cAMP signalling in trypanosomatids: role in pathogenesis and as a drug target

Despite recent research linking cAMP signalling to virulence in trypanosomatids and detailed studies of trypanosomatid adenylyl cyclases (ACs) and phosphodiesterases (PDEs) since their discoveries 40 years ago, downstream components of the pathway and their biological functions have remained remarkably elusive. However, in recent years, significant discoveries have been made: a role for parasite ACs has been proposed in cytokinesis, evasion of the host immune response, and social motility. cAMP phosphodiesterases PDEB1 and PDEB2 were found to be essential for survival and virulence of Trypanosoma brucei and, in Trypanosoma cruzi, PDEC2 was shown to be required for normal osmoregulation. As we discuss here, these breakthroughs have led to an ongoing surge in the development of PDE inhibitors as lead compounds for trypanocidal drugs

Understanding alcohol use and changes in drinking habits among people with a severe mental illness: a qualitative framework analysis study

Introduction: Individuals with a severe mental illness (SMI) are more likely to drink at harmful levels or abstain. While it is known that drinking patterns change over time, the reasons for this among those with a SMI are unclear. This study aimed to (i) explore the experiences with alcohol, particularly in relation to mental health symptoms, and (ii) how drinking patterns have changed over time, among individuals who have a SMI diagnosis, who either currently drink alcohol or no longer drink.Methods: One-to-one semi-structured telephone interviews were conducted to address the study aims. Current drinkers' alcohol use was assessed using the Alcohol Use Disorder Identification Test. A framework analysis was used to address the study aims with a specific focus on the differences in the experiences with alcohol use between current and former drinkers.Results: 16 participants were interviewed, and five themes were developed. The analysis highlighted how alcohol was increasingly used to cope with (i) trauma, (ii) SMI-related symptoms, or (iii) stress. Among those with a SMI, non-drinking was facilitated through declines in SMI-related symptoms, previous negative consequences due to alcohol and changing the social environment. Current drinking habits were facilitated through changes in the reasons for drinking and adopting different alcohol moderation techniques.Discussion: Among those with a SMI diagnosis and who either currently drink alcohol or no longer drink, our findings support the self-medication hypothesis and drinking motives model. However, our findings indicate the need for further development of drinking to cope with a focus on symptoms of a SMI and trauma. Our findings also have implications on specialist alcohol and mental health services, the need to improve individuals' understanding of SMI, and the need to identify reasons for drinking among those with a recent diagnosis of a SMI

Lifelong learning of cognitive styles for physical problem-solving: The effect of embodied experience

‘Embodied cognition’ suggests that our bodily experiences broadly shape our cognitive capabilities. We study how embodied experience affects the abstract physical problem-solving styles people use in a virtual task where embodiment does not affect action capabilities. We compare how groups with different embodied experience – 25 children and 35 adults with congenital limb differences versus 45 children and 40 adults born with two hands – perform this task, and find that while there is no difference in overall competence, the groups use different cognitive styles to find solutions. People born with limb differences think more before acting but take fewer attempts to reach solutions. Conversely, development affects the particular actions children use, as well as their persistence with their current strategy. Our findings suggest that while development alters action choices and persistence, differences in embodied experience drive changes in the acquisition of cognitive styles for balancing acting with thinking

Body perception in newborns

Body ownership and awareness has recently become an active topic of research in adults using paradigms such as the “rubber hand illusion” and “enfacement” [1, 2, 3, 4, 5, 6, 7, 8, 9, 10 and 11]. These studies show that visual, tactile, postural, and anatomical information all contribute to the sense of body ownership in adults [12]. While some hypothesize body perception from birth [13], others have speculated on the importance of postnatal experience [14 and 15]. Through studying body perception in newborns, we can directly investigate the factors involved prior to significant postnatal experience. To address this issue, we measured the looking behavior of newborns presented with visual-tactile synchronous and asynchronous cues, under conditions in which the visual information was either an upright (body-related stimulus; experiment 1) or inverted (non-body-related stimulus; experiment 2) infant face. We found that newborns preferred to look at the synchronous condition compared to the asynchronous condition, but only when the visual stimulus was body related. These results are in line with findings from adults and demonstrate that human newborns detect intersensory synchrony when related to their own bodies, consistent with the basic processes underlying body perception being present at birth

Malleability of the cortical hand map following a finger nerve block

Electrophysiological studies in monkeys show that finger amputation triggers local remapping within the deprived primary somatosensory cortex (S1). Human neuroimaging research, however, shows persistent S1 representation of the missing hand\u27s fingers, even decades after amputation. Here, we explore whether this apparent contradiction stems from underestimating the distributed peripheral and central representation of fingers in the hand map. Using pharmacological single-finger nerve block and 7-tesla neuroimaging, we first replicated previous accounts (electrophysiological and other) of local S1 remapping. Local blocking also triggered activity changes to nonblocked fingers across the entire hand area. Using methods exploiting interfinger representational overlap, however, we also show that the blocked finger representation remained persistent despite input loss. Computational modeling suggests that both local stability and global reorganization are driven by distributed processing underlying the topographic map, combined with homeostatic mechanisms. Our findings reveal complex interfinger representational features that play a key role in brain (re)organization, beyond (re)mapping

Malleability of the cortical hand map following a finger nerve block

Electrophysiological studies in monkeys show that finger amputation triggers local remapping within the deprived primary somatosensory cortex (S1). Human neuroimaging research, however, shows persistent S1 representation of the missing hand's fingers, even decades after amputation. Here, we explore whether this apparent contradiction stems from underestimating the distributed peripheral and central representation of fingers in the hand map. Using pharmacological single-finger nerve block and 7-tesla neuroimaging, we first replicated previous accounts (electrophysiological and other) of local S1 remapping. Local blocking also triggered activity changes to nonblocked fingers across the entire hand area. Using methods exploiting interfinger representational overlap, however, we also show that the blocked finger representation remained persistent despite input loss. Computational modeling suggests that both local stability and global reorganization are driven by distributed processing underlying the topographic map, combined with homeostatic mechanisms. Our findings reveal complex interfinger representational features that play a key role in brain (re)organization, beyond (re)mapping

Technical challenges of working with extracellular vesicles

Extracellular Vesicles (EVs) are gaining interest as central players in liquid biopsies, with potential applications in diagnosis, prognosis and therapeutic guidance in most pathological conditions. These nanosized particles transmit signals determined by their protein, lipid, nucleic acid and sugar content, and the unique molecular pattern of EVs dictates the type of signal to be transmitted to recipient cells. However, their small sizes and the limited quantities that can usually be obtained from patient-derived samples pose a number of challenges to their isolation, study and characterization. These challenges and some possible options to overcome them are discussed in this review

If I were a grown-up: Children's response to the Rubber Hand Illusion with different hand sizes

During childhood, children’s bodies undergo rapid physical growth, which may affect their ability to accurately perceive their own bodies as well as the external environment. Concurrently, multisensory processes underlying bodily self-consciousness gradually develop. However, little is known of the relation between changes in body size and corresponding update in bodily self-consciousness. In this study, 6- to 8-year-old children experienced the “rubber hand illusion” while watching a regular (child-like) or larger (adult-like) rubber hand being touched either synchronously or asynchronously with their own real hand. We measured proprioceptive drift and subjective ownership as well as changes in weight estimation of objects. Synchronous versus asynchronous visuotactile stroking with both the regular and larger hands caused a change in subjective body ownership but did not make a difference in perceived hand location and weight estimation of objects having the same size but different weight. Intriguingly, simply viewing the regular hand led to greater proprioceptive drift and to overestimation of the objects’ weight relative to the larger hand. In addition, weight estimation was also influenced by hand size after visuotactile stroking. These results demonstrate that visuotactile information modulates the intrinsic properties of body representation in terms of size in children and further corroborate previous findings suggesting late developing optimal calibration of visual and proprioceptive signals

Motor Properties of Peripersonal Space in Humans

Background: A stimulus approaching the body requires fast processing and appropriate motor reactions. In monkeys, fronto-parietal networks are involved both in integrating multisensory information within a limited space surrounding the body (i.e. peripersonal space, PPS) and in action planning and execution, suggesting an overlap between sensory representations of space and motor representations of action. In the present study we investigate whether these overlapping representations also exist in the human brain. Methodology/Principal Findings: We recorded from hand muscles motor-evoked potentials (MEPs) induced by single-pulse of transcranial magnetic stimulation (TMS) after presenting an auditory stimulus either near the hand or in far space. MEPs recorded 50 ms after the near-sound onset were enhanced compared to MEPs evoked after far sounds. This near-far modulation faded at longer inter-stimulus intervals, and reversed completely for MEPs recorded 300 ms after the sound onset. At that time point, higher motor excitability was associated with far sounds. Such auditory modulation of hand motor representation was specific to a hand-centred, and not a body-centred reference frame. Conclusions/Significance: This pattern of corticospinal modulation highlights the relation between space and time in the PPS representation: an early facilitation for near stimuli may reflect immediate motor preparation, whereas, at later time intervals, motor preparation relates to distant stimuli potentially approaching the body

Biochemical and aggregation analysis of Bence Jones proteins from different light chain diseases

Deposition of immunoglobulin light chains is a result of clonal proliferation of monoclonal plasma cells that secrete free immunoglobulin light chains, also called Bence Jones proteins (Bence Jones proteins). These Bence Jones proteins are present in circulation in large amounts and excreted in urine in various light chain diseases such as light chain amyloidosis (AL), light chain deposition disease (LCDD) and multiple myeloma (MM). BJP from patients with AL, LCDD and MM were purified from their urine and studies were performed to determine their secondary structure, thermodynamic stability and aggregate formation kinetics. Our results show that LCDD and MM proteins have the lowest free energy of folding while all proteins show similar melting temperatures. Incubation of the BJP at their melting temperature produced morphologically different aggregates: amyloid fibrils from the AL proteins, amorphous aggregates from the LCDD proteins and large spherical species from the MM proteins. The aggregates formed under in vitro conditions suggested that the various proteins derived from patients with different light chain diseases might follow different aggregation pathways