration is dependent on a multitude of signals ranging from growth factors to chemokines secreted by injured cells and/or respondent immune cells . MigratiMSCs have the capacity to differentiate into mesenchymal lineages including osteoblasts, adipocytes, and chondroblasts under both in vitro and in vivo conditions . StudiesThe evidence that MSCs were able to differentiate into specialized cells of tissues such as epithelial cells or nervous cells, opened up the possibility of using MSCs to substitute damaged cells for disease treatment. We showed that in a C57BL/6 mouse model of ischemia-reperfusion (I/R) kidney, transplanted MSCs were able to differentiate toward renal tubular epithelium at an early stage of injury. The differentiated donor cells replaced the vacant space left over by the dead cells, therefore contributing to the maintenance of structural integrity and preceded to a subsequent tissue repair process . SeveralMSCs could secrete multiple bioactive molecules including many known growth factors, cytokines and chemokines which have profound effects on local cellular dynamics Table . AdminisA protein-array analysis of MSC-CM detected 69 of 174 assayed proteins and most of these detected molecules are growth factors, cytokines, and chemokines. They have known anti-apoptotic and regeneration-stimulating effects . These eThe ability of MSCs to modulate the immune system was first recognized in 2000 when Liechty KW et al found that MSCs have unique immunologic characteristics that allow their persistence in a xenogeneic environment . Since tMSCs could interact with a wide range of immune cells, including T lymphocytes, B lymphocytes, natural killer cells and dendritic cells. A brief summary of the in vitro interaction of MSCs and immune cells was shown in Table The immunomodulatory functions of MSCs have generated a great amount of interest in their potential for treatment of immune disorders such as GVHD.Over the past decade, there have been a large number of publications on MSCs, reporting their biological properties, experimental and clinical applications or underlying molecular mechanisms. Although tremendous advancements have been made from both preclinical and clinical studies using MSCs, substantial challenges are still to be overcome before MSC therapy can fulfill its promise in wider clinical practice. (1) Safety issue: up to now, few adverse effects have been reported after MSC administration, in terms of immediate, infusional toxicity and of late effects. However, the relatively small number of patients being treated with MSCs does not allow the drawing of definitive conclusions on the safety of MSCs. Furthermore, MSCs has been reported to promote tumor growth  and metaMSC therapies are undergoing rapid development and have generated great excitement amongst scientists and physicians. Currently, more randomized, controlled, multi-centre clinical trials are needed to find the optimal conditions for MSC therapy. We believe that eventually a novel and safe therapy with MSCs can emerge and revolutionize treatment and therapies for patients with severe diseases.MS, Mesenchymal stem cells; GVHD, Graft-versus-host-disease; ESC, Embryonic stem cell; iPSC, Pluripotent stem cell; AMI, Acute myocardial ischemia; ALS, Amyotrophic lateral sclerosis; aGVHD, Acute graft-versus-host disease; PCI, Percutaneous coronary intervention; LVEF, Left ventricular ejection fraction; PBC, Primary biliary cirrhosis; PDGF, Platelet-derived growth factor; IGF-1, Insulin-like growth factor 1; FHF, Fulminant hepatic failure; DCs, Dendritic cells; GMP, Good manufacturing practice.We declare that we have no competing interests.SW drafted the manuscript; XQ formatted the figures and tables, participated in manuscript revision; RCZ designed and drafted the manuscript, gave financial and administrative support. All authors read and approved the final manuscript.


Vascular cognitive impairment (VCI)  describes a continuum of cognitive disorders ranging from mild cognitive impairment (MCI) to dementia, in which vascular brain injury involving regions important for memory, cognition and behavior plays an important role. Clinical diagnostic criteria show moderate sensitivity (ca 50%) and variable specificity (range 64–98%). In Western clinical series, VaD is suggested in 8–10% of cognitively impaired elderly subjects. Its prevalence in autopsy series varies from 0.03 to 58%, with means of 8 to 15% (in Japan 22–35%). Major types of sporadic VaD are multi-infarct encephalopathy, small vessel and strategic infarct type dementias, subcortical arteriosclerotic leukoencephalopathy (SAE) (Binswanger), multilacunar state, mixed cortico-subcortical type, granular cortical atrophy (rare), postischemic encephalopathy, and a mixture of cerebrovascular lesions (CVLs). They result from systemic, cardiac and local large or small vessel disease (SVD); their pathogenesis is multifactorial. Hereditary forms of VaD caused by gene mutations are rare. Cognitive decline is commonly associated with widespread small ischemic vascular lesions involving subcortical brain areas . The lesions affect neuronal networks involved in cognition, memory, and behavior . CVLs often coexist with Alzheimer-type lesions and other pathologies; 25–80% of elderly demented show mixed pathologies. The lesion pattern of “pure” VaD differs from that in mixed dementia (AD + CVLs) suggesting different pathogenesis of both phenotypes. Minor CVLs, except for severe amyloid angiopathy, appear not essential for cognitive impairment in full-blown AD, while both mild AD-type pathology and SVD may interact synergistically in promoting dementia. However, in a large percentage of non-demented elderly individuals, both AD-related and vascular brain pathologies have been reported. Despite recent suggestions for staging and grading CVLs in specific brain areas, due to the high variability of CVLs associated with cognitive impairment, no validated neuropathological criteria are currently available for VaD and mixed dementia. Further clinico-pathological studies and harmonization of neuropathological procedures are needed to validate the diagnostic criteria for VaD and mixed dementia in order to clarify the impact of CVLs and other coexistent pathologies on cognitive impairment as a basis for further successful therapeutic options. Cerebrovascular disease (CVD) is increasingly recognized as a cause of cognitive impairment and dementia in later life either alone or in conjunction with Alzheimer disease (AD) or other pathologies. Cognitive vascular disorder describes a heterogenous group of disorders with different types of cerebrovascular lesions (CVLs) contributing to cognitive decline and finally to the development of dementia. Dementia related to vascular disorders, first described as “arteriosclerotic dementia”  and variable specificity  with variable interrater reliability  between 0.42 and 2.68, increasing with age , arteriosclerosis or cerebral small vessel disease (SVD), and cerebral amyloid angiopathy (CAA) Ince, . These vAtherosclerosis (AS) is a degenerative disorder of large and medium sized arteries that leads to intima proliferation and accumulation of cholesterol within the vessel wall. These processes result in the generation and calcification of atherosclerotic plaques, that rupture frequently and induce local thrombosis. It can cause large brain infarcts, whereas embolism of atherogenic thrombi can lead to a broad variety of infarcts  comprises small vessel arteriosclerosis, lipohyalinosis, and arteriolosclerosis. These vessel wall changes are similar to that of larger blood vessels except for calcifications not seen in small arteries . Sporadic CAA is characterized by the deposition of the amyloid β-protein (Aβ) in the wall of leptomeningeal and cerebral blood vessels , including large lobar hemorrhages, deep bleeds in the basal ganglia, microscopic brain hemorrhages or cerebral micro-bleeds (CMBs), microinfarcts (seen only in microscopic sections), and subarachnoid hemorrhages may all be caused by SVD. It may also cause white matter hyperintensities (WMHs), lacunes and both ischemic and hemorrhagic infarcts. The prevalence and incidence of SVD increases with age, however, the prevalence of the lesions caused by SVD varies in the oldest old: macroscopic ICHs are comparatively rare, while microscopic hemorrhages and CMBs that are often associated with severe CAA  infarcts, mainly related to hemodynamic events and carotid artery stenosis, microinfarcts throughout the brain, often due to embolic disease, small and medium-sized lesions in subcortical functionally important brain areas, lacunes, and white matter lesions (WML). Others are subcortical arteriosclerotic leukoencephalopathy (SAE) or Binswanger's disease, resulting from chronic hypoperfusion . They are caused by vascular and ischemic mechanisms due to large and SVD, cardiac embolic events, hemodynamic events and cerebral ischemia of various etiology, e.g., degenerative or inflammatory angiopathies, genetic arteriopathies, and other rare causes  is characterized by multiple large and small infarcts involving the areas of major cerebral arteries—(sub)territorial lesions of variable size, due to atherosclerosis of extra- and intracranial vessels giving rise to local thromboembolism or hypoperfusion, and cardiac sources of cerebral emboli, while inflammatory angiopathies and hereditary arteriopthies, e.g., CADASIL, more frequently cause lacunar infarcts /microangiopathic dementia: This type is characterized by the presence of lacunes or microinfarcts and microbleeds, predominantly involving central white matter and subcortical structures including thalamus, basal ganglia, internal capsule, brainstem, and cerebellar white matter. They are caused by hypoperfusion due to age- and hypertension-related changes of microvessels , and damage of the blood-brain barrier (BBB), etc.  are histologically defined as blood extravasations into the perivascular and/or Virchow-Robin space usually without disruption of the surrounding tissue and/or very small intracerebral hemorrhages measuring less than 5 mm in diameter. Hemosiderin-laden macrophages and hemosiderin depositions within the perivascular space are generally considered to indicate prior CBMs lacunar state with multiple cortico-subcortical microinfarcts or lacunes“Strategic” infarct dementia (SID) with solitary or multiple small infarcts in functionally important brain areas  that cause cognitive deficits when damaged by CVLs)  infarcts in cerebral convexities or end-field territories between small deep and superficial vessels  caused by diminished perfusion due to atherosclerosis, prolonged episodes of hypotension.Subcortical arteriosclerotic (leuko) encephalopathy type Binswanger (SAE) associated with confluent WMLs or “leukoaraoisis.” The pathology of WMLs includes a triad of demyelination, axonal loss and lacunar infarcts in the periventricular/deep and subcortical white matter ranging from dilatation of the Virchow–Robin spaces to diffuse myelin pallor and microinfarcts, usually sparing the subcortical U-fibers related to the specific pattern of vascular supply. They are caused by microvascular changes due to arteriosclerosis, hyalinosis and focal fibrinoid necrosis of vessels with and without occlusion. SVD may be associated with dilatative arteriopathy Post-ischemic encephalopathy that can be separated into three major groups according to their predominant distribution pattern:Cortical laminar necrosis and their sequelae resulting from cardiac or respiratory arrest, often occurring in arterial border zones and associated with diffuse white matter damage.Multiple post-ischemic lesions after hypotension and focal narrowing of brain-feeding vessels, leading to multiple cortical and subcortical (micro)infarcts.Hippocampal sclerosis (HS), a relatively common neuropathological finding (~10%) in individuals over age 85, is characterized by cell loss and gliosis that is not explained by AD. Caused by hypoxic-ischemic etiology in old subjects with cardiac failure and cerebral hypoperfusion it is often associated with dementia  and behavioral factors  are associated with both CVD and, when present in mid-life, dementia  representing 70% than of large infarcts (volume =10 ml) involving one or both hemispheres (32.5%) Table . This pa ml repreIn conclusion, subcortical lacunes and multiple disseminated microinfarcts appear to represent the most common morphologic features of VaD, while large cystic infarcts are less common (Kalaria et al., Recent emphasis on co-morbidity of AD and CVD, detected in 30–60% of AD brains and showing a large variety of lesions (Jellinger and Attems, VaD/VCD is a heterogeneous disorder, caused by vascular and/or ischemic lesions involving various, often functionally important brain areas and neuronal networks with deafferentation of frontal and limbic cortical structures and interruption of basal ganglia-cortical, cortico-cortical as well as ascending pathways by lesions in basal ganglia, thalamus, white matter, and subfrontal areas. The pattern of cognitive impairment is consistent with models of disturbed cortical and subcortical circuits in producing cognitive decline (Kramer et al., Neurochemical studies in VaD showed abnormalities in key neurotransmitter systems, in particular in the basal forebrain cholinergic system related to diffuse WMLs and other vascular lesions involving the central axonal radiation fields for this projection pathway (Swartz et al., VCI/VaD is a heterogenic group of disorders that provides many challenges to the clinician, neuroradiologist and neuropathologist, in particular because evidence-based studies that seek to provide definite answers often lack clear definitions and validated consensus criteria of the disease (Murray et al., Neuropathology has to describe the nature and severity of vascular pathology using harmonized morphologic procedures and criteria (Alafuzoff et al., Despite various proposals for a categorization of major CVLs (Román et al., Mixed type dementia, being frequent in elderly demented persons, is diagnosed when a combination of several pathologies, e.g., AD with cerebrovascular and/or Lewy pathology, is present (Jellinger, Further development of homogeneous and harmonized neuropathologic definitions and procedures in classifying vascular lesions and/or methods to more accurately characterize the independent severity of vascular and other brain lesions remain an important priority for the future. Development of common standards represents a first step in a process of use, validation and refinement. Universal and interinstitutional use of the same standards will help to identify individuals with cognitive impairment, will make future clinico-pathologic studies comparable, and, by integrating knowledge, will accelerate the pace of progress. An integrative, rather than a strictly taxonomic, approach to the study and elucidation of how vascular disease mechanisms contribute to the development of dementias has been proposed (Kling et al., The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Thanks to the progress in oncostatic treatments, young women affected by cancer have afairly good chance of surviving the disease and leading a normal post-cancer life. Quiteoften, however, polychemiotherapy and/or radiotherapy can induce ovarian damage andsignificantly reduce the content of follicles and oocytes inside the ovary, thus predisposingthe patient to menstrual disorders, infertility, and precocious menopause. Severaltechniques have been proposed to preserve fertility in these patients; among them oocytecollection and cryopreservation prior to the oncostatic treatment has been widely appliedin the last decade. The proper indications, the permitting conditions, the availablehormonal stimulation protocols, as well as the effectiveness and limits of this option will bediscussed herein, with a comprehensive and up-to-date review of the two techniquescommonly used to cryostore oocytes, the slow-freezing technique and the vitrification technique. During the past decade, fertility preservation has become an important issue in cancer patients' management. Survival rates after malignancy treatment have improved markedly, especially for young women affected by melanoma, oncohaematological diseases, and breast cancer, leading to the generation of long-term cancer survivors , 2; noneMany approaches have been considered to preserve fertility and avoid POI. Embryo cryostorage has been considered for years the only valid option, albeit this procedure is applicable only to stable couples and not to singles, and still raises a lot of ethical, legal, and practical concerns. Ovarian cortex ablation and cryostorage, with subsequent autografting, is the only strategy which can be proposed to prepubertal girls, though it is still considered an experimental approach with limited results.in vitro fertilization (IVF), over 2000 babies were born in nononcological, routine IVF patients.Nowadays, oocyte cryostorage is considered an important tool for fertility preservation worldwide, as no surgery is required and minimally invasive ovarian stimulation protocols are available. Moreover, storing oocytes implies no concerns regarding possible cancer cells contamination, a problem that affects ovarian cortex retransplantation strategy . As a reSince oocyte cryostorage was introduced in the mid 1980s, general interest rose around the possibility of increasing pregnancy rates using frozen eggs, overcoming the ethical and legal concerns related to embryo freezing.Since the very beginning oocyte freezing was quite problematic, with survival and fertility rates below 50%, and pregnancy rates as low as 1-2% –10. ChenCryobiologists encountered several problems in freezing oocytes, including ice crystal formation, osmotic stress, and cryoprotectant agents (CPAs) toxicity , 18, 19.Cryobiology aims at minimizing these harmful effects on the human oocyte, and by now, two well-established laboratory protocols have been proposed and are widely diffused in the clinical practice: the slow freezing protocol and the vitrification procedure.Fertility preservation should be discussed with all young women at high risk of POI. The most common cause of POI are ovarotoxic anticancer therapies, and cancer patients are by far the main candidates to fertility preservation. However, benign diseases like some genetic syndromes , ovarian diseases (severe endometriosis or ovarian cysts requiring ablative surgery), or autoimmune disorders requiring immunosuppressive therapy may determine POI as well.Cancer in women in reproductive age is an increasing problem. The American Cancer Society estimates that 1/47 women will develop a cancer before the age of 39 . Every year, about 200.000 new cases of breast cancer are diagnosed in USA, 15% of which occur in women under the age of 45. Most of these patients will receive adjuvant chemotherapy with alkylating drugs 4 to 6 weeks after surgery, developing a high risk of POI  (NationaEven nonneoplastic diseases (autoimmune disorders or benign haematologic diseases being treated with chemo- or radiotherapy) should routinely implicate the offer of oocyte cryopreservation , 33.The selection of candidates for fertility preservation is crucial in order to offer the best suitable technique for each patient. Oocyte cryopreservation is probably the best technique to preserve fertility of women without an established partner or wishing to avoid ethical and legal problems associated with embryo cryostorage. When feasible, oocyte cryostorage may be preferable to ovarian tissue freezing because it does not require surgery and has already resulted in many live births . The most important limiting factor for oocyte cryopreservation is age: storing oocytes in women after 40 years of age will probably result in a very poor chance to get a pregnancy in the future. Indeed, patients with a poor ovarian reserve have to be screened carefully, since they may not benefit from the treatment. Ovarian reserve assessment is crucial for patients requiring oocyte cryostorage: besides age, the antral follicle count and hormonal parameters such as FSH and anti-Mullerian hormone (AMH) have to be carefully considered. On the other side, oocyte cryopreservation is unavailable for prepubertal girls because the ovarian stimulation used to obtain oocytes needs the full maturity of the hypothalamus-pituitary-ovarian axis.Another limiting issue is the timing of the procedure: oocyte cryopreservation requires an average of 12 days for ovarian stimulation and ovum pickup (OPU) to occur . Women sOocyte cryopreservation implies a controlled ovarian hyperstimulation with exogenous gonadotropins that leads to largely supraphysiological levels of serum estradiol. Type and stage of the neoplastic disease and the patient's overall health influence the feasibility of an ovarian stimulation, and stimulation protocols must be individualized for every woman. In this perspective, the use of conventional ovarian stimulation protocols is possible only in women with estrogen-insensitive tumours, while hormone-responsive diseases require appropriate regimens .Each protocol that aims at obtaining oocytes for cryostorage should be (i) safe, with limited risk of stimulating the growth of a pre-existing neoplasia, (ii) fast, with very limited delay in starting cancer therapy, (iii) effective, with good chances of oocyte retrieval.Ovarian stimulation requires approximately 10–14 days to achieve mature oocytes at OPU. In case of estrogen-sensitive diseases, the protocol with letrozole  plus gonadotropins (150–300 IU of recombinant FSH) and GnRH-antagonists , a GnRH-in vitro maturation (IVM) followed by vitrification for cryostorage is now available [in vitro maturation (IVM) resulted in several live births [in vitro and then frozen [A growing literature showing encouraging results of oocyte vailable , 39. Thie births  and it in frozen . The potn frozen , 43. in vitro to metaphase II [Overall, some data suggest that immature oocytes could be less sensible to cryodamage than mature oocytes because their nuclear apparatus is still not fully developed, and after thawing, they can be matured phase II , 57. Cryphase II .The slow freezing/rapid thawing method was the first cryostorage protocol adopted for oocytes in IVF laboratories. It was originally introduced with the aim to preserve supernumerary embryos obtained from assisted reproduction procedures , 60.Oocyte freezing was initially a damping technique: rates of survival and cleavage after thawing were significantly lower than those obtained using zygote or cleavage stage embryos. The major burden of mammalian egg cryopreservation was found to be membrane permeability to cryoprotectants: after fertilization, in the zygote and in the cleavage-stage embryo, water permeability kinetics change, rendering the cells more prone to freezing .The original protocol introduced for mouse embryo cryopreservation was slightly modified and adapted to human cells . Small pAnother crucial point of the oocyte freezing technique is the rate of freezing, which has to be performed under strictly controlled conditions: room temperature, as well as equilibration temperature of cryopreservation media, is able to interfere with membrane permeability to cryoprotectants, possibly affecting the oocyte survival chance . MoreoveThe slow freezing protocol has been considered the gold standard technique for oocyte cryopreservation for years; it is a well-established procedure with survival rates usually as high as 60–80%  45, 47,, 67, 68.Clinical reports on slow freezing show a pregnancy rate ranging between 13 and 20% (pregnancy/embryo transfer)  and implIn standard IVF procedures, cryopreserving oocytes combines the chances to achieve a pregnancy by both fresh and thawing cycles, thus yielding a rather high cumulative pregnancy rate .Early studies on oocyte vitrification were performed at the end of 1980s, when the first attempts on mouse or hamster eggs were reported , 71. TheThe scientific basis of vitrification consists in the ultrarapid freezing of cells, whose intra- and extracellular aqueous environment turns into a glassy-like state. Vitrification combines two different biophysical processes: a preliminary equilibration step, in which oocytes are exposed to low concentrations of cryoprotectants to allow water outflow, and a subsequent vitrification phase in which cells undergo a high osmotic gradient that completes cells dehydration. Under these conditions, oocytes can be directly merged into liquid nitrogen and then stored. Similarly, warming of oocytes must be rapid in order to avoid recrystallization of water.The cryoprotectants used during vitrification are the same employed for slow freezing, but they are three-to-four-folds more concentrated in vitrificaton than in slow freezing. DMSO, PROH, and ethylene glycol (EG) (5-6 M) as well as sucrose (1 M) are currently used, though their toxicity is still under evaluation . Appropriate carriers for freezing oocytes are also very important. Successful vitrification occurs when samples are loaded in a minimal fluid volume and then frozen/thawed at an extremely fast rate (1500–2000°C/min). Open systems guarantee direct contact with liquid nitrogen , 75: opeAlthough no cross-contamination between liquid nitrogen and stored oocytes has been signalled to date, closed systems may provide the safer and probably most effective vitrification procedure. In particular, many carriers have been approved by FDA in the last years, and several of them are now commercially available: Cryotip , high-security vitrification (HSV) straw , VitriSafe , Cryopette , and Rapid-i (Vitrolife Sweden AB) . DNA int Oocyte survival after vitrification reaches 90% in several reports  38, 42,, 54, 81.Data on the clinical use of vitrified eggs in routine IVF show that pregnancy rates can be comparable to those achieved with fresh oocytes  9, 54, , 54, 85.Cryostoring oocytes is an effective method to preserve fertility in postpubertal young women at risk of POI. In the last years, significant improvements in the clinical effectiveness of oocyte freezing/thawing techniques have been achieved using both slow freezing method and vitrification. The available trials comparing these two different approaches are still insufficient to establish the superiority of one over the other, but the growing interest of scientist and the increasing awareness of women about the possibility of storing oocytes will likely lead to the development of an optimal protocol for oocyte storage in the next few years.


The assembly of functional neural circuits is critical for complex thoughts, behavior and general brain function. Precise construction of neural circuits requires orderly transition of sequential events from axon outgrowth, pathfinding, branching, to synaptogenesis. Each of these steps is required to be tightly regulated in order to achieve meticulous formation of neuronal connections. MicroRNAs (miRNAs), which silence gene expression post-transcriptionally via either inhibition of translation or destabilization of messenger RNAs, have emerged as key regulators of neuronal connectivity. The expression of miRNAs in neurons is often temporally and spatially regulated, providing critical timing and local mechanisms that prime neuronal growth cones for dynamic responses to extrinsic cues. Here we summarize recent findings of miRNA regulation of neuronal connectivity in a variety of experimental platforms. The diverse behaviors of organisms rely on fast information processing performed by the brain. Trillions of neurons comprising the brain form complex networks that enable animals to exhibit consciousness, accumulate memories, engage in learning, and adopt behaviors. The complexity of brain networks is greatly increased by the facts that one neuron can influence its target through multiple pathways , and thaNeurons connect with targets through a series of events: axon initiation, axon pathfinding, axon branching, and synapse formation . A singlMiRNA-mediated gene regulation is involved in many aspects of neuronal development and function . Recent MiRNA expression is either spatially restricted or temporally regulated in neuronal development. The spatially restricted expression of miRNAs within neurons suggests roles for miRNAs in diverse differentiation events from axon pathfinding to synapse formation. Many miRNAs are expressed specifically in the nervous system, and even in distinct neuronal subsets, implying potentially unique roles in specific cell types. . FurtherTable 1). miR-132, for example, induces neurite sprouting of cortical neurons. It does so by inhibiting the p250 GTPase-activating protein that acts upstream of small GTPases Cdc42 and RhoA, to regulate neuronal morphogenesis  projects a single axon to the ventral nerve cord in the fourth larva (L4) stage  stage . The hetormation . No axon neurons . The tarommitted .Axons are directed to their synaptic targets via the guidance of attractive or repellent cues presented in the environment . The senC. elegans anterior ventral microtubule (AVM) sensory neurons is guided to the ventral midline through combined actions of Slit repulsion from the dorsal body wall muscles and netrin attraction to the ventral nerve cord . An unexpected role was recently reported for the conserved heterochronic miRNA lin-4 and its target the LIN-14 transcription factor in AVM neuronal connectivity (lin-4 functions as a potent and specific negative regulator of netrin signaling in AVM neuronal connectivity by targeting the LIN-14 transcription factor to control the availability of the netrin receptor UNC-40/DCC (Deleted in Colorectal Cancer; Figure 1B; Netrins are highly conserved guidance molecules that can function as both attractants and repellents in many stage-dependent biological events, such as axon guidance and motile cell migration , but therve cord . Once reectivity . ThroughXenopus (The Semaphorin family contains both secreted and transmembrane proteins that can function in long- or short-range guidance . Many SeXenopus . The SemXenopus , 2013. TXenopus , 2013. AXenopus , 2013. TXenopus , 2013. TSlit is another key guidance molecule that is able to elicit axonal repulsion from a distance . The miRin vitro, shorter exposure to BDNF results in reduced miR-9 expression, which leads to high level of Map1b expression and steady axon outgrowth. Prolonged exposure to BDNF, which could mimic the target recognition phase in vivo, results in elevated miR-9 expression, which leads to axon branching as a result of the repressed Map1b expression (Once axons are in the vicinity of synaptic targets, they slow down outgrowth and branch out to form elaborate neural networks . Similarpression . In hipppression . The Rhopression .The exquisite precision with which neural circuits are assembled is crucial for proper brain function, as inappropriate wiring in the nervous system results in various debilitating neurological diseases. Neurons are able to form appropriate connections using processes that involve spatial and temporal regulatory mechanisms, which ensure rapid responses to diverse environmental cues and faithful transition of sequential events in neuronal connectivity. miRNAs have proven to be essential and efficient regulators at several steps of this integral process due to their spatiotemporal specificity, versatile targeting, speed of gene repression, and ease of reversibility. Further study on how miRNAs contribute to the formation of neural circuits will ultimately provide insights into how mis-wiring by miRNA mis-regulation can lead to diseases.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.