|Year : 2022 | Volume
| Issue : 1 | Page : 59-67
Neuropeptides in psychiatry
Vatsal Suchak, Shashwath Sathyanath, Anil Kakunje
Department of Psychiatry, Yenepoya Medical College, Mangalore, Karnataka, India
|Date of Submission||27-Apr-2022|
|Date of Decision||20-May-2022|
|Date of Acceptance||24-May-2022|
|Date of Web Publication||23-Jun-2022|
Dr. Vatsal Suchak
Department of Psychiatry, Yenepoya Medical College, Mangalore, Karnataka
Source of Support: None, Conflict of Interest: None
In the past few decades, the apprehension of the human brain is on the rise. There has been vast research in the past decades which have contributed not just to structural form, but even to neuroanatomical, neurophysiological, and neurochemical correlates. In terms of neurochemistry, neurotransmitters already had a principal role. However, recently, attention is drawn to neuropeptides and their role in various physiological and pathological effects on the human body. The purpose of the present article is to review data in general about the relevance of neuropeptides in psychiatry. Our article highlights the findings of previous studies concerning the role of neuropeptides in various psychiatric disorders and its implications as a target for future treatment modalities.
Keywords: Neuropeptide, pathophysiology, psychiatry
|How to cite this article:|
Suchak V, Sathyanath S, Kakunje A. Neuropeptides in psychiatry. Arch Med Health Sci 2022;10:59-67
| Introduction|| |
For over two decades, theorists have suggested that psychiatric disorders are related to the involvement of neurotransmitters. In the previous years, the research has contributed to neuroanatomical, neurophysiological, and neurochemical details too.
Recent attention is drawn to neuropeptides and their role in various physiological and pathological effects on the human body. The purpose of the present article is to review data in general about the relevance of neuropeptides in psychiatry.
| Brief History|| |
The initial neuropeptide, Substance P, was tracked down by Ulf von Euler and John Gaddum in 1931., The notion of neuropeptide transmitters was launched by the late Dutch scientist David de Wied and Colls in the 1970s. He formulated the hypothesis that peptides localized within neurons may directly influence brain function and consequently human and animal behavior., This steered the way to the concept of neuropeptides: a concept that incorporates the physiological functions of neuropeptides at the integrative level and the cellular level.
| Definition|| |
A neuropeptide is a chain of two or more amino acids linked by peptide bonds and differs from other proteins only in the length of the amino acid chain.
Neuropeptides are quite different from neurotransmitters, in terms of synthesis, from large precursor molecules and prepropeptides, packaging in storage vesicles, axonal transport, and finally exocytosis, to summarize in short. Neuropeptides are the most diverse signaling molecules which are widely distributed in the central nervous system (CNS). They exert direct or neuromodulatory effects, wherein the effects range from modulating neurotransmitter release and neuronal firing patterns to regulating emotionality and complex behaviors.
They range in length from two (e.g., carnosine and anserine) to over 40 amino acids (e.g., corticotropin-releasing factor [CRF] and urocortin) and over 100 neuropeptides exist to date.
Peptides exceeding 90 amino acids in length are considered proteins.
Neuropeptides are involved in physiological functions such as social cognition, thermoregulation, sleep, appetite, thirst, sex, and others. That draws attention to the fact that these are the functions that get affected in psychiatric illnesses such as depression, PTSD, dementia, autism, and many more. The majority of previous articles have focused on solitary illnesses. However, in this article, we focus on major illnesses in psychiatry in association with neuropeptides and, the need to study them comprehensively.
Over the past few decades, a general outline of the distribution of most neuropeptides based on anatomical localization, biological function, derivation from a common precursor, and others have been hypothesized. In this article, we mention the classification based on anatomical localization.
Met-enkephalin, leu-enkephalin, alpha-endorphin, dynorphin).
Hypothalamic releasing hormones
CRF, melanin-concentrating hormone, hypocretin.
Cholecystokinin (CCK), substance P, bombesin, galanin, Neuropeptide Y, neurotensin.
Adrenocorticotrophic hormone, arginine vasopressin, Miscellaneous: Bradykinin.
Biosynthesis, distribution, signaling, and inactivation of neuropeptides
1. Neuropeptides are derived from a gene that expresses its mRNA and edits it by RNA splicing. This includes the transcription of an mRNA from a specific gene, in the nucleus.
This edited RNA then makes prepropeptide which includes: translation of a polypeptide preprohormone encoded by that mRNA. Inside endoplasmic reticulum, peptidase acts on prepropeptide, forming propeptide.
Posttranslational processing entailing proteolytic cleavage of the preprohormone results in the active neuropeptide (Golgi and granules).
That neuropeptide is prepared for axonal transport by packaging into neurosecretory vesicles, or granules within the Golgi complex. During the transport, the precursor protein is processed by specific cleavage enzymes into the active and inactive peptide fragments.
After release, the peptides are further degraded into smaller fragments or constituent amino acids [Figure 1].
|Figure 1: Neuropeptide production and processing. A peptidergic neuron with production steps, from gene transcription to storage of mature peptides is shown,|
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2. The peptides involved in regulating pituitary secretion are concentrated in the hypothalamus. Hypothalamic releasing and inhibiting factors are generated in neurosecretory neurons adjoining the third ventricle, which forwards the projections to the median eminence where they contact and release peptides into the hypothalamohypophysial portal circulatory system. Peptides produced in these neurons are often subject to feedback regulation by the peripheral hormones that they regulate.
For Ex-The thyrotropin-releasing hormone: regulates the activity of the hypothalamic–pituitary–thyroid (HPT) axis and thyroid hormones negatively feedback thyrotropin-releasing hormone (TRH) gene expression.
However, neuropeptide-expressing neurons and their projections are found in many other brain regions, including limbic structures, midbrain, hindbrain, and spinal cord.
Neuropeptides are often colocalized and released with other neuropeptide or nonpeptide neurotransmitters-refuting the “ one neuron-one neurotransmitter” tenet.
The co-localization of neuropeptides within the classical neurotransmitter circuits suggests an interaction between these systems, and the modulation of norepinephrine (a monoamine neurotransmitter) by Neuropeptide Y is well established, wherein Neuropeptide Y is known to reduce stress response exerted by norepinephrine. Considering all of the above, there is stimulated speculation concerning the involvement of neuropeptides in the pathophysiology of psychiatric disorders.
3. Neuropeptides act as neurotransmitters, neuromodulators, or neurohormones. Their release is not restricted to synapses or axon terminals and occurs throughout the axon or even from dendrites. In the end, they are released by exocytosis of the granules in response to electrical or hormonal stimulation of neurons. Stimulation of these neurons increases intracellular calcium concentration which leads to the fusion of peptidergic granules to the plasma membrane, leading to the expulsion of the peptide into endothelial cells. Specific neuropeptide receptors conciliate the cellular signaling of neuropeptides. Recent studies direct toward future applications of receptor identification, along with technological advancements to address their limitations.
Most neuropeptide receptors are G-protein-coupled, seven-transmembrane domain receptors, belonging to the same family of proteins as monoamine receptors.
Each neuropeptide receptor is specifically coupled to one type of G-protein (Gs, Gi, Gq) depending on the subtype of G-protein with which the receptor interacts, which may result in stimulation or inhibition of specific second messenger pathways.
Most common signaling pathways involve activated G-protein modulating the activity of either adenylate cyclase or phospholipase C.
4. Far from what happens with monoamine neurotransmitters, peptides are not actively taken up by presynaptic nerve terminals.
The released peptides are degraded into smaller fragments, and into single amino acids by specific enzymes termed peptidases.
Peptidases: bound to presynaptic/postsynaptic neural membranes or in solution in the cytoplasm and extracellular fluid, distributed widely in peripheral organs, serum, and CNS.
Hence, neuropeptides generally have half-lives on the order of minutes.
The onus of psychiatric illnesses is rapidly increasing, whereas the range of available pharmacotherapies to treat these disorders is limited. Recent findings throw light on the major role of neuropeptides by identifying neuropeptide systems as future novel therapeutic targets for the treatment of depression and anxiety disorders by conciliating the stress response.
In this article, we also review the burgeoning empirical literature on the involvement of neuropeptides in various psychiatric disorders which include depressive disorders, schizophrenia, autism, and dementia.
| Neuropeptides and Depression|| |
Plenty of neuropeptides have been implicated in depressive disorders ranging from substance P, CRF, TRH, vasopressin, neuropeptide Y, and galanin.
Large evidence as suggested by Prange et al. reports that the thyrotropin-releasing hormone is known to modulate neurotransmitters, including dopamine, serotonin, and acetylcholine.
Given that depression is associated with changes in hypothalamus-pituitary-thyroid activity, studies have reported its positive correlation with overt hypothyroidism [Figure 2].
|Figure 2: The thyrotropic axis (HPT Axis) during normal states. The thyrotropic axis (HPT Axis) during acute and chronic stress. During acute stress, glucocorticoids stimulate T4 production directly in the pituitary thyrotrope. Chronic stress inhibits the HPT axis through different mechanisms: (a) high levels of glucocorticoids inhibit THR production by the TRH neuron; (b) CRH produced outside the paraventricular nucleus stimulates somatostatin production by neurons located in the periventricular area (in orange), which inhibits TSH production; and (c) Glucocorticoids reduce the conversion of T4 to T3 by inhibiting D2. TRH neurons are located in the paraventricular nucleus and contain Thyroid Hormone Receptors and respond to increases in thyroid hormone secretion with a decrease in TRH gene expression and synthesis: This is the NEGATIVE FEEDBACK seen in the Hypothalmopituitary thyroid axis. HPT: Hypothalamic-pituitary-thyroid|
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It was also found that a TRH stimulation test done in patients with major depression revealed blunting of TSH response. This blunting is a reflection of pituitary TRH receptor downregulation due to median eminence hypersecretion of endogenous TRH. The observed TSH blunting in depressed patients does not appear to be the result of excessive negative feedback due to hyperthyroidism because thyroid measures such as basal plasma concentrations of TSH and thyroid hormones are generally in the normal range in these patients. TSH blunting may be a reflection of pituitary TRH receptor downregulation as a result of median eminence hypersecretion of endogenous TRH.
Indeed, the observation that cerebrospinal fluid (CSF) TRH concentrations are elevated in depressed patients as compared to those of controls supports the hypothesis of TRH hypersecretion.
It is not clear whether the adapted HPT axis represents the root cause of underlying the symptoms of depression or simply a secondary effect of depression-related changes in other neural systems.
Another finding to support TRH involvement in depression is that TRH mRNA expression in the paraventricular nucleus (PVN) of the hypothalamus is decreased in patients with major depression.
CRF projections arising in the amygdala are believed to play an important role, distinct from the neuropeptide consequences in the hypothalamic–pituitary–adrenal (HPA) axis, concerning the expression of stress-induced responses.
Overactivity in the hypothalamus-pituitary-adrenal axis in depressive disorders has been known for several decades and contributed by recent research. In this context, it is of interest to note that plasma corticosterone correlates positively with CRF mRNA in the amygdala.
Studies demonstrated a significant reduction of elevated CSF CRF concentrations in patients with major depression who remained depression-free for at least 6 months following antidepressant treatment, as compared to no reduction in CSF CRF concentrations in 9 patients who relapsed in these 6 months.,, This put forward the idea that poor response in major depression despite early symptomatic improvement may be showcased by elevated or increasing CSF CRF concentrations in the course of antidepressant treatment. Hence, efforts are being made for the development of small-molecule CRF1 receptor antagonists that can effectively penetrate the blood–brain barrier as hypothesized by the fact that, if CRF hypersecretion is a factor in the pathophysiology of depression, then reducing or interfering with CRF neurotransmission might be an effective strategy to alleviate depressive symptoms.
Hence, the development of CRF 1 receptor Antagonist: Now “CRF receptor antagonist” that can penetrate blood–brain barrier (BBB) is a new class of agent for the treatment of anxiety and depression, for example, R-121,919.
The neuroanatomical distribution of vasopressin pathways and their receptors has prompted speculation about the functional role of vasopressin in emotional processes and the pathophysiology of affective disorders as explained by: vasopressin-mediated HPA stimulation.
This peptide is crucial for the adaptation of the HPA axis during stress, through its ability to potentiate the stimulatory effect of CRF.
Exposure to stress stimulates the release of vasopressin from the median eminence into the pituitary portal circulation and increases the expression of vasopressin in the PVN of the hypothalamus in rodents.
Moreover, there is evidence suggesting that melancholic depression is associated with enhanced pituitary vasopressinergic responsitivity.
Even postmortem studies have shown an increase in the number of arginine-vasopressin neurons co-localized with CRF cells in depressed patients compared to controls.
In this context, normalizing vasopressinergic activity via the blockade of the V1B receptor may be beneficial for the treatment of V1B stress-related disorders, and this has driven the search for small-molecule vasopressin V1B receptor antagonists.
The AVPR1B antagonist, SSR149415, has been shown to have anti-aggressive actions in hamsters and anti-depressant- and anxiety (anxiolytic)-like behaviors in rats but was discontinued in 2008 due to a lack of clinical efficacy.
Galanin is involved in several human functions such as food and alcohol intake, metabolism, osmoregulation, seizure threshold, and reproduction. In terms of clinical relevance, stimulation of GalR1 and/or GalR3 receptors results in a depression-like phenotype, while activation of the GalR2 receptor attenuates depression-like behavior. Animal models show that long-lasting symptoms of depression and recovery to normal activity in the home cage are accelerated by infusion of a galanin receptor antagonist, galantide (M15), into VTA. Data are also described suggesting that all effective antidepressant treatments decrease the activity of LC neurons. Studies also focus on the pharmacologic aspect of targeting galanin receptors to treat depression. Gal-selective antagonists produce anxiolytic-and antidepressant-like effects, at the level of the dorsal raphe nucleus.
Neuropeptide Y is involved in several physiologic processes in the brain, including the regulation of mood, anxiety, energy, memory, and learning. Neuropeptide Y (NPY) is co-localized with serotonergic and noradrenergic neurons and its levels were correlated with the feelings of dominance and confidence during the stress. The central NPY transmission has been associated with anxiolytic and antidepressant properties in animal models. Anxiolytic and antidepressant effects have been demonstrated after the activation of receptors Y1 in animals, whereas the activation of Y2 is related to anxiogenic effects.
The biological actions of Substance P, are mediated via the receptors NK1, NK2, and NK3. Both NK1 and NK3 receptors are widely distributed in the CNS, whereas the NK2 receptor is found in the smooth muscle of the gastrointestinal, respiratory, and urinary tracts, but it has also been located in discrete regions of the rodent CNS, such as the prefrontal cortex and the hippocampus. It also serves as a pain neurotransmitter, and administration to animals elicits behavioral and cardiovascular effects resembling the stress response and related disorders.
It is co-localized with NE and serotonin and it was also found that serotonergic activity in the hippocampus and lateral septum was enhanced by NK1 antagonism. It was also observed that both depressed and PTSD patients had elevated CSF substance P concentrations. Besides this, central administration of substance P has been found to induce anxiogenic effects in the elevated plus-maze, whereas administration of substance P antagonists helped alleviate social anxiety also contributing to the anti-depressant effect. Furthermore, it seems that these effects rely on both the specific brain region and neuropeptide dose. One study indicated that a substance P receptor (termed the neurokinin 1[NK1] receptor) antagonist MK-869 is more effective than placebo and as effective as paroxetine in major depression with moderate-to-severe symptom severity.
Coming to the role in suicide, the hyperactivity and dysregulation of the CRF system may trigger and/or involve the maintenance of these alterations as chronic stress or depression have been associated with increased levels of CRF.
Overall, there is a large body of evidence suggesting the involvement of CRF in the pathophysiology of major affective disorders.,
Several findings including those derived by postmortem analyses suggested that AVP was increased in either the brain or plasma of suicide victims.
In terms of oxytocin, reduced plasma levels of oxytocin have been found in patients with MDD.
| Neuropeptides and Schizophrenia|| |
CCK has found its role in humans in terms of gastric emptying, gallbladder contraction, pancreatic enzyme release, and suppression of appetite. The interaction of CCK with CCKR2 has been reported to inhibit dopamine release-blocking dopamine-mediated behaviors in the anterior nucleus accumbens, whereas the binding with CCKR1 into the posterior nucleus accumbens is associated with opposite effects., CCK agonists that may be active in the treatment of schizophrenia should be nonselective or CCKR1 selective. Overall, there is also evidence suggesting that CCK may be involved in both affective-and stress-related disorders.
Neurotensin is closely related to the transmission of neurotransmitters in the mesolimbic, mesocortical, and nucleus accumbens pathways which are the major sites of dysregulation in schizophrenia neurotensins are predominantly located on gamma-aminobutyric acid (GABA-ergic) neurons which release GABA on dopaminergic nerve terminals and thereby inhibiting their release. Post-mortem studies on brain tissues of schizophrenic patients showed a decreased expression of neurotensin receptors and also a decrease in CSF concentration of neurotenin compared to their controls and after 4 weeks of treatment with antipsychotics, the levels of NT increased with the improvement of symptoms., Thus, neurotensin may act as an endogenous antipsychotic-like substance and awaits the development of a neurotensin receptor agonist that can penetrate the BBB. Possibly, most importantly, both neurotensin neurotransmission and antipsychotic drugs enhance sensorimotor gating.
CSF studies of schizophrenic patients showed higher opioid receptor active fraction levels of endorphins and a higher level of this fraction was related to a low level of homovanillic acid, a metabolic product of dopamine. Postmortem brain studies showed a high level of γ and ∝endorphin levels in the hypothalamus. It was found that β-endorphin inhibits the release of dopamine mediated by N-methyl-D-aspartic acid receptors in the nucleus accumbens and caudate nucleus and Putamen. Again infusion of dynorphin into the bilateral dorsal part of the hippocampus showed impairment of spatial learning and memory that is mediated through the opioid receptor. This impairment was blocked by the administration of naloxone (an opioid receptor antagonist). Thus, it seems that opioid peptides may be responsible for the cognitive and learning impairments in schizophrenia and which can be reversed by the use of opioid receptor antagonists.
The orexins are hypothalamic neuropeptides elaborated in the regulation of a variety of complex behaviors, ranging from feeding to sleep and arousal.
The latest evidence has shown that these peptides have been implicated in the pathology of many psychiatric disorders, including depression, schizophrenia, and addictions as they can modulate the mesocorticolimbic dopamine circuit., Orexin-carrying neurons project widely throughout the brain, encompassing a substantial projection to the ventral tegmental area (VTA), a region involved in reinforcement and motivation processes, even though they constitute a small proportion of lateral and perifornical hypothalamic neurons. Hence, orexin can modulate dopaminergic firing, enhance synaptic transmission, and increase dopamine release in target areas of VTA neurons, such as the nucleus accumbens and the prefrontal cortex. Furthermore, in patients suffering from schizophrenia, CSF levels of orexin-A are lower in those treated with neuroleptic drugs. Thus, the orexin system may be a hopeful candidate for pharmacological treatment in schizophrenia and a potential target for the side effects of neuroleptic drugs.
| Neuropeptides and Autism|| |
Oxytocin/arginine vasopressin neurons projections from PVN to the forebrain and brain stem regulate learning, memory, complex social behavior, and female sexual behavior and facilitate maternal behavior. CSF studies of oxytocin levels in persons with early exposure to stressful life situations showed a reduced concentration of OT indicating dysregulation of this peptide in psychiatric illnesses like autism. Recently, it has been demonstrated that recognition memory for faces but not nonsocial stimuli has been enhanced in humans by intranasal administration of oxytocin
Insulin-like growth factor-1 promotes a decrease in intraneuronal chloride ion concentration leading to hyperpolarization in neuronal membrane and a subsequent decrease in neuronal hyperexcitability. This physiologic effect has been considered to be behind the relative efficacy of bumetanide in improving symptoms of autism spectrum disorder (ASD). In addition, the important neurobiological feature in ASD and schizophrenia: brain network dysconnectivity may also be improved by insulin-like growth factor 1. It may also improve oxytocin secretion through the enhancement of the transient potential receptor V2 channel function.
| Neuropeptides and Dementia|| |
CRF seems to be significantly reduced in cortical areas of patients with dementia. The changes in the distribution and brain levels of this neuropeptide in demented patients are impressive. Reduced concentrations have been described in several areas of the brain, including the frontal and temporal cerebral cortices, the amygdala, and the caudate nucleus in AD patients., A diminished concentration of temporal and occipital neocortical CRH was found also in dementia-elderly patients, CRH receptors are reciprocally upregulated in those cortical areas where CRH is reduced.
The concentration of somatostatin has been investigated either in postmortem human brain material or in the CSF of patients with dementia. These reports convincingly show that there are reduced concentrations of somatostatin in cortical areas of the brains of dementia patients. In some investigations also the somatostatin concentration ill the hippocampus is estimated and found reduce. Postmortem human brain investigations have shown that there are reduced concentrations of vasopressin in the cortex. Chan-Palay could report structural changes in the nucleus basalis of Meynert and locus coeruleus indicating an overactivity of galanin as marked by an increased number of dendrites on galanin neurons. These findings are in line with data reported by Wallin et al., showing significantly increased concentrations of galanin in the hypothalamus. The substance P is according to Crystal and Davies and Beal and Mazurek significantly decreased in cortical areas and the hippocampus.
This peptide, electively secreted in the pars intermedia of the pituitary, is widely distributed in the neural cells of the hypothalamus and other areas of the brain. De Wied pioneered research on the demonstration of its effects on the acquisition and maintenance of behavioral processes. In AD patients, lower levels were found in the cingulate cortex, the caudate nucleus, and the substantia nigra. More recently, decreased concentrations have been reported also in the CSF in patients with late-onset AD.
| Neuropeptides and Addiction|| |
An extended literature has emerged mentioning salient features of neuropeptides in regulating neurobiological responses to alcohol and other substances. Research suggests that neuropeptide systems may modulate excessive alcohol intake, based on evidence that ethanol drinking and energy balance influence numerous neuropeptide systems, and that manipulating these systems similarly influences ethanol intake. Neuroeptides in the hypothalamus can act locally, or project to other regions to link with other systems, such as the mesolimbic dopamine reward system which regulates the reinforcing properties of natural rewards and drugs.
More recently, the orexin system has found its role in drug seeking, with several groups describing mediation of alcohol, food, morphine, and cocaine intake via orexin-A. Furthermore, increase in orexin mRNA was found in the perifornical area and lateral HYP of the Long-Evans rat during intermittent two-bottle free-choice access to ethanol.
CRH being involved in moderating responses to stress is well established and several studies have implicated this peptide in regulating alcohol-seeking behavior. CRH 1 has been shown to modulate relapse in nicotine-dependent animals and withdrawal symptoms.,,
| Neuropeptides and Personality Disorders|| |
A critical role of neuropeptides, including oxytocin, opioids, and vasopressin may also be implicated in borderline personality disorder due to the involvement of these systems in the regulation of affective behaviors. The social and affective regulation seen in borderline personality disorder is associated with the m-opioid receptor system. Barbara Stanley and Larry J Siever propose a model of reduced basal opioid activity in critical limbic circuitry, including the amygdala and cingulate cortex, in individuals with borderline personality disorder. A behavior that occurs frequently in the context of borderline personality disorder and dissociation, nonsuicidal self-injury, has also involved the implication of endogenous opioids.,
Oxytocin is implicated in prosocial behavior, ascertainment of others' internal states, and evaluation of others. While data available regarding the biological activity of oxytocin appears limited in borderline personality disorder and its effects, initial data suggest that stress-induced increases in cortisol are reduced by oxytocin in the Trier Social Stress Test and skews responses of patients in a cooperation paradigm for borderline personality disorder. With regard to anti-social personality disorder, studies show that there are diversified effects with oxytocin showing some benefits in promoting positive effects on symptoms of ASPD. Other neuropeptides hypothesized in ASPD are interferon-gamma, NPY, beta-endorphin dysregulation.
In patients with intermittent explosive disorder, many of whom have comorbid borderline personality disorder, CSF vasopressin concentration is positively correlated with a history of disinhibited aggression, including temper tantrums and physical aggression. Nonetheless, another study found no differences in CSF vasopressin between violent offenders and comparison subjects, which raises the possibility that the vasopressin increases may not be particularly associated in antisocial individuals lacking interpersonal sensitivity, but with aggression in an interpersonal context in those who are interpersonally sensitive.
| Conclusion|| |
This brief overview of the involvement of neuropeptides in psychiatry underlines the importance of these molecules in individual psychiatric illnesses. As a result, drug research is frequently attracting the discovery of brain-penetrant and small compounds that target several of these neuropeptides to provide innovative modalities for the treatment of these disorders. Recent studies on novel neuropeptide signaling in drosophila, guides the path toward treatment targets.
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Conflicts of interest
There are no conflicts of interest.
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