Prokaryotes harbor a variety of genetic replicators, including plasmids, viruses, and chromosomes, each having differing effects on the phenotype of the hosting cell. Here, we propose a classification for replicators of bacteria and archaea on the basis of their horizontal-transfer potential and the type of relationships (mutualistic, symbiotic, commensal, or parasitic) that they have with the host cell vehicle. Horizontal movement of replicators can be either active or passive, reflecting whether or not the replicator encodes the means to mediate its own transfer from one cell to another. Some replicators also have an infectious extracellular state, thus separating viruses from other mobile elements. From the perspective of the cell vehicle, the different types of replicators form a continuum from genuinely mutualistic to completely parasitic replicators. This classification provides a general framework for dissecting prokaryotic systems into evolutionarily meaningful components.
bacteria; archaea; prokaryotes; classification; replicators; cell vehicles
Infection with Plasmodium species parasites causes malaria. Plasmodium parasites are purine auxotrophs. In all life cycle stages, they require purines for RNA and DNA synthesis and other cellular metabolic processes. Purines are imported from the host erythrocyte by equilibrative nucleoside transporters (ENTs). They are processed via purine salvage–pathway enzymes to form the required purine nucleotides. The P. falciparum genome encodes four putative ENTs (PfENT1–4). Genetic, biochemical, and physiologic evidence suggest that PfENT1 is the primary purine transporter supplying the purine-salvage pathway. Protein mass spectrometry shows that PfENT1 is expressed in all parasite stages. PfENT1 knockout parasites are not viable in culture at purine concentrations found in human blood (< 10 µM). Thus, PfENT1 is a potential target for novel antimalarial drugs, but no PfENT1 inhibitors have been identified to test the hypothesis. Identifying inhibitors of PfENT1 is an essential step to validate PfENT1 as a potential antimalarial drug target.
purines; nucleoside transporter; malaria; drug development
The complicated life cycle of the malaria parasite involves a vertebrate host and a mosquito vector, and translational regulation plays a prominent role in orchestrating the developmental events in the two transition stages, gametocytes and sporozoites. Translational regulation is executed in both global and transcript-specific manners. Plasmodium uses a conserved mechanism involving phosphorylation of eIF2α to repress global protein synthesis during the latent period of sporozoite development in the mosquito salivary glands. Transcript-specific translational regulation is achieved by a network of RNA-binding proteins (RBPs), among which the Dhh1 RNA helicase DOZI and Puf family RBPs are by far the best studied in Plasmodium. While the DOZI complex defines a new P granule with a role in protecting certain gametocyte mRNAs from degradation, the Puf proteins appear to repress expression of mRNAs in both gametocytes and sporozoites. These examples underscore the significance of translational regulation in Plasmodium development.
Plasmodium; translation; gametocytes; sporozoites; RNA-binding protein
Malaria is a mosquito-borne disease caused by the Plasmodium parasite. Of the four Plasmodium species that routinely cause human malaria, P. vivax is the most widespread species outside Africa, causing ~ 18.9 million cases in 2012. P. vivax cannot be cultured continuously in vitro, which severely hampers research in non-endemic and endemic countries alike. Consequently, whole-genome sequencing has become an effective means to interrogate the biology of the P. vivax parasite. Our comparative genomic analysis of five P. vivax reference genomes and several whole-genome sequences of the closely related monkey malaria species Plasmodium cynomolgi has revealed an extraordinary level of genetic diversity and enabled characterization of novel multi-gene families and important single-copy genes. The generation of whole-genome sequences from multiple clinical isolates is also driving forward knowledge concerning the biology and evolution of the species. Understanding the biology of P. vivax is crucial to develop potential antimalarial drugs and vaccines and to achieve the goal of eliminating malaria.
malaria; genomics; Plasmodium vivax; Plasmodium cynomolgi
A malaria infection begins when an infected mosquito takes a blood meal and inoculates parasites into the skin of its mammalian host. The parasite then has to exit the skin and escape the immune cells that protect the body from infection and alert the system to intruding pathogens. It has become apparent that this earliest stage of infection is amenable to vaccine interventions. Here, we discuss how the innate and adaptive host response to both mosquito saliva and the parasite may interfere with the infection, as well as possible mechanisms the parasite might use to circumvent the host defense.
malaria; sporozoite; mosquito saliva; dermal immune system; human innate immunity; human adaptive immunity; rodent malaria model
Drugs that target the folate synthesis pathway have a long history of effectiveness against a variety of pathogens. As antimalarials, the antifolates were safe and well tolerated, but resistance emerged quickly and has persisted even with decreased drug pressure. The primary determinants of resistance in Plasmodium falciparum are well-described point mutations in the enzymes dihydropteroate synthase (DHPS) and dihydrofolate reductase (DHFR) targeted by the combination sulfadoxine–pyrimethamine (SP). Recent work has highlighted the contributions of additional parasite adaptation to antifolate resistance. In fact, the evolution of antifolate-resistant parasites is multifaceted and complex. Gene amplification of the first enzyme in the parasite folate synthesis pathway, GTP-cyclohydrolase (GCH1) is strongly associated with resistant parasites and potentially contributes to persistence of resistant parasites. Further understanding of how parasites adjust flux through the folate pathway is important to the further development of alternative agents targeting this crucial synthesis pathway.
malaria; Plasmodium falciparum; antifolates; pyrimethamine; sulfadoxine; GTP-cyclohydrolase (GCH1)
Several advances in our understanding of pediatric cerebral malaria (CM) have been made over the past 25 years. Accurate clinical diagnosis is enhanced by the identification of a characteristic retinopathy, visible by direct or indirect ophthalmoscopy, the retinal changes (retinal whitening, vessel color changes, white-centered hemorrhages) being consistently associated with intracerebral sequestration of parasites in autopsy studies. Autopsies have yielded information at tissue levels in fatal CM, but new insights into critical pathogenetic processes have emerged from neuro-imaging studies which, unlike autopsy-based studies, permit serial observations over time and allow comparisons between fatal cases and survivors. Brain swelling has emerged as the major risk factor for death, and, among survivors, brain volume diminishes spontaneously over 24-48 hours. Studies of life-threatening and fatal malaria are suggesting new approaches to identifying and caring for those at highest risk; potential adjuvants should be evaluated and implemented where they are most needed.
cerebral malaria; African children; pathogenesis; sequestration; brain swelling
The ocular motor system provides several advantages for studying the brain, including well-defined populations of neurons that contribute to specific eye movements. Generation of rapid eye movements (saccades) depends on excitatory burst neurons (EBNs) and omnipause neurons (OPNs) within the brain stem; both types of cell are highly active. Experimental lesions of EBNs and OPNs cause slowing or complete loss of saccades. We report a patient who developed a permanent, selective saccadic palsy following cardiac surgery. When she died several years later, surprisingly, autopsy showed preservation of EBNs and OPNs. We therefore considered other mechanisms that could explain her saccadic palsy. Recent work has shown that both EBNs and OPNs are ensheathed by perineuronal nets (PNs), which are specialized extracellular matrix structures that may help stabilize synaptic contacts, promote local ion homeostasis, or play a protective role in certain highly active neurons. Here, we review the possibility that damage to PNs, rather than to the neurons they support, could lead to neuronal dysfunction—such as saccadic palsy. We also suggest how future studies could test this hypothesis, which may provide insights into the vulnerability of other active neurons in the nervous system that depend on PNs.
supranuclear gaze palsy; omnipause neurons; burst neurons; PPRF; RIMLF; eye movements
Individuals working next to strong static magnetic fields occasionally report disorientation and vertigo. With the increasing strength of magnetic fields used for magnetic resonance imaging (MRI) studies, these reports have become more common. It was recently learned that humans, mice and zebrafish all demonstrate behaviors consistent with constant peripheral vestibular stimulation while inside a strong, static magnetic field. The proposed mechanism for this effect involves a Lorentz force resulting from the interaction of a strong static magnetic field with naturally occurring ionic currents flowing through the inner ear endolymph into vestibular hair cells. The resulting force within the endolymph is strong enough to displace the lateral semicircular canal cupula, inducing vertigo and the horizontal nystagmus seen in normal mice and in humans. This review explores the evidence for interactions of magnetic fields with the vestibular system.
Magnetic; vestibular; Lorentz
Mal de debarquement syndrome (MdDS) is an enigmatic neurotological disorder with high morbidity, psychosocial burden, and few treatment options. Fortunately, there has been recent growth in scientific interest in understanding the biological basis of and in treating MdDS. Recent studies using functional neuroimaging have shown increased glucose metabolism in the left entorhinal cortex and amygdala in the setting of decreased prefrontal and temporal cortex metabolism in subjects with persistent MdDS. The entorhinal cortex is a key player in processing and gating spatial information to be stored in the hippocampus and is a major driver of brain oscillations. A limbic focus may also be key to spontaneous MdDS-like symptoms occurring in individuals with a history of anxiety or chronic stress. Treatment with repetitive transcranial magnetic stimulation over the dorsolateral prefrontal cortex can decrease the rocking dizziness of MdDS, with successful responses associated with decreases in the coherence between brain networks with nodes in the parietal and occipital lobes. A new theory of MdDS is proposed as pathology secondary to entrainment of intrinsic brain networks driven by oscillatory motion exposure coupled with an inability to subsequently desynchronize the activity of these nodes. Future treatment strategies may be directed toward unyoking these networks.
mal de debarquement syndrome; entrainment; fMRI; rTMS; neuromodulation
Humans carry two copies of Survival Motor Neuron gene: SMN1 and SMN2. Loss of SMN1 coupled with skipping of SMN2 exon 7 causes spinal muscular atrophy (SMA), a leading genetic disease associated with infant mortality. Our discovery of intronic splicing silencer N1 (ISS-N1) is a promising target, currently in phase 3 clinical trial, for an antisense-oligonucleotide-mediated splicing correction in SMA. We have recently shown that the first residue of ISS-N1 is locked in a unique RNA structure that we term ISTL1 (Internal Stem Through Long-distance interaction-1). Complementary strands of ISTL1 are separated from each other by 279 nucleotides. Using site-specific mutations and chemical structure probing we confirmed the formation and functional significance of ISTL1. Located in the middle of intron 7, the 3′ strand of ISTL1 falls within an inhibitory region that we term ISS-N2. We demonstrate that an antisense-oligonucleotide-mediated sequestration of ISS-N2 fully corrects SMN2 exon 7 splicing and restores high levels of SMN in SMA patient cells. These results underscore the therapeutic potential of the regulatory information present in a secondary and high-order RNA structure of a human intron.
The National Institutes of Health’s Clinical and Translational Science Award (CTSA) program has had a profound impact on clinical research and training methods at the University of California, Davis (UC Davis). UC Davis was among the first 12 institutions to receive NIH funding for this award, and created its Clinical and Translational Science Center (CTSC) in 2006. The funding accelerated and further integrated an existing conscientious and careful planning effort for translational research with a stepwise approach to gradually increase our institutional competencies, capabilities, and resources in this area. The development of our CTSC has led us to develop new ways of bringing together a diverse faculty and facilitating research. The CTSC has impacted virtually every area and infrastructure resource involved in promoting clinical and translational research at our institution.
Nutrition; Translation; Clinical research
In previous studies, we have demonstrated that exposure of astroglial cells to A3 adenosine receptor agonists results in dual actions on cell survival, with “trophic” and antiapoptotic effects at nanomolar concentrations and induction of cell death at micromolar agonist concentrations. The protective actions of A3 agonists have been associated with a reinforcement of the actin cytoskeleton, which likely results in increased resistance of cells to cytotoxic stimuli. The molecular mechanisms at the basis of this effect and the signalling pathway(s) linking the A3 receptor to the actin cytoskeleton have never been elucidated. Based on previous literature data suggesting that the actin cytoskeleton is controlled by small GTP-binding proteins of the Rho family, in the study reported here we investigated the involvement of these proteins in the effects induced by A3 agonists on human astrocytoma ADF cells. The presence of the A3 adenosine receptor in these cells has been confirmed by immunoblotting analysis. As expected, exposure of human astrocytoma ADF cells to nanomolar concentrations of the selective A3 agonist 2-chloro-N6-(3-iodobenzyl)-adenosine-5'-N-methyluronamide (Cl-IB-MECA) resulted in formation of thick actin positive stress fibers. Preexposure of cells to the C3B toxin that inactivates Rho-proteins completely prevented the actin changes induced by Cl-IB-MECA. Exposure to the A3 agonist also resulted in significant reduction of Rho-GDI, an inhibitory protein known to maintain Rho proteins in their inactive state, suggesting a potentiation of Rho-mediated effects. This effect was fully counteracted by the concomitant exposure to the selective A3 receptor antagonist MRS1191. These results suggest that the reinforcement of the actin cytoskeleton induced by A3 receptor agonists is mediated by an interference with the activation/inactivation cycle of Rho proteins, which may, therefore, represent a biological target for the identification of novel neuroprotective strategies.
Adenosine; A3 receptor; Neuroprotection; Rho proteins
This paper reviews the mounting evidence for shared cognitive mechanisms and neural resources for rhythm and grammar. Evidence for a role of rhythm skills in language development and language comprehension is reviewed here in three lines of research: (a) behavioral and brain data from adults and children, showing that prosody and other aspects of timing of sentences influence online morpho-syntactic processing; (b) co-morbidity of impaired rhythm with grammatical deficits in children with language impairment; and (c) our recent work showing a strong positive association between rhythm perception skills and expressive grammatical skills in young school-age children with typical development. Our preliminary follow-up study presented here revealed that musical rhythm perception predicted variance in six-year-old children’s production of complex syntax, as well as online reorganization of grammatical information (transformation); these data provide an additional perspective on the hierarchical relations potentially shared by rhythm and grammar. A theoretical framework for shared cognitive resources for the role of rhythm in perceiving and learning grammatical structure is elaborated on in light of potential implications for using rhythm-emphasized musical training to improve language skills in children.
rhythm; music; syntax; prosody; children
Timing abnormalities have been reported in many neurological disorders, including Parkinson’s disease (PD). In PD, motor-timing impairments are especially debilitating in gait. Despite impaired audiomotor synchronization, PD patients’ gait improves when they walk with an auditory metronome or with music. Building on that research, we make recommendations for optimizing sensory cues to improve the efficacy of rhythmic cuing in gait rehabilitation. Adaptive rhythmic metronomes (that synchronize with the patient’s walking) might be especially effective. In a recent study we showed that adaptive metronomes synchronized consistently with Parkinson patients’ footsteps without requiring attention; this improved stability and reinstated healthy gait dynamics. Other strategies could help optimize sensory cues for gait rehabilitation. Groove music strongly engages the motor system and induces movement; bass-frequency tones are associated with movement and provide strong timing cues. Thus, groove and bass-frequency pulses could deliver potent rhythmic cues. These strategies capitalize on the close neural connections between auditory and motor networks; and auditory cues are typically preferred. However, moving visual cues greatly improve visuomotor synchronization and could warrant examination in gait rehabilitation. Together, a treatment approach that employs groove, auditory, bass-frequency, and adaptive (GABA) cues could help optimize rhythmic sensory cues for treating motor and timing deficits.
gait rehabilitation; Parkinson’s disease; rhythmic auditory stimulation; adaptive timing; groove
Whereas much of research in music and neuroscience is aimed at understanding the mechanisms by which the human brain facilitates music, emerging interest in the neuromusic community aims to translate basic music research into clinical and educational applications. In the present workshop, we explore the problems of poor pitch perception and production from both neurological and developmental/educational perspectives. We begin by reviewing previous and novel findings on the neural regulation of pitch perception and production. We then discuss issues in measuring singing accuracy consistently between the laboratory and educational settings. We review the Seattle Singing Accuracy Protocol—a new assessment tool that we hope can be adopted by cognitive psychologists as well as music educators—and we conclude with some suggestions that the present interdisciplinary approach might offer for future research.
singing; neuroimaging; measurement; lifespan; development
Neuronal oscillations are comprised of rhythmic fluctuations of excitability that are synchronized in ensembles of neurons and thus function as temporal filters that dynamically organize sensory processing. When perception relies on anticipatory mechanisms, ongoing oscillations also provide a neurophysiological substrate for temporal prediction. In this article we review evidence for this account with a focus on auditory perception. We argue that such “oscillatory temporal predictions” can selectively amplify neuronal sensitivity to inputs that occur in a predicted, task-relevant rhythm and optimize temporal selection. We elaborate this argument for a prototypic example, speech processing, where information is present at multiple time scales, with delta, theta, and low-gamma oscillations being specifically and simultaneously engaged, enabling multiplexing. We then consider the origin of temporal predictions, specifically the idea that the motor system is involved in the generation of such prior information. Finally, we place temporal predictions in the general context of internal models, discussing how they interact with feature-based or spatial predictions. We propose that complementary predictions interact synergistically according to a dominance hierarchy, shaping perception in the form of a multidimensional filter mechanism.
perception; sensorimotor; expectation; neurophysiology; active sensing
Fragile X-associated tremor/ataxia syndrome (FXTAS) is a late-onset neurodegenerative disorder that affects some but not all carriers of small, non-coding CGG-repeat expansions (55–200 repeats; premutation) within the fragile X gene (FMR1). Principal features of FXTAS include intention tremor, cerebellar ataxia, Parkinsonism, memory and executive function deficits, autonomic dysfunction, brain atrophy with white matter disease, and cognitive decline. Although FXTAS was originally considered to be confined to the premutation range, rare individuals with a gray zone (45 to 54 repeats) or an unmethylated full mutation (>200 repeats) allele have now been described; the constant feature of the disorder remaining the requirement for FMR1 expression, in contradistinction to the gene silencing mechanism of fragile X syndrome. Although transcriptional activity is required for FXTAS pathogenesis, the specific trigger(s) for FXTAS pathogenesis remains elusive, highlighting the need for more research in this area. This need is underscored by recent neuroimaging findings of changes in the central nervous system that consistently appear well before the onset of clinical symptoms, thus creating an opportunity to delay or prevent the appearance of FXTAS.
neurodegeneration; dementia; premutation; RNA toxicity; CGG repeat; FXTAS
A number of studies have indicated that antagonists of the N-methyl-d-aspartate (NMDA) subtypes of glutamate receptors can cause schizophrenia-like symptoms in healthy individuals and exacerbate symptoms in individuals with schizophrenia. These findings have led to the glutamate hypothesis of schizophrenia. Here we review the evidence for this hypothesis in postmortem studies of brain tissue from individuals affected by schizophrenia, summarizing studies of glutamate neuron morphology, of expression of glutamate receptors and transporters, and of the synthesizing and metabolizing enzymes for glutamate and its co-agonists. We found consistent evidence of morphological alterations of dendrites of glutamatergic neurons in the cerebral cortex of subjects with schizophrenia and of reduced levels of the axon bouton marker synaptophysin. There were no consistent alterations of mRNA expression of glutamate receptors, although there has been limited study of the corresponding proteins. Studies of the glutamate metabolic pathway have been limited, although there is some evidence that excitatory amino acid transporter-2, glutamine synthetase, and glutaminase have altered expression in schizophrenia. Future studies would benefit from additional direct examination of glutamatergic proteins. Further advances, such as selective testing of synaptic microdomains, cortical layers, and neuronal subtypes, may also be required to elucidate the nature of glutamate signaling impairments in schizophrenia.
Over the last 10 years the continual discovery of novel forms of encephalitis associated with antibodies to cell-surface or synaptic proteins has changed the paradigms for diagnosing and treating disorders that were previously unknown or mischaracterized. We review here the process of discovery, the symptoms, and the target antigens of twelve autoimmune encephatilic disorders, grouped by syndromes and approached from a clinical perspective. Anti-NMDAR encephalitis, several subtypes of limbic encephalitis, stiff-person spectrum disorders, and other autoimmune encephalitides that result in psychosis, seizures, or abnormal movements are described in detail. We include a novel encephalopathy with prominent sleep dysfunction that provides an intriguing link between chronic neurodegeneration and cell-surface autoimmunity (IgLON5). Some of the caveats of limited serum testing are outlined. In addition, we review the underlying cellular and synaptic mechanisms that for some disorders confirm the antibody pathogenicity. The multidisciplinary impact of autoimmune encephalitis has been expanded recently by the discovery that herpes simplex encephalitis is a robust trigger of synaptic autoimmunity, and that some patients may develop overlapping syndromes, including anti-NMDAR encephalitis and neuromyelitis optica or other demyelinating diseases.
autoimmune encephalitis; limbic encephalitis; anti-NMDAR antibodies; psychosis; treatment
Competition is ubiquitous in perception. For example, items in the visual field compete for processing resources, and attention controls their priority (biased competition). The inevitable ambiguity in the interpretation of sensory signals yields another form of competition: distinct perceptual interpretations compete for access to awareness. Rivalry, where two equally likely percepts compete for dominance, explicates the latter form of competition. Building upon the similarity between attention and rivalry, we propose to model rivalry by a generic competitive circuit that is widely used in the attention literature—a winner-take-all (WTA) network. Specifically, we show that a network of two coupled WTA circuits replicates three common hallmarks of rivalry: the distribution of dominance durations, their dependence on input strength (“Levelt’s propositions”) and the effects of stimulus removal (blanking). This model introduces a form of memory by forming discrete states and explains experimental data better than competitive models of rivalry without memory. This result supports the crucial role of memory in rivalry specifically and in competitive processes in general. Our approach unifies the seemingly distinct phenomena of rivalry, memory, and attention in a single model with competition as the common underlying principle.
psychophysics; modeling; vision; binocular rivalry; attention; winner-take-all network
Priority maps are winner-take-all neural mechanisms thought to guide the allocation of covert and overt attention. Here, we go beyond this standard definition and argue that priority maps play a much broader role in controlling goal-directed behavior. We start by defining what priority maps are and where they might be found in the brain; we then ask why they exist—the function that they serve. We propose that this function is to communicate a goal state to the different effector systems, thereby guiding behavior. Within this framework, we speculate on how priority maps interact with visual working memory and introduce our common source hypothesis, the suggestion that this goal state is maintained in visual working memory and used to construct all of the priority maps controlling the various motor systems. Finally, we look ahead and suggest questions about priority maps that should be asked next.
saliency map; prioritization; salience
In two experiments, we examined the influence of visual working memory (VWM) on oculomotor selection, testing whether the landing positions of rapidly generated saccades are biased toward the region of an object that matches a feature held in VWM. Participants executed a saccade to the center of a single saccade target, divided into two colored regions and presented on the horizontal midline. Concurrently, participants maintained a color in VWM for an unrelated memory task. This color either matched one of the two regions or neither of the regions. Relative to the no-match baseline, the landing positions of rapidly generated saccades (mean latency < 150 ms) were biased toward the region that matched the remembered color. The results are consistent with the hypothesis that VWM modulates early, spatially organized sensory representations to bias selection toward locations with features that match VWM content. In addition, the results demonstrate that saccades to spatially extended objects are sensitive to within-object differences in salience.
visual working memory; visual short-term memory; eye movements; saccade
Many daily activities involve looking for something. The ease with which these searches are performed often allows one to forget that searching represents complex interactions between visual attention and memory. While a clear understanding exists of how search efficiency will be influenced by visual features of targets and their surrounding distractors or by the number of items in the display, the role of memory in search is less well understood. Contextual cueing studies have shown that implicit memory for repeated item configurations can facilitate search in artificial displays. When searching more naturalistic environments, other forms of memory come into play. For instance, semantic memory provides useful information about which objects are typically found where within a scene, and episodic scene memory provides information about where a particular object was seen the last time a particular scene was viewed. In this paper, we will review work on these topics, with special emphasis on the role of memory in guiding search in organized, real-world scenes.
memory; visual search; scene perception; eye movements
The concept that frontotemporal dementia (FTD) is a purely “cortical” dementia has largely been refuted by the recognition of its close association with motor neuron disease, and the identification of transactive response DNA-binding protein 43 (TDP-43) as a major pathological substrate underlying both diseases. Genetic findings have transformed this field and revealed connections between disorders that were previous thought clinically unrelated. The discovery of the C9ORF72 locus as responsible for majority of hereditary FTD, ALS and FTD-ALS cases and the understanding that repeat-containing RNA plays a crucial role in pathogenesis of both disorders has paved the way for development of potential biomarkers and therapeutic targets for these devastating diseases. In this review, we summarize the historical aspects leading up to our current understanding of the genetic, clinical and neuropathological overlap between FTD and ALS, and include brief discussions on chronic traumatic encephalopathy (CTE) given its association with TDP-43 pathology, increased dementia risk and reports of ALS in CTE patients. Additionally we describe other genetic associations between dementia and neuromuscular disease, such as inclusion body myositis with Paget’s disease and frontotemporal dementia (IBMPFD).
frontotemporal dementia; amyotrophic lateral sclerosis; motor neuron disease; neuromuscular disease; C9ORF72