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Recognition of the mRNA 5' end is a critical step needed for translation initiation. This step is performed by the cap binding protein eIF4E, which joins the larger eIF4G subunit to form the eIF4F complex. Trypanosomatids have a minimum of five different eIF4F-like complexes formed through specific but not well-defined interactions between four different eIF4E and five eIF4G homologues. The EIF4E6/EIF4G5 complex has been linked with the stage-specific translation of mRNAs encoding the major Trypanosoma brucei virulence factors. Here, to better define the molecular basis for the TbEIF4E6/TbEIF4G5 interaction, we describe the identification of the peptide interacting with TbEIF4E6 in the region comprising residues 79-166 of TbEIF4G5. The TbEIF4E6-TbEIF4G5_79-116 complex reconstituted with recombinant proteins is highly stable even in the absence of cap-4. The crystal structure of the complex was subsequently solved, revealing extensive interacting surfaces. Comparative analyses highlight the conservation of the overall structural arrangement of different eIF4E/eIF4G complexes. However, highly different interacting surfaces are formed with distinct binding contacts occurring both in the canonical and noncanonical elements within eIF4G and the respective eIF4E counterpart. These specific pairs of complementary interacting surfaces are likely responsible for the selective association needed for the formation of distinct eIF4F complexes in trypanosomatids., (© 2024. The Author(s).)

Visual perception waxes and wanes periodically over time at low frequencies (theta: 4-7 Hz; alpha: 8-13 Hz), creating "perceptual cycles." These perceptual cycles can be induced when stimulating the brain with a flickering visual stimulus at the theta or alpha frequency. Here, we took advantage of the well-known organization of the visual system into retinotopic maps (topographic correspondence between visual and cortical spaces) to assess the spatial organization of induced perceptual cycles. Specifically, we tested the hypothesis that they can propagate across the retinotopic space. A disk oscillating in luminance (inducer) at 4, 6, 8, or 10 Hz was presented in the periphery of the visual field to induce perceptual cycles at specific frequencies. EEG recordings verified that the brain responded at the corresponding inducer frequencies and their first harmonics. Perceptual cycles were assessed with a concurrent detection task-target stimuli were displayed at threshold contrast (50% detection) at random times during the inducer. Behavioral results confirmed that perceptual performance was modulated periodically by the inducer at each frequency. We additionally manipulated the distance between the target and the inducer (three possible positions) and showed that the optimal phase, that is, moment of highest target detection, shifted across target distance to the inducer, specifically when its flicker frequency was in the alpha range (8 and 10 Hz). These results demonstrate that induced alpha perceptual cycles travel across the retinotopic space in humans at a propagation speed of 0.3-0.5 m/sec, consistent with the speed of unmyelinated horizontal connections in the visual cortex., (© 2023 Massachusetts Institute of Technology. Published under a Creative Commons Attribution 4.0 International (CC BY 4.0) license.)

Urban gardening is becoming increasingly popular. Air pollution, which is a major concern in cities might, however, threaten food safety and thus must be assessed. Health risks arise particularly from toxic persistent organic pollutants such as Polycyclic Aromatic Hydrocarbons (PAHs) which are formed by incomplete combustion. A first assessment of crop contamination in two different atmospheric environments in the urban area of Nice reveals a predominance of light PAHs. These pollutants present in the gaseous phase, seem to bioaccumulate while heavy PAHs are absent in vegetation. By understanding the PAH sources and their behavior in the atmosphere but also by analyzing the spatial and temporal data since the European directive in 2004, a link between concentrations found in vegetables grown in experimental gardens and PAH cadastral emission data is presented. The first results could be used as a possible guidance for urban agriculture., (© 2022 The Authors. ChemPlusChem published by Wiley-VCH GmbH.)

Sampling of information is thought to be an important aspect of explorative behaviour. Evidence for it has been gained in behavioural assessments of a variety of overt and covert cognitive domains, including sensation, attention, memory, eye movements and dexterity. A common aspect across many findings is that sampling tends to exhibit a rhythmicity at low frequencies (theta, 4-8 Hz; alpha, 9-12 Hz). Neurophysiological investigations in a wide range of species, including rodents, non-human primates and humans have demonstrated the presence of sampling related neural oscillations in a number of brain areas ranging from early sensory cortex, hippocampus to high-level cognitive areas. However, to assess whether rhythmic sampling represents a general aspect of exploratory behaviour one must critically evaluate the task parameters, and their potential link with neural oscillations. Here we focus on sampling during attentive vision to present an overview on the experimental conditions that are used to investigate rhythmic sampling and associated oscillatory brain activity in this domain. This review aims to (1) provide guidelines to efficiently quantify behavioural rhythms, (2) compare results from human and non-human primate studies and (3) argue that the underlying neural mechanisms of sampling can co-occur in both sensory and high-level areas., (© 2021 The Authors. European Journal of Neuroscience published by Federation of European Neuroscience Societies and John Wiley & Sons Ltd.)

Accumulating evidence suggests that visual perception operates in an oscillatory fashion at an alpha frequency (around 10 Hz). Moreover, visual attention also seems to operate rhythmically, albeit at a theta frequency (around 5 Hz). Both rhythms are often associated to "perceptual snapshots" taken at the favorable phases of these rhythms. However, less is known about the unfavorable phases: do they constitute "blind gaps," requiring the observer to guess, or is information sampled with reduced precision insufficient for the task demands? As simple detection or discrimination tasks cannot distinguish these options, we applied a continuous report task by asking for the exact orientation of a Landolt ring's gap to estimate separate model parameters for precision and the amount of guessing. We embedded this task in a well-established psychophysical protocol by densely sampling such reports across 20 cue-target stimulus onset asynchronies in a Posner-like cueing paradigm manipulating involuntary spatial attention. Testing the resulting time courses of the guessing and precision parameters for rhythmicities using a fast Fourier transform, we found an alpha rhythm (9.6 Hz) in precision for invalidly cued trials and a theta rhythm (4.8 Hz) in the guess rate across validity conditions. These results suggest distinct roles of the perceptual alpha and the attentional theta rhythm. We speculate that both rhythms result in environmental sampling characterized by fluctuating spatial resolution, speaking against a strict succession of blind gaps and perceptual snapshots., (© 2021 The Authors. European Journal of Neuroscience published by Federation of European Neuroscience Societies and John Wiley & Sons Ltd.)

Attention has been found to sample visual information periodically, in a wide range of frequencies below 20 Hz. This periodicity may be supported by brain oscillations at corresponding frequencies. We propose that part of the discrepancy in periodic frequencies observed in the literature is due to differences in attentional demands, resulting from heterogeneity in tasks performed. To test this hypothesis, we used visual search and manipulated task complexity, i.e., target discriminability (high, medium, low) and number of distractors (set size), while electro-encephalography was simultaneously recorded. We replicated previous results showing that the phase of pre-stimulus low-frequency oscillations predicts search performance. Crucially, such effects were observed at increasing frequencies within the theta-alpha range (6-18 Hz) for decreasing target discriminability. In medium and low discriminability conditions, correct responses were further associated with higher post-stimulus phase-locking than incorrect ones, in increasing frequency and latency. Finally, the larger the set size, the later the post-stimulus effect peaked. Together, these results suggest that increased complexity (lower discriminability or larger set size) requires more attentional cycles to perform the task, partially explaining discrepancies between reports of attentional sampling. Low-frequency oscillations structure the temporal dynamics of neural activity and aid top-down, attentional control for efficient visual processing., (© 2022. The Author(s).)

Spontaneous α oscillations (∼10 Hz) have been associated with various cognitive functions, including perception. Their phase and amplitude independently predict cortical excitability and subsequent perceptual performance. However, the causal role of α phase-amplitude tradeoffs on visual perception remains ill-defined. We aimed to fill this gap and tested two clear predictions from the pulsed inhibition theory according to which α oscillations are associated with periodic functional inhibition. (1) High-α amplitude induces cortical inhibition at specific phases, associated with low perceptual performance, while at opposite phases, inhibition decreases (potentially increasing excitation) and perceptual performance increases. (2) Low-α amplitude is less susceptible to these phasic (periodic) pulses of inhibition, leading to overall higher perceptual performance. Here, cortical excitability was assessed in humans using phosphene (illusory) perception induced by single pulses of transcranial magnetic stimulation (TMS) applied over visual cortex at perceptual threshold, and its postpulse evoked activity recorded with simultaneous electroencephalography (EEG). We observed that prepulse α phase modulates the probability to perceive a phosphene, predominantly for high-α amplitude, with a nonoptimal phase for phosphene perception between -π/2 and -π/4. The prepulse nonoptimal phase further leads to an increase in postpulse-evoked activity [event-related potential (ERP)], in phosphene-perceived trials specifically. Together, these results show that α oscillations create periodic inhibitory moments when α amplitude is high, leading to periodic decrease of perceptual performance. This study provides strong causal evidence in favor of the pulsed inhibition theory., (Copyright © 2022 Fakche et al.)

Parieto-occipital alpha rhythms (8-12 Hz) underlie cortical excitability and influence visual performance. Whether the synchrony of intrinsic alpha rhythms in the occipital cortex can be entrained by transcranial magnetic stimulation (TMS) is an open question. We applied 4-pulse, 10-Hz rhythmic TMS to entrain intrinsic alpha oscillators targeting right V1/V2, and tested four predictions with concurrent electroencephalogram (EEG): (1) progressive enhancement of entrainment across time windows, (2) output frequency specificity, (3) dependence on the intrinsic oscillation phase, and (4) input frequency specificity to individual alpha frequency (IAF) in the neural signatures. Two control conditions with an equal number of pulses and duration were arrhythmic-active and rhythmic-sham stimulation. The results confirmed the first three predictions. Rhythmic TMS bursts significantly entrained local neural activity. Near the stimulation site, evoked oscillation amplitude and inter-trial phase coherence (ITPC) were increased for 2 and 3 cycles, respectively, after the last TMS pulse. Critically, ITPC following entrainment positively correlated with IAF rather than with the degree of similarity between IAF and the input frequency (10 Hz). Thus, we entrained alpha-band activity in occipital cortex for ~ 3 cycles (~ 300 ms), and IAF predicts the strength of entrained occipital alpha phase synchrony indexed by ITPC., (© 2021. The Author(s).)

How do endogenous (voluntary) and exogenous (involuntary) attention modulate activity in visual cortex? Using ROI-based fMRI analysis, we measured fMRI activity for valid and invalid trials (target at cued/un-cued location, respectively), pre- or post-cueing endogenous or exogenous attention, while participants performed the same orientation discrimination task. We found stronger modulation in contralateral than ipsilateral visual regions, and higher activity in valid- than invalid-trials. For endogenous attention, modulation of stimulus-evoked activity due to a pre-cue increased along the visual hierarchy, but was constant due to a post-cue. For exogenous attention, modulation of stimulus-evoked activity due to a pre-cue was constant along the visual hierarchy, but was not modulated due to a post-cue. These findings reveal that endogenous and exogenous attention distinctly modulate activity in visuo-occipital areas during orienting and reorienting; endogenous attention facilitates both the encoding and the readout of visual information whereas exogenous attention only facilitates the encoding of information.

Antibiotic resistance is a worldwide threat due to the decreasing supply of new antimicrobials. Novel targets and innovative strategies are urgently needed to generate pathbreaking drug compounds. NAD kinase (NADK) is essential for growth in most bacteria, as it supports critical metabolic pathways. Here, we report the discovery of a new class of antibacterials that targets bacterial NADK. We generated a series of small synthetic adenine derivatives to screen those harboring promising substituents in order to guide efficient fragment linking. This led to NKI1, a new lead compound inhibiting NADK that showed in vitro bactericidal activity against Staphylococcus aureus . In a murine model of infection, NKI1 restricted survival of the bacteria, including methicillin-resistant S. aureus . Collectively, these findings identify bacterial NADK as a potential drug target and NKI1 as a lead compound in the treatment of staphylococcal infections.

Visual search, looking for a target embedded among distractors, has long been used to study attention. Current theories postulate a two-stage process in which early visual areas perform feature extraction, whereas higher-order regions perform attentional selection. Such a model implies iterative communication between low- and high-level regions to sequentially select candidate targets in the array, focus attention on these elements, and eventually permit target recognition. This leads to two independent predictions: (1) high-level, attentional regions and (2) early visual regions should both be involved periodically during the search. Here, we used transcranial magnetic stimulation (TMS) applied over the frontal eye field (FEF) in humans, known to be involved in attentional selection, at various delays while observers performed a difficult, attentional search task. We observed a periodic pattern of interference at ∼6 Hz (theta) suggesting that the FEF is periodically involved during this difficult search task. We further compared this result with two previous studies (Dugué et al., 2011, 2015a) in which a similar TMS procedure was applied over the early visual cortex (V1) while observers performed the same task. This analysis revealed the same pattern of interference, i.e., V1 is periodically involved during this difficult search task, at the theta frequency. Past V1 evidence reappraised for this paper, together with our current FEF results, confirm both of our independent predictions, and suggest that difficult search is supported by low- and high-level regions, each involved periodically at the theta frequency., (Copyright © 2019 Dugué et al.)

Association of the initiation factor eIF4E with the mRNA cap structure is a key step for translation. Trypanosomatids present six eIF4E homologues, showing a low conservation and also differing significantly from the IF4Es of multicellular eukaryotes. On the mRNA side, while in most eukaryotes the mRNA contains cap-0 (7-methyl-GTP), the trypanosomatid mRNA features a cap-4, which is formed by a cap-0, followed by the AACU sequence containing 2'-O-ribose methylations and base methylations on nucleotides 1 and 4. The studies on eIF4E-cap-4 interaction have been hindered by the difficulty to synthesize this rather elaborated cap-4 sequence. To overcome this problem, we applied a liquid-phase oligonucleotide synthesis strategy and describe for the first time the crystal structure of a trypanosomatid eIF4E (T. cruzi EIF4E5) in complex with cap-4. The TcEIF4E5-cap-4 structure allowed a detailed description of the binding mechanism, revealing the interaction mode for the AACU sequence, with the bases packed in a parallel stacking conformation and involved, together with the methyl groups, in hydrophobic contacts with the protein. This binding mechanism evidences a distinct cap interaction mode in comparison with previously described eIF4E structures and may account for the difference of TcEIF4E5-cap-4 dissociation constant in comparison with other eIF4E homologues., (© The Author(s) 2019. Published by Oxford University Press on behalf of Nucleic Acids Research.)

Voluntary attention is at the core of a wide variety of cognitive functions. Attention can be oriented to and sustained at a location or reoriented in space to allow processing at other locations-critical in an ever-changing environment. Numerous studies have investigated attentional orienting in time and space, but little is known about the spatiotemporal dynamics of attentional reorienting. Here we explicitly manipulated attentional reorienting using a cuing procedure in a two-alternative forced-choice orientation-discrimination task. We interrogated attentional distribution by flashing two probe stimuli with various delays between the precue and target stimuli. Then we used the probabilities that both probes and neither probe were correctly reported to solve a second-degree equation, which estimates the report probability at each probe location. We demonstrated that attention reorients periodically at ∼4 Hz (theta) between the two stimulus locations. We further characterized the processing dynamics at each stimulus location, and demonstrated that attention samples each location periodically at ∼11 Hz (alpha). Finally, simulations support our findings and show that this method is sufficiently powered, making it a valuable tool for studying the spatiotemporal dynamics of attention.

Inosine-5'-monophosphate dehydrogenase (IMPDH) is an essential enzyme in many bacterial pathogens and is considered as a potential drug target for the development of new antibacterial agents. Our recent work has revealed the crucial role of one of the two structural domains (i.e. Bateman domain) in the regulation of the quaternary structure and enzymatic activity of bacterial IMPDHs. Thus, we have screened chemical libraries to search for compounds targeting the Bateman domain and identified first in-class allosteric inhibitors of a bacterial IMPDH. These inhibitors were shown to counteract the activation by the natural positive effector, MgATP, and to block the enzyme in its apo conformation (low affinity for IMP). Our structural studies demonstrate the versatility of the Bateman domain to accommodate totally unrelated chemical scaffolds and pave the way for the development of allosteric inhibitors, an avenue little explored until now., (Copyright © 2019 Elsevier Masson SAS. All rights reserved.)

We developed a versatile access to a series of 4-substituted imidazole 2'-deoxynucleoside triphosphate bearing functionalized phenyl or pyrimidinyl rings. 4-Iodo-1H-imidazole was enzymatically converted into the corresponding 2'-deoxynucleoside, which was then chemically derived into its 5'-triphosphate, followed by 4-arylation via Suzuki-Miyaura coupling using (hetero)arylboronic acids. Both KF (exo-) and Deep Vent (exo-) DNA polymerases incorporated these modified nucleotides in primer-extension assays, adenine being the preferred pairing partner in the template. The 4-(3-aminophenyl)imidazole derivative (3APh) was the most efficiently inserted opposite A by KF (exo-) with only a 37-fold lower efficiency (Vmax/KM) than that of the correct dTTP. No further extension occurred after the incorporation of a single aryl-imidazole nucleotide. Interestingly, the aryl-imidazole dNTPs were found to undergo successive incorporation by calf thymus terminal deoxynucleotidyl transferase with different tailing efficiencies among this series and with a marked preference for 2APyr polymerization.

The temporo-parietal junction (TPJ) has been associated with various cognitive and social functions, and is critical for attentional reorienting. Attention affects early visual processing. Neuroimaging studies dealing with such processes have thus far concentrated on striate and extrastriate areas. Here, we investigated whether attention orienting or reorienting modulate activity in visually driven TPJ subregions. For each observer we identified 3 visually responsive subregions within TPJ: 2 bilateral (vTPJant and vTPJpost) and 1 right lateralized (vTPJcent). Cortical activity in these subregions was measured using fMRI while observers performed a 2-alternative forced-choice orientation discrimination task. Covert spatial endogenous (voluntary) or exogenous (involuntary) attention was manipulated using either a central or a peripheral cue with task, stimuli and observers constant. Both endogenous and exogenous attention increased activity for invalidly cued trials in right vTPJpost; only endogenous attention increased activity for invalidly cued trials in left vTPJpost and in right vTPJcent; and neither type of attention modulated either right or left vTPJant. These results demonstrate that vTPJpost and vTPJcent mediate the reorientation of covert attention to task relevant stimuli, thus playing a critical role in visual attention. These findings reveal a differential reorienting cortical response after observers' attention has been oriented to a given location voluntarily or involuntarily.

A versatile two-step synthesis of C4- and C5-arylated 2'-deoxyribosylimidazoles was elaborated using enzymatic N-transglycosylation followed by microwave-assisted Pd-catalysed arylation reactions. We report herein the reaction conditions that permit managing regioselectivity (N3 versus N1-isomers) in the enzymatic glycosylation of 4-iodoimidazole using the nucleoside N-deoxyribosyltransferase from L. leichmannii. Regiocontrolled glycosylation was also observed among several other imidazole derivatives studied, providing simple access to isomers not readily accessible by chemical routes. Finally, a series of flexible nucleosides was obtained in one step from 4- or 5-iodo-imidazole nucleosides by the Suzuki-Miyaura cross-coupling reaction with (hetero)aryl-boronic acids in aqueous media. Moreover, this chemoenzymatic approach is compatible with a one-pot two-step process affording a straightforward access to a broad array of potential anticancer and antiviral drugs as well as new DNA building blocks.

Oscillatory brain activity has functional relevance for perceptual and cognitive processes, as proven by numerous electrophysiology studies accumulating over the years. However, only within the past two decades have researchers been able to study the causal role of such oscillations using transcranial magnetic stimulation (TMS) technology. Two complementary approaches exist. A majority of research employs rhythmic TMS (rTMS) to entrain oscillatory activity and investigate its effect on targeted brain functions. On the other hand, single pulses of TMS (spTMS) that can be delivered with a high spatio-temporal resolution, can be used to precisely probe the state of the system. In this mini-review, we concentrate on this second approach. We argue that, with no a priori hypothesis on the oscillatory frequency of the targeted cortical regions, spTMS can help establish causal links between spontaneous oscillatory activity and perceptual and cognitive functions. Notably, this approach helped to demonstrate that the occipital cortex is periodically involved during specific attentional tasks at the theta (~5 Hz) frequency. We propose that this frequency reflects periodic inter-areal communication for attentional exploration and selection. In the future, clever combination of non-invasive recording and stimulation with well-controlled psychophysics protocols will allow us to further our understanding of the role of brain oscillations for human brain functions.

Feature and conjunction searches are widely used to study attentional deployment. However, the spatiotemporal behavior of attention integration in these tasks remains under debate. Are multiple search stimuli processed in parallel or sequentially? Does sampling of visual information and attentional deployment differ between these two types of search? If so, how? We used an innovative methodology to estimate the distribution of attention on a single-trial basis for feature and conjunction searches. Observers performed feature- and conjunction-search tasks. They had to detect and discriminate a tilted low-spatial-frequency grating among three low-spatial-frequency vertical gratings (feature search) or low-spatial-frequency vertical gratings and high-spatial-frequency tilted gratings (conjunction search). After a variable delay, two probes were flashed at random locations. Performance in reporting the probes was used to infer attentional deployment to those locations. By solving a second-degree equation, we determined the probability of probe report at the most (P1) and least (P2) attended locations on a given trial. Were P1 and P2 equal, we would conclude that attention had been uniformly distributed across all four locations. Otherwise, we would conclude that visual information sampling and attentional deployment had been nonuniformly distributed. Our results show that processing was nonuniformly distributed across the four locations in both searches, and was modulated periodically over time at ∼5 Hz for the conjunction search and ∼12 Hz for the feature search. We argue that the former corresponds to the periodicity of attentional deployment during the search, whereas the latter corresponds to ongoing sampling of visual information. Because different locations were not simultaneously processed, this study rules out a strict parallel model for both search types.

Reorienting of voluntary attention enables the processing of stimuli at previously unattended locations. Although studies have identified a ventral fronto-parietal network underlying attention [1, 2], little is known about whether and how early visual areas are involved in involuntary [3, 4] and even less in voluntary [5] reorienting, and their temporal dynamics are unknown. We used transcranial magnetic stimulation (TMS) over the occipital cortex to interfere with attentional reorienting and study its role and temporal dynamics in this process. Human observers performed an orientation discrimination task, with either valid or invalid attention cueing, across a range of stimulus contrasts. Valid cueing induced a behavioral response gain increase, higher asymptotic performance for attended than unattended locations. During subsequent TMS sessions, observers performed the same task, with high stimulus contrast. Based on phosphene mapping, TMS double pulses were applied at one of various delays to a consistent brain location in retinotopic areas (V1/V2), corresponding to the evoked signal of the target or distractor, in a valid or invalid trial. Thus, the stimulation was identical for the four experimental conditions (valid/invalid cue condition × target/distractor-stimulated). TMS modulation of the target and distractor were both periodic (5 Hz, theta) and out of phase with respect to each other in invalid trials only, when attention had to be disengaged from the distractor and reoriented to the target location. Reorientation of voluntary attention periodically involves V1/V2 at the theta frequency. These results suggest that TMS probes theta phase-reset by attentional reorienting and help link periodic sampling in time and attention reorienting in space., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

A straightforward route to original imidazole-based nucleosides that makes use of an enzymatic N-transglycosylation step is reported in both the ribo- and deoxyribo-series. To illustrate the scope of this approach, a diverse set of 4-aryl and 4-heteroaryl-1H-imidazoles featuring variable sizes and hydrogen-bonding patterns was prepared using a microwave-assisted Suzuki-Miyaura cross-coupling reaction. These imidazole derivatives were examined as possible substrates for the nucleoside 2'-deoxyribosyltransferase from L. leichmannii and the purine nucleoside phosphorylase from E. coli. The optimum transglycosylation conditions, including the use of co-adjuvants to address solubility issues, were defined. Enzymatic conversion of 4-(hetero)arylimidazoles to 2'-deoxyribo- or ribo-nucleosides proceeded in good to high conversion yields, except bulky hydrophobic imidazole derivatives. Nucleoside deoxyribosyltransferase of class II was found to convert the widest range of functionalized imidazoles into 2'-deoxyribonucleosides and was even capable of bis-glycosylating certain heterocyclic substrates. Our findings should enable chemoenzymatic access to a large diversity of flexible nucleoside analogues as molecular probes, drug candidates and original building blocks for synthetic biology.

Difficult search tasks are known to involve attentional resources, but the spatiotemporal behavior of attention remains unknown. Are multiple search targets processed in sequence or in parallel? We developed an innovative methodology to solve this notoriously difficult problem. Observers performed a difficult search task during which two probes were flashed at varying delays. Performance in reporting probes at each location was considered a measure of attentional deployment. By solving a second-degree equation, we determined the probability of probe report at the most and least attended probe locations on each trial. Because these values differed significantly, we conclude that attention was focused on one stimulus or subgroup of stimuli at a time, and not divided uniformly among all search stimuli. Furthermore, this deployment was modulated periodically over time at ∼ 7 Hz. These results provide evidence for a nonuniform spatiotemporal deployment of attention during difficult search.

Objective: The purpose of the study was to analyze clinical presentation, surgical management, and long-term outcome of patients suffering from biliary diverticulum, namely Todani type II congenital bile duct cyst (BDC)., Background: The disease incidence ranges between 0.8% and 5% of all reported BDC cases with a lack of information about clinical presentation, management, and outcome., Methods: A multicenter European retrospective study was conducted by the French Surgical Association. The patients' medical records were included in a Web site database. Diagnostic imaging studies, operative and pathology reports underwent central revision., Results: Among 350 patients with congenital BDC, 19 type II were identified (5.4%), 17 in adults (89.5%) and 2 in children. The biliary diverticulum was located at the upper, middle, and lower part of the extrahepatic biliary tree in 11, 4, and 4 patients (58%, 21%, and 21%, respectively). Complicated presentation occurred in 6 patients (31.6%), including one case of synchronous carcinoma. Surgical techniques included diverticulum excision in all patients. Associated resection of the extrahepatic biliary tree was required in 11 cases (58%) and could be predicted by the presence of complicated clinical presentation. There was no mortality. Long-term outcome was excellent in 89.5% of patients (median follow-uptime: 52 months)., Conclusions: According to the present largest Western series of Todani type II BDC, the type of clinical presentation rather than BDC location, was able to guide the extent of biliary resection. Excellent long-term outcome can be achieved in expert centers.

Visual search--finding a target element among similar-looking distractors--is one of the prevailing experimental methods to study attention. Current theories of visual search postulate an early stage of feature extraction interacting with an attentional process that selects candidate targets for further analysis; in difficult search situations, this selection is iterated until the target is found. Although such theories predict an intrinsic periodicity in the neuronal substrates of attentional search, this prediction has not been extensively tested in human electrophysiology. Here, using EEG and TMS, we study attentional periodicities in visual search. EEG measurements indicated that successful and unsuccessful search trials were associated with different amounts of poststimulus oscillatory amplitude and phase-locking at ∼6 Hz and opposite prestimulus oscillatory phase at ∼6 Hz. A trial-by-trial comparison of pre- and poststimulus ∼6 Hz EEG phases revealed that the functional interplay between prestimulus brain states, poststimulus oscillations, and successful search performance was mediated by a partial phase reset of ongoing oscillations. Independently, TMS applied over occipital cortex at various intervals after search onset demonstrated a periodic pattern of interference at ∼6 Hz. The converging evidence from independent TMS and EEG measurements demonstrates that attentional search is modulated periodically by brain oscillations. This periodicity is naturally compatible with a sequential exploration by attention, although a parallel but rhythmically modulated attention spotlight cannot be entirely ruled out.

This case report concerns a man with appendicitis following right colectomy., (Copyright © 2014 Elsevier Masson SAS. All rights reserved.)

Protein synthesis is involved in the consolidation of short-term memory into long-term memory. Previous electrophysiological data concerning LTP in CA3 suggest that protein synthesis in that region might also be necessary for short-term memory. We tested this hypothesis by locally injecting the protein synthesis inhibitor anisomycin in hippocampal area CA1 or CA3 immediately after contextual fear conditioning. As previously shown, injections in CA1 impaired long-term memory but spared short-term memory. Conversely, injections in CA3 impaired both long-term and short-term memories. We conclude that early steps of experience-induced plasticity occurring in CA3 and underlying short-term memory require protein synthesis., (© 2014 Remaud et al.; Published by Cold Spring Harbor Laboratory Press.)

What are the temporal dynamics of perceptual sampling during visual search tasks, and how do they differ between a difficult (or inefficient) and an easy (or efficient) task? Does attention focus intermittently on the stimuli, or are the stimuli processed continuously over time? We addressed these questions by way of a new paradigm using periodic fluctuations of stimulus information during a difficult (color-orientation conjunction) and an easy (+ among Ls) search task. On each stimulus, we applied a dynamic visual noise that oscillated at a given frequency (2-20 Hz, 2-Hz steps) and phase (four cardinal phase angles) for 500 ms. We estimated the dynamics of attentional sampling by computing an inverse Fourier transform on subjects' d-primes. In both tasks, the sampling function presented a significant peak at 2 Hz; we showed that this peak could be explained by nonperiodic search strategies such as increased sensitivity to stimulus onset and offset. Specifically in the difficult task, however, a second, higher-frequency peak was observed at 9 to 10 Hz, with a similar phase for all subjects; this isolated frequency component necessarily entails oscillatory attentional dynamics. In a second experiment, we presented difficult search arrays with dynamic noise that was modulated by the previously obtained grand-average attention sampling function or by its converse function (in both cases omitting the 2 Hz component to focus on genuine oscillatory dynamics). We verified that performance was higher in the latter than in the former case, even for subjects who had not participated in the first experiment. This study supports the idea of a periodic sampling of attention during a difficult search task. Although further experiments will be needed to extend these findings to other search tasks, the present report validates the usefulness of this novel paradigm for measuring the temporal dynamics of attention.

We report the case of a patient with appendicitis due to actinomycosis, complicated by multiple liver abscesses. Definitive diagnosis was based on histopathologic examination of the resected appendix. Accurate identification of the pathogen led to curative antibiotic therapy of the liver abscesses., (Copyright © 2013 Elsevier Masson SAS. All rights reserved.)

Background and Aims: We evaluated the prevalence of low phospholipid-associated cholelithiasis, a specific form of cholelithiasis associated with at least 2 of the 3 following criteria: first symptoms before the age of 40; intrahepatic comet tail artefacts, sludge or microlithiasis on ultrasound imaging; and recurrence of symptoms after cholecystectomy., Methods: We prospectively studied the cases of 60 consecutive female patients under 30 with symptomatic cholelithiasis., Results: A diagnosis of low phospholipid-associated cholelithiasis was made in 14/60 patients (23%). The molecular analysis showed ABCB4 (n=4) and ABCB11 (n=4) gene mutations. Low phospholipid-associated cholelithiasis was frequently observed in non-overweight patients [13/27 (48%)], was present in most patients whose biliary symptoms occurred before the age of 18 [7/10 (70%)] and was often associated with cholangitis or acute pancreatitis [9/14 (64%), p<0.05] while "common" cholelithiasis was mainly associated with cholecystitis [16/46 (35%), p<0.05]., Conclusion: Nearly one quarter of the female patients under the age of 30 admitted for symptomatic cholelithiasis had low phospholipid-associated cholelithiasis; particularly if body weight was normal, the symptoms began before the age of 18 or in the presence of severe biliary complications., (Copyright © 2013 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.)

Making new ligands for a given protein by in situ ligation of building blocks (or fragments) is an attractive method. However, it suffers from inherent limitations, such as the limited number of available chemical reactions and the low information content of usual chemical library deconvolution. Here, we describe a focused screening of adenosine derivatives using X-ray crystallography. We discovered an unexpected and biocompatible chemical reactivity and have simultaneously identified the mode of binding of the resulting products. We observed that the NAD kinase from Listeria monocytogenes (LmNADK1) can promote amide formation between 5'-amino-5'-deoxyadenosine and carboxylic acid groups. This unexpected reactivity allowed us to bridge in situ two adenosine derivatives to fully occupy the active NAD site. This guided the design of a close analog showing micromolar inhibition of two human pathogenic NAD kinases and potent bactericidal activity against Staphylococcus aureus in vitro., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Why does neuronal activity in sensory brain areas sometimes give rise to perception, and sometimes not? Although neuronal noise is often invoked as the key factor, a portion of this variability could also be due to the history and current state of the brain affecting cortical excitability. Here we directly test this idea by examining whether the phase of prestimulus oscillatory activity is causally linked with modulations of cortical excitability and with visual perception. Transcranial magnetic stimulation (TMS) was applied over human visual cortex to induce illusory perceptions (phosphenes) while electroencephalograms (EEGs) were simultaneously recorded. Subjects reported the presence or absence of an induced phosphene following a single pulse of TMS at perceptual threshold. The phase of ongoing alpha (∼10 Hz) oscillations within 400 ms before the pulse significantly covaried with the perceptual outcome. This effect was observed in occipital regions around the site of TMS, as well as in a distant frontocentral region. In both regions, we found a systematic relationship between prepulse EEG phase and perceptual performance: phosphene probability changed by ∼15% between opposite phases. In summary, we provide direct evidence for a chain of causal relations between the phase of ongoing oscillations, neuronal excitability, and visual perception: ongoing oscillations create periodic "windows of excitability," with sensory perception being more likely to occur at specific phases.

Visual search tasks have been used to understand how, where and when attention influences visual processing. Current theories suggest the involvement of a high-level "saliency map" that selects a candidate location to focus attentional resources. For a parallel (or "pop-out") task, the first chosen location is systematically the target, but for a serial (or "difficult") task, the system may cycle on a few distractors before finally focusing on the target. This implies that attentional effects upon early visual areas, involving feedback from higher areas, should be visible at longer latencies during serial search. A previous study from Juan & Walsh (2003) had used Transcranial Magnetic Stimulation (TMS) to support this conclusion; however, only a few post-stimulus delays were compared, and no control TMS location was used. Here we applied TMS double-pulses (sub-threshold) to induce a transient inhibition of area V1 at every post-stimulus delay between 100 ms and 500 ms (50 ms steps). The search array was presented either at the location affected by the TMS pulses (previously identified by applying several pulses at supra-threshold intensity to induce phosphene perception), or in the opposite hemifield, which served as a retinotopically-defined control location. Two search tasks were used: a parallel (+ among Ls) and a serial one (T among Ls). TMS specifically impaired the serial, but not the parallel search. We highlight an involvement of V1 in serial search 300 ms after the onset; conversely, V1 did not contribute to parallel search at delays beyond 100 ms. This study supports the idea that serial search differs from parallel search by the presence of additional cycles of a select-and-focus iterative loop between V1 and higher-level areas.

Nucleoside 2'-deoxyribosyltransferases catalyze the transfer of 2-deoxyribose between bases and have been widely used as biocatalysts to synthesize a variety of nucleoside analogs. The genes encoding nucleoside 2'-deoxyribosyltransferase (ndt) from Lactobacillus leichmannii and Lactobacillus fermentum underwent random mutagenesis to select variants specialized for the synthesis of 2',3'-dideoxynucleosides. An Escherichia coli strain, auxotrophic for uracil and unable to use 2',3'-dideoxyuridine, cytosine, and 2',3'-dideoxycytidine as a source of uracil was constructed. Randomly mutated lactobacilli ndt libraries from two species, L. leichmannii and L. fermentum, were screened for the production of uracil with 2',3'-dideoxyuridine as a source of uracil. Several mutants suitable for the synthesis of 2',3'-dideoxynucleosides were isolated. The nucleotide sequence of the corresponding genes revealed a single mutation (G --> A transition) leading to the substitution of a small aliphatic amino acid by a nucleophilic one, A15T (L. fermentum) or G9S (L. leichmannii), respectively. We concluded that the "adaptation" of the nucleoside 2'-deoxyribosyltransferase activity to 2,3-dideoxyribosyl transfer requires an additional hydroxyl group on a key amino acid side chain of the protein to overcome the absence of such a group in the corresponding substrate. The evolved proteins also display significantly improved nucleoside 2',3'-didehydro-2',3'-dideoxyribosyltransferase activity.