Subcortical Structures in Humans Can Be Facilitated by Transcranial Direct Current Stimulation

Transcranial direct current stimulation (tDCS) is a noninvasive brain stimulation technique that alters cortical excitability. Interestingly, in recent animal studies facilitatory effects of tDCS have also been observed on subcortical structures. Here, we sought to provide evidence for the potential of tDCS to facilitate subcortical structures in humans as well. Subjects received anodal-tDCS and sham-tDCS on two separate testing days in a counterbalanced order. After stimulation, we assessed the effect of tDCS on two responses that arise from subcortical structures; (1) wrist and ankle responses to an imperative stimulus combined with a startling acoustic stimulus (SAS), and (2) automatic postural responses to external balance perturbations with and without a concurrent SAS. During all tasks, response onsets were significantly faster following anodal-tDCS compared to sham-tDCS, both in trials with and without a SAS. The effect of tDCS was similar for the dominant and non-dominant leg. The SAS accelerated the onsets of ankle and wrist movements and the responses to backward, but not forward perturbations. The faster onsets of SAS-induced wrist and ankle movements and automatic postural responses following stimulation provide strong evidence that, in humans, subcortical structures - in particular the reticular formation - can be facilitated by tDCS. This effect may be explained by two mechanisms that are not mutually exclusive. First, subcortical facilitation may have resulted from enhanced cortico-reticular drive. Second, the applied current may have directly stimulated the reticular formation. Strengthening reticulospinal output by tDCS may be of interest to neurorehabilitation, as there is evidence for reticulospinal compensation after corticospinal lesions.     

Export of the pseudopilin XcpT of the Pseudomonas aeruginosa type II secretion system via the signal recognition particle-Sec pathway

Type IV pilins and pseudopilins are found in various prokaryotic envelope protein complexes, including type IV pili and type II secretion machineries of gram-negative bacteria, competence systems of gram-positive bacteria, and flagella and sugar-binding structures in members of the archaeal kingdom. The precursors of these proteins have highly conserved N termini, consisting of a short, positively charged leader peptide, which is cleaved off by a dedicated peptidase during maturation, and a hydrophobic stretch of approximately 20 amino acid residues. Which pathway is involved in the inner membrane translocation of these proteins is unknown. We used XcpT, the major pseudopilin from the type II secretion machinery of Pseudomonas aeruginosa, as a model to study this process. Transport of an XcpT-PhoA hybrid was shown to occur in the absence of other Xcp components in P. aeruginosa and in Escherichia coli. Experiments with conditional sec mutants and reporter-protein fusions showed that this transport process involves the cotranslational signal recognition particle targeting route and is dependent on a functional Sec translocon.     

StartReact Effects Support Different Pathophysiological Mechanisms Underlying Freezing of Gait and Postural Instability in Parkinson’s Disease

Introduction

The pathophysiology underlying postural instability in Parkinson’s disease is poorly understood. The frequent co-existence with freezing of gait raises the possibility of shared pathophysiology. There is evidence that dysfunction of brainstem structures contribute to freezing of gait. Here, we evaluated whether dysfunction of these structures contributes to postural instability as well. Brainstem function was assessed by studying the StartReact effect (acceleration of latencies by a startling acoustic stimulus (SAS)).

Methods

We included 25 patients, divided in two different ways: 1) those with postural instability (HY = 3, n = 11) versus those without (HY<3, n = 14); and 2) those with freezing (n = 11) versus those without freezing (n = 14). We also tested 15 matched healthy controls. We tested postural responses by translating a balance platform in the forward direction, resulting in backward balance perturbations. In 25% of trials, the start of the balance perturbation was accompanied by a SAS.

Results

The amplitude of automatic postural responses and length of the first balance correcting step were smaller in patients with postural instability compared to patients without postural instability, but did not differ between freezers and non-freezers. In contrast, the StartReact effect was intact in patients with postural instability but was attenuated in freezers.

Discussion

We suggest that the mechanisms underlying freezing of gait and postural instability in Parkinson’s disease are at least partly different. Underscaling of automatic postural responses and balance-correcting steps both contribute to postural instability. The attenuated StartReact effect was seen only in freezers and likely reflects inadequate representation of motor programs at upper brainstem level.     

Type I interferon promotes cell‐to‐cell spread of Listeria monocytogenes

Type I interferons (IFNs) play a critical role in antiviral immune responses, but can be deleterious to the host during some bacterial infections. Listeria monocytogenes (Lm) induces a type I IFN response by activating cytosolic antiviral surveillance pathways. This is beneficial to the bacteria as mice lacking the type I IFN receptor (IFNAR1^?/?) are resistant to systemic infection by Lm. The mechanisms by which type I IFNs promote Lm infection are unclear. Here, we show that IFNAR1 is required for dissemination of Lm within infection foci in livers of infected mice and for efficient cell‐to‐cell spread in vitro in macrophages. IFNAR1 promotes ActA polarization and actin‐based motility in the cytosol of host cells. Our studies suggest type I IFNs directly impact the intracellular life cycle of Lm and provide new insight into the mechanisms used by bacterial pathogens to exploit the type I IFN response.