Drosophila melanogaster have uncovered that DANs in the fly brain are also spontaneously active, and that this activity reflects the behavioral/internal states of the animal. Strikingly, genetic manipulation of basal DAN activity resulted in behavioral alterations in the fly, providing critical evidence that links spontaneous DAN activity to behavioral states. Furthermore, circuit-level analyses have started to reveal cellular and molecular mechanisms that mediate or regulate spontaneous DAN activity. Through reviewing recent findings in different animals with the major focus on flies, we will discuss potential roles of this physiological phenomenon in directing animal behaviors.Dopamine modulates a variety of animal behaviors that range from sleep and learning to courtship and aggression. Besides its well-known phasic firing to natural reward, a substantial number of dopamine neurons (DANs) are known to exhibit ongoing intrinsic activity in the absence of an external stimulus. While accumulating evidence points at functional implications for these intrinsic “spontaneous activities” of DANs in cognitive processes, a causal link to behavior and its underlying mechanisms has yet to be elucidated. Recent physiological studies in the model organism  Animals need to modify behaviors according not only to the external world but also to their internal states, such as sleep need, hunger, or sexual motivation  was observed when animals are in REM sleep  has a central role in the regulation of the sleep-wake balance. A single pair of DANs projecting to the dFB promotes wakefulness, and dopamine receptors are necessary in the dFB neurons to process the waking signal  strongly correlates with the behavioral activity of rats    without external stimuli. In flies, repetitive training of paired presentations of odor cues and electric shocks with intervals (spaced training) is commonly used for the induction of aversive LTM , a gustatory center in the insect brain, is reported to control taste sensitivity to sucrose  cluster encode protein hunger : D1- to D5-type receptors (D1R–D5R). It is commonly accepted that D1R and D5R mainly recruit the GαDrosophila, four dopamine receptors, DopR1 , Dop2R, DopR2  and DopEcR exist in the genome (Adams et al., Xenopus oocyte suggested it to be excitatory (Reale et al., in vitro but with different cell lines, and never been directly compared. It is thus important to measure the threshold of these receptors for correct interpretation of functional results.In Nonetheless, accumulating behavioral and physiological evidence suggests the critical role of DopR2 in the detection of spontaneous activity of DANs. DopR2 was shown to be critical in regulation of sleep in the dFB (Pimentel et al., in-vivo electrophysiology experiments demonstrated that DopR2 in the dFB neurons mediates the wake-promoting dopamine signaling (Pimentel et al., o and thereby hyperpolarizes the membrane potential through modulating specific K+ channels (Pimentel et al., in vitro (Han et al., Exquisite DopR2 in the MB is also responsible for detecting the spontaneous activity of MV1 or MP1 DANs during memory maintenance (Berry et al., Drosophila addressed intracellular signaling molecules that mediate the effect of spontaneous DAN activity (Cervantes-Sandoval et al., o family (Thambi et al., Xenopus oocyte system (Reale et al., Two of the recent studies in Drosophila studies. Importantly, different internal animal states, e.g., hunger, sleep need, or sexual drive, are represented by different yet partially overlapping DAN cell types. This combinatorial state coding is reminiscent of various reinforcement signals conveyed by different combinations of DANs (Aso et al., In this article, we have reviewed diverse functions of spontaneous activity of DANs, paying special attention to recent In some cases, spontaneous DAN activity functions as an information filter to enable animals to respond differently to the same sensory input, such as food, food-associated cues or potential mating partners, depending on the physiological state (Inagaki et al., TI, HT, and NY wrote the manuscript and designed the figures.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.


Musculoskeletal pain due to ischemia is present in a variety of clinical conditions including peripheral vascular disease (PVD), sickle cell disease (SCD), complex regional pain syndrome (CRPS), and even fibromyalgia (FM). The clinical features associated with deep tissue ischemia are unique because although the subjective description of pain is common to other forms of myalgia, patients with ischemic muscle pain often respond poorly to conventional analgesic therapies. Moreover, these patients also display increased cardiovascular responses to muscle contraction, which often leads to exercise intolerance or exacerbation of underlying cardiovascular conditions. This suggests that the mechanisms of myalgia development and the role of altered cardiovascular function under conditions of ischemia may be distinct compared to other injuries/diseases of the muscles. It is widely accepted that group III and IV muscle afferents play an important role in the development of pain due to ischemia. These same muscle afferents also form the sensory component of the exercise pressor reflex (EPR), which is the increase in heart rate and blood pressure (BP) experienced after muscle contraction. Studies suggest that afferent sensitization after ischemia depends on interactions between purinergic (P2X and P2Y) receptors, transient receptor potential (TRP) channels, and acid sensing ion channels (ASICs) in individual populations of peripheral sensory neurons. Specific alterations in primary afferent function through these receptor mechanisms correlate with increased pain related behaviors and altered EPRs. Recent evidence suggests that factors within the muscles during ischemic conditions including upregulation of growth factors and cytokines, and microvascular changes may be linked to the overexpression of these different receptor molecules in the dorsal root ganglia (DRG) that in turn modulate pain and sympathetic reflexes. In this review article, we will discuss the peripheral mechanisms involved in the development of ischemic myalgia and the role that primary sensory neurons play in EPR modulation. Pain is a common clinical complaint resulting in a significant financial burden to both patients and society. In the U.S. alone, studies have estimated the mean cost of pain per patient at about $9K in adults and $12K in adolescents. The annual cost to society is over $635 billion  injury that is characterized by the generation of free radicals Debold,  and reacex vivo , a well-studied cardiovascular reflex arc that causes an increase in heart rate and blood pressure (BP) during exercise  and unmyelinated (C) neurons, whose cell bodies rest in the dorsal root ganglia (DRG), consist primarily of a long axon that gives rise to free nerve endings in the muscle tissue Stacey, . Some stInitially, group III and IV muscle afferents were studied to determine their roles in the generation of the EPR  were chemosensitive. In line with the work of Light et al. , as well as polymodal nociceptors have been extensively characterized electrophysiologically both t et al. , two dist et al. .The two previously mentioned sub-populations of metaboreceptors (“low metabolite” responders) and metabo-nociceptors (“high metabolite” responders) along with their response properties are extensively altered following ischemic injury. Transient or prolonged ischemic insult to the muscles decreased mechanical thresholds and increased firing to mechanical stimulation in group III and IV muscle afferents (Ross et al., The increased mechanical sensitivity in primary afferents as well as the enhanced response to “low metabolites”, combined with the greater number of afferents responding to both noxious and non-noxious metabolite stimuli, correlate with increased behavioral responses after ischemic injury. In rats, models that cause ischemia-reperfusion via a hind limb tourniquet induced mechanical hyperalgesia and allodynia in the treated animals, accompanied by cold hyperalgesia (Coderre et al., After ischemic injury to the periphery, a diversity of channels and membrane receptors are upregulated in the DRGs Figure . Many ofin vitro from these animals showed increased responses to capsaicin, a TRPV1 agonist, compared to neurons from sham animals. Also in this model, there was an increase in the sympathetic response to arterial injection of capsaicin in the animals exposed to femoral artery occlusion compared to controls. In another femoral occlusion model, the pressor response evoked by intra-arterial injection of capsaicin into the injured hind limb more than doubled the response elicited by the same injection in the contralateral, uninjured limb (Tsuchimochi et al., TRPV1 has been associated with the development of ischemic pain in different models. Studies in humanized hemoglobin transgenic SCD mice have shown that TRPV1 plays a role in cutaneous afferent sensitization (Hillery et al., However, these findings are in contrast with other reports in which gene expression analysis in male mouse DRGs that innervate muscle tissue exposed to I/R or prolonged BAO injury did not show changes in TRPV1 mRNA expression 24 h after injury (Ross et al., There is ample evidence for the role of P2 receptors and how they affect afferent response to ischemia. As an example, the non-selective P2 receptor inhibitor PPADS, attenuates the EPR elicited by static contraction of the muscle (Kindig et al., ASIC and P2X receptors may also be key players in the afferent sensitization that is observed after ischemic injury (Dunn et al., The role of other P2X receptors in the development of ischemic myalgia is less clear. P2X3 is upregulated after I/R injuries and the total number of positive neurons in the DRG innervating ischemia-affected muscle tissue are also increased (Cairns et al., in vitro study showing that ATP enhances the response of ASIC3 to low pH. In this report, only the interaction between P2X5 and ASIC3 activation mimics the enhanced response to low pH and ATP that is observed in sensory neurons. Furthermore, about 25% of DRG neurons express P2X5 and of these neurons, about half co-express ASIC3 (Birdsong et al., in vivo or ex vivo is still required.P2X receptors also modulate the function of ASIC3, another key mediator of pain generation. Targeting this acid-sensing ion channel can effectively reduce muscle pain in different animal models (Sluka et al., In the specific context of ischemia, total DRG ASIC3 mRNA expression is increased in different injury models, and the total number of ASIC3 positive cells in the DRG increases (Queme et al., P2X receptors are not the only purinergic receptors that are relevant after ischemic injuries. In a prolonged ischemia model, expression of the ADP sensitive, P2Y1 receptor, was found to be upregulated in the DRGs (Ross et al., Ischemic injury alone does not likely drive all of the aforementioned changes in primary muscle afferents. Increased gene expression and concomitant afferent sensitization can also be linked to increased signaling from the damaged muscle tissue. Current evidence points at two important sources: cytokines and growth factors. These molecules are released into the intramuscular environment in response to the tissue damage caused by ischemia (Ascer et al., NGF has been frequently linked with the development of pain and hyperalgesia in various animal models and clinical conditions (Amaya et al., GDNF, another growth factor frequently tied to pain perception, is highly expressed in the muscles after ischemic injuries (Ross et al., One of the better characterized pro-nociceptive signals that is increased in injured muscles after ischemic injury is IL1β. This cytokine has been associated with pain development in multiple models ranging from muscle overuse (Noma et al., Another possible site of action for these various cytokines and growth factors is the DRG itself. Reports have highlighted the contributions of glial cells through cytokine release in models of neuropathic pain (Mika et al., Chronic pain conditions are more prevalent in women (Wijnhoven et al., in vivo behavioral results suggesting lower mechanical thresholds in females, mechanical thresholds were found to be significantly higher in females during patch clamp recordings of retrogradely labeled afferents (Hendrich et al., Recent studies have provided evidence for sex-dependent immune reactions that lead to differential brain and spinal cord sensitization mechanisms in a variety of rodent injury models (Sorge et al., In our own investigation of female muscle afferents, we have found distinct changes in gene expression within the affected DRGs following I/R. Whereas males show a robust upregulation of ASIC3 after I/R, which corresponded with alterations in behavior and afferent sensitivity (Ross et al., Interestingly, human and animal studies have shown that females also have decreased EPRs compared to males (Ettinger et al., Adequate management of the multiple complications in patients with ischemic injuries presents a variety of challenges. While patients with conditions like PVD and FM experience great benefits from an active lifestyle and physical therapy (Busch et al., SCD presents different challenges. Many patients with this condition are children and teenagers (Wilson and Nelson, Skeletal muscle ischemia is a strong driver of peripheral afferent sensitization, exerting robust effects through complex signaling cascades, resulting in the development of deep tissue pain and altered EPRs Figure . MultiplLFQ and MPJ planned the manuscript. LFQ and JLR analyzed the literature and wrote the manuscript with guidance from MPJ. All authors edited, read and approved the manuscript.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.


Although MCS between endoplasmic reticulum and mitochondria have been well studied and characterized in different contexts, emerging evidence indicates that lysosomes also exhibit close proximity with mitochondria, which translates in their mutual functional regulation. Indeed, as best illustrated in NPC disease, alterations in the lysosomal-mitochondrial liaisons underlie the secondary accumulation of specific lipids, such as cholesterol in mitochondria, resulting in mitochondrial dysfunction and defective antioxidant defense, which contribute to disease progression. Thus, a better understanding of the lysosomal and mitochondrial interactions and trafficking may identify novel targets for the treatment of Niemann-Pick disease.Lysosomal storage disorders (LSD) are characterized by the accumulation of diverse lipid species in lysosomes. Niemann-Pick type A/B (NPA/B) and type C diseases Niemann-Pick type C (NPC) are progressive LSD caused by loss of function of distinct lysosomal-residing proteins, acid sphingomyelinase and NPC1, respectively. While the primary cause of these diseases differs, both share common biochemical features, including the accumulation of sphingolipids and cholesterol, predominantly in endolysosomes. Besides these alterations in lysosomal homeostasis and function due to accumulation of specific lipid species, the lysosomal functional defects can have far-reaching consequences, disrupting  NPC1 and NPC2 genes, resulting in functional defects in the lysosomal proteins NPC1 and NPC2, involved in cholesterol efflux from lysosomes.Niemann-Pick (NP) diseases encompass a group of autosomal recessive lysosomal storage disorders (LSD), characterized by the accumulation of diverse lipid species in lysosomes. While these diseases were initially considered a single entity with overlapping biochemical, pathological and clinical features, developing evidence demonstrated differential etiological causes phosphate, glucocerebroside, GM2 and GM3 gangliosides and sphingosine also accumulate in lysosomes  and NPC diseases are caused by defects in lysosomal homeostasis and function, there are significant differences between these diseases in relation to the degree of cholesterol trafficking to mitochondria, with the consequent impact in mitochondrial dysfunction and impairment in antioxidant defense strategies. In this review, we summarize the biochemical and genetic features of both diseases, highlighting their commonalities and differences regarding lysosomal-mitochondrial cholesterol trafficking and communication as the molecular basis to understand the differential involvement of mitochondrial dysfunction in NPC disease. Further understanding the lysosomal and mitochondrial liaisons in NP diseases may thus provide the opportunity to improve and expand the current armamentarium for the treatment of these lysosomal disorders.The clinical diagnosis of NPA and NPB diseases is mainly based on the presence or absence of neurological symptons , which is located on chromosome 11 locus 11p15.4-p15.1. More than 180 pathogenic mutations in the SMPD1 gene in patients with NPA and NPB have been identified, which are concentrated in exon two  and represent a valid model to examine lysosomal-mitochondrial communications that underlie the widespread defects in intracellular lipid transport.NPC1 is a multi transmembrane protein located in late endosomes and lysosomes  constitutes a highly dynamic membrane structure that plays a key role in the maintenance of cellular homeostasis, as well as in the digestion and recycling of cellular components and in lipid metabolism and trafficking  to the inner mitochondrial membrane (IMM), where it is converted to pregnenolone by P450scc Stocco, . MutatioThe trafficking of free cholesterol to OMM is mediated by several steps that involve various intracellular organelles, including lysosomes and lipid droplets (LD) and specific proteins, such as the translocator protein (TSPO) and voltage-dependent anion channel (VDAC) (Elustondo et al., Interestingly, 15 genes identified by sequence homology with the StAR hydrophobic lipid-binding pocket domain of approximately 210 amino acids have been described in human and mouse (Ponting and Aravind, The extramitochondrial source of the cholesterol pool that reaches mitochondria is not fully understood and could originate from LD, ER, the endosomal pathway or the plasma membrane (Rone et al., Another source of mitochondrial cholesterol is the ER. To reach mitochondria, cholesterol from the ER is transported by cytosolic proteins, such as the PAP7 protein, which interacts with TSPO and StARD proteins (Liu et al., Due to the relevance of lysosomal-mitochondrial liaisons in NPC, understanding the trafficking of lysosomal cholesterol to mitochondria may be essential for the pathophysiology of the disease. Interestingly, although astrocytes from NPC1 deficient mice exhibit decreased expression of StARD1 protein and mRNA levels (Chen et al., Mln64 mutant allele exhibited minor perturbations in the metabolism and in the intracellular distribution of cholesterol, questioning its contribution in the intramitochondrial trafficking of cholesterol (Kishida et al., critical role of this protein in steroidogenesis and hence in the trafficking of cholesterol to IMM for processing. Thus, although the understanding of the pathways of mitochondrial cholesterol trafficking and accumulation in NPC disease still remains elusive, this process is important for the progression of the disease and its further characterization may be key for the design of future therapies. Whether StARD1 in partnership with StARD3 are critical in this process remains to be fully established.Despite this evidence for a putative role of StARD3 in mitochondrial cholesterol trafficking, targeted mutation of the StARD3 StART domain has been shown to cause only modest alterations in cellular sterol metabolism and mice homozygous for the Mitochondria are double-membrane organelles that are essential for energy supply, metabolism, production of reactive oxygen species and apoptosis signaling Hatefi, . MitochoBesides Parkin and PINK1, which play a key role in mitophagy (McLelland et al., −/− mice than in NPC fibroblasts (Ordonez, A considerable body of evidence suggests that impaired autophagy contributes to lysosomal lipid storage in LSDs through the accumulation of ubiquitinated proteins and dysfunctional organelles, including mitochondria (Platt et al., Ordonez, . MoreoveOrdonez, .Another factor that can contribute to impaired autophagy and defective clearance of dysfunctional mitochondria is the accumulation of sphingosine in lysosomes, which has been shown to disrupt calcium homeostasis (Lloyd-Evans et al., −/− mice exhibit impaired autophagy flux determined by the combination of rapamycin with or without chloroquine, an effect that was accompanied by increased LC3BII and p62 levels. In addition, ASMase−/− hepatocytes displayed impaired fusion of autophagosome-containing mitochondria with lysosomes in response to acetaminophen, which translated in increased susceptibility to acetaminophen-mediated liver injury by sustaining mitochondrial damage (Baulies et al., −/− mice from acetaminophen-mediated liver injury. Moreover, human B lymphocytes from patients with NPB disease exhibit alterations in the rate of autophagic vacuole accumulation, mitochondrial fragmentation and mitophagy induction, indicating impaired clearance of damaged mitochondria (Canonico et al., In parallel with these findings in NPC, there is also evidence of autophagy defects in NPA/B diseases (Fucho et al., −/− mice (Figure In contrast to defective autophagy, which is common to NPA and NPC, intracellular cholesterol trafficking and accumulation in mitochondria is a differential feature between NPA/B and NPC diseases Figure . Althouge Figure , and thie Figure . Moreovee Figure . The mece Figure . As acide Figure , it remae Figure , which ie Figure . As the e Figure .−/− mice and in fibroblasts from NPC patients, leading to increased median survival and maximal life span of Npc1−/− mice, protection against oxidative stress and oxidant-induced cell death and restoration of calbindin levels in cerebellar Purkinje cells, which improved locomotor impairment in Npc1−/− mice. In addition, high-resolution respirometry analyses showed that GSH-EE treatment improved oxidative phosphorylation, coupled respiration and maximal electron transfer in cerebellum of Npc1−/− mice (Torres et al., −/− mice (Fu et al., −/− mice (Marín et al., Increased mitochondrial cholesterol content in NPC cells can lead to important functional consequences, such as decreased mitochondrial membrane fluidity (Colell et al., 2+ buffering capacity of mitochondria (Kiselyov and Muallem, 2+ homeostasis (Jennings et al., 2+ homeostasis preceded by the accumulation of sphingosine that impairs the endocytic pathway (Lloyd-Evans et al., 2+ content and function remains to be established. In addition, further work is needed to demonstrate a causal role for the disruption of Ca2+ homeostasis in the death of the Purkinje neurons in NPC disease, as shown in other related diseases (Girard et al., In addition to these events, mitochondrial cholesterol loading may impair mitochondrial dynamics reflected in the balance between fusion and fission events. Disruption of appropriate mitochondrial fluidity following cholesterol accumulation can prevent the fusion of mitochondria with adjacent healthy mitochondria (Baker et al., Although the genetic causes of NPA and NPC disease are well understood, the consequences at the level of disruption of intracelular trafficking and interorganelle communication is still incomplete, thus limiting the availability of effective therapy. Enzyme replacement therapy for ASMase and NPC1 deficiency is expected to successfully treat peripheral non-neuronal symptoms of both diseases (Schuchman and Desnick, ST, EB, SZ, CE, CG-R, and JF-C discussed findings, analyzed literature and wrote the manuscript. ST, CG-R, and JF-C designed the schematic Figures.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.


An overview of the most relevant papers in the International Journal of Cardiovascular Imaging over the year 2016 for the different modalities. Relatively few manuscripts in the field of X-ray imaging were published in 2016. The far majorities were in MSCT, MRI and echocardiography, followed by nuclear cardiology and intravascular imaging, of which the last one is not included in this overview.Author He et al. described the use of the Myocardial Perfusion Frame Count (TMPFC) technique as an indicator to predict left ventricular systolic dysfunction in the sub-acute phase of STEMI . They coThe team of Starek et al. tested various acquisition protocols for the right atrium and the left atrium to create 3D models of the atria and esophagus using 3D rotational angiography . They usAnother topic that received attention was longitudinal stent deformation and the longer term clinical outcomes . Guler eTimmins et al. compared in a very small cohort of patients (n = 5) with non-obstructive coronary artery disease biplane angiographic versus intravascular ultrasound derived reconstructed coronary geometries, assessed wall shear stress and the association of wall shear stress and CAD progression after 6 months [Donmet et al. studied in a population of 81 patients the changes over time in non-culprit lesions in patients wih ST segment elevated myocardial infarction using QCA . They foIn 2016 different excellent paper in the field of nuclear cardiology were published in the journal. In this review we selected a few papers on technical advances, atherosclerosis imaging, imaging in heart failure and FDG PET/CT imaging in infective endocarditis.Perfusion SPECT imaging may be technically challenging in obese patients and data on its prognostic value in the obese are rather scarce. De Lorenzo et al.  studied High efficiency CZT cameras provide also an opportunity to lower the injected activities of radiopharmaceuticals for SPECT myocardial imaging. Kincl et al.  evaluateSeveral excellent reviews on the topics of atherosclerosis and multi-modality imaging were published in 2016. FDG-PET has shown promise in detecting metabolically active inflammatory cell infiltrates associated with vulnerable atherosclerotic plaque. In contrast to previous ex vivo studies incuatong plaque specimens with FDG after excision, Liu et al.  investigLeft ventricular dyssynchrony (LVD) is an independent predictor of adverse cardiovascular events and progression to heart failure. It can also be potentially corrected with cardiac resynchronization therapy. LVD can be diagnosed using phase analysis on myocardial perfusion imaging with ECG-gated SPECT. Tavares et al.  evaluateRecent studies have shown promising results using (18)F-FDG PET/CT for the diagnosis of prosthetic valve endocarditis (PVE) and the use of this nuclear imaging technique has been recently advocated in American and European guidelines on the management of endocarditis. However, negative controls were usually lacking in these studies. Fagman et al.  comparedIn the 2016 edition of the International Journal of Cardiovascular Imaging several interesting studies were published in the field of cardiac ultrasound. Some of them are discussed in this overview.The American and European scientific echo community have published an algorithm for the grading of diastolic function. However, the ability to use this algorithm effectively in daily clinical practice has not been investigated. Van Dalen et al. hypothesized that in some patients it may be difficult to grade diastolic dysfunction with this scheme, since there may be discrepancies in the assessed parameters . The ASE2 of 44.9% was obtained. When excluding either of LAVImin or E/e′ the model fit was significantly reduced. In contrast, when LAVImax was excluded the model fit was preserved. To detect an NT-proBNP level of >125 ng/L, LAVImin yielded a significantly larger area under the receiver operating characteristic curve than LAVImax and E/e′. In this community-based sample, LAVImin was more strongly associated with NT-proBNP than LAVImax. Moreover, the discriminatory power to detect an elevated NT-proBNP level was stronger in LAVImin than in LAVImax and E/e′. These findings support previous data that LAVImin may be more closely related to left ventricular filling function than LAVImax.Previous data have demonstrated that left atrial (LA) minimum volume indexed for body surface area (LAVImin) is more strongly associated with the Doppler echocardiographic E/e′ ratio than LA maximum volume index (LAVImax). Hedberg et al. sought to explore if LAVImin was more closely related to serum levels of NT-proBNP than LAVImax and E/e′ in the community . A commuDe Groot-de Laat et al. assessed the incremental value of two-dimensional and three-dimensional transoesophageal echocardiography over two-dimensional transthoracic echocardiography in three reader groups with different expertise  in a total of twenty patients and five healthy persons . OverallParavalvular leak after transcatheter aortic valve implantation (TAVI) is challenging to quantitate. Transthoracic echocardiography is the main tool used for the assessment of paravalvular leak but is modestly reproducible. Abdelghani et al. sought to develop a reproducible echocardiographic approach to assess paravalvular leak in the post-TAVI setting . Four obDespite successful aortic coarctation (CoA) repair, systemic hypertension often recurs which may influence left ventricular function. Menting et al. aimed to detect early left ventricular dysfunction using left ventricular global longitudinal strain (GLS) in adults with repaired CoA, and to identify associations with patient and echocardiographic characteristics . In thisOxborough et al. simultaneously assessed longitudinal strain and left ventricular volume/ right ventricular area in 92 male athletes subdivided according to varying sporting demographics . AthleteSchinkel et al. wrote an interesting overview on the role of contrast-enhanced ultrasound (CEUS) in the evaluation of patients with known or suspected atherosclerosis . CEUS isThere were a number of interesting advancements in cardiovascular MRI (CMR) in 2016.Reval et al.  studied Improved border sharpness of post infarct scar was demonstrated by Rutz et al.  with a sThe prognostic value of stenosis class as measured by magnetic resonance angiography over traditional risk factors in patients with peripheral arterial disease was demonstrated by van den Bosch et al. . ImproveFaletti et al.  found th1-regularization (IS SENSE) was demonstrated [The performance of an accelerated CMR protocol using iterative SENSE reconstruction and spatio-temporal Lnstrated . In relanstrated  used thinstrated .The feasibility of heart deformation analysis for measuring regional myocardial velocity with CMR was tested in normal volunteers . CardiacMarkl et al.  performeA dose correction for post-contrast T1 mapping of the heart was proposed by Gai et al.  and applA semi-automated cardiac segmentation tool was found to improve the reproducibility and speed of right heart MRA .KnowledgIn 2016 a large number of original articles, covering a variety of topics related to CT, were submitted to the journal and underwent a rigorous review/selection process. While the submission, review, and editorial selection process has well-known biases, the articles published reflect current trends in computed tomography.Coronary artery disease is a major focus of cardiac CT. While clinical prevention guidelines suggest a limited role, coronary calcium scoring (CAC) remains a topic of ongoing research. Published papers describe the effective radiation exposure among participants from the MESA cohort , and disIn contrast to CAC, which identifies only calcified plaque, contrast-enhanced CTA can assess overall plaque burden and plaque characteristics. While it is not an indication for CTA itself, plaque burden is evaluated by experienced clinical readers in coronary CTA indicated for suspected obstructive CAD and is a topic of significant interest in research. Published papers describe a correlation between elevated HBA1c and higher frequency of obstructive CAD and vulnerable atherosclerotic coronary plaque characteristics (positive vessel remodeling and low-attenuation plaques) in patients with type 2 diabetes , 57 An oCT) has gained significant interest. One published study examined the feasibility of FFRCT in a small ‘unselected’ cohort of patients with suspected significant CAD [CTcould be measured in the majority of consecutive, patients who had suspected significant CAD by CCTA and demonstrated good diagnostic performance for detecting hemodynamically significant CAD even in patients with calcified vessels. Another important study demonstrated the impact of image resolution on geometrical reconstruction and subsequent FFR calculation with invasive and CT FFR [Based on the experience with invasive coronary angiography as well as CTA, the limitations of luminal stenosis assessment for the prediction of hemodynamic significance of CAD are well known. CT techniques to evaluate lesion functional significance are therefore a major focus of research. Among them, non-invasive fractional flow reserve measured by coronary computed tomography angiography  by micro-computed tomography (mCT) in a coronary bifurcation model . The traAn important focus of CT are indications in the context of structural heart disease intervention. For TAVR planning, one study evaluated an automatic aortic root landmarks detection method with automated determination of annulus radius, annulus orientation, and distance from annulus plane to right and left coronary ostia . Other sExciting progress is described in analysis of CT data. Published studies examined quantitative semi-automated methods for assessment of coronary luminal stenosis severity  and fullThe above selection of published articles about cardiovascular CT reflects current clinical use and research interests. Use of CT, like any other diagnostic test, has to balance anticipated benefit against potential risk, specifically for CT radiation exposure and contrast administration. This risk assessment takes into account the susceptibility of specific patient populations , 79. The


Despite the characterization of ribosomal S6 kinase 2 (RSK2) as a protein kinase acting as a downstream effector of the well characterized ERK MAP-kinase signaling pathway, it turns out to be a challenging task to link RSK2 to specific neuronal processes dysregulated in case of mutation. Animal models such as mouse and Drosophila combine advanced genetic manipulation tools with in vivo imaging techniques, high-resolution connectome analysis and a variety of behavioral assays, thereby allowing for an in-depth analysis for gene functions in the nervous system. Although modeling mental disability in animal systems has limitations because of the complexity of phenotypes, the influence of genetic variation and species-specific characteristics at the neural circuit and behavioral level, some common aspects of RSK2 function in the nervous system have emerged, which will be presented. Only with this knowledge our understanding of the pathophysiology of CLS can be improved, which might open the door for development of potential intervention strategies.Loss of function mutations in the  RSK2 knock-out mice (RSK2−) and mutants of the single RSK ortholog in Drosophila (D-RSK) were analyzed at the behavioral and neurophysiological level. We summarize findings with both animal models and their implications to better understand the neuropathophysiology of CLS.Coffin-Lowry syndrome  is a rare X-chromosome linked disorder with an incidence of 1:50,000–100,000. Clinical characteristics are heterogeneous and variable in expressivity. They include facial dysmorphism, digit and skeletal abnormalities, and growth delay. Prominently, CLS patients suffer from severe mental disabilities (IQ: 15–60). Less frequently, stimulus-induced drop attacks, epileptic seizures and hearing loss are manifested. The risk to develop psychiatric diseases like depression and psychosis might be increased. No treatment exists for this disease  family. With the exception of a 140 amino acid N-terminal extension, D-RSK shows equal sequence similarities of about 70% to RSK1–4. Notably, all sequence motifs required for RSK activation are also present in D-RSK  belongs to the AGC kinase family and the C-terminal kinase domain (CTKD) is related to the CaK Figure . From biK Figure . HoweverDrosophila eye development, D-RSK acts as a cytoplasmic anchor for ERK, thereby inhibiting ERK nuclear translocation and phosphorylation of nuclear targets  carried a mutation in RSK2 and later on developed clearer characteristics of CLS, which generally resemble those of RASopathies  induces features of depression, expressed as general inactivity. Furthermore, activity recordings allow correlating disease associated genes with circadian and sleep disturbances as one characteristic of some mental illnesses.The similarities of molecular pathways controlling the generation and differentiation of neurons, neural circuit wiring and synaptic communication make animal models a powerful tool to characterize cellular and physiological processes and link them to human disorders. A more challenging task is to model mental disabilities or mental health disorders in animal systems because of the complexity of symptoms, the influence of genetic variation on disease outcome and species-specific characteristics at the molecular, neural circuit and behavioral level  and the habenula, playing a role in motivational and rewarding aspects of behavior  from CLS patients uncovered a reduction in total brain volume with a particular impact on temporal lobe, cerebellar and hippocampal volumes  but more pre-existing neurons (Castillon et al., RSK2− mice in a context-dependent manner.Do the behavioral phenotypes seen in mice and RSK2− mice (Mehmood et al., RSK2− animals showed a growth and developmental delay (Ammar et al., in vivo (Fischer et al., RSK2− behavioral deficits.Loss of RSK2 interferes at several levels with neuronal properties (Figure de novo synthesis, trafficking, variations in heterotetrameric subunit composition, posttranslational modifications and interaction with scaffold proteins at postsynaptic densities (Huganir and Nicoll, RSK2− mice, upregulated levels of the GluA2 subunit of AMPA-receptors at synaptic sites were observed (Mehmood et al., RSK2− mice or from hippocampal slices demonstrated decreased synaptic transmission, altered AMPA and NMDA receptor properties, but normal paired-pulse facilitation and long-term potentiation. Altogether, these findings argued for a postsynaptic function of RSK2 in neurotransmission (Morice et al., Accumulating data support the view that RSK2 influences ionotropic glutamatergic synapses. A focus of RSK2 research is the AMPA-subfamily of glutamate receptors because of their fundamental role in synaptic plasticity as a crucial step for learning and memory formation. The number of AMPA-receptors and their channel properties are influenced by RSK2− mice. Thus, RSK2 seems to mediate at least some of its effects by modulation of scaffold proteins of the postsynaptic density in an activity-dependent manner.Another function of RSK2 at the postsynapse is interaction with proteins of the Shank family, which act as major scaffolds for AMPA-, NMDR- and metabotropic glutamate receptors (Sala et al., RSK2− animals are increased with an accompanying up-regulation of dopamine receptor2 expression (Pereira et al., 2A receptor, thereby linking growth factor induced MAP-kinase signaling with regulation of a G-protein coupled receptor (Sheffler et al., RSK2− brains were detected (Pereira et al., Emotional behaviors like anxiety, depression or hyperactivity are regulated by the neurotransmitters dopamine and serotonin. Dopamine levels in the mouse cortex of Drosophila, analysis has focused on the larval neuromuscular system as a well-established model for synapse formation, neurotransmission and synaptic plasticity (Harris and Littleton, D-RSK mutants, overall bouton number is increased but this phenotype is counteracted by a much stronger decrease in synapse number per bouton (Fischer et al., Drosophila D-RSK is a postsynaptic requirement for efficient synaptic transmission.In Drosophila gave first insights into the impact of RSK2 on neuronal functions. In CLS patients it is still unknown, if similar neurite growth and synaptic defects exist like in animal models. Patient derived iPSCs could be differentiated into distinct neuron subtypes and analyzed at the molecular, biochemical and physiological level. Besides analysis of molecular interactions, a particular emphasis for further studies should be the analysis of RSK2 in experience-dependent synaptic changes. A good example for future research about CLS is the fragile-X mental retardation syndrome, where parallel experiments in animal models have paved the way to bridge the gap to better understand the human disease phenotypes. For example, metabotropic glutamate receptor and ERK-pathway dependent protein synthesis were affected, which led to clinical trials in patients with a mGluR5 antagonist, unfortunately turning out to be not effective (Berry-Kravis et al., RSK2/D-RSK phenotypes, our understanding of neuronal dysfunction is far from complete at all levels of analysis.While no information exists about the neuronal basis of the clinical phenotype in CLS patients, recent findings in mouse and MF and TR wrote the manuscript.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.


The earlier identification of selective inhibitors of fungal SL biosynthesis promised potent broad-spectrum anti-fungal agents, which later encouraged testing some of those agents against protozoan parasites. In this review we focus on the key enzymes of the SL de novo biosynthetic pathway in protozoan parasites of the Apicomplexa and Kinetoplastidae, outlining the divergence and interconnection between host and pathogen metabolism. The druggability of the SL biosynthesis is considered, alongside recent technology advances that will enable the dissection and analyses of this pathway in the parasitic protozoa. The future impact of these advances for the development of new therapeutics for both globally threatening and neglected infectious diseases is potentially profound.Sphingolipids (SLs) are an integral part of all eukaryotic cellular membranes. In addition, they have indispensable functions as signalling molecules controlling a myriad of cellular events. Disruption of either the  Protozoa (kingdom Protista) are single-cell organisms that can be free-living or parasitic in nature Baron, . Out of Trypanosoma brucei , Leishmania spp.  and Trypanosoma cruzi ; Sporozoa – the apicomplexan Toxoplasma gondii (toxoplasmosis), Cryptosporidium spp. (cryptosporidiosis) and Eimeria spp. (coccidiosis in poultry and cattle), Theileria spp. (East Coast Fever in cattle) and Plasmodium spp., including Plasmodium falciparum the causative agent of severe malaria and one of the ‘Big Three’ global infectious diseases alongside HIV and tuberculosis  or Neglected Zoonotic Diseases King,  and wereThis review presents sphingolipid (SL) biosynthesis and ceramide (CER) homoeostasis as a potential gold mine of tractable drug targets for these protozoan parasites.In general, available treatments for the diseases caused by the Kinetoplastidae and Apicomplexa are outdated (if not historic), with relatively few examples that were introduced recently, toxic and require a long treatment regimen, and therefore close monitoring of patients.The kinetoplastid pathogens in focus here all cause NTDs and as such there are significant problems with the available drug regimens:et al.et al.et al.et al.et al.et al.et al.et al.The treatment of leishmaniasis often requires a long course of intravenous pentavalent antimony drugs (e.g. Glucantime and Pentostam), aminosidine (paromomycin) or liposomal amphotericin B , and 660 000 (429 000 in 2015) associated deaths; although the actual numbers might be even higher , as the primary complex mammalian SL; and inositol phosphorylceramide (IPC) in fungi, plants and numerous protozoa  and ceramide-1-phosphate (C1P)  that can be protozoa . These ma et al.. Furthertrans double bond) affect their biophysical properties rendering these molecules different from their glycerolipid counterparts, i.e. SM vs phosphatidylcholine (PC)  to Lα (lamellar phase) transition near the physiological temperature of 37 °C, in contrast, this transition for naturally occurring glycerolipids is near or below 0 °C. Additionally, the long saturated alkyl chains of SLs allow them to pack tightly with sterols, stabilized by hydrogen bonding  of SPH allows it to remain partially uncharged at physiological pH retaining the ability to move across membranes  for new drug targets or regimens  via serine palmitoyltransferase (SPT), to produce dihydrosphingosine. The latter comprises first the formation of CER in the ER by the action of ceramide synthase (CerS), and then the formation of complex SLs in the Golgi. These products vary depending on the species, and are formed under the catalysis of what could be generically termed SL synthases: SM synthase in mammals and IPC synthase in fungi, plants and protozoa. It is worth mentioning that another Golgi localized metabolic pathway results in the formation of glycosylated CER species, and also contributes to the regulation CER levels  . However, clear divergence is observed in the second and the third steps, both of which represent a cell-fate modulator process. CerSs exhibit differential preferences for the chain length of the acyl-CoA substrate  around the PLP-binding lysine (in bold) -dependent . Subsequent minor metabolic differences are encountered across different species; mainly concerning the order of the hydroxylation (in fungi and higher plants) and acylation to produce CERs  has previously indicated the presence of CerS activity in transfer protein CERT in mammals  to produce IPC via IPC synthase  with respect to the animal SM synthases  and SLs ([phyto]ceramide and IPC/SM/EPC). Accordingly, these enzymes act as regulators of a delicate balance between pro-apoptotic CER and pro-mitogenic DAG , a depsipeptide, was first reported by Ikai et al.  and soon. et al.. The tarLeishmania major and T. gondii are not susceptible to AbA inhibition  compared with the single copy found, for example, in L. major and T. gondii , chain length variation, the hydrophobic nature of the involved enzymes and the presence of multiple pathways that can operate in parallel  subcellular localisation, (b) regulation (c) chain length specificity, (d) kinetics of trafficking and (e) mechanism of action. For example, phosphorylation of 1–3% cytosolic SPH may double the levels of S1P that acts on G protein-coupled receptor (GPCR) to elicit a specific response in a particular cellular locality for certain period of time , in the pursuit of identifying new compound scaffolds active against the Leishmania spp IPC synthase utilising yeast  and function makes SL biosynthesis highly alluring for drug intervention, after all, everybody needs SLs, right?


Atrial fibrillation (AF) is maintained by reentrant excitation forming stable or meandering rotors, leading circle reentry, or multiple circulating wavelets  repolarization in antiarrhythmic drug therapy. AF circuits were found to be less stable and more likely to self-terminate when APDINa blockade using Class I drugs has been extensively tested in clinical, experimental, and in silico studies. While these drugs are effective in treating paroxysmal AF, their efficacy may be related to suppression of triggered activity via non-canonical effects on RYR2 rather than INa (Salvage et al., INaK blockade impacts nodal cell firing via regulation of the so-called calcium clock (Sirenko et al., INaK blockade than a whole-heart virtual model that incorporates neural feedback and the conduction system, simulates the ventricular response rate to AF, and tests the potential risk of proarrhythmia by digitalis toxicity. Finally, the importance of IK1 in fibrillatory dynamics is well-established. Noujaim and colleagues (Noujaim et al., via its inhibitory effects on IK1. However, this strategy must be approached with caution since IK1 density is greater in ventricular compared to atrial myocardium. A notable concern is the potential for unmasking ventricular ectopy (Miake et al., This line of inquiry has clear implications for ion channel pharmacotherapy, an area of major challenge considering the suboptimal efficacy of many ion channel drugs against AF as well as their risk of inducing ventricular pro-arrhythmia. The focus on the aforementioned targets in an atria-only model is interesting from a theoretical perspective but less so from a pragmatic one. For example, in silico studies are always constrained by strong experimental and clinical measurements to guarantee their relevance for human AF.Nonetheless, the present work by Sanchez et al.  establisFA and CC drafted, revised, and approved the manuscript.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.


Neurodegenerative diseases affect millions of individuals in North America and cost the health-care industry billions of dollars for treatment. Current treatment options for degenerative diseases focus on physical rehabilitation or drug therapies, which temporarily mask the effects of cell damage, but quickly lose their efficacy. Cell therapies for the central nervous system remain an untapped market due to the complexity involved in growing neural tissues, controlling their differentiation, and protecting them from the hostile environment they meet upon implantation. Designing tissue constructs for the discovery of better drug treatments are also limited due to the resolution needed for an accurate cellular representation of the brain, in addition to being expensive and difficult to translate to biocompatible materials. 3-D printing offers a streamlined solution for engineering brain tissue for drug discovery or, in the future, for implantation. New microfluidic and bioplotting devices offer increased resolution, little impact on cell viability and have been tested with several bioink materials including fibrin, collagen, hyaluronic acid, poly(caprolactone), and poly(ethylene glycol). This review details current efforts at bioprinting neural tissue and highlights promising avenues for future work. Neurodegenerative diseases affect over 55 million individuals annually in North America, creating a multi-billion dollar burden on the health-care industry due to the costs associated with treatment, and rehabilitation therapy , which are pluripotent stem cells derived from a human embryo; mesenchymal stem cells (MSCs), which are multipotent stromal cells that can differentiate into osteoblasts, chondrocytes, myocytes, and adipocytes; neural stem/progenitor stem cells, which are multipotent and can differentiate into neurons, astrocytes, and oligodendrocytes; and human induced pluripotent stem cells (hiPSCs), which are adult cells taken back to a pluripotent state   methacrylamide, and poly(a-hydroxy-acids)  from hESCs and hiPSCs, but they impose unnatural geometric constraints on the cells  uses a melted thermoplastic which is deposited layer-by-layer onto a flat substrate to build a 3-D construct  (Tan et al., Selective laser sintering uses a similar process as FDM, but SLS has a higher resolution (O’Brien et al., Stereolithography is the highest resolution option for bioprinting (O’Brien et al., Inkjet bioprinting uses a modified inkjet printer to deposit cells encapsulated in a bioink onto a chosen substrate (O’Brien et al., Bioplotting using syringes to print tubes or spheroids layered on top of each other (O’Brien et al., Microfluidic extrusion represents an extension of bioplotting (Pfister et al., Several groups have bioprinted neural tissue using various cell types with varying levels of success Table . In 2006In 2014, Lorber et al. inkjet printed retinal glial cells and disassociated retinal cells, resulting in 57% cell death in glial cells and 33% cell death in retinal cells compared with controls of unprinted cells grown on tissue culture plates (Lorber et al., Suri et al.  photopatCurley et al.  also useLee et al.  combinedGu et al.  extrudedin vivo study implanted 3-D printed constructs into cerebellum-lesioned zebrafish. Treated fish showed increased spontaneous coiling contraction and increased hatching rate compared with lesioned untreated fish, indicating cellular restoration.Similarly, Lozano et al.  extrudedLee et al.  used micThese studies differ greatly in the number of cells lost due to the stress of the printing process. Cell viability allows the user to seed at the correct cell density. However, some studies do not report cell death while others report up to 57% cell death during the printing (Lorber et al., Current work indicates that a wide variety of bioink materials may be suitable for 3-D printing neural tissue. However, more research needs to be done comparing the printability of each of these materials in terms of efficiency and ease-of-use, both which become important when scaling up production. This review has covered multiple methods of 3-D printing neural constructs. Inkjet bioprinting is the most well documented but is limited in both bioink material and geometries. Microfluidic extrusion has recently seen success in printing complex shapes with various neural cell types and remains an option of interest that needs further research in creating ideal bioink compositions. Other possibilities, such as stereolithography and SLS, remain underused for neural tissue applications.What remains to be done is finding a cohesive unit of bioink and bioprinting method which results in a high cell viability post-printing and is adaptable enough to print multiple different neural cell types with a bioink which has controllable elastic properties and porosity and can be loaded with factors to further control differentiation.In addition, most studies lack a hands-off manner of controlling bioprinting. Incorporating CAD and microtechnology into printing projects would help fully realize the high-throughput nature of 3-D bioprinting tissue, as the field is still largely limited by human-controlled systems. The use of CAD would further assist in increasing cell resolution within printed constructs. Advancing the resolution of bioprinting could also allow the printing of vascular networks within a designed tissue, something which would allow neural models to be scaled-up beyond a maximum achieved size of mm. This development would allow more physiologically relevant constructs to be printed for disease modeling and drug discovery.Bioprinting can change how neural tissue are engineered, moving it from a time consuming, hands-on process that can vary from lab-to-lab to a sterile, high-throughput process that can rapidly produce physiologically accurate brain constructs for applications in cell therapy and drug screening. The low throughout methods for engineering brain tissue limit their applicability for drug screening. Cell therapy has had limited success for the same reason: the number of cells required for injection requires lengthy culture time in addition to the difficulty controlling cell diffusion and differentiation. For bioprinting to succeed as the new standard for engineering neural tissue more bioinks must be done to accurately control brain region development, and the issue of vascularization must be solved to print accurate constructs suitable for long-term culture. However, such bioprinted neural tissues hold great promise for applications in both cell therapy and for drug screening.MT and SW both contributed to the authorship. SW proposed the topic and provided feedback through the writing process. MT wrote the initial draft and completed revisions based on feedback provided.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.


Protein kinases are major regulators of mitosis, with over 30% of the mitotic proteome phosphorylated on serines, threonines and tyrosines. The human genome encodes for 518 kinases that have a structurally conserved catalytic domain and includes about a dozen of cell division specific ones. Yet each kinase has unique structural features that allow their distinct substrate recognition and modes of regulation. These unique regulatory features determine their accurate spatio-temporal activation critical for correct progression through mitosis and are exploited for therapeutic purposes. In this review, we will discuss the principles of mitotic kinase activation and the structural determinants that underlie functional specificity. Protein phosphorylation is a key regulatory mechanism influencing various cellular processes such as cell growth, cell motility, cell differentiation and cell division. Most notably, protein phosphorylation peaks during mitosis and the timing coincides with the cell division-related chromosomal and cytoskeletal reorganization  and an α-helical C-terminal lobe  at each end  family . Though the activation loop auto-phosphorylation is sufficient for basal activity, facilitating the right conformation of the loop is required for full activation, and is achieved by the binding of TPX2 and INCENP to Aurora A and Aurora B kinases, respectively  and kinetochore-microtubule attachment Elowe, . Cdc20, CDK Activating Kinase belonging to the family of CDKs)  which is essential for their increased kinase activity  and the budding yeast Hrr25 (Casein kinase) critical for meiosis co-orientation of kinetochore do not require the activation loop phosphorylation and their kinase domains are constitutively active (Eswaran et al., Kinases achieve substrate specificity through multiple mechanisms in mitosis (Ubersax and Ferrell, in vitro and in vivo thus far has helped define kinase substrate specificity. Typically about 4-6 amino acids flanking the phospho-acceptor residue P can contribute to the selectivity of kinases for their substrate. The molecular basis for substrate recognition mainly comes from the structural work on CDK2/cyclin A bound to its substrate (Brown et al., Kinase substrate specificity is generally determined by the architecture of the substrate binding site, which might select negatively against certain residues flanking the phosphorylation site. The identification of substrates in vitro phosphorylation of kinetochore proteins by Bub1 followed by phosphorylation-directed staining and mass spectrometric analyses identified many prospective Bub1 substrates with a putative consensus motif ϕ-X5-S/T (Breit et al., The identification of multiple budding yeast kinetochore Aurora B kinase substrates, allowed to define an Aurora consensus phosphorylation sequences (Cheeseman et al., in vivo (Dephoure et al., The use of peptide libraries against kinases has greatly contributed to the identification of optimal peptide sequence motifs and “anti-motifs” for kinases (Hutti et al., Kinases may use docking sites or sites that are primed by another kinase to enhance their substrate selectivity. For example, to bind and to be phosphorylated by Plk1, a substrate generally needs to be primed by another kinase (Lee et al., CDK-cyclins also use docking sites to recognize and phosphorylate temporally their substrates. Certain cyclin partners have a hydrophobic docking patch that recognizes an “RXL” motif on substrates 40Å away from the catalytic site of the CDK active site (Schulman et al., Many mitotic kinases rely on spatial targeting to phosphorylate their specific substrates. This restricts the activity of the kinase to generate gradients of kinase activity. The most well characterized spatially-targeted kinases are Aurora A and B kinases and they appear to share the same substrate specificity (Fu et al., The molecular basis for the recruitment of Mps1 kinase to the outer kinetochore is also well established. Multiple kinases including CDK1, Aurora B, Plk1, and Mps1 itself are implicated in Mps1 kinetochore targeting (Morin et al., High resolution mechanistic understanding of kinase regulation is essential not only to define how kinases achieve error-free cell division, but also to exploit the differences in their regulatory mechanisms to specifically target them in mitosis-related human disorders. Structural studies of kinases thus far have provided key insights into the similarities and differences in the modes of activation and regulation of many mitotic kinases. Although kinases possess a broadly conserved catalytic core, their level of kinase activity and substrate specificity are determined by specific inter/intra molecular interactions and phosphorylation. In this review, we summarize how key structural regulatory elements such as the relative orientation of the C-helix, activation segment conformation and spatial regulatory elements responsible for correct kinase sub-cellular localization achieve accurate kinase function. However, there are still many open questions, particularly on factors determining the graded level of kinase activation and its implications on their mitotic role. More structural analyses of kinases in complex with their regulatory binding partners with and without bound substrates, and their functional implications in cells will undoubtedly further advance our mechanistic understanding of this essential class of mitotic regulators.JW and AJ have made a substantial, direct and intellectual contribution to the work, and approved it for publication.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.


A small proportion of patients with Parkinson’s disease (PD), chronically under dopamine replacement therapy, may undergo an addiction-like behavioral disturbance, named dopamine dysregulation syndrome (DDS). This behavioral disorder is characterized by the increase of doses beyond those required for motor control, and its management remains difficult; thus, early recognition and careful monitoring of at-risk individuals are crucial. We report the cases of two PD patients with a previous unsatisfactory switching from an immediate release (IR) to an extended release (ER) pramipexole formulation who developed DDS. PD patients unsatisfactorily switched from an IR to an ER formulation of dopamine agonists should be considered as at-risk individuals for DDS development.


The increasing use of nipple-sparing mastectomy (NSM) and skin-sparing mastectomy (SSM) in the treatment of nonmetastatic breast cancer is justified by considerations linked to their therapeutic index. In selected patients, efficacy results tend to be similar to those observed after radical modified mastectomy and at the same time, subcutaneous mastectomies preserve the patient’s body image. Yet the oncologic safety of the two former surgical approaches is still a matter of debate, also in consideration of the almost complete absence of clinical studies directed to prospective, controlled comparisons between subcutaneous and radical modified mastectomies. In addition, no clear statement—and consequently no consensus—emerges from the rather rare reports addressing the issue of whether or not there exist robust algorithms for guiding decision-making in delivering postoperative radiotherapy after NSM or SSM. The objective of the present review article is to revisit the dataset recently provided by the literature, which might help oncology teams optimise local treatment in this patient population. Throughout the past two decades, both nipple-sparing mastectomy (NSM) and skin-sparing mastectomy (SSM) have been gaining ground in the surgical management of nonmetastatic breast cancer patients. The main reason for this trend relates to the therapeutic index elicited for NSM and SSM, which was shown to compare favourably with that observed for modified radical mastectomy (MRM). Indeed, the literature suggests that treatment outcomes of NSM, SSM and MRM tend to be similar as regards efficacy endpoints, and at the same time, patients draw a number of advantages from the two former surgical modalities, especially in terms of organ and body image preservation , 2–9.Whether to deliver postoperative radiotherapy (PORT) after NSM or SSM or not is nowadays an issue essentially addressed by multi-disciplinary tumour boards involving not only surgeons and radio-oncologists but also diagnosticians, pathologists and medical oncologists. Often, such a decision-making process turns out to be a challenging task, for no straightforward, prospective comparison between subcutaneous radical mastectomies and MRMs has emerged so far from reports analysing the exact relevance of PORT after NSM and SSM , 11.The objective of this review article is to revisit the messages recently provided by the literature which might help oncology teams optimise local treatment in this patient population.http://www.ncbi.nlm.nih.gov/pubmed).We used search strings on studies addressing the issue of interaction between NSM and SSM and adjuvant radiotherapy, via the following search terms: breast cancer, SSM, NSM, MRM, PORT, treatment outcome and late complications. This review article is essentially based on full articles published since 2000 and retrieved from the PubMed search engine  by tumour microfoci was demonstrated by Cense et al  in nearlet al . Neverthet al .et al [The persistence of mammary tissue after SSM or NSM obviously increases the risk of local failure if tumour cells are present in this residual tissue –19. In tet al , the locAfter SSM, the most significant risk factors for local recurrence identified in two studies are nodal involvement, tumour size, poorly differentiated carcinomas, and lympho-vascular invasion (LVI) , 21. In In 2007, Meretoja published a report on a cohort of 207 consecutive women who underwent, from 1992 to 2001, SSM and immediate breast reconstruction immediate breast reconstruction (IBR) without any adjuvant radiotherapy [et al [It has been repeatedly substantiated that PORT delivered to reconstructed breast carries a higher risk of complications compared to that of no PORT –26. Befoet al  showed tet al .et al [P = 0.03), nipple loss , and rates of reconstruction failure . On multivariate regression analysis, PORT , age >55 years , breast volume ≥800 cm3 , smoking , and peri-areolar incision  were independent risk factors for complications. The authors concluded that despite higher complication rates after PORT, reconstruction failure and nipple/areola necrosis remained infrequent. Moreover, capsule formation can readily be treated with capsulotomy or capsulectomy [In a recent report published in 2015, Tang et al  analysedet al . Compareulectomy .et al [et al [et al [et al [et al [Out of 17 studies analysed by Janssen et al  in 2015,l [et al  and Burdl [et al  deliverel [et al  deliverel [et al , PORT wal [et al . The uneet al [n = 800) and those receiving delayed PORT (n = 201), on 5 days per week [At the European Institute of Oncology in Milan, Petit et al  performeper week , 32, 34.et al [Finally, an international survey, conducted by Marta et al , collect p < 0.001 for each of them).Answers to the questionnaire resulted in the identification of nine risk factors, practitioners include into the decision to deliver PORT or not after NSM/SSM and IBR. These factors were: 1) nodal involvement; 2) LVI; 3) grade III carcinomas; 4) triple negative histo-type; 5) young age; 6) positive surgical margins; 7) tumour size; 8) extracapsular extension (ECE) and 9) multi-centric presentation. As expected, radio-oncologists and surgeons did not fully agree on the magnitude of the risk level affecting each of these factors. For instance, the answers from the two professional disciplines most significantly diverged for the first five factors reported here above  than mastectomy patients.In a recent analysis of the current role of PORT after NSM, a total of 112,817 patients were isolated from the SEER database . Over thet al [Up until recently, the European Institute of Oncology in Milan recommended the use of intraoperative RT to the NAC in this latter patient population . In patiet al  indeed sRetrospective studies on NAC indicate that 10% to 30% of cases receive PORT , 39–46. There is also a grey zone in the literature as regards the specific impact of nodal status on treatment outcome after NSM or SSM. It is therefore legitimate to take into consideration the data retrieved from the Early Breast Cancer Trialists’ Collaborative Group’s meta-analysis . Compareet al [In the present state of knowledge, the current review strongly suggests that the recommendations by Marta et al  are in aFinally, this review confirms that, despite the fact that an increase in complications is documented in patients receiving PORT, immediate breast reconstruction using tissue expansion and implant is an acceptable option for women undergoing NSM and SSM for breast cancer .Whether SSM or NSM is safe in patients to whom no PORT is delivered remains a matter of controversy, especially in the absence of direct, controlled comparisons between patients with or without adjuvant radiotherapy. The literature on PORT after NSM and SSM continues to elicit rather large inconsistencies when treatment efficacy is the main endpoint. In particular, NSM, which spares a small amount of glandular tissue to protect the areola blood supply, raises concerns about the oncologic safety of this type of surgery, especially in high-risk patients. PORT is likely to reduce the risk of local failure in patients treated with subcutaneous mastectomy. Although some reasonable recommendations emerge from large-scale pooled analyses or surveys, the absence of prospective studies still prevents surgeons and radio-oncologists to identify those cases that are bound to draw a clear benefit from PORT after SSM or NSM. This definitely warrants the activation of randomised trials in these clinical settings.The author has no conflicts of interest and did not receive any funding to publish this review article.


The induction of brown-like adipocyte development in white adipose tissue (WAT) confers numerous metabolic benefits by decreasing adiposity and increasing energy expenditure. Therefore, WAT browning has gained considerable attention for its potential to reverse obesity and its associated co-morbidities. However, this perspective has been tainted by recent studies identifying the detrimental effects of inducing WAT browning. This review aims to highlight the adverse outcomes of both overactive and underactive browning activity, the harmful side effects of browning agents, as well as the molecular brake-switch system that has been proposed to regulate this process. Developing novel strategies that both sustain the metabolic improvements of WAT browning and attenuate the related adverse side effects is therefore essential for unlocking the therapeutic potential of browning agents in the treatment of metabolic diseases. Adipose tissue is sensitive to changes in nutrient supply and ambient temperature: an evolutionary development that has allowed animal species to adapt to food shortage and cold temperatures. In higher vertebrates, white adipose tissue (WAT) primarily stores energy in the form of triglycerides in unilocular white adipocytes, which can then be released as fatty acids when food is scarce , as well as various peptides and hormones  adipocytes, the activation of which upregulates Ucp1 and other genes involved in energy expenditure in WAT. Browning of WAT is an adaptive and reversible response to environmental stimuli, including cold exposure, pharmacological agents such as βde novo differentiation   centers the browning transcriptional network. It has been proven to be necessary and sufficient for adipocyte differentiation and function Farmer . ChronicModulations of PPARγ through ligands, posttranslational modifications, isoform distinction . Adipoq knock-out mice show increased thermogenic response , and fibroblast growth factor 21 (FGF21)—are produced in response to βBesides the mainstreams of transcriptional and hormonal regulations, various mechanisms have been identified to regulate browning that include cytoskeleton remodeling  genetically obese mice resulted in reductions in total body weight and subcutaneous fat stores , an enzyme involved in prostaglandin synthesis, also induced browning of WAT and consequently increased energy expenditure and reduced adiposity  are PPARγ agonists that were widely used as insulin sensitizers in the treatment of type 2 diabetes. In addition to their insulin sensitizing function, TZDs are well known to induce thermogenic gene expression in both white and brown adipocytes , whereas Fgf21-deficient mice show an impaired response to cold stress due to diminished thermogenic activity  emerges as an insulin-mimetic hormone that regulates systemic energy balance and has beneficial effects on body weight, insulin sensitivity, dyslipidemia, and pancreatic β-cell growth  mediate thermogenesis in BAT and lipolysis in WAT; thus, activating these receptors with selective pharmacological agonists is an attractive strategy for stimulating the browning of WAT. A number of β3-AR agonists have been developed as anti-obesity agents. However, their harmful side effects have called into question whether the long-term stimulation of β3-ARs is safe and beneficial. Himms-Hagen et al. demonstrated that chronic treatment with a β3-AR agonist, CL 316,243, led to the appearance of multilocular brown adipocytes in WAT, promoted thermogenesis, and delayed the development of obesity in rats fed a high-fat diet  and T3 (triiodothyronine) are key regulators of metabolism and energy homeostasis, and have been shown to induce WAT browning , induced ectopic expression of UCP1 in rat abdominal WAT  T Moolman . THs hav Moolman , which d Moolman . This fuUcp1 and the appearance of brown adipocyte clusters  is a member of the superfamily of transforming growth factor-β. It has been shown to singularly promote the differentiation of mesenchymal progenitor C3H10T1/2 cells to a brown adipocyte lineage , and chronic diseases   and Parathyroid-hormone-related protein (PTHrP) have been implicated in the browning of WAT in cachexia. PTHrP was originally recognized for its beneficial effects on skin, cartilage, placenta, and bone development (Maioli et al. Burn trauma causes hypermetabolism due to marked increases in catecholamines, which have been reported years after the initial injury (Kulp et al. Foxa3 resulted in a lean, energy inefficient and more insulin sensitive phenotype in mice older than one year old (Ma et al. Aging is arguably a major risk factor for metabolic syndrome (Tchkonia et al. In recently years, significant progress has been made in identifying stimuli and signaling pathways that can induce browning of WAT and trigger adaptive thermogenesis. These advancements in knowledge have garnered great support in exploiting adipose tissue plasticity together with browning agents as therapeutic tools for obesity, albeit with side effects as discussed above. The revelation of the two sides of the coin regarding the browning of WAT—namely, that it mitigates the metabolic consequences of obesity but propagates a hypermetabolic state in other pathologic conditions—suggests that browning “wastes energy” and thus is not a favorable physiological state. Therefore, we hypothesized that the body needs to tightly regulate this browning process via a “brake-switch” system to prevent the negative outcomes of both hyper- and hypo-activation of browning activity (Ferrannini et al. Prmd16 gene expression (Ng et al. Zfp423 in white adipocytes led to the accumulation of beige adipocytes in WAT in adult mice, while its gain-of-function converted brown adipocytes into a more white-like phenotype (Shao et al. This “brake-switch” hypothesis is supported by the recent identification of HOXC10, a homeobox domain-containing transcription factor, as a negative regulator of browning of WAT (Ferrannini et al. The browning of WAT has become an increasingly favorable strategy for ameliorating the effects of obesity and subsequent metabolic dysfunction. However, it is energetically inefficient and thus is physiologically unfavorable. Furthermore, recent evidence has implicated browning in the development of cachexia, lipotoxicity, and other detrimental outcomes under acute and chronic hypermetabolic conditions (as summarized in Fig.


Alcohol is one of the most commonly abused substances in the United States. Chronic consumption of ethanol has been responsible for numerous chronic diseases and conditions globally. The underlying mechanism of liver injury has been studied in depth, however, far fewer studies have examined other organs especially the heart and the central nervous system (CNS). The authors conducted a narrative review on the relationship of alcohol with heart disease and dementia. With that in mind, a complex relationship between inflammation and cardiovascular disease and dementia has been long proposed but inflammatory biomarkers have gained more attention lately. In this review we examine some of the consequences of the altered cytokine regulation that occurs in alcoholics in organs other than the liver. The article reviews the potential role of inflammatory markers such as TNF-α in predicting dementia and/or cardiovascular disease. It was found that TNF-α could promote and accelerate local inflammation and damage through autocrine/paracrine mechanisms. Unraveling the mechanisms linking chronic alcohol consumption with proinflammatory cytokine production and subsequent inflammatory signaling pathways activation in the heart and CNS, is essential to improve our understanding of the disease and hopefully facilitate the development of new remedies. Alcohol is one of the most commonly abused substances in the United States. The effect of alcohol on organ systems of the body extends beyond the liver, where it is metabolized, to include the central nervous system, cardiovascular system, kidneys, lung, gastrointestinal tract, pancreas, and the immune system  is another recognizable complication of chronic excessive alcohol consumption  deficits. The severity of this damage depends on the duration, and frequency of exposure to ethanol during gestation. There is strong evidence that during prenatal development alcohol exposure has negative consequences, however, the causes ethanol-induced neurodegeneration are poorly understood. Alcohol has been linked to hyper-inflammation, reactive oxygen species (ROS) generation and ultimately neuronal death , which can increase the influx of proinflammatory mediators and leukocytes into the brain. The BBB consists of the mainly of specialized endothelial cells lining the cerebral blood vessels, surrounded by pericytes, astrocytical processes, and neurons. It is known that alcohol can directly pass through the BBB, ultimately reaching the brain cells and causing subsequent neuronal toxicity, however the underlying mechanism is not fully understood. It was indeed suggested that chronic ethanol exposure induces oxidative stress and neuroinflammation in part by affecting platelet endothelial cell adhesion molecule-1 (PECAM-1) expression.Endothelial PECAM-1 is a cell adhesion molecule that allows for the interaction of immune cells and the endothelium which facilitates the transmigration of leukocytes and thus contributes to the endothelial cell permeability barrier , not only is there abnormal production of TNF-α, but TNF-α has also been linked to the pathological neuromodulation of the disease (McAlpine et al., Alcohol is well-known for its dysregulation of cytokines levels in several body organs such as the liver, brain, lung, and plasma. It has been postulated that such changes are responsible for undesirables CNS alterations, which results in long term effects in behavior and permanent neurodegenerative effect. Hence, understanding the role of such cytokines is essential to determine the exact pathogenesis of alcohol-associated neurological disorders (Achur et al., Along with other cytokines, TNF-α was found to be dysregulated by alcohol-related tissue destruction as is evident by the abnormal levels of circulating cytokines in alcoholic patients (Achur et al., Alcohol can be beneficial or harmful and may affect the heart and whole cardiovascular system in many ways. Some of the cardiovascular diseases that are associated with heavy drinking are: cardiomyopathy, cardiac arrhythmias, hypertension, atherosclerosis and heart failure Table . In thisAccording to Djousse and Gaziano, approximately half a million Americans are diagnosed with heart failure each year and some of those cases are associated with alcohol consumption (Djousse and Gaziano, Cardiac disease remains an essential burden that causes death in chronic alcoholic population Kannel, . ExcessiDespite the lack of clear understanding of the exact mechanism by which chronic alcohol consumption causes heart failure, stroke volume reduction and low ejections fraction was found in alcoholic population (Patel et al., Recent evidence shows that cardiomyocyte apoptosis appears to play a major role in many alcoholic cardiomyopathies leading to heart failure (Fernandez-Sola et al., K, by IGF-1 mainly through PI-3K/Akt activation (Teos et al., K reported earlier maybe mediated by IGF-1-dependent signaling pathway.Sparagna et al. has shown that low-dose alcohol attenuates apoptosis in neonatal rat cardiocytes through Akt and AMP-activated kinase (Sparagna et al., Even though long-term alcohol abuse has been associated with defect in cardiac contractility and eventual development of dilated cardiomyopathy and low-output heart failure Table , interes2+ (2+ channels nor their inactivation parameters. Interestingly, no data is available on the electrophysiological effects of low alcohol exposure or on the exposure frequency. Clinically relevant concentrations of ethanol induced elevation of Ca,L (Brown et al., + currents of rats (Nakamura et al., 2+i in a concentration dependent manner (Ren, Most of the experimental evidence indirectly relates chronic alcohol-dependent changes in intracellular Caner Ren, . Interes Lieber, . Interes Lieber, .Although once thought of as part of inflammatory cells only, cytokines and chemokines are now recognized to play pivotal role in cardiac homeostasis and repair (Tarzami et al., in vivo study on pregnant Wistar Rats, the authors extrapolated that the inflammation and oxidative stress are the mechanisms of the destructive effect of ethanol on their hearts (Shirpoor et al., The relationship between inflammation and inflammatory markers with alcoholic heart disease has gained much attention lately. In an Among these inflammatory markers, TNF-α was particularly interesting for its role in cardiovascular diseases Ferrari, . In addiThe locally produced autocrine TNF-α was found to have a noticeable role in alcohol-related heart failure (Meldrum et al., Alcoholism is a multifactorial disorder that requires a multidisciplinary approach to treat depending on the organs affected. Heavy drinkers suffer from many organ damages; among the most effected organs are liver and kidney. As we mentioned before, heart and brain can be affected either directly or indirectly by alcohol and or its breakdown metabolites. So far, conventional treatment strategies have used a combination of a reduction of ethanol-dependent inflicted damage by control drinking and increasing local and systemic protective mechanisms of the body by using antioxidant supplementation (Mailloux, Other non-conventional suggested approaches included the use of microRNAs since they are shown to play an important role in multi-organ alcohol-induced damages including brain and heart (Natarajan et al., Alcohol consumption effects cardiovascular system and predisposes to the development of cardiac abnormalities such as cardiac remodeling, cardiac arrhythmia, cardiomyopathy myocardia infarction, and even SCD Table . ConsequHeavy drinking has been shown to increase the risk of heart failure, thus in addition to the conventional approach to control alcoholism, it is critical to focus on preventive measures that could reduce the risk to heart failure in these patients. It was reported that normal heart does not express TNF but failing heart procures robust amount of TNF-α, Hence, more studies are dedicated to understanding the role of TNF-α in heart failure patients. It is known that TNF-α is elevated in chronic heart failure patient in accordance with their functional class (Heberto Herrera Garza et al., Attempts to integrate TNF-α antagonist into the realms of therapeutic medicine has been suggested, with possible effectiveness for symptomatic heart failure patients (Heberto Herrera Garza et al., Interestingly, in brain injury, TNF-α has been postulated to potentiate glutamate-mediated cytotoxicity in astrocyte leading to neuronal degeneration (Pickering et al., SDF-1, otherwise known as CXCL12, plays a major role in regulating stem cell recruitments, inflammation and inflammation mediated injury (Doring et al., In the heart, various cells including cardiomyocytes, stromal cells, endothelial cells, fibroblasts, and dendritic cells express SDF-1 (Wei et al., Helicobacter Pylori induced peptic ulcer, rotator cuff disease, skin inflammation squamous cell carcinoma of the lung, renal ischemia-reperfusion injury, glioblastoma tumor, and AIDS-associated neurologic disorders (Han et al., in vitro, which indicates the pathological roles of SDF-1 in increasing the severity of neurological impairment due to increased astrocyte cell death (Table SDF-1 alpha has also been shown to play roles in other disease conditions that affect other systems in the body commonly affected by heavy alcohol exposure. SDF-1 has been shown to increase in toxic liver damage, neonatal sepsis, autoimmune, inflammatory diseases, th Table . Moreoveth Table . TogetheActivation of TNF-α by SDF-1 has also been postulated to promote the reactivation of latent HIV in macrophages and microglial cells Table . Other pCollectively, these data suggest that the alcohol induced alteration in circulating chemokines is a major contributor in alcoholic mediated organ damages via both direct and indirect mechanisms Figure . The preIn conclusion, alcohol's action are complex, chronic alcohol consumption can increase the risk of heart disease, brain damage, dementia, neuropathy, metabolic disturbances, nutritional deficiencies, certain cancers, liver, and other faces of morbidity and mortality. In this review we have highlighted the contribution of inflammatory process in alcohol-mediated tissue damage and organ dysfunction. What is apparent from literature review is that the full understanding of the related cytokine signaling pathways in alcoholic injuries will be essential for further understanding of their potential contribution and their complex biological effects on alcohol-induced organ damage. Investigation of agents that interfere with inflammatory cytokine production is needed in order to enhance our understanding on their potential contributions into pathogenesis of diseases that are associated with excessive alcohol consumption.AO and AP: performed the literature search and designed the tables/figures and edited the manuscript; ST: wrote the manuscript; JL and GH: performed the literature search and discussed the content of the manuscript.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.


Cancer is a leading cause of death worldwide, and its incidence is rising with numbers expected to increase 70% in the next two decades. The fact that current mainline treatments for cancer patients are accompanied by debilitating side effects prompts a growing demand for new therapies that not only inhibit growth and proliferation of cancer cells, but also control invasion and metastasis. One class of targets gaining international attention is the aquaporins, a family of membrane-spanning water channels with diverse physiological functions and extensive tissue-specific distributions in humans. Aquaporins−1,−2,−3,−4,−5,−8, and−9 have been linked to roles in cancer invasion, and metastasis, but their mechanisms of action remain to be fully defined. Aquaporins are implicated in the metastatic cascade in processes of angiogenesis, cellular dissociation, migration, and invasion. Cancer invasion and metastasis are proposed to be potentiated by aquaporins in boosting tumor angiogenesis, enhancing cell volume regulation, regulating cell-cell and cell-matrix adhesions, interacting with actin cytoskeleton, regulating proteases and extracellular-matrix degrading molecules, contributing to the regulation of epithelial-mesenchymal transitions, and interacting with signaling pathways enabling motility and invasion. Pharmacological modulators of aquaporin channels are being identified and tested for therapeutic potential, including compounds derived from loop diuretics, metal-containing organic compounds, plant natural products, and other small molecules. Further studies on aquaporin-dependent functions in cancer metastasis are needed to define the differential contributions of different classes of aquaporin channels to regulation of fluid balance, cell volume, small solute transport, signal transduction, their possible relevance as rate limiting steps, and potential values as therapeutic targets for invasion and metastasis. Xenopus laevis expression system, introduced AQP1 channels enabled high osmotic water flux across the plasma membrane as compared to non-AQP control oocytes  are a family of water channels that also include a subset of classes shown to mediate transport of glycerol, ions, and other molecules , which stimulates endothelial cell proliferation and angiogenesis in response to hypoxia , induce AQP1 expression in low oxygen conditions  occurs in normal physiological conditions such as implantation, embryogenesis, and organ development, as well as pathological processes such as cancer invasion and metastasis  degradation and retraction Figure . Cell poA migrating cell extends its leading edge into the ECM by assembling a branched network of intracellular actin filaments, predicted to yield a physical force that dynamically pushes the membrane out, alternating with relaxation and actin depolymerization Wang, . Membranin vitro, and augmented metastasis in a mouse model -mediated phosphorylation of AQP4 at serine 180 correlated with a decreased glioma cell invasion  have been shown to interact with adhesion molecules and to influence adhesive properties of migrating cells. Increased AQP1 in mesenchymal stem cells enhances migration by a mechanism involving β-catenin and the focal adhesion kinase (FAK)    chloride HgCl  cells (Gao et al., + is an inhibitor of voltage-gated potassium channels, calcium-dependent potassium channels, the nicotinic acetylcholine receptor, and it has also been shown to block AQP-1,−2, and−4 water permeability in Xenopus laevis oocytes and kidney derived cell lines (Brooks et al., + is variable, having been confirmed by some groups (Detmers et al., + in erythrocytes with native AQP1, or in epithelial cells transfected with AQP1, and suggested previous positive results might have been due to inhibition of K+ channels and altered baseline cell volume; however, the observation that site-directed mutation of AQP1 altered TEA sensitivity (Brooks et al., + block of AQP1 water permeability reduced cell migration and invasion in in vitro models of osteosarcoma and hepatocellular carcinoma (Pelagalli et al., + as a possible AQP1 inhibitor. However, given the variability in efficacy and cross-talk with other channels, TEA+ is not an ideal candidate for clinical development, although the targets causing the observed block of cancer cell migration and invasion might merit further investigation.TEAXenopus laevis oocytes (Migliati et al., in vitro (Dorward et al., 2, and NO (Nakhoul et al., 2 and cation transport properties (Yang et al., Xenopus oocytes stimulated with forskolin was first reported in 1996 (Yool et al., in vitro, but not in vivo (Klebe et al., in vitro remains to be determined.Bumetanide is a sulfamoylanthranilic acid derivative used clinically to increase diuresis by blocking sodium cotransporter activity at the loop of Henle in the nephron. Molecular derivatives of bumetanide have been synthesized and found to exhibit inhibitory effects on classes of AQP channels. For example, the bumetanide derivative AqB013 blocks osmotic water fluxes mediated by mammalian AQP1 and AQP4 channels expressed in Plant-based derivatives that reduce cancer cell migration and invasion include agents that have also have been found to inhibit AQPs. Bacopa monnieri is a perennial herb native to the wetlands of India that is used in alternative medicinal therapies. Chemical constituents bacopaside-I and bacopaside-II, were shown to block AQP1 but not AQP4 water channels (Pei et al., 2 (Zelenina et al., 4 (Zelenina et al., Mercury has classically been used as an AQP1 inhibitor. In the human AQP1 monomer, the NPA motif in loop E is near cysteine 189, which is the site at which mercury inhibits osmotic water permeability (Preston et al., Aquaporin-dependent mechanisms serve as key steps throughout the process of metastasis, in angiogenesis, cellular dissociation, cell migration and invasion. AQPs−1,−2,−3,−4,−5,−8, and−9 contribute to one or more processes, generally potentiating cancer invasion and metastasis by boosting tumor angiogenesis, enhancing cell volume regulation, regulating cell-cell and cell-matrix adhesions, interacting with the actin cytoskeleton, regulating proteases and ECM degrading molecules, contributing to the regulation of epithelial-mesenchymal transition in cancer cells, and interacting with specific signaling pathways important in cancer cell motility and invasions. Pharmacological agents for aquaporin channels have therapeutic promise for improving cancer treatment, and include derivatives of bumetanide, organic metal compounds, plant medicinal agents, and other small molecule compounds. Although conflicting evidence has been raised for some compounds, there is nevertheless a compelling need to continue identifying novel candidates for AQP-specific modulators relevant not only for the treatment of cancer, but other pathological conditions. In conclusion, although much remains to be defined for molecular mechanisms in cancer invasion and metastasis, the roles of AQP channel function in cancer progression will inspire new therapeutic targets for improving treatment of malignant and invasive carcinomas.MD: wrote the manuscript; AY: reviewed and edited the manuscript.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.


AD is a multifactorial disease that occurs in familial and sporadic forms, but is always accompanied by neurotoxic accumulations of amyloid and tau proteins. The deposition of amyloid was postulated to be central for AD pathogenesis in the “amyloid cascade hypothesis” , which belongs to a small family of transmembrane proteins together with amyloid precursor-like proteins (APLP) 1 and 2. APP can undergo distinct secretase-mediated cleavages, following either the “non-amyloidogenic” or “amyloidogenic” pathway. The first serves a range of important physiological functions, including regulation of transcription and synaptic plasticity (reviewed by Müller et al., In this commentary, we want to highlight two recent papers that addressed this question using overlapping and complementary methods: Puzzo et al.  and WangOn the other hand, Puzzo et al.  investigTaken together, the results from Wang et al.  and PuzzAnother important open question is whether similar results would have been obtained using mice with a more acute, conditional APP reduction, such as a tamoxifen-inducible APP-KO line (Callahan et al., The new pathological role for APP has implications for studies using transgenic AD mouse models, which typically overexpress human APP (recent overview in Jankowsky and Zheng, In conclusion, the studies by Wang et al.  and PuzzAS conceived the study and wrote the original draft with critical and substantial input from AU. AL-H provided valuable ideas and revisions. All authors reviewed relevant literature, participated in discussions, and approved the final version of the manuscript.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.