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Abstract Quantum information carriers, just like most physical systems, naturally occupy high-dimensional Hilbert spaces. Instead of restricting them to a two-level subspace, these high-dimensional (qudit) quantum systems are emerging as a powerful resource for the next generation of quantum processors. Yet harnessing the potential of these systems requires efficient ways of generating the desired interaction between them. Here, we experimentally demonstrate an implementation of a native two-qudit entangling gate up to dimension 5 in a trapped-ion system. This is achieved by generalizing a recently proposed light-shift gate mechanism to generate genuine qudit entanglement in a single application of the gate. The gate seamlessly adapts to the local dimension of the system with a calibration overhead that is independent of the dimension.

Abstract Memory, one of the hallmarks of human cognition, can be modified when humans voluntarily modulate neural population activity using neurofeedback. However, it is currently unknown whether neurofeedback can influence the integration of memories, and whether memory is facilitated or impaired after such neural perturbation. In this study, participants memorized objects while we provided them with abstract neurofeedback based on their brain activity patterns in the ventral visual stream. This neurofeedback created an implicit face or house context in the brain while memorizing the objects. The results revealed that participants created associations between each memorized object and its implicit context solely due to the neurofeedback manipulation. Our findings shed light onto how memory formation can be influenced by synthetic memory tags with neurofeedback and advance our understanding of mnemonic processing.

Summary: IgG antibodies are important mediators of vaccine-induced immunity through complement- and Fc receptor-dependent effector functions. Both are influenced by the composition of the conserved N-linked glycan located in the IgG Fc domain. Here, we compared the anti-Spike (S) IgG1 Fc glycosylation profiles in response to mRNA, adenoviral, and protein-based COVID-19 vaccines by mass spectrometry (MS). All vaccines induced a transient increase of antigen-specific IgG1 Fc galactosylation and sialylation. An initial, transient increase of afucosylated IgG was induced by membrane-encoding S protein formulations. A fucose-sensitive ELISA for antigen-specific IgG (FEASI) exploiting FcγRIIIa affinity for afucosylated IgG was used as an orthogonal method to confirm the LC-MS-based afucosylation readout. Our data suggest that vaccine-induced anti-S IgG glycosylation is dynamic, and although variation is seen between different vaccine platforms and individuals, the evolution of glycosylation patterns display marked overlaps.

Summary: High secretion of the metabolites citrate and spermine is a unique hallmark for normal prostate epithelial cells, and is reduced in aggressive prostate cancer. However, the identity of the genes controlling this biological process is mostly unknown. In this study, we have created a gene signature of 150 genes connected to citrate and spermine secretion in the prostate. We have computationally integrated metabolic measurements with multiple transcriptomics datasets from the public domain, including 3826 tissue samples from prostate and prostate cancer. The accuracy of the signature is validated by its unique enrichment in prostate samples and prostate epithelial tissue compartments. The signature highlights genes AZGP1, ANPEP and metallothioneins with zinc-binding properties not previously studied in the prostate, and the expression of these genes are reduced in more aggressive cancer lesions. However, the absence of signature enrichment in common prostate model systems can make it challenging to study these genes mechanistically.

Tobacco use is the leading cause of preventable death worldwide, and relapse during abstinence remains the critical barrier to successful treatment of tobacco addiction. During abstinence, environmental contexts associated with nicotine use can induce craving and contribute to relapse. The insular cortex (IC) is thought to be a critical substrate of nicotine addiction and relapse. However, its specific role in context-induced relapse of nicotine-seeking is not fully known. In this study, we report a novel rodent model of context-induced relapse to nicotine-seeking after punishment-imposed abstinence, which models self-imposed abstinence through increasing negative consequences of excessive drug use. Using the neuronal activity marker Fos we find that the anterior (aIC), but not the middle or posterior IC, shows increased activity during context-induced relapse. Combining Fos with retrograde labeling of aIC inputs, we show projections to aIC from contralateral aIC and basolateral amygdala exhibit increased activity during context-induced relapse. Next, we used fiber photometry in aIC and observed phasic increases in aIC activity around nicotine-seeking responses during self-administration, punishment, and the context-induced relapse tests. Next, we used chemogenetic inhibition in both male and female rats to determine whether activity in aIC is necessary for context-induced relapse. We found that chemogenetic inhibition of aIC decreased context-induced nicotine-seeking after either punishment- or extinction-imposed abstinence. These findings highlight the critical role nicotine-associated contexts play in promoting relapse, and they show that aIC activity is critical for this context-induced relapse following both punishment and extinction-imposed abstinence.

Spatial navigation and memory depend on neural coding of an organism’s location as well as large-scale knowledge of the environment, but how animals organize information in task-relevant spatial segments is not well understood. Here the authors show that, in rats, perirhinal neurons perform integrative operations, globally specifying where, in the task context, an animal is located.

There is a necessity to increase the performance of food production in agriculture, this means, that precise management support in farming systems is required to reduce water use and drainage while avoiding crop stress. Management support based on model predictions is used to increase the performance of food production. However, sources of uncertainty affect the model predictions. Uncertainty in soil properties and uncertain evapotranspiration translate into uncertain predictions, and consequently in risk of performance loss. This paper presents the code and method to analyze performance uncertainty (and risk of performance loss) due to uncertain circumstances. The method is based on using the De Graaf evapotranspiration model and the EMMAN3G model, a Richards equation-based soil water model, as modules to conduct a performance uncertainty study.

BACKGROUND:There is little evidence on the child and family factors that affect the intensity of care use by children with complex problems. We therefore wished to identify changes in these factors associated with changes in care service use and its intensity, for care use in general and psychosocial care in particular. METHODS:Parents of 272 children with problems in several life domains completed questionnaires at baseline (response 69.1%) and after 12 months. Negative binominal Hurdle analyses enabled us to distinguish between using care services (yes/ no) and its intensity, i.e. number of contacts when using care. RESULTS:Change in care use was more likely if the burden of adverse life events (ALE) decreased (odds ratio, OR = 0.94, 95% confidence interval, CI = 0.90-0.99) and if parenting concerns increased (OR = 1.29, CI = 1.11-1.51). Psychosocial care use became more likely for school-age children (vs. pre-school) (OR = 1.99, CI = 1.09-3.63) if ALE decreased (OR = 0.93, CI = 0.89-0.97) and if parenting concerns increased (OR = 1.26, CI = 1.10-1.45). Intensity of use (>0 contacts) of any care decreased when ALE decreased (relative risk, RR = 0.95, CI = 0.92-0.98) and when psychosocial problems became less severe (RR = 0.38, CI = 0.20-0.73). Intensity of psychosocial care also decreased when severe psychosocial problems became less severe (RR = 0.39, CI = 0.18-0.84). CONCLUSIONS:Changes in care-service use (vs. no use) and its intensity (>0 contacts) are explained by background characteristics and changes in a child's problems. Care use is related to factors other than changes in its intensity, indicating that care use and its intensity have different drivers. ALE in particular contribute to intensity of any care use.

There is converging evidence that distinct neuronal processes leave distinguishable footprints in the laminar BOLD response. However, even though the achievable spatial resolution in functional MRI has much improved over the years, it is still challenging to separate signals arising from different cortical layers. In this work, we propose a new method to extract laminar signals. We use a spatial General Linear Model in combination with the equivolume principle of cortical layers to unmix laminar signals instead of interpolating through and integrating over a cortical area: thus reducing partial volume effects. Not only do we provide a mathematical framework for extracting laminar signals with a spatial GLM, we also illustrate that the best case scenarios of existing methods can be seen as special cases within the same framework. By means of simulation, we show that this approach has a sharper point spread function, providing better signal localisation. We further assess the partial volume contamination in cortical profiles from high resolution human ex vivo and in vivo structural data, and provide a full account of the benefits and potential caveats. We eschew here any attempt to validate the spatial GLM on the basis of fMRI data as a generally accepted ground-truth pattern of laminar activation does not currently exist. This approach is flexible in terms of the number of layers and their respective thickness, and naturally integrates spatial regularisation along the cortex, while preserving laminar specificity. Care must be taken, however, as this procedure of unmixing is susceptible to sources of noise in the data or inaccuracies in the laminar segmentation.

With continuing advances in MRI techniques and the emergence of higher static field strengths, submillimetre spatial resolution is now possible in human functional imaging experiments. This has opened up the way for more specific types of analysis, for example investigation of the cortical layers of the brain. With this increased specificity, it is important to correct for the geometrical distortions that are inherent to echo planar imaging (EPI). Inconveniently, higher field strength also increases these distortions. The resulting displacements can easily amount to several millimetres and as such pose a serious problem for laminar analysis. We here present a method, Recursive Boundary Registration (RBR), that corrects distortions between an anatomical and an EPI volume. By recursively applying Boundary Based Registration (BBR) on progressively smaller subregions of the brain we generate an accurate whole-brain registration, based on the grey-white matter contrast. Explicit care is taken that the deformation does not break the topology of the cortical surface, which is an important requirement for several of the most common subsequent steps in laminar analysis. We show that RBR obtains submillimetre accuracy with respect to a manually distorted gold standard, and apply it to a set of human in vivo scans to show a clear increase in spacial specificity. RBR further automates the process of non-linear distortion correction. This is an important step towards routine human laminar fMRI for large field of view acquisitions. We provide the code for the RBR algorithm, as well as a variety of functions to better investigate registration performance in a public GitHub repository, https://github.com/TimVanMourik/OpenFmriAnalysis, under the GPL 3.0 license.

IntroductionAcute respiratory distress syndrome (ARDS) is characterized by acute, diffuse, inflammatory lung injury leading to increased pulmonary vascular permeability, pulmonary oedema and loss of aerated tissue. Previous literature showed that restrictive fluid therapy in ARDS shortens time on mechanical ventilation and length of ICU-stay. However, the effect of intravenous fluid use on mortality remains uncertain. We investigated the relationship between cumulative fluid balance (FB), time on mechanical ventilation and mortality in ARDS patients.Materials and methodsRetrospective observational study. Patients were divided in four cohorts based on cumulative FB on day 7 of ICU-admission: ≤0 L (Group I); 0-3.5 L (Group II); 3.5-8 L (Group III) and ≥8 L (Group IV). In addition, we used cumulative FB on day 7 as continuum as a predictor of mortality. Primary outcomes were 28-day mortality and ventilator-free days. Secondary outcomes were 90-day mortality and ICU length of stay.ResultsSix hundred ARDS patients were included, of whom 156 (26%) died within 28 days. Patients with a higher cumulative FB on day 7 had a longer length of ICU-stay and fewer ventilator-free days on day 28. Furthermore, after adjusting for severity of illness, a higher cumulative FB was associated with 28-day mortality (Group II, adjusted OR (aOR) 2.1 [1.0-4.6], p = 0.045; Group III, aOR 3.3 [1.7-7.2], p = 0.001; Group IV, aOR 7.9 [4.0-16.8], pConclusionsA higher cumulative fluid balance is independently associated with increased risk of death, longer time on mechanical ventilation and longer length of ICU-stay in patients with ARDS. This underlines the importance of implementing restrictive fluid therapy in ARDS patients.

Transcatheter aortic valve implantation (TAVI) is a well-established treatment for patients with severe aortic valve stenosis. This procedure requires pre-operative planning by assessment of aortic dimensions on CT Angiography (CTA). It is well-known that the aortic root dimensions vary over the heart cycle. However, sizing is commonly performed at either mid-systole or end-diastole only, which has resulted in an inadequate understanding of its full dynamic behavior.We studied the variation in annulus measurements during the cardiac cycle and determined if this variation is dependent on the amount of calcification at the annulus.We measured and compared aortic root annular dimensions and calcium volume in CTA acquisitions at 10 cardiac cycle phases in 51 aortic stenosis patients. Sub-group analysis was performed based on the volume of calcium by splitting the population into mildly and severely calcified valves subgroups.For most annulus measurements, the largest differences were found between 10% and 70 to 80% cardiac cycle phases. Mean difference (±standard deviation) in annular minimum diameter, maximum diameter, area, and aspect ratio between mid-systole and end-diastole phases were 1.0 ± 0.29 mm (p = 0.065), 0.30 ± 0.24 mm (p = 0.7), 24.1 ± 7.6 mm2 (p < 0.001), and 0.041 ± 0.012 (p = 0.039) respectively. Calcium volume measurements varied strongly during the cardiac cycle. The dynamic annulus area was behaving differently between mildly and severely calcified subgroups (p = 0.02). Furthermore, patients with severe aortic calcification were associated with larger annulus diameters.There is a significant variation of annulus area and calcium volume measurement during the cardiac cycle. In our measurements, only the dynamic variation of the annulus area is dependent on the severity of the aortic calcification. For TAVI candidates, the annulus area is significantly larger in mid-systole compared to end-diastole.

In cells lacking telomerase, telomeres shorten progressively during each cell division due to incomplete end-replication. When the telomeres become very short, cells enter a state that blocks cell division, termed senescence. A subset of these cells can overcome senescence and maintain their telomeres using telomerase-independent mechanisms. In Saccharomyces cerevisiae, these cells are called 'survivors' and are dependent on Rad52-dependent homologous recombination and Pol32-dependent break-induced replication. There are two main types of survivors: type I and type II. The type I survivors require Rad51 and maintain telomeres by amplification of subtelomeric elements, while the type II survivors are Rad51-independent, but require the MRX complex and Sgs1 to amplify the C1-3A/TG1-3 telomeric sequences. Rad52, Pol32, Rad51, and Sgs1 are also important to prevent accelerated senescence, indicating that recombination processes are important at telomeres even before the formation of survivors. The Shu complex, which consists of Shu1, Shu2, Psy3, and Csm2, promotes Rad51-dependent homologous recombination and has been suggested to be important for break-induced replication. It also promotes the formation of recombination intermediates that are processed by the Sgs1-Top3-Rmi1 complex, as mutations in the SHU genes can suppress various sgs1, top3, and rmi1 mutant phenotypes. Given the importance of recombination processes during senescence and survivor formation, and the involvement of the Shu complex in many of the same processes during DNA repair, we hypothesized that the Shu complex may also have functions at telomeres. Surprisingly, we find that this is not the case: the Shu complex does not affect the rate of senescence, does not influence survivor formation, and deletion of SHU1 does not suppress the rapid senescence and type II survivor formation defect of a telomerase-negative sgs1 mutant. Altogether, our data suggest that the Shu complex is not important for recombination processes at telomeres.

We examine how different forms of co-action give rise to feelings of solidarity. We propose that (a) coordinated action elicits a sense of solidarity, and (b) the process through which such solidarity emerges differs for different forms of co-action. We suggest that whether solidarity within groups emerges from uniform action (e.g. synchronizing, as when people speak in unison) or from more complementary forms of action (e.g. alternating, when speaking in turns) has important consequences for the emergent position of individuals within the group. Uniform action relies on commonality, leaving little scope for individuality. In complementary action each individual makes a distinctive contribution to the group, thereby increasing a sense of personal value to the group, which should contribute to the emergence of solidarity. The predictions receive support from five studies, in which we study groups in laboratory and field settings. Results show that both complementary and uniform co-action increase a sense of solidarity compared to control conditions. However, in the complementary action condition, but not in the uniform action (or synchrony) condition, the effect on feelings of solidarity is mediated by a sense of personal value to the group.

Various environmental signals integrate into a network of floral regulatory genes leading to the final decision on when to flower. Although a wealth of qualitative knowledge is available on how flowering time genes regulate each other, only a few studies incorporated this knowledge into predictive models. Such models are invaluable as they enable to investigate how various types of inputs are combined to give a quantitative readout. To investigate the effect of gene expression disturbances on flowering time, we developed a dynamic model for the regulation of flowering time in Arabidopsis thaliana. Model parameters were estimated based on expression time-courses for relevant genes, and a consistent set of flowering times for plants of various genetic backgrounds. Validation was performed by predicting changes in expression level in mutant backgrounds and comparing these predictions with independent expression data, and by comparison of predicted and experimental flowering times for several double mutants. Remarkably, the model predicts that a disturbance in a particular gene has not necessarily the largest impact on directly connected genes. For example, the model predicts that SUPPRESSOR OF OVEREXPRESSION OF CONSTANS (SOC1) mutation has a larger impact on APETALA1 (AP1), which is not directly regulated by SOC1, compared to its effect on LEAFY (LFY) which is under direct control of SOC1. This was confirmed by expression data. Another model prediction involves the importance of cooperativity in the regulation of APETALA1 (AP1) by LFY, a prediction supported by experimental evidence. Concluding, our model for flowering time gene regulation enables to address how different quantitative inputs are combined into one quantitative output, flowering time.

Infection with Human Immunodeficiency virus (HIV) is an important risk factor for Tuberculosis (TB). Anti-Retroviral Therapy (ART) has improved the prognosis of HIV and reduced the risk of TB infected patients. Isoniazid Preventive Therapy (IPT) aims to reduce the development of active TB in patients with latent TB.Systematically review and synthesize effect estimates of IPT for TB prevention in adult HIV patients. Secondary objectives were to assess the effect of IPT on HIV disease progression, all-cause mortality and adverse drug reaction (ADR).Electronic databases were searched to identify relevant articles in English available by September 11th 2015.Research articles comparing IPT to placebo or no treatment in HIV infected adults using randomized clinical trials.A qualitative review included study-level information on randomization and treatment allocation. Effect estimates were pooled using random-effects models to account for between-study heterogeneity.This review assessed ten randomized clinical trials that assigned 7619 HIV patients to IPT or placebo. An overall 35% of TB risk reduction (RR = 0.65, 95% CI (0.51, 0.84)) was found in all participants, however, larger benefit of IPT was observed in Tuberculin Skin Test (TST) positive participants, with pooled relative risk reduction of 52% [RR = 0.48; 95% CI (0.29, 0.82)] and with a prediction interval ranging from 0.13 to 1.81. There was no statistically significant effect of IPT on TB occurrence in TST negative or unknown participants. IPT also reduced the risk of HIV disease progression in all participants (RR = 0.69; 95% CI (0.48, 0.99)) despite no benefits observed in TST strata. All-cause mortality was not affected by IPT although participants who had 12 months of IPT tend to have a reduced risk (RR = 0.65; 95% CI(0.47, 0.90)). IPT had an elevated, yet statistically non-significant, risk of adverse drug reaction [RR = 1.20; 95% CI (1.20, 1.71)]. Only a single study assessed the effect of IPT in combination with ART in preventing TB and occurrence of multi-drug resistant tuberculosis.IPT use substantially contributes in preventing TB in persons with HIV in general and in TST positive individuals in particular. More evidence is needed to explain discrepancies in the protective effect of IPT in these individuals.

Biochemical systems involving a high number of components with intricate interactions often lead to complex models containing a large number of parameters. Although a large model could describe in detail the mechanisms that underlie the system, its very large size may hinder us in understanding the key elements of the system. Also in terms of parameter identification, large models are often problematic. Therefore, a reduced model may be preferred to represent the system. Yet, in order to efficaciously replace the large model, the reduced model should have the same ability as the large model to produce reliable predictions for a broad set of testable experimental conditions. We present a novel method to extract an "optimal" reduced model from a large model to represent biochemical systems by combining a reduction method and a model discrimination method. The former assures that the reduced model contains only those components that are important to produce the dynamics observed in given experiments, whereas the latter ensures that the reduced model gives a good prediction for any feasible experimental conditions that are relevant to answer questions at hand. These two techniques are applied iteratively. The method reveals the biological core of a model mathematically, indicating the processes that are likely to be responsible for certain behavior. We demonstrate the algorithm on two realistic model examples. We show that in both cases the core is substantially smaller than the full model.

Mutational robustness of gene regulatory networks refers to their ability to generate constant biological output upon mutations that change network structure. Such networks contain regulatory interactions (transcription factor-target gene interactions) but often also protein-protein interactions between transcription factors. Using computational modeling, we study factors that influence robustness and we infer several network properties governing it. These include the type of mutation, i.e. whether a regulatory interaction or a protein-protein interaction is mutated, and in the case of mutation of a regulatory interaction, the sign of the interaction (activating vs. repressive). In addition, we analyze the effect of combinations of mutations and we compare networks containing monomeric with those containing dimeric transcription factors. Our results are consistent with available data on biological networks, for example based on evolutionary conservation of network features. As a novel and remarkable property, we predict that networks are more robust against mutations in monomer than in dimer transcription factors, a prediction for which analysis of conservation of DNA binding residues in monomeric vs. dimeric transcription factors provides indirect evidence.

An intriguing phenomenon in plant development is the timing and positioning of lateral organ initiation, which is a fundamental aspect of plant architecture. Although important progress has been made in elucidating the role of auxin transport in the vegetative shoot to explain the phyllotaxis of leaf formation in a spiral fashion, a model study of the role of auxin transport in whorled organ patterning in the expanding floral meristem is not available yet. We present an initial simulation approach to study the mechanisms that are expected to play an important role. Starting point is a confocal imaging study of Arabidopsis floral meristems at consecutive time points during flower development. These images reveal auxin accumulation patterns at the positions of the organs, which strongly suggests that the role of auxin in the floral meristem is similar to the role it plays in the shoot apical meristem. This is the basis for a simulation study of auxin transport through a growing floral meristem, which may answer the question whether auxin transport can in itself be responsible for the typical whorled floral pattern. We combined a cellular growth model for the meristem with a polar auxin transport model. The model predicts that sepals are initiated by auxin maxima arising early during meristem outgrowth. These form a pre-pattern relative to which a series of smaller auxin maxima are positioned, which partially overlap with the anlagen of petals, stamens, and carpels. We adjusted the model parameters corresponding to properties of floral mutants and found that the model predictions agree with the observed mutant patterns. The predicted timing of the primordia outgrowth and the timing and positioning of the sepal primordia show remarkable similarities with a developing flower in nature.

OBJECTIVE: Automated surveillance of healthcare-associated infections can improve efficiency and reliability of surveillance. The aim was to validate and update a previously developed multivariable prediction model for the detection of drain-related meningitis (DRM). DESIGN: Retrospective cohort study using traditional surveillance by infection control professionals as reference standard. PATIENTS: Patients receiving an external cerebrospinal fluid drain, either ventricular (EVD) or lumbar (ELD) in a tertiary medical care center. Children, patients with simultaneous drains,

In spite of the significant mortality associated with Plasmodium falciparum infection, the mechanisms underlying severe disease remain poorly understood. We have previously shown evidence of endothelial activation in Ghanaian children with malaria, indicated by elevated plasma levels of both von Willebrand factor (VWF) and its propeptide. In the current prospective study of children in Malawi with retinopathy confirmed cerebral malaria, we compared these markers with uncomplicated malaria, non malarial febrile illness and controls.Children with cerebral malaria, mild malaria and controls without malaria were recruited into the study. All comatose patients were examined by direct and indirect ophthalmoscopy. Plasma VWF and propeptide levels were measured by ELISA. Median VWF and propeptide levels were significantly higher in patients with uncomplicated malaria than in children with non-malarial febrile illness of comparable severity, in whom levels were higher than in non-febrile controls. Median concentrations of both markers were higher in cerebral malaria than in uncomplicated malaria, and were similar in patients with and without retinopathy. Levels of both VWF and propeptide fell significantly 48 hours after commencing therapy and were normal one month later.In children with malaria plasma VWF and propeptide levels are markedly elevated in both cerebral and mild paediatric malaria, with levels matching disease severity, and these normalize upon recovery. High levels of both markers also occur in retinopathy-negative 'cerebral malaria' cases, many of whom are thought to be suffering from diseases other than malaria, indicating that further studies of these markers will be required to determine their sensitivity and specificity.

OBJECTIVE: Monitoring of healthcare-associated infection rates is important for infection control and hospital benchmarking. However, manual surveillance is time-consuming and susceptible to error. The aim was, therefore, to develop a prediction model to retrospectively detect drain-related meningitis (DRM), a frequently occurring nosocomial infection, using routinely collected data from a clinical data warehouse. METHODS: As part of the hospital infection control program, all patients receiving an external ventricular (EVD) or lumbar drain (ELD) (2004 to 2009; n = 742) had been evaluated for the development of DRM through chart review and standardized diagnostic criteria by infection control staff; this was the reference standard. Children, patients dying