The existence of loss and gain of chromosomes, known as aneuploidy, has been previously described within the central nervous system. During development, at least one-third of neural progenitor cells (NPCs) are aneuploid. Notably, aneuploid NPCs may survive and functionally integrate into the mature neural circuitry. Given the unanswered significance of this phenomenon, we tested the hypothesis that neural differentiation induced by all-trans retinoic acid (RA) in pluripotent stem cells is accompanied by increased levels of aneuploidy, as previously described for cortical NPCs in vivo. In this work we used embryonal carcinoma (EC) cells, embryonic stem (ES) cells and induced pluripotent stem (iPS) cells undergoing differentiation into NPCs. Ploidy analysis revealed a 2-fold increase in the rate of aneuploidy, with the prevalence of chromosome loss in RA primed stem cells when compared to naïve cells. In an attempt to understand the basis of neurogenic aneuploidy, micronuclei formation and survivin expression was assessed in pluripotent stem cells exposed to RA. RA increased micronuclei occurrence by almost 2-fold while decreased survivin expression by 50%, indicating possible mechanisms by which stem cells lose their chromosomes during neural differentiation. DNA fragmentation analysis demonstrated no increase in apoptosis on embryoid bodies treated with RA, indicating that cell death is not the mandatory fate of aneuploid NPCs derived from pluripotent cells. In order to exclude that the increase in aneuploidy was a spurious consequence of RA treatment, not related to neurogenesis, mouse embryonic fibroblasts were treated with RA under the same conditions and no alterations in chromosome gain or loss were observed. These findings indicate a correlation amongst neural differentiation, aneuploidy, micronuclei formation and survivin downregulation in pluripotent stem cells exposed to RA, providing evidence that somatically generated chromosomal variation accompanies neurogenesis in vitro.

Unilateral brachial plexus injury (BPI) impairs sensory and motor functions of the upper limb. This study aimed to map in detail brachial plexus sensory impairment both in the injured and the uninjured upper limb. Touch sensation was measured through Semmes-Weinstein monofilaments at the autonomous regions of the brachial plexus nerves, hereafter called points of exclusive innervation (PEIs). Seventeen BPI patients (31.35 years±6.9 SD) and 14 age-matched healthy controls (27.57 years±5.8 SD) were tested bilaterally at six selected PEIs (axillary, musculocutaneous, median, radial, ulnar, and medial antebrachial cutaneous [MABC]). As expected, the comparison between the control group and the brachial plexus patients' injured limb showed a robust difference for all PEIs ( p ≤ 0.001). Moreover, the comparison between the control group and the brachial plexus uninjured limb revealed a difference for the median ( p = 0.0074), radial ( p = 0.0185), ulnar ( p = 0.0404), and MABC ( p = 0.0328) PEIs. After splitting the sample into two groups with respect to the dominance of the injured limb, higher threshold values were found for the uninjured side when it occurred in the right dominant limb compared to the control group at the median ( p = 0.0456), radial ( p = 0.0096), and MABC ( p = 0.0078) PEIs. This effect was absent for the left, non-dominant arm. To assess the effect of the severity of sensory deficits observed in the injured limb upon the alterations of the uninjured limb, a K-means clustering algorithm (k = 2) was applied resulting in two groups with less or more severe sensory impairment. The less severely affected patients presented higher thresholds at the median ( p = 0.0189), radial ( p = 0.0081), ulnar ( p = 0.0253), and MABC ( p = 0.0187) PEIs in the uninjured limb in comparison with the control group, whereas higher thresholds at the uninjured limb were found only for the median PEI ( p = 0.0457) in the more severely affected group. In conclusion, an expressive reduction in touch threshold was found for the injured limb allowing a precise mapping of the impairment caused by the BPI. Crucially, BPI also led to reduced tactile threshold in specific PEIs in the uninjured upper limb. These new findings suggest a superordinate model of representational plasticity occurring bilaterally in the brain after a unilateral peripheral injury.

17We hereby present the first worldwide public digital database centred on adult Traumatic Brachial 18Plexus Injury (TBPI). This initiative aims at reducing distance between clinical and experimental 19 practice and encouraging data sharing and reuse. Detailed electronic questionnaires made with the 20 free software LimeSurvey were designed to collect patients' epidemiological, physical and clinical 21data. The freely available software Neuroscience Experiments System (NES) was employed to 22 support data storage and management. First results of this effort concern data collected from 109 23 Brazilian adult TBPI patients with varying degrees of functional impairment. The sample is 24 composed by large majority of men (84.4%), mean age of 32.1 (11.3 SD) years old, victims of 25 motorcycle accidents (67%). The similarity of this dataset basic descriptors with those from previous 26 reports in TBPI validates the strategies employed herein. Managing data from diverse provenance in 27 TBPI may allow identifying functional markers related to the patients' clinical improvement and 28 foster the development of new investigative tools to unveil its mechanisms. 29 30 31 32

Reorganization of the sensorimotor cortex following permanent (e.g., amputation) or temporary (e.g., local anaesthesia) deafferentation of the hand has revealed large‐scale plastic changes between the hand and face representations that are accompanied by perceptual correlates. The physiological mechanisms underlying this reorganization remain poorly understood. The aim of this study was to investigate sensorimotor interactions between the face and hand using an afferent inhibition transcranial magnetic stimulation protocol in which the motor evoked potential elicited by the magnetic pulse is inhibited when it is preceded by an afferent stimulus. We hypothesized that if face and hand representations in the sensorimotor cortex are functionally coupled, then electrocutaneous stimulation of the face would inhibit hand muscle motor responses. In two separate experiments, we delivered an electrocutaneous stimulus to either the skin over the right upper lip (Experiment 1) or right cheek (Experiment 2) and recorded muscular activity from the right first dorsal interosseous. Both lip and cheek stimulation inhibited right first dorsal interosseous motor evoked potentials. To investigate the specificity of this effect, we conducted two additional experiments in which electrocutaneous stimulation was applied to either the right forearm (Experiment 3) or right upper arm (Experiment 4). Forearm and upper arm stimulation also significantly inhibited the right first dorsal interosseous motor evoked potentials, but this inhibition was less robust than the inhibition associated with face stimulation. These findings provide the first evidence for face‐to‐hand afferent inhibition.

In this chapter, we aim to discuss the neurophysiological basis of the brain reorganization (also called plasticity) that associates with a traumatic brachial plexus injury (TBPI), as well as following the brachial plexus surgical reconstruction and its physical rehabilitation. We start by reviewing core aspects of plasticity following peripheral injuries such as amputation and TBPI as well as those associated with chronic pain conditions. Then, we present recent results collected by our team centered on physiological measurements of plasticity after TBPI. Finally, we discuss that an important limitation in the field is the lack of systematic measurement of TBPI clinical features. We finish by proposing possible future venues in the domain of brain plasticity following a TBPI.

Zidovudine (3'-azido-3'-deoxythymidine; AZT) is a nucleoside analogue widely used for the treatment of acquired immune deficiency syndrome (AIDS). Medical guidelines recommend the use of AZT by pregnant women in order to reduce risk of HIV vertical transmission. Although it is efficacious, little is known about the side effects of AZT on embryonic development. In this sense, we used murine embryonic stem (mES) cells as a model to investigate the consequences of AZT exposure for embryogenesis. Firstly, mES colonies were incubated with AZT (50 or 100 μM) and cell cycle profile was evaluated. While 27.7 ± 5.43% of untreated mES cells were in G2/M phase, this percentage raised to 45.96 ± 4.18% after AZT exposure (100 μM). To identify whether accumulation of cells in G2/M phase could be related to chromosome missegregation with consequent cell cycle arrest, aneuploidy rate was evaluated after AZT treatment. Untreated colonies presented 39.6 ± 8.4% of cells aneuploid, while after AZT 100 μM treatment, the proportion of aneuploid cells raised to 67.8 ± 3.4% with prevalence of chromosome loss. This event was accompanied by micronuclei formation as AZT 100 μM treated mES cells presented a 2-fold increase compared to untreated ones. These data suggest that AZT exerts genotoxic effects and increases chromosome instability at early stages of embryonic development.

Background: Traumatic brachial plexus injury (TBPI) is a potentially debilitating event, that usually affects young men following car or motorbike accidents. TBPI interferes with hand sensorimotor function, is associated with chronic pain, and causes cortical reorganization. Interactions between the somatosensory and motor cortices are of fundamental importance for motor control. The hands and face stand out as regions of high functionality with a privileged interaction existing between them, as reflected by the proximity and extension of their representations. Face-hand sensorimotor interactions have been demonstrated in healthy subjects. Objective: The aim of this study was to investigate changes in the sensorimotor interaction in the hand and between the face and the hand in TBPI patients in order to better understand the plasticity of face-hand sensorimotor circuits following TBPI. Method: The experimental design consisted of activating the representation of a hand muscle using transcranial magnetic stimulation (TMS) preceded by an electrical stimulation (ES) applied to the hand or face, which allows the investigation of the cortical reorganization resulting from TBPI. In the paradigm called afferent inhibition (AI), the motor evoked potential (MEP) in a target muscle is significantly reduced by a previous peripheral ES. AI can be evoked in short-latency (SAI) or long-latency (LAI) interstimulus intervals. Nine TBPI patients participated: five had partial sensorimotor function in their hands and were evaluated on the injured side (TBPI-I group) and four had complete loss of sensorimotor function in their hands and were evaluated on the uninjured side (TBPI-UI group). A control group (CG) included 18 healthy adults. A detailed clinical evaluation complemented the analysis. Results: The results showed preserved hand sensorimotor integration for TBPI patients at SAI intervals, but not at LAI intervals. For the face-to-hand sensorimotor integration, the results showed no inhibition at SAI intervals for the TBPI patients. For LAI intervals, a facilitation effect was observed for the TBPI patients, an effect we termed long afferent facilitation or LAF. LAF positively correlated with results in the Central Sensitization Inventory and in the Disabilities Arm, Shoulder, and Hand questionnaire. Conclusion: These results point to the existence of an inhibitory regulation system between the representations of the face and the hand that seems to be suppressed in TBPI and correlates with pain. Moreover, brain changes arising from TBPI are not restricted to the hemisphere contralateral to the injured limb, but extend to both hemispheres.

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