Successful long-term systemic sclerosis treatment by high-frequent low-dose B cell-depleting therapy.

OBJECTIVES: Systemic sclerosis (SSc) is a multiorgan disease with a 10-year mortality rate of up to 50 %. B cell-depleting therapy with rituximab (RTX) appears effective in SSc treatment, but data from randomized controlled trials (RCTs) are lacking, and the frequency and dosage of RTX in SSc have no consensus. We aimed to evaluate the long-term efficacy and safety of quarterly RTX administration in SSc. METHODS: This study retrospectively analyzed 40 patients with SSC treated with RTX twice within 14 days every 3 months from 2010 to 2020. The patients fulfilled the LeRoy and the American College of Rheumatology/European League Against Rheumatism Criteria for SSc. Modified Rodnan skin score (mRSS), lung function test results, and serum immunoglobulin (IgG, IgA, and IgM) concentrations were analyzed. RESULTS: A total of 40 patients with SSc received RTX over a median time of 3.9 years (range: 1-10 years). The median mRSS (baseline: 19, 24 months: 16, p < 0.001) demonstrated a significant improvement, and the predicted forced vital capacity was stable. No new or unexpected safety signals, especially regarding treatment-related infectious adverse events, were observed. Immunoglobulin concentrations were within normal range, and specific antibodies to pneumococcal polysaccharides were preserved despite long-term B cell-depleting therapy. None of the patients died during the observation period of up to 10 years. CONCLUSION: SSc was effectively and safely treated with low-dose RTX quarterly. RCTs are warranted to validate the advantage of continuous B cell depletion by quarterly low-dose RTX administration compared to other treatment intervals.

P2RX7 gene variants associate with altered inflammasome assembly and reduced pyroptosis in chronic nonbacterial osteomyelitis (CNO).

Chronic nonbacterial osteomyelitis (CNO), an autoinflammatory bone disease primarily affecting children, can cause pain, hyperostosis and fractures, affecting quality-of-life and psychomotor development. This study investigated CNO-associated variants in P2RX7, encoding for the ATP-dependent trans-membrane K+ channel P2X7, and their effects on NLRP3 inflammasome assembly. Whole exome sequencing in two related transgenerational CNO patients, and target sequencing of P2RX7 in a large CNO cohort (N = 190) were conducted. Results were compared with publicly available datasets and regional controls (N = 1873). Findings were integrated with demographic and clinical data. Patient-derived monocytes and genetically modified THP-1 cells were used to investigate potassium flux, inflammasome assembly, pyroptosis, and cytokine release. Rare presumably damaging P2RX7 variants were identified in two related CNO patients. Targeted P2RX7 sequencing identified 62 CNO patients with rare variants (32.4%), 11 of which (5.8%) carried presumably damaging variants (MAF <1%, SIFT "deleterious", Polyphen "probably damaging", CADD >20). This compared to 83 of 1873 controls (4.4%), 36 with rare and presumably damaging variants (1.9%). Across the CNO cohort, rare variants unique to one (Median: 42 versus 3.7) or more (≤11 patients) participants were over-represented when compared to 190 randomly selected controls. Patients with rare damaging variants more frequently experienced gastrointestinal symptoms and lymphadenopathy while having less spinal, joint and skin involvement (psoriasis). Monocyte-derived macrophages from patients, and genetically modified THP-1-derived macrophages reconstituted with CNO-associated P2RX7 variants exhibited altered potassium flux, inflammasome assembly, IL-1ß and IL-18 release, and pyroptosis. Damaging P2RX7 variants occur in a small subset of CNO patients, and rare P2RX7 variants may represent a CNO risk factor. Observations argue for inflammasome inhibition and/or cytokine blockade and may allow future patient stratification and individualized care.

WWC2 expression in the testis: Implications for spermatogenesis and male fertility.

The family of WWC proteins is known to regulate cell proliferation and organ growth control via the Hippo signaling pathway. As WWC proteins share a similar domain structure and a common set of interacting proteins, they are supposed to fulfill compensatory functions in cells and tissues. While all three WWC family members WWC1, WWC2, and WWC3 are found co-expressed in most human organs including lung, brain, kidney, and liver, in the testis only WWC2 displays a relatively high expression. In this study, we investigated the testicular WWC2 expression in spermatogenesis and male fertility. We show that the Wwc2 mRNA expression level in mouse testes is increased during development in parallel with germ cell proliferation and differentiation. The cellular expression of each individual WWC family member was evaluated in published single-cell mRNA datasets of murine and human testes demonstrating a high WWC2 expression predominantly in early spermatocytes. In line with this, immunohistochemistry revealed cytosolic WWC2 protein expression in primary spermatocytes from human testes displaying full spermatogenesis. In accordance with these findings, markedly lower WWC2 expression levels were detected in testicular tissues from mice and men lacking germ cells. Finally, analysis of whole-exome sequencing data of male patients affected by infertility and unexplained severe spermatogenic failure revealed several heterozygous, rare WWC2 gene variants with a proposed damaging function and putative impact on WWC2 protein structure. Taken together, our findings provide novel insights into the testicular expression of WWC2 and show its cell-specific expression in spermatocytes. As rare WWC2 variants were identified in the background of disturbed spermatogenesis, WWC2 may be a novel candidate gene for male infertility.

A mathematical model of competition between fiber and mucin degraders in the gut provides a possible explanation for mucus thinning.

The human gut microbiota relies on complex carbohydrates (glycans) for energy and growth, primarily dietary fiber and host-derived mucins. We introduce a mathematical model of a glycan generalist and a mucin specialist in a two-compartment chemostat model of the human colon. Our objective is to characterize the influence of dietary fiber and mucin supply on the abundance of mucin-degrading species within the gut ecosystem. Current mathematical gut reactor models that include the enzymatic degradation of glycans do not differentiate between glycan types and their degraders. The model we present distinguishes between a generalist that can degrade both dietary fiber and mucin, and a specialist species that can only degrade mucin. The integrity of the colonic mucus barrier is essential for overall human health and well-being, with the mucin specialist Akkermanisa muciniphila being associated with a healthy mucus layer. Competition, particularly between the specialist and generalists like Bacteroides thetaiotaomicron, may lead to mucus layer erosion, especially during periods of dietary fiber deprivation. Our model treats the colon as a gut reactor system, dividing it into two compartments that represent the lumen and the mucus of the gut, resulting in a complex system of ordinary differential equations with a large and uncertain parameter space. To understand the influence of model parameters on long-term behavior, we employ a random forest classifier, a supervised machine learning method. Additionally, a variance-based sensitivity analysis is utilized to determine the sensitivity of steady-state values to changes in model parameter inputs. By constructing this model, we can investigate the underlying mechanisms that control gut microbiota composition and function, free from confounding factors.

ERPs and alpha oscillations track the encoding and maintenance of object-based representations in visual working memory.

When memorizing an integrated object such as a Kanizsa figure, the completion of parts into a coherent whole is attained by grouping processes which render a whole-object representation in visual working memory (VWM). The present study measured event-related potentials (ERPs) and oscillatory amplitudes to track these processes of encoding and representing multiple features of an object in VWM. To this end, a change detection task was performed, which required observers to memorize both the orientations and colors of six "pacman" items while inducing configurations of the pacmen that systematically varied in terms of their grouping strength. The results revealed an effect of object configuration in VWM despite physically constant visual input: change detection for both orientation and color features was more accurate with increased grouping strength. At the electrophysiological level, the lateralized ERPs and alpha activity mirrored this behavioral pattern. Perception of the orientation features gave rise to the encoding of a grouped object as reflected by the amplitudes of the Ppc. The grouped object structure, in turn, modulated attention to both orientation and color features as indicated by the enhanced N1pc and N2pc. Finally, during item retention, the representation of individual objects and the concurrent allocation of attention to these memorized objects were modulated by grouping, as reflected by variations in the CDA amplitude and a concurrent lateralized alpha suppression, respectively. These results indicate that memorizing multiple features of grouped, to-be-integrated objects involves multiple, sequential stages of processing, providing support for a hierarchical model of object representations in VWM.

Microbiological toxicity tests using standardized ISO/OECD methods-current state and outlook.

Microbial toxicity tests play an important role in various scientific and technical fields including the risk assessment of chemical compounds in the environment. There is a large battery of normalized tests available that have been standardized by ISO (International Organization for Standardization) and OECD (Organization for Economic Co-operation and Development) and which are worldwide accepted and applied. The focus of this review is to provide information on microbial toxicity tests, which are used to elucidate effects in other laboratory tests such as biodegradation tests, and for the prediction of effects in natural and technical aqueous compartments in the environment. The various standardized tests as well as not normalized methods are described and their advantages and disadvantages are discussed. In addition, the sensitivity and usefulness of such tests including a short comparison with other ecotoxicological tests is presented. Moreover, the far-reaching influence of microbial toxicity tests on biodegradation tests is also demonstrated. A new concept of the physiological potential of an inoculum (PPI) consisting of microbial toxicity tests whose results are expressed as a chemical resistance potential (CRP) and the biodegradation adaptation potential (BAP) of an inoculum is described that may be helpful to characterize inocula used for biodegradation tests. KEY POINTS: • Microbial toxicity tests standardized by ISO and OECD have large differences in sensitivity and applicability. • Standardized microbial toxicity tests in combination with biodegradability tests open a new way to characterize inocula for biodegradation tests. • Standardized microbial toxicity tests together with ecotoxicity tests can form a very effective toolbox for the characterization of toxic effects of chemicals.

Task-irrelevant valence-preferred colors boost visual search for a singleton-shape target.

Some studies have suggested that emotion-associated features might influence attentional capture. However, demonstrating valence-dependent distractor interference has proven challenging, possibly due to the neglect of individuals' color-valence preferences in standard, averaged reaction-time (RT) measures. To address this, we investigated valence-driven attentional-capture using an association phase in which emotionally neutral vs. positive-feedback photographs were paired with two alternative target colors, red vs. green. This was followed by a test phase requiring participants to search for a pop-out shape target in the presence or absence of an emotion-associated color. In Experiments 1 and 2, this color could only appear in a distractor, while in Experiment 3, it appeared in the target. Analyzing the standard, averaged RT measures, we found no significant valence association or valence-modulated attentional capture. However, correlational analyses revealed a positive relationship between individual participants' color-valence preference during the association phase and their valence-based effect during the test phase. Moreover, most individuals favored red over green in the association phase, leading to marked color-related asymmetries in the average measures. Crucially, the presence of the valence-preferred color anywhere in the test display facilitated RTs. This effect persisted even when the color appeared in one of the distractors (Experiments 1 and 2), at variance with this distractor capturing attention. These findings suggest that task-irrelevant valence-preferred color signals were registered pre-attentively and boosted performance, likely by raising the general (non-spatial) alertness level. However, these signals were likely kept out of attentional-priority computation to prevent inadvertent attentional capture.

Hierarchy of Intra- and Cross-modal Redundancy Gains in Visuo-tactile Search: Evidence from the Posterior Contralateral Negativity.

Redundant combination of target features from separable dimensions can expedite visual search. The dimension-weighting account explains these "redundancy gains" by assuming that the attention-guiding priority map integrates the feature-contrast signals generated by targets within the respective dimensions. The present study investigated whether this hierarchical architecture is sufficient to explain the gains accruing from redundant targets defined by features in different modalities, or whether an additional level of modality-specific priority coding is necessary, as postulated by the modality-weighting account (MWA). To address this, we had observers perform a visuo-tactile search task in which targets popped out by a visual feature (color or shape) or a tactile feature (vibro-tactile frequency) as well as any combination of these features. The RT gains turned out larger for visuo-tactile versus visual redundant targets, as predicted by the MWA. In addition, we analyzed two lateralized event-related EEG components: the posterior (PCN) and central (CCN) contralateral negativities, which are associated with visual and tactile attentional selection, respectively. The CCN proved to be a stable somatosensory component, unaffected by cross-modal redundancies. In contrast, the PCN was sensitive to cross-modal redundancies, evidenced by earlier onsets and higher amplitudes, which could not be explained by linear superposition of the earlier CCN onto the later PCN. Moreover, linear mixed-effect modeling of the PCN amplitude and timing parameters accounted for approximately 25% of the behavioral RT variance. Together, these behavioral and PCN effects support the hierarchy of priority-signal computation assumed by the MWA.

Learning-Induced Plasticity Enhances the Capacity of Visual Working Memory.

Visual working memory (VWM) is limited in capacity, though memorizing meaningful objects may refine this limitation. However, meaningful and meaningless stimuli typically differ perceptually, and objects' associations with meaning are usually already established outside the laboratory, potentially confounding experimental findings. Here, in two experiments with young adults (N = 45 and N = 20), we controlled for these influences by having observers actively learn associations of (for them) initially meaningless stimuli: Chinese characters, half of which were consistently paired with pictures of animals or everyday objects in a learning phase. This phase was preceded and followed by a (pre- and postlearning) change-detection task to assess VWM performance. The results revealed that short-term retention was enhanced after learning, particularly for meaning-associated characters, although participants did not quite reach the accuracy level attained by native Chinese observers (young adults, N = 20). These results thus provide direct experimental evidence that participants' VWM of objects is boosted by them having acquired a long-term-memory association with meaning.

Electrophysiological signatures of temporal context in the bisection task.

Despite having relatively accurate timing, subjective time can be influenced by various contexts, such as stimulus spacing and sample frequency. Several electroencephalographic (EEG) components have been associated with timing, including the contingent negative variation (CNV), offset P2, and late positive component of timing (LPCt). However, the specific role of these components in the contextual modulation of perceived time remains unclear. In this study, we conducted two temporal bisection experiments to investigate this issue. Participants had to judge whether a test duration was close to a short or long standard. Unbeknownst to them, we manipulated the stimulus spacing (Experiment 1) and sample frequency (Experiment 2) to create short and long contexts while maintaining consistent test ranges and standards across different sessions. The results revealed that the bisection threshold shifted towards the ensemble mean, and both CNV and LPCt were sensitive to context modulation. In the short context, the CNV exhibited an increased climbing rate compared to the long context, whereas the LPCt displayed reduced amplitude and latency. These findings suggest that the CNV represents an expectancy wave preceding a temporal decision process, while the LPCt reflects the decision-making process itself, with both components influenced by the temporal context.

Preparatory Control Against Distraction Is Not Feature-Based.

Salient-but-irrelevant stimuli (distractors) co-occurring with search targets can capture attention against the observer's will. Recently, evidence has accumulated that preparatory control can prevent this misguidance of spatial attention in predictable situations. However, the underlying mechanisms have remained elusive. Most pertinent theories assume that attention is guided by specific features. This widespread theoretical claim provides several strong predictions with regard to distractor handling that are disconfirmed here: Employing electrophysiological markers of covert attentional dynamics, in three experiments, we show that distractors standing out by a feature that is categorically different from the target consistently captures attention. However, equally salient distractors standing out in a different feature dimension are effectively down-weighted, even if unpredictably swapping their defining feature with the target. This shows that preparing for a distractor's feature is neither necessary nor sufficient for successful avoidance of attentional capture. Rather, capture is prevented by preparing for the distractor's feature dimension.

Statistical Learning of Frequent Distractor Locations in Visual Search Involves Regional Signal Suppression in Early Visual Cortex.

Observers can learn locations where salient distractors appear frequently to reduce potential interference-an effect attributed to better suppression of distractors at frequent locations. But how distractor suppression is implemented in the visual cortex and within the frontoparietal attention networks remains unclear. We used fMRI and a regional distractor-location learning paradigm with two types of distractors defined in either the same (orientation) or a different (color) dimension to the target to investigate this issue. fMRI results showed that BOLD signals in early visual cortex were significantly reduced for distractors (as well as targets) occurring at the frequent versus rare locations, mirroring behavioral patterns. This reduction was more robust with same-dimension distractors. Crucially, behavioral interference was correlated with distractor-evoked visual activity only for same- (but not different-) dimension distractors. Moreover, with different- (but not same-) dimension distractors, a color-processing area within the fusiform gyrus was activated more when a distractor was present in the rare region versus being absent and more with a distractor in the rare versus frequent locations. These results support statistical learning of frequent distractor locations involving regional suppression in early visual cortex and point to differential neural mechanisms of distractor handling with different- versus same-dimension distractors.

Toward the future of OECD/ISO biodegradability testing-new approaches and developments.

In the past decades, industrial and scientific communities have developed a complex standardized system (e.g., OECD, ISO, CEN) to evaluate the biodegradability of chemical substances. This system includes for OECD three levels of testing (ready and inherent biodegradability tests, simulation tests). It was adopted by many countries and is completely integrated into European legislation (registration, evaluation, authorization, and restriction of chemicals, REACH). Nevertheless, the different tests have certain deficiencies, and the question arises of how accurately these tests display the situation in the real environment and how the results can be used for predictions. This review will focus on the technical advantages and weaknesses of current tests concerning the technical setup, the inoculum characterization, and its biodegradation potential as well as the use of adequate reference compounds. A special focus of the article will be on combined test systems offering enhanced possibilities to predict biodegradation. The properties of microbial inocula are critically discussed, and a new concept concerning the biodegradation adaptation potential (BAP) of inocula is proposed. Furthermore, a probability model and different in silico QSAR (quantitative structure-activity relationships) models to predict biodegradation from chemical structures are reviewed. Another focus lies on the biodegradation of difficult single compounds and mixtures of chemicals like UVCBs (unknown or variable composition, complex reaction products, or biological materials) which will be an important challenge for the forthcoming decades. KEY POINTS: • There are many technical points to be improved in OECD/ISO biodegradation tests • The proper characterization of inocula is a crucial point in biodegradation tests • Combined biodegradation test systems offer extended possibilities for biodegradation tests.

DeepQMC: An open-source software suite for variational optimization of deep-learning molecular wave functions.

Computing accurate yet efficient approximations to the solutions of the electronic Schrödinger equation has been a paramount challenge of computational chemistry for decades. Quantum Monte Carlo methods are a promising avenue of development as their core algorithm exhibits a number of favorable properties: it is highly parallel and scales favorably with the considered system size, with an accuracy that is limited only by the choice of the wave function Ansatz. The recently introduced machine-learned parametrizations of quantum Monte Carlo Ansätze rely on the efficiency of neural networks as universal function approximators to achieve state of the art accuracy on a variety of molecular systems. With interest in the field growing rapidly, there is a clear need for easy to use, modular, and extendable software libraries facilitating the development and adoption of this new class of methods. In this contribution, the DeepQMC program package is introduced, in an attempt to provide a common framework for future investigations by unifying many of the currently available deep-learning quantum Monte Carlo architectures. Furthermore, the manuscript provides a brief introduction to the methodology of variational quantum Monte Carlo in real space, highlights some technical challenges of optimizing neural network wave functions, and presents example black-box applications of the program package. We thereby intend to make this novel field accessible to a broader class of practitioners from both the quantum chemistry and the machine learning communities.

The C-Mannosylome of Human Induced Pluripotent Stem Cells Implies a Role for ADAMTS16 C-Mannosylation in Eye Development.

C-mannosylation is a modification of tryptophan residues with a single mannose and can affect protein folding, secretion, and/or function. To date, only a few proteins have been demonstrated to be C-mannosylated, and studies that globally assess protein C-mannosylation are scarce. To interrogate the C-mannosylome of human induced pluripotent stem cells, we compared the secretomes of CRISPR-Cas9 mutants lacking either the C-mannosyltransferase DPY19L1 or DPY19L3 to WT human induced pluripotent stem cells using MS-based quantitative proteomics. The secretion of numerous proteins was reduced in these mutants, including that of A Disintegrin And Metalloproteinase with ThromboSpondin Motifs 16 (ADAMTS16), an extracellular protease that was previously reported to be essential for optic fissure fusion in zebrafish eye development. To test the functional relevance of this observation, we targeted dpy19l1 or dpy19l3 in embryos of the Japanese rice fish medaka (Oryzias latipes) by CRISPR-Cas9. We observed that targeting of dpy19l3 partially caused defects in optic fissure fusion, called coloboma. We further showed in a cellular model that DPY19L1 and DPY19L3 mediate C-mannosylation of a recombinantly expressed thrombospondin type 1 repeat of ADAMTS16 and thereby support its secretion. Taken together, our findings imply that DPY19L3-mediated C-mannosylation is involved in eye development by assisting secretion of the extracellular protease ADAMTS16.

Adaptation of the metolachlor-degrading fungus Trichoderma harzianum to the simultaneous presence of low-density polyethylene (LDPE) microplastics.

Although it is known that microplastics (MPs) in soils cause a threat to this complex environment, the actual effects of MPs on soil microorganisms and their catabolic activities, particularly with the biodegradation of herbicides, remain unclear. Hence, the objective of this study was to investigate the effects of a simultaneous presence of metolachlor and low-density polyethylene (LDPE) microplastics on growth inhibition and adaptive responses of Trichoderma harzianum in soil microcosms. Using ergosterol content as an indicator of fungal biomass, it was observed that MPs alone had a marginal inhibitory effect on the growth of the fungus, whereas MET exhibited a dose-dependent inhibitory effect on T. harzianum. However, the presence of MPs did not influence the fungal transforming activity toward the herbicide. Conversely, analysis of lipid profiles in the presence of MPs and herbicides revealed a reduction in the overall fluidity of phospholipid fatty acids, primarily attributed to an increase in lysophospholipids. The activities of six extracellular enzymes in the soil, measured using methylumbelliferone-linked substrates, were significantly enhanced in the presence of MET. These findings contribute to a broader understanding of the alterations in fungal activity in soil resulting from the influence of MPs and MET.

Multisensory Rather than Unisensory Representations Contribute to Statistical Context Learning in Tactile Search.

Using a combination of behavioral and EEG measures in a tactile odd-one-out search task with collocated visual items, we investigated the mechanisms underlying facilitation of search by repeated (vs. nonrepeated) spatial distractor-target configurations ("contextual cueing") when either the tactile (same-modality) or the visual array (different-modality) context was predictive of the location of the tactile singleton target. Importantly, in both conditions, the stimulation was multisensory, consisting of tactile plus visual items, although the target was singled out in the tactile modality and so the visual items were task-irrelevant. We found that when the predictive context was tactile, facilitation of search RTs by repeated configurations was accompanied by, and correlated with, enhanced lateralized ERP markers of pre-attentive (N1, N2) and, respectively focal-attentional processing (contralateral delay activity) not only over central ("somatosensory"), but also posterior ("visual") electrode sites, although the ERP effects were less marked over visual cortex. A similar pattern-of facilitated RTs and enhanced lateralized (N2 and contralateral delay activity) ERP components-was found when the predictive context was visual, although the ERP effects were less marked over somatosensory cortex. These findings indicate that both somatosensory and visual cortical regions contribute to the more efficient processing of the tactile target in repeated stimulus arrays, although their involvement is differentially weighted depending on the sensory modality that contains the predictive information.

Subjective cognitive decline predicts lower cingulo-opercular network functional connectivity in individuals with lower neurite density in the forceps minor.

Cognitive complaints of attention/concentration problems are highly frequent in older adults with subjective cognitive decline (SCD). Functional connectivity in the cingulo-opercular network (CON-FC) supports cognitive control, tonic alertness, and visual processing speed. Thus, those complaints in SCD may reflect a decrease in CON-FC. Frontal white-matter tracts such as the forceps minor exhibit age- and SCD-related alterations and, therefore, might influence the CON-FC decrease in SCD. Here, we aimed to determine whether SCD predicts an impairment in CON-FC and whether neurite density in the forceps minor modulates that effect. To do so, we integrated cross-sectional and longitudinal analyses of multimodal data in a latent growth curve modeling approach. Sixty-nine healthy older adults (13 males; 68.33 ± 7.95 years old) underwent resting-state functional and diffusion-weighted magnetic resonance imaging, and the degree of SCD was assessed at baseline with the memory functioning questionnaire (greater score indicating more SCD). Forty-nine of the participants were further enrolled in two follow-ups, each about 18 months apart. Baseline SCD did not predict CON-FC after three years or its rate of change (p-values > 0.092). Notably, however, the forceps minor neurite density did modulate the relation between SCD and CON-FC (intercept; b = 0.21, 95% confidence interval, CI, [0.03, 0.39], p = 0.021), so that SCD predicted a greater CON-FC decrease in older adults with relatively lower neurite density in the forceps minor. The neurite density of the forceps minor, in turn, negatively correlated with age. These results suggest that CON-FC alterations in SCD are dependent upon the forceps minor neurite density. Accordingly, these results imply modifiable age-related factors that could help delay or mitigate both age and SCD-related effects on brain connectivity.

A Bacterial Mannose Binding Lectin as a Tool for the Enrichment of C- and O-Mannosylated Peptides.

Mass spectrometry (MS) easily detects C-mannosylated peptides from purified proteins but not from complex biological samples. Enrichment of specific glycopeptides by lectin affinity prior to MS analysis has been widely applied to support glycopeptide identification but was until now not available for C-mannosylated peptides. Here, we used the α-mannose-specific Burkholderia cenocepacia lectin A (BC2L-A) and show that, in addition to its previously demonstrated high-mannose N-glycan binding capability, this lectin is able to retain C- and O-mannosylated peptides. Besides testing binding abilities to standard peptides, we applied BC2L-A affinity to enrich C-mannosylated peptides from complex samples of tryptic digests of HEK293 and MCF10A whole cell extracts, which led to the identification of novel C-mannosylation sites. In conclusion, BC2L-A enabled specific enrichment of C- and O-mannosylated peptides and might have superior properties over other mannose binding lectins for this purpose.

Inter-trial effects in priming of pop-out: Comparison of computational updating models.

In visual search tasks, repeating features or the position of the target results in faster response times. Such inter-trial 'priming' effects occur not just for repetitions from the immediately preceding trial but also from trials further back. A paradigm known to produce particularly long-lasting inter-trial effects-of the target-defining feature, target position, and response (feature)-is the 'priming of pop-out' (PoP) paradigm, which typically uses sparse search displays and random swapping across trials of target- and distractor-defining features. However, the mechanisms underlying these inter-trial effects are still not well understood. To address this, we applied a modeling framework combining an evidence accumulation (EA) model with different computational updating rules of the model parameters (i.e., the drift rate and starting point of EA) for different aspects of stimulus history, to data from a (previously published) PoP study that had revealed significant inter-trial effects from several trials back for repetitions of the target color, the target position, and (response-critical) target feature. By performing a systematic model comparison, we aimed to determine which EA model parameter and which updating rule for that parameter best accounts for each inter-trial effect and the associated n-back temporal profile. We found that, in general, our modeling framework could accurately predict the n-back temporal profiles. Further, target color- and position-based inter-trial effects were best understood as arising from redistribution of a limited-capacity weight resource which determines the EA rate. In contrast, response-based inter-trial effects were best explained by a bias of the starting point towards the response associated with a previous target; this bias appeared largely tied to the position of the target. These findings elucidate how our cognitive system continually tracks, and updates an internal predictive model of, a number of separable stimulus and response parameters in order to optimize task performance.