Thalamostriatal disconnection underpins long-term seizure freedom in frontal lobe epilepsy surgery.

Around 50% of patients undergoing frontal lobe surgery for focal drug-resistant epilepsy become seizure free post-operatively; however, only about 30% of patients remain seizure free in the long-term. Early seizure recurrence is likely to be caused by partial resection of the epileptogenic lesion, whilst delayed seizure recurrence can occur even if the epileptogenic lesion has been completely excised. This suggests a coexistent epileptogenic network facilitating ictogenesis in close or distant dormant epileptic foci. As thalamic and striatal dysregulation can support epileptogenesis and disconnection of cortico-thalamostriatal pathways through hemispherotomy or neuromodulation can improve seizure outcome regardless of focality, we hypothesize that projections from the striatum and the thalamus to the cortex may contribute to this common epileptogenic network. To this end, we retrospectively reviewed a series of 47 consecutive individuals who underwent surgery for drug-resistant frontal lobe epilepsy. We performed voxel-based and tractography disconnectome analyses to investigate shared patterns of disconnection associated with long-term seizure freedom. Seizure freedom after 3 and 5 years was independently associated with disconnection of the anterior thalamic radiation and anterior cortico-striatal projections. This was also confirmed in a subgroup of 29 patients with complete resections, suggesting these pathways may play a critical role in supporting the development of novel epileptic networks. Our study indicates that network dysfunction in frontal lobe epilepsy may extend beyond the resection and putative epileptogenic zone. This may be critical in the pathogenesis of delayed seizure recurrence as thalamic and striatal networks may promote epileptogenesis and disconnection may underpin long-term seizure freedom.

Distributed and dynamic intracellular organization of extracellular information.

Although cells respond specifically to environments, how environmental identity is encoded intracellularly is not understood. Here, we study this organization of information in budding yeast by estimating the mutual information between environmental transitions and the dynamics of nuclear translocation for 10 transcription factors. Our method of estimation is general, scalable, and based on decoding from single cells. The dynamics of the transcription factors are necessary to encode the highest amounts of extracellular information, and we show that information is transduced through two channels: Generalists (Msn2/4, Tod6 and Dot6, Maf1, and Sfp1) can encode the nature of multiple stresses, but only if stress is high; specialists (Hog1, Yap1, and Mig1/2) encode one particular stress, but do so more quickly and for a wider range of magnitudes. In particular, Dot6 encodes almost as much information as Msn2, the master regulator of the environmental stress response. Each transcription factor reports differently, and it is only their collective behavior that distinguishes between multiple environmental states. Changes in the dynamics of the localization of transcription factors thus constitute a precise, distributed internal representation of extracellular change. We predict that such multidimensional representations are common in cellular decision-making.

Distinctive interactions of oleic acid covered magnetic nanoparticles with saturated and unsaturated phospholipids in Langmuir monolayers.

The growing number of innovations in nanomedicine and nanobiotechnology are posing new challenges in understanding the full spectrum of interactions between nanomateriales and biomolecules at nano-biointerfaces. Although considerable achievements have been accomplished by in vivo applications, many issues regarding the molecular nature of these interactions are far from being well-understood. In this work, we evaluate the interaction of hydrophobic magnetic nanoparticles (MNP) covered with a single layer of oleic acid with saturated and unsaturated phospholipids found in biomembranes through the use of Langmuir monolayers. We find distinctive interactions among the MNP with saturated and unsaturated phospholipids that are reflected by both, the compression isotherms and the surface topography of the films. The interaction between MNP and saturated lipids causes a noticeable reduction of the mean molecular area in the interfacial plane, while the interaction with unsaturated lipids promotes area expansion compared to the ideally mixed films. Moreover, when liquid expanded and liquid condensed phases of the phospholipid(s) coexist, the MNP preferably partition to the liquid-expanded phase, thus hindering the coalescence of the condensed domains with increasing surface pressure. In consequence organizational information on long-range order is attained. These results evidence the existence of a sensitive composition-dependent surface regulation given by phospholipid-nanoparticle interactions which enhance the biophysical relevance of understanding nanoparticle surface functionalization in relation to its interactions in biointerfaces constituted by defined types of biomolecules.

Combinatorial expression motifs in signaling pathways.

In animal cells, molecular pathways often comprise families of variant components, such as ligands or receptors. These pathway components are differentially expressed by different cell types, potentially tailoring pathway function to cell context. However, it has remained unclear how pathway expression profiles are distributed across cell types and whether similar profiles can occur in dissimilar cell types. Here, using single-cell gene expression datasets, we identified pathway expression motifs, defined as recurrent expression profiles that are broadly distributed across diverse cell types. Motifs appeared in core pathways, including TGF-ß, Notch, Wnt, and the SRSF splice factors, and involved combinatorial co-expression of multiple components. Motif usage was weakly correlated between pathways in adult cell types and during dynamic developmental transitions. Together, these results suggest a mosaic view of cell type organization, in which different cell types operate many of the same pathways in distinct modes.

Autonomous navigation of catheters and guidewires in mechanical thrombectomy using inverse reinforcement learning.

PURPOSE: Autonomous navigation of catheters and guidewires can enhance endovascular surgery safety and efficacy, reducing procedure times and operator radiation exposure. Integrating tele-operated robotics could widen access to time-sensitive emergency procedures like mechanical thrombectomy (MT). Reinforcement learning (RL) shows potential in endovascular navigation, yet its application encounters challenges without a reward signal. This study explores the viability of autonomous guidewire navigation in MT vasculature using inverse reinforcement learning (IRL) to leverage expert demonstrations. METHODS: Employing the Simulation Open Framework Architecture (SOFA), this study established a simulation-based training and evaluation environment for MT navigation. We used IRL to infer reward functions from expert behaviour when navigating a guidewire and catheter. We utilized the soft actor-critic algorithm to train models with various reward functions and compared their performance in silico. RESULTS: We demonstrated feasibility of navigation using IRL. When evaluating single- versus dual-device (i.e. guidewire versus catheter and guidewire) tracking, both methods achieved high success rates of 95% and 96%, respectively. Dual tracking, however, utilized both devices mimicking an expert. A success rate of 100% and procedure time of 22.6 s were obtained when training with a reward function obtained through 'reward shaping'. This outperformed a dense reward function (96%, 24.9 s) and an IRL-derived reward function (48%, 59.2 s). CONCLUSIONS: We have contributed to the advancement of autonomous endovascular intervention navigation, particularly MT, by effectively employing IRL based on demonstrator expertise. The results underscore the potential of using reward shaping to efficiently train models, offering a promising avenue for enhancing the accessibility and precision of MT procedures. We envisage that future research can extend our methodology to diverse anatomical structures to enhance generalizability.

Artificial intelligence in the autonomous navigation of endovascular interventions: a systematic review.

Background: Autonomous navigation of catheters and guidewires in endovascular interventional surgery can decrease operation times, improve decision-making during surgery, and reduce operator radiation exposure while increasing access to treatment. Objective: To determine from recent literature, through a systematic review, the impact, challenges, and opportunities artificial intelligence (AI) has for the autonomous navigation of catheters and guidewires for endovascular interventions. Methods: PubMed and IEEEXplore databases were searched to identify reports of AI applied to autonomous navigation methods in endovascular interventional surgery. Eligibility criteria included studies investigating the use of AI in enabling the autonomous navigation of catheters/guidewires in endovascular interventions. Following Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA), articles were assessed using Quality Assessment of Diagnostic Accuracy Studies 2 (QUADAS-2). PROSPERO: CRD42023392259. Results: Four hundred and sixty-two studies fulfilled the search criteria, of which 14 studies were included for analysis. Reinforcement learning (RL) (9/14, 64%) and learning from expert demonstration (7/14, 50%) were used as data-driven models for autonomous navigation. These studies evaluated models on physical phantoms (10/14, 71%) and in-silico (4/14, 29%) models. Experiments within or around the blood vessels of the heart were reported by the majority of studies (10/14, 71%), while non-anatomical vessel platforms "idealized" for simple navigation were used in three studies (3/14, 21%), and the porcine liver venous system in one study. We observed that risk of bias and poor generalizability were present across studies. No procedures were performed on patients in any of the studies reviewed. Moreover, all studies were limited due to the lack of patient selection criteria, reference standards, and reproducibility, which resulted in a low level of evidence for clinical translation. Conclusion: Despite the potential benefits of AI applied to autonomous navigation of endovascular interventions, the field is in an experimental proof-of-concept stage, with a technology readiness level of 3. We highlight that reference standards with well-identified performance metrics are crucial to allow for comparisons of data-driven algorithms proposed in the years to come. Systematic review registration: identifier: CRD42023392259.

Chemical Profile and Biological Potential of Hornodermoporus martius (Agaricomycetes) from Paraguay.

To further knowledge of the biological activity of native neotropical fungal species, this study aimed to determine the chemical composition and microbiological activity of Hornodermoporus martius. Ethanol, hexane, diethyl ether, and ethyl acetate fractions and the water residue were analyzed and resulted in a total phenolic compound content between 13 and 63 mg of gallic acid equivalents per gram of crude extract. The total antioxidants ranged between 3 and 19 mg of ascorbic acid equivalents per gram of crude extract, and the percentage of antioxidant activity was determined to be between 6 and 25%. A preliminary profile of compounds is provided for the first time for the species; the results from the nonpolar fraction showcased the presence of saturated and unsaturated acids, fatty alcohol, sterols, and cis-vaccenic acid. Our findings also revealed antimicrobial properties from compounds within the hexane and diethyl ether fractions at concentrations of 1 mg mL-1, which inhibited the growth of certain gram-positive and gram-negative bacteria. For the first time in academic literature, our work analyzed and documented the chemical characteristics and microbial properties of H. martius, suggesting potential for medicinal applications.

Single-nuclei characterization of pervasive transcriptional signatures across organs in response to COVID-19.

Background: Infection by coronavirus SARS-CoV2 is a severe and often deadly disease that has implications for the respiratory system and multiple organs across the human body. While the effects in the lung have been extensively studied, less is known about the impact COVID-19 has across other organs. Methods: Here, we contribute a single-nuclei RNA-sequencing atlas comprising six human organs across 20 autopsies where we analyzed the transcriptional changes due to COVID-19 in multiple cell types. The integration of data from multiple organs enabled the identification of systemic transcriptional changes. Results: Computational cross-organ analysis for endothelial cells and macrophages identified systemic transcriptional changes in these cell types in COVID-19 samples. In addition, analysis of gene modules showed enrichment of specific signaling pathways across multiple organs in COVID-19 autopsies. Conclusions: Altogether, the COVID Tissue Atlas enables the investigation of both cell type-specific and cross-organ transcriptional responses to COVID-19, providing insights into the molecular networks affected by the disease and highlighting novel potential targets for therapies and drug development. Funding: The Chan-Zuckerberg Initiative, The Chan-Zuckerberg Biohub.

Assessing informative tract segmentation and nTMS for pre-operative planning.

BACKGROUND: Deep learning-based (DL) methods are the best-performing methods for white matter tract segmentation in anatomically healthy subjects. However, tract annotations are variable or absent in clinical data and manual annotations are especially difficult in patients with tumors where normal anatomy may be distorted. Direct cortical and subcortical stimulation is the gold standard ground truth to determine the cortical and sub-cortical lo- cation of motor-eloquent areas intra-operatively. Nonetheless, this technique is invasive, prolongs the surgical procedure, and may cause patient fatigue. Navigated Transcranial Magnetic Stimulation (nTMS) has a well-established correlation to direct cortical stimulation for motor mapping and the added advantage of being able to be acquired pre-operatively. NEW METHOD: In this work, we evaluate the feasibility of using nTMS motor responses as a method to assess corticospinal tract (CST) binary masks and estimated uncertainty generated by a DL-based tract segmentation in patients with diffuse gliomas. RESULTS: Our results show CST binary masks have a high overlap coefficient (OC) with nTMS response masks. A strong negative correlation is found between estimated uncertainty and nTMS response mask distance to the CST binary mask. COMPARISON WITH EXISTING METHODS: We compare our approach (UncSeg) with the state-of-the-art TractSeg in terms of OC between the CST binary masks and nTMS response masks. CONCLUSIONS: In this study, we demonstrate that estimated uncertainty from UncSeg is a good measure of the agreement between the CST binary masks and nTMS response masks distance to the CST binary mask boundary.

Developmental origin and local signals cooperate to determine septal astrocyte identity.

Astrocyte specification during development is influenced by both intrinsic and extrinsic factors, but the precise contribution of each remains poorly understood. Here we show that septal astrocytes from Nkx2.1 and Zic4 expressing progenitor zones are allocated into non-overlapping domains of the medial (MS) and lateral septal nuclei (LS) respectively. Astrocytes in these areas exhibit distinctive molecular and morphological features tailored to the unique cellular and synaptic circuit environment of each nucleus. Using single-nucleus (sn) RNA sequencing, we trace the developmental trajectories of cells in the septum and find that neurons and astrocytes undergo region and developmental stage-specific local cell-cell interactions. We show that expression of the classic morphogens Sonic hedgehog (Shh) and Fibroblast growth factors (Fgfs) by MS and LS neurons respectively, functions to promote the molecular specification of local astrocytes in each region. Finally, using heterotopic cell transplantation, we show that both morphological and molecular specifications of septal astrocytes are highly dependent on the local microenvironment, regardless of developmental origins. Our data highlights the complex interplay between intrinsic and extrinsic factors shaping astrocyte identities and illustrates the importance of the local environment in determining astrocyte functional specialization.

Simulating various levels of clinical challenge in the assessment of clinical procedure competence.

STUDY OBJECTIVE: Immersive simulation is increasingly used for competency assessment of emergency physicians. This group's concept of hybrid simulation (HS) (combining simulated patients and part-task trainers (a simulator that simulates a limited component of a clinical procedure) to create a multimodal clinical context) requires clinicians to integrate technical and nontechnical skills in a holistic clinical performance for assessment. It also offers the potential to provide authentic simulation of a given clinical procedure across multiple levels of challenge. The aims of this study are to systematically design and validate 2 patient-focused HS scenarios (each combining a simulated patient with a part-task simulator) for assessment of the management of a commonly encountered problem in an emergency department (ED) at different levels of clinical challenge, and to explore the effect of level of challenge of the HS scenario on physicians' performance. METHODS: A simple (HS1) and a complex (HS2) HS scenario (based on the management of a patient with a traumatic skin laceration within the ED) was developed according to expert opinion through cognitive task analysis. Interns and emergency medicine residents (stratified into expert and novice groups according to experience) were recruited to participate in both scenarios. Participants were randomized to perform either the HS1 or HS2 scenario first. Participants completed a questionnaire for face validity (realism of simulation) and content validity (comprehensiveness of simulation). Performances were assessed by 2 independent raters using validated rating tools modified to the needs of this study: the Modified Objective Structured Assessment of Technical Skills-Task Specific Checklist, the Objective Structured Assessment of Technical Skills-Global Rating Score, and the Direct Observation of Procedural Skills. RESULTS: Ten novice and 10 expert clinicians completed both scenarios. Mean face and content validity ratings were high for both HS1 (mean 4.4 [SD 0.52] and 4.2 [SD 0.48], respectively) and HS2 scenarios (mean 4.5 [SD 0.35] and 4.3 [SD 0.43], respectively). In HS1, no difference was found between experts' and novices' Modified Objective Structured Assessment of Technical Skills-Task Specific Checklist, Objective Structured Assessment of Technical Skills-Global Rating Score, and Direct Observation of Procedural Skills ratings. Experts performed significantly better than novices in HS2 in terms of the 3 tools' ratings. Novices' Modified Objective Structured Assessment of Technical Skills-Task Specific Checklist and Direct Observation of Procedural Skills ratings were significantly worse in HS2 compared with HS1, but no difference was found with the Objective Structured Assessment of Technical Skills-Global Rating Score. No statistical difference was found in experts' Modified Objective Structured Assessment of Technical Skills-Task Specific Checklist, Objective Structured Assessment of Technical Skills-Global Rating Score, and Direct Observation of Procedural Skills ratings between HS2 and HS1 scenarios. CONCLUSION: Recreating clinical challenge is an important consideration in the design of simulation-based assessment of procedural skills of clinicians. In this study, we have demonstrated a systematic approach to developing HS scenarios, which may be able to recreate various levels of clinical challenge for purpose of assessment of procedural skills.

Déjà vu: a reappraisal of the taphonomy of quarry VM4 of the Early Pleistocene site of Venta Micena (Baza Basin, SE Spain).

Venta Micena, an Early Pleistocene site of the Baza Basin (SE Spain), preserves a rich and diverse assemblage of large mammals. VM3, the main excavation quarry of the site, has been interpreted as a den of the giant hyaena Pachycrocuta brevirostris in the plain that surrounded the Baza palaeolake. Taphonomic analysis of VM3 has shown that the hyaenas scavenged the prey previously hunted by the hypercarnivores, transported their remains to the communal den, and consumed the skeletal parts according to their marrow contents and mineral density. In a recent paper (Luzón et al. in Sci Rep 11:13977, https://doi.org/10.1038/s41598-021-93261-1 , 2021), a small sample of remains unearthed from VM4, an excavation quarry ~ 350 m distant from VM3, is analysed. The authors indicate several differences in the taphonomic features of this assemblage with VM3, and even suggest that a different carnivore could have been the agent involved in the bone accumulation process. Here, we make a comparative analysis of both quarries and analyse more skeletal remains from VM4. Our results indicate that the assemblages are broadly similar in composition, except for slight differences in the frequency of megaherbivores, carnivores and equids according to NISP values (but not to MNI counts), the degree of bone weathering, and the intensity of bone processing by the hyaenas. Given that VM4 and VM3 were not coeval denning areas of P. brevirostris, these differences suggest that during the years when the skeletal remains were accumulated by the hyaenas at VM3, the rise of the water table of the Baza palaeolake that capped with limestone the bones was delayed compared to VM4, which resulted in their more in-depth consumption by the hyaenas.

Geochemical and sedimentary constraints on the formation of the Venta Micena early Pleistocene site (Guadix-Baza Basin, Spain).

Despite the paleontological relevance of the terrestrial Early Pleistocene Venta Micena bonebed (Baza Basin, Spain), it lacks a comprehensive geochemical/sedimentological study. Here, we demonstrate that the 1.5-m-thick Venta Micena limestone formed in a relatively small freshwater wetland/pond located at the periphery of the large saline Baza paleolake. Two microfacies are observed, with high and low contents of invertebrate fossils, and which originated in the centre and margin of the wetland, respectively. X-ray diffraction (XRD) mineralogy and paleohydrological characterization based on ostracod and bulk-rock geochemistry (δ13C and δ18O) indicate that the limestone reflects a general lowstand of the Baza lake, permitting the differentiation of freshwater wetlands that were fed by adjacent sources. Conversely, during highstands, the Baza lake flooded the Venta Micena area and the freshwater fauna was replaced by a saline one. Bulk-rock isotopic data indicate that the lower interval C1 of the limestone (bone-rich in marginal settings) displays general negative values, while the upper interval C2 (bone free) displays less negative values. The bones of predated mammals accumulated in the marginal areas, which were flooded and buried by recurring water-table fluctuations. Lake dynamics played a critical role in bone accumulation, which was previously considered as representing a hyena den.

Comparison of robotic and manual implantation of intracerebral electrodes: a single-centre, single-blinded, randomised controlled trial.

There has been a significant rise in robotic trajectory guidance devices that have been utilised for stereotactic neurosurgical procedures. These devices have significant costs and associated learning curves. Previous studies reporting devices usage have not undertaken prospective parallel-group comparisons before their introduction, so the comparative differences are unknown. We study the difference in stereoelectroencephalography electrode implantation time between a robotic trajectory guidance device (iSYS1) and manual frameless implantation (PAD) in patients with drug-refractory focal epilepsy through a single-blinded randomised control parallel-group investigation of SEEG electrode implantation, concordant with CONSORT statement. Thirty-two patients (18 male) completed the trial. The iSYS1 returned significantly shorter median operative time for intracranial bolt insertion, 6.36 min (95% CI 5.72-7.07) versus 9.06 min (95% CI 8.16-10.06), p = 0.0001. The PAD group had a better median target point accuracy 1.58 mm (95% CI 1.38-1.82) versus 1.16 mm (95% CI 1.01-1.33), p = 0.004. The mean electrode implantation angle error was 2.13° for the iSYS1 group and 1.71° for the PAD groups (p = 0.023). There was no statistically significant difference for any other outcome. Health policy and hospital commissioners should consider these differences in the context of the opportunity cost of introducing robotic devices.Trial registration: ISRCTN17209025 ( https://doi.org/10.1186/ISRCTN17209025 ).

Imaging cell lineage with a synthetic digital recording system.

During multicellular development, spatial position and lineage history play powerful roles in controlling cell fate decisions. Using a serine integrase-based recording system, we engineered cells to record lineage information in a format that can be read out in situ. The system, termed integrase-editable memory by engineered mutagenesis with optical in situ readout (intMEMOIR), allowed in situ reconstruction of lineage relationships in cultured mouse cells and flies. intMEMOIR uses an array of independent three-state genetic memory elements that can recombine stochastically and irreversibly, allowing up to 59,049 distinct digital states. It reconstructed lineage trees in stem cells and enabled simultaneous analysis of single-cell clonal history, spatial position, and gene expression in Drosophila brain sections. These results establish a foundation for microscopy-readable lineage recording and analysis in diverse systems.

Patient-specific prediction of SEEG electrode bending for stereotactic neurosurgical planning.

PURPOSE : Electrode bending observed after stereotactic interventions is typically not accounted for in either computer-assisted planning algorithms, where straight trajectories are assumed, or in quality assessment, where only metrics related to entry and target points are reported. Our aim is to provide a fully automated and validated pipeline for the prediction of stereo-electroencephalography (SEEG) electrode bending. METHODS : We transform electrodes of 86 cases into a common space and compare features-based and image-based neural networks on their ability to regress local displacement ([Formula: see text]) or electrode bending ([Formula: see text]). Electrodes were stratified into six groups based on brain structures at the entry and target point. Models, both with and without Monte Carlo (MC) dropout, were trained and validated using tenfold cross-validation. RESULTS : mage-based models outperformed features-based models for all groups, and models that predicted [Formula: see text] performed better than for [Formula: see text]. Image-based model prediction with MC dropout resulted in lower mean squared error (MSE) with improvements up to 12.9% ([Formula: see text]) and 39.9% ([Formula: see text]), compared to no dropout. Using an image of brain tissue types (cortex, white and deep grey matter) resulted in similar, and sometimes better performance, compared to using a T1-weighted MRI when predicting [Formula: see text]. When inferring trajectories of image-based models (brain tissue types), 86.9% of trajectories had an MSE[Formula: see text] mm. CONCLUSION : An image-based approach regressing local displacement with an image of brain tissue types resulted in more accurate electrode bending predictions compared to other approaches, inputs, and outputs. Future work will investigate the integration of electrode bending into planning and quality assessment algorithms.

A generative model of hyperelastic strain energy density functions for multiple tissue brain deformation.

PURPOSE: Estimation of brain deformation is crucial during neurosurgery. Whilst mechanical characterisation captures stress-strain relationships of tissue, biomechanical models are limited by experimental conditions. This results in variability reported in the literature. The aim of this work was to demonstrate a generative model of strain energy density functions can estimate the elastic properties of tissue using observed brain deformation. METHODS: For the generative model a Gaussian Process regression learns elastic potentials from 73 manuscripts. We evaluate the use of neo-Hookean, Mooney-Rivlin and 1-term Ogden meta-models to guarantee stability. Single and multiple tissue experiments validate the ability of our generative model to estimate tissue properties on a synthetic brain model and in eight temporal lobe resection cases where deformation is observed between pre- and post-operative images. RESULTS: Estimated parameters on a synthetic model are close to the known reference with a root-mean-square error (RMSE) of 0.1 mm and 0.2 mm between surface nodes for single and multiple tissue experiments. In clinical cases, we were able to recover brain deformation from pre- to post-operative images reducing RMSE of differences from 1.37 to 1.08 mm on the ventricle surface and from 5.89 to 4.84 mm on the resection cavity surface. CONCLUSION: Our generative model can capture uncertainties related to mechanical characterisation of tissue. When fitting samples from elastography and linear studies, all meta-models performed similarly. The Ogden meta-model performed the best on hyperelastic studies. We were able to predict elastic parameters in a reference model on a synthetic phantom. However, deformation observed in clinical cases is only partly explained using our generative model.

Benchmarked approaches for reconstruction of in vitro cell lineages and in silico models of C. elegans and M. musculus developmental trees.

The recent advent of CRISPR and other molecular tools enabled the reconstruction of cell lineages based on induced DNA mutations and promises to solve the ones of more complex organisms. To date, no lineage reconstruction algorithms have been rigorously examined for their performance and robustness across dataset types and number of cells. To benchmark such methods, we decided to organize a DREAM challenge using in vitro experimental intMEMOIR recordings and in silico data for a C. elegans lineage tree of about 1,000 cells and a Mus musculus tree of 10,000 cells. Some of the 22 approaches submitted had excellent performance, but structural features of the trees prevented optimal reconstructions. Using smaller sub-trees as training sets proved to be a good approach for tuning algorithms to reconstruct larger trees. The simulation and reconstruction methods here generated delineate a potential way forward for solving larger cell lineage trees such as in mouse.

Role of the hydrophobicity on the thermodynamic and kinetic acidity of Fischer thiocarbene complexes.

Rate constants for the reversible deprotonation of (CO)(5)W=C(SR)CH(3) (W-SR) by OH(-), water and a number of primary aliphatic and secondary alicyclic amines, have been determined in 50% MeCN:50% water at 25 degrees C. In addition, solvation energy and proton affinities values for M-SR (M = Cr and W) in the gas phase and in acetonitrile have been computed at DFT level. Although there is not a linear correlation between the calculated proton affinities and the measured pK(a)s, the calculations reveal that when solvent effects are taken into account the substituted compounds studied show differences in their proton affinities. There is a good correlation between the change in cavitation energy (DeltaG(cav)) for the Fischer carbene complexes and log P of the thioalkyl substituents. In proton transfer reactions with amines, steric effects are more important for W complexes with respect to their Cr analogues as a consequence of differences in transition state progress. On the other hand, in reactions with OH(-), hydrophobicity of the R substituent is responsible for the observed changes in intrinsic kinetic acidities, which is supported by the good correlation obtained between log k(0) and log P. W complexes are more sensitive to hydrophobic effects due to the tighter solvation sphere with respect to their Cr counterparts. However, in the limit of log P = 0, the energy involved in the solvent reorganization process is the same regardless of the metal.

Taking the Pressure Off the Patient - Understanding Digital Rectal Examinations on a Real Subject.

Better understanding of palpation techniques during unsighted physical examinations has mostly been limited to qualitative and quantitative studies of performance of experts whilst conducting examinations on plastic benchtop models. However, little is known about their performance when conducting such examinations on real subjects. OBJECTIVE: The aim of this paper is to better understand palpation techniques of experts whilst conducting a Digital Rectal Examination on a real subject. METHODS: We recruited four consultants from relevant specialties and asked them to conduct two DREs on a Rectal Teaching Assistant whilst wearing small position and pressure sensors on their examining finger. We segmented the relevant anatomy from an MRI taken of the pelvic region, registered 3D models and analysed retrospectively performance in relation to executed tasks, supination/pronation, palpation convex hull and pressure applied. RESULTS: Primary care consultants examined the anatomy more holistically compared to secondary care experts, the maximum pressure applied across experiments is 3.3N, overall the pressure applied on the prostate is higher than that applied to rectal walls, and the urologist participant not only applied the highest pressure but also did so with the highest most prominent frequency (15.4 and 25.3 Hz). CONCLUSIONS: The results of our research allow for better understanding of experts' technical performance from relevant specialities when conducting a DRE, and suggest the range of pressure applied whilst palpating anatomy. SIGNIFICANCE: This research will be valuable in improving the design of haptics-based learning tools, as well as in encouraging reflection on palpation styles across different specialities to develop metrics of performance.