•We investigate the role of the left PFC in resolving interference in word selection.•Left PFC-injured patients and controls performed two picture naming tasks.•Left PFC patients are differentially ...impaired depending on task manipulations.•The left PFC is not always necessary for word selection.•Its involvement is reduced when proactive cognitive control demands are reduced.
Word selection allows us to choose words during language production. This is often viewed as a competitive process wherein a lexical representation is retrieved among semantically-related alternatives. The left prefrontal cortex (LPFC) is thought to help overcome competition for word selection through top-down control. However, whether the LPFC is always necessary for word selection remains unclear. We tested 6 LPFC-injured patients and controls in two picture naming paradigms varying in terms of item repetition. Both paradigms elicited the expected semantic interference effects (SIE), reflecting interference caused by semantically-related representations in word selection. However, LPFC patients as a group showed a larger SIE than controls only in the paradigm involving item repetition. We argue that item repetition increases interference caused by semantically-related alternatives, resulting in increased LPFC-dependent cognitive control demands. The remaining network of brain regions associated with word selection appears to be sufficient when items are not repeated.
•The dorsal stream may support sentence formation in language processing.•Direct cortical and subcortical stimulation was used during awake language mapping.•Subcortically, patients made more errors ...in sentence vs. single word production.•This was true in the dorsal stream only, supporting a role in sentence formation.•Connectivity maps also support a dorsal/ventral division in language production.
Human language is organized along two main processing streams connecting posterior temporal cortex and inferior frontal cortex in the left hemisphere, travelling dorsal and ventral to the Sylvian fissure. Some views propose a dorsal motor versus ventral semantic division. Others propose division by combinatorial mechanism, with the dorsal stream responsible for combining elements into a sequence and the ventral stream for forming semantic dependencies independent of sequential order. We acquired data from direct cortical stimulation in the left hemisphere in 17 neurosurgical patients and subcortical resection in a subset of 10 patients as part of awake language mapping. Two language tasks were employed: a sentence generation (SG) task tested the ability to form sequential and semantic dependencies, and a picture-word interference (PWI) task manipulated semantic interference. Results show increased error rates in the SG versus PWI task during subcortical testing in the dorsal stream territory, and high error rates in both tasks in the ventral stream territory. Connectivity maps derived from diffusion imaging and seeded in the tumor sites show that patients with more errors in the SG than in the PWI task had tumor locations associated with a dorsal stream connectivity pattern. Patients with the opposite pattern of results had tumor locations associated with a more ventral stream connectivity pattern. These findings provide initial evidence using fiber tract disruption with electrical stimulation that the dorsal pathways are critical for organizing words in a sequence necessary for sentence generation, and the ventral pathways are critical for processing semantic dependencies.
Recent actions can benefit or disrupt our current actions and the prefrontal cortex (PFC) is thought to play a major role in the regulation of these actions before they occur. The left PFC has been ...associated with overcoming interference from past events in the context of language production and working memory. The right PFC, and especially the right IFG, has been associated with preparatory inhibition processes. But damage to the right PFC has also been associated with impairment in sustaining actions in motor intentional disorders. Moreover, bilateral dorsolateral PFC has been associated with the ability to maintain task-sets, and improve the performance of current actions based on previous experience. However, potential hemispheric asymmetries in anticipatory regulation of action have not yet been delineated. In the present study, patients with left (n=7) vs. right (n=6) PFC damage due to stroke and 14 aged- and education-matched controls performed a picture naming and a verbal Simon task (participants had to say “right” or “left” depending on the color of the picture while ignoring its position). In both tasks, performance depended on the nature of the preceding trial, but in different ways. In the naming task, performance decreased if previous pictures were from the same rather than from different semantic categories (i.e., semantic interference effect). In the Simon task, performance was better for both compatible (i.e., response matching the position of the stimulus) and incompatible trials when preceded by a trial of the same compatibility (i.e. Gratton effect) relative to sequential trials of different compatibility. Left PFC patients were selectively impaired in picture naming; they had an increased semantic interference effect compared to both right PFC patients and aged-matched controls. Conversely, right PFC patients were selectively impaired in the Simon task compared to controls or left PFC patients; they showed no benefit when sequential trials were compatible (cC vs. iC trials) or a decreased Gratton effect. These results provide evidence for a double dissociation between left and right PFC in the anticipatory regulation of action. Our results are in agreement with a preponderant role of the left PFC in overcoming proactive interference from competing memory representations and provide evidence that the right PFC, plays a role in sustaining goal-directed actions consistent with clinical data in right PFC patients with motor intentional disorders.
•We investigate two measures of proactive control in chronic frontal stroke patients.•All patients and controls performed a picture naming and a verbal Simon task.•Left and right PFC patients are differentially impaired in proactive control.•The left PFC helps to overcome proactive interference from memory representations.•The right PFC helps sustain goal-directed actions from one trial to the next.
•Lack of reliable epidemiological data concerning diabetic neuropathy.•Rapid lowering of blood glucose levels can worsen symptoms associated with diabetic neuropathy.•Findings from MR-neurography and ...histology suggest proximal primary nerve injury in diabetic polyneuropathy.•There are no specific treatment options for diabetic neuropathy, with the drugs commonly used showing inconsistent results.
A 62-year-old diabetologist diagnosed himself to have diabetes type-2, with an HbA1c of 9.5. Five months after lifestyle intervention and a multi-drug approach, HbA1c was 6.3, systolic blood pressure was below 135mmHg and BMI reduced to 27. But he suffered from severe painful diabetic neuropathy. Therefore he decided to visit his friend, a famous neuroscientist at an even more famous university. He asked him several plain questions: 1. What is the natural course of painful diabetic neuropathy? 2. Why do I have, despite almost normalizing HbA1c, more problems than before? 3. Are you sure my problems are due to diabetes or should we do a nerve biopsy? 4. Are there imaging techniques helpful for the diagnosis of this diabetic complication, starting in the distal nerve endings of the foot and slowly moving ahead? 5. Can you suggest any drug, specific and effective, for relieving painful diabetic neuropathy?
This review will use the experts’ answers to the questions of the diabetologist, not only to give a summary of the current knowledge, but even more to highlight areas of research needed for improving the fate of patients with painful diabetic neuropathy. Based on the unknowns, which exceed the knowns in diabetic neuropathy, a quest for more public support of research is made.
We propose and demonstrate evidence accumulation as a plausible theoretical and/or empirical model for the lexical selection process of lexical retrieval. A number of current psycholinguistic ...theories consider lexical selection as a process related to selecting a lexical target from a number of alternatives, which each have varying activations (or signal supports), that are largely resultant of an initial stimulus recognition. We thoroughly present a case for how such a process may be theoretically explained by the evidence accumulation paradigm, and we demonstrate how this paradigm can be directly related or combined with conventional psycholinguistic theory and their simulatory instantiations (generally, neural network models). Then with a demonstrative application on a large new real data set, we establish how the empirical evidence accumulation approach is able to provide parameter results that are informative to leading psycholinguistic theory, and that motivate future theoretical development.
Although seemingly easy, speech production is a complex action involving several processes and brain regions and is often studied through the use of picture naming paradigms. Several brain regions ...have been identified as being involved in speech production and lexical retrieval, including several areas of the left lateral, ventral, and medial temporal cortex, and of the left lateral and medial prefrontal cortex (PFC). However, little is known about how these regions interact to allow us to produce and retrieve words so efficiently as we speak. In this study, we used graph signal processing, and in particular graph learning, to analyze intracranial electroencephalography data recorded directly at the cortical surface (i.e., electrocorticography, ECoG) in the blocked cyclic picture naming task (recently reported in Riès et al., 2017). In this task, pictures are named several times in semantically homogeneous (HOM) versus heterogeneous (HET) blocks. Lexical retrieval, and in particular our ability to select words from competing alternatives, is hampered in HOM vs. HET blocks with increasing repetitions of the pictures, an effect referred to as the semantic interference effect. The method we used can infer the connectivity between different brain regions from the recorded ECoG signals through an optimization process that considers the entire connectivity map instead of pair-wise methods such as more commonly used correlation measures. Our results show that distant left frontal and temporal brain regions as well as PFC regions are functionally connected in picture naming, and that connection strength is variable between pairs of brain regions and between participants. Semantic interference on naming latencies was not present in all participants and varied in terms of when naming latencies became slower in HOM versus HET blocks. Connection weights were generally sensitive to semantic context in the participants showing a semantic interference effect on behavior but in highly variable ways across participants and in different region pairs. In sum, our results are consistent with the hypotheses that left frontal and temporal regions are functionally connected during picture naming and that intra-frontal connections seem particularly important in this paradigm manipulating lexical retrieval difficulty. Further research is needed to explore the cortical interactions supporting lexical retrieval.
•We used Graph Learning to infer functional connectivity during picture naming.•ECoG data from 5 patients with left fronto-temporal coverage was analyzed.•We used blocked cyclic picture naming, manipulating lexical retrieval difficulty.•Fronto-temporal as well as intra-frontal regions were functionally connected.•Semantic context effects on connectivity weights varied between participants.
The global burden of tuberculosis (TB) is aggravated by the continuously increasing emergence of drug resistance, highlighting the need for innovative therapeutic options. The concept of ...host-directed therapy (HDT) as adjunctive to classical antibacterial therapy with antibiotics represents a novel and promising approach for treating TB. Here, we have focused on repurposing the clinically used anticancer drug tamoxifen, which was identified as a molecule with strong host-directed activity against intracellular Mycobacterium tuberculosis (
). Using a primary human macrophage
infection model, we demonstrate the potential of tamoxifen against drug-sensitive as well as drug-resistant
bacteria. The therapeutic effect of tamoxifen was confirmed in an
TB model based on Mycobacterium marinum infection of zebrafish larvae. Tamoxifen had no direct antimicrobial effects at the concentrations used, confirming that tamoxifen acted as an HDT drug. Furthermore, we demonstrate that the antimycobacterial effect of tamoxifen is independent of its well-known target the estrogen receptor (ER) pathway, but instead acts by modulating autophagy, in particular the lysosomal pathway. Through RNA sequencing and microscopic colocalization studies, we show that tamoxifen stimulates lysosomal activation and increases the localization of mycobacteria in lysosomes both
and
, while inhibition of lysosomal activity during tamoxifen treatment partly restores mycobacterial survival. Thus, our work highlights the HDT potential of tamoxifen and proposes it as a repurposed molecule for the treatment of TB.
Tuberculosis (TB) is the world's most lethal infectious disease caused by a bacterial pathogen, Mycobacterium tuberculosis. This pathogen evades the immune defenses of its host and grows intracellularly in immune cells, particularly inside macrophages. There is an urgent need for novel therapeutic strategies because treatment of TB patients is increasingly complicated by rising antibiotic resistance. In this study, we explored a breast cancer drug, tamoxifen, as a potential anti-TB drug. We show that tamoxifen acts as a so-called host-directed therapeutic, which means that it does not act directly on the bacteria but helps the host macrophages combat the infection more effectively. We confirmed the antimycobacterial effect of tamoxifen in a zebrafish model for TB and showed that it functions by promoting the delivery of mycobacteria to digestive organelles, the lysosomes. These results support the high potential of tamoxifen to be repurposed to fight antibiotic-resistant TB infections by host-directed therapy.
The increasing prevalence of antimicrobial-resistant
strains, especially methicillin-resistant
(MRSA), poses a threat to successful antibiotic treatment. Unsuccessful attempts to develop a vaccine ...and rising resistance to last-resort antibiotics urge the need for alternative treatments. Host-directed therapy (HDT) targeting critical intracellular stages of
emerges as a promising alternative, potentially acting synergistically with antibiotics and reducing the risk of
drug resistance. We assessed 201 ATP-competitive kinase inhibitors from Published Kinase Inhibitor Sets (PKIS1 and PKIS2) against intracellular MRSA. Seventeen hit compounds were identified, of which the two most effective and well-tolerated hit compounds (i.e., GW633459A and GW296115X) were selected for further analysis. The compounds did not affect planktonic bacterial cultures, while they were active in a range of human cell lines of cervical, skin, lung, breast and monocyte origin, confirming their host-directed mechanisms. GW633459A, structurally related to lapatinib, exhibited an HDT effect on intracellular MRSA independently of its known human epidermal growth factor receptor (EGFR)/(HER) kinase family targets. GW296115X activated adenosine monophosphate-activated protein kinase (AMPK), thereby enhancing bacterial degradation via autophagy. Finally, GW296115X not only reduced MRSA growth in human cells but also improved the survival rates of MRSA-infected zebrafish embryos, highlighting its potential as HDT.
The chemical interactions between single walled carbon nanotubes (SWNTs) and two structurally similar polymers, poly{(m-phenylenevinylene)-co-(2,5-dioctyloxy-p-phenylene)vinylene}, or PmPV, and ...poly{(2,6-pyridinylenevinylene)-co-(2,5-dioctyloxy-p-phenylene)vinylene}, or PPyPV, are investigated. The fundamental difference between these two polymers is that PPyPV is a base and is readily protonated via the addition of HCl. Both polymers promote chloroform solubilization of SWNTs. We find that the SWNT/PPyPV interaction lowers the pK a of PPyPV. Optoelectronic devices, fabricated from single polymer-wrapped SWNT structures, reveal a photogating effect on charge transport which can rectify or amplify current flow through the tubes. For PmPV wrapped tubes, the wavelength dependence of this effect correlates to the absorption spectrum of PmPV. For PPyPV, the wavelength dependence correlates with the absorption spectrum of protonated PPyPV, indicating that SWNTs assist in charge stabilization.
A method for the spatially selective biofunctionalization of silicon micro- and nanostructures is reported, and results are presented for both single-crystal silicon (111) or (100) surfaces. An ...electroactive monolayer of hydroquinone was formed on the surface of H-terminated silicon working electrodes via an olefin reaction with UV-generated surface radicals. Molecules presenting either cyclopentadiene or a thiol group can be immobilized onto the regions where the hydroquinone has been oxidized. Molecular size and crystal orientation are evaluated as important factors that dictate the electrode stability in aqueous solution under anodic potentials. Monolayers composed of smaller molecules on (111) surfaces exhibit the highest packing density and are more effective in preventing anodic oxidation of the underlying substrate. Voltammetry, X-ray photoelectron spectroscopy, and atomic force and fluorescence microscopy are utilized to interrogate the kinetic rates of biofunctionalization, the extent of surface coverage, monolayer quality, and the spatial selectivity of the process.
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