Genomic profile analysis of leiomyomas with bizarre nuclei and fumarate hydratase deficient leiomyomas: Strengths, weaknesses, and limitations of array-CGH interpretation.

A close relationship has been demonstrated between genomic complexity and clinical outcome in uterine smooth muscle tumors. We studied the genomic profiles by array-CGH of 28 fumarate hydratase deficient leiomyomas and 37 leiomyomas with bizarre nuclei (LMBN) from 64 patients. Follow-up was available for 46 patients (from three to 249 months, mean 87.3 months). All patients were alive without evidence of disease. For 51 array-CGH interpretable tumors the mean Genomic Index (GI) was 16.4 (median: 9.8; from 1 to 57.8), significantly lower than the mean GI in LMS (mean GI 51.8, p < 0.001). We described three groups: (1) a group with FH deletion (24/58) with low GI (mean GI: 11 vs. 22,4, p = 0.02), (2) a group with TP53 deletion (17/58) with higher GI (22.4 vs. 11 p = 0.02), and (3) a group without genomic events on FH or TP53 genes (17/58) (mean GI:18.3; from 1 to 57.8). Because none of these tumors recurred and none showed morphological features of LMS we concluded that GI at the cut-off of 10 was not applicable in these subtypes of LM. By integration of all those findings, a GI <10 in LMBN remains a valuable argument for benignity. Conversely, in LMBN a GI >10 or alteration in tumor suppressor genes, should not alone warrant a diagnosis of malignancy. Nine tumors were tested with Nanocind CINSARC® signature and all were classified in low risk of recurrence. We propose, based on our observations, a diagnostic approach of these challenging lesions.

Electrochemical Tip-Enhanced Raman Spectroscopy for the Elucidation of Complex Electrochemical Reactions.

Tip-enhanced Raman spectroscopy (TERS) is an emerging nanospectroscopy technique whose implementation in situ/operando, namely, in the liquid phase and under electrochemical polarization (EC-TERS), remains challenging. The investigation of electrochemical processes at the nanoscale, in real time and over wide potential windows can be of particular interest but tedious when using EC-STM-TERS. This approach was successfully applied to the investigation of a well-established but yet complex system (a thiolated nitrobenzene derivative 4-NBM) whose reduction mechanism involves various multistep reaction paths, most likely pH-dependent. In light of the EC-TERS analysis carried out under specific conditions limiting the full (6 e-/6 H+) electrochemical reduction of 4-NBM and its photocoupling, a bimolecular electrochemical reaction path, difficult to evidence from the electrochemical response only, is proposed.

Application of SWATH Mass Spectrometry and Machine Learning in the Diagnosis of Inflammatory Bowel Disease Based on the Stool Proteome.

Inflammatory bowel disease (IBD) flare-ups exhibit symptoms that are similar to other diseases and conditions, making diagnosis and treatment complicated. Currently, the gold standard for diagnosing and monitoring IBD is colonoscopy and biopsy, which are invasive and uncomfortable procedures, and the fecal calprotectin test, which is not sufficiently accurate. Therefore, it is necessary to develop an alternative method. In this study, our aim was to provide proof of concept for the application of Sequential Window Acquisition of All Theoretical Mass Spectra-Mass spectrometry (SWATH-MS) and machine learning to develop a non-invasive and accurate predictive model using the stool proteome to distinguish between active IBD patients and symptomatic non-IBD patients. Proteome profiles of 123 samples were obtained and data processing procedures were optimized to select an appropriate pipeline. The differentially abundant analysis identified 48 proteins. Utilizing correlation-based feature selection (Cfs), 7 proteins were selected for proceeding steps. To identify the most appropriate predictive machine learning model, five of the most popular methods, including support vector machines (SVMs), random forests, logistic regression, naive Bayes, and k-nearest neighbors (KNN), were assessed. The generated model was validated by implementing the algorithm on 45 prospective unseen datasets; the results showed a sensitivity of 96% and a specificity of 76%, indicating its performance. In conclusion, this study illustrates the effectiveness of utilizing the stool proteome obtained through SWATH-MS in accurately diagnosing active IBD via a machine learning model.

Deciphering the Interplay between Local and Global Dynamics of Anodic Metal Oxidation.

The stark difference between global and local metal oxidation dynamics underscores the need for methodologies capable of performing precise sub-µm-scale and wide-field measurements. In this study, we present reflective microscopy as a tool developed to address this challenge, illustrated by the example of chronoamperometric Fe oxidation in a NaCl solution. Analysis at a local scale of 10 s of µm has revealed three distinct periods of Fe oxidation: the initial covering of the metal interface with a surface film, followed by the electrochemical conversion of the formed surface film, and finally, the in-depth oxidation of Fe. In addition, thermodynamic calculations and the quantitative analysis of changes in optical signal (light intensity), correlated with variations in refractive indexes, suggest the initial formation of maghemite, followed by its subsequent conversion to magnetite. The reactivity maps for all three periods are heterogeneous, which can be attributed to the preferential oxidation of certain crystallographic grains. Notably, at the global scale of 100 s of µm, reactivity initiates at the electrode border and progresses toward its center, demonstrating a unique pattern that is independent of the local metal structure. This finding underscores the significance of simultaneously employing sub-µm-precise, quantitative, and wide-field measurements for a comprehensive description of metal oxidation processes.

Lightning Pose: improved animal pose estimation via semi-supervised learning, Bayesian ensembling, and cloud-native open-source tools.

Contemporary pose estimation methods enable precise measurements of behavior via supervised deep learning with hand-labeled video frames. Although effective in many cases, the supervised approach requires extensive labeling and often produces outputs that are unreliable for downstream analyses. Here, we introduce "Lightning Pose," an efficient pose estimation package with three algorithmic contributions. First, in addition to training on a few labeled video frames, we use many unlabeled videos and penalize the network whenever its predictions violate motion continuity, multiple-view geometry, and posture plausibility (semi-supervised learning). Second, we introduce a network architecture that resolves occlusions by predicting pose on any given frame using surrounding unlabeled frames. Third, we refine the pose predictions post-hoc by combining ensembling and Kalman smoothing. Together, these components render pose trajectories more accurate and scientifically usable. We release a cloud application that allows users to label data, train networks, and predict new videos directly from the browser.

Borderline phyllodes tumour of the breast with eosinophilic inclusion bodies: Case report and molecular sequencing.

INTRODUCTION AND IMPORTANCE: The presence of eosinophilic inclusion bodies in the breast is very rare and fewer than 20 cases were described in the literature. Herein we report the first case of borderline phyllodes tumour associated with this kind of cells. To the best of our knowledge, this is also the first time that a molecular sequencing is made targeting the stroma cells with inclusion bodies. CASE PRESENTATION: A 33-yr-old woman presented a large mass in the right breast. Imaging techniques by mammogram and ultrasonographic examination were performed. After multidisciplinary approach, a breast conserving surgery has been decided. Microscopic analysis, immunohistochemical stains and molecular tests were performed on the lesion. The proposed diagnosis is borderline phyllodes tumour with eosinophilic inclusion bodies. CLINICAL DISCUSSION: Inclusion bodies are typically found in the infantile digital fibromatosis. Finding them in extradigital fibromatosis is rare. Their signification is still unclear. Some studies suggest a disturbance in the metabolism of proliferating myofibroblasts. CONCLUSION: The presence of inclusion bodies in breast tumour do not seem to have a prognosis impact. It might be interesting to perform others molecular tests on lesions with eosinophilic inclusion bodies to discover potential mutations.

Comparison Between Manual and Automated Assessment of Ki-67 in Breast Carcinoma: Test of a Simple Method in Daily Practice.

BACKGROUND: In the era of "precision medicine," the availability of high-quality tumor biomarker tests is critical and tumor proliferation evaluated by Ki-67 antibody is one of the most important prognostic factors in breast cancer. But the evaluation of Ki-67 index has been shown to suffer from some interobserver variability. The goal of the study is to develop an easy, automated, and reliable Ki-67 assessment approach for invasive breast carcinoma in routine practice. PATIENTS AND METHODS: A total of 151 biopsies of invasive breast carcinoma were analyzed. The Ki-67 index was evaluated by 2 pathologists with MIB-1 antibody as a global tumor index and also in a hotspot. These 2 areas were also analyzed by digital image analysis (DIA). RESULTS: For Ki-67 index assessment, in the global and hotspot tumor area, the concordances were very good between DIA and pathologists when DIA focused on the annotations made by pathologist (0.73 and 0.83, respectively). However, this was definitely not the case when DIA was not constrained within the pathologist's annotations and automatically established its global or hotspot area in the whole tissue sample (concordance correlation coefficients between 0.28 and 0.58). CONCLUSIONS: The DIA technique demonstrated a meaningful concordance with the indices evaluated by pathologists when the tumor area is previously identified by a pathologist. In contrast, basing Ki-67 assessment on automatic tissue detection was not satisfactory and provided bad concordance results. A representative tumoral zone must therefore be manually selected prior to the measurement made by the DIA.

Context-invariant beliefs are supported by dynamic reconfiguration of single unit functional connectivity in prefrontal cortex.

Natural behaviors occur in closed action-perception loops and are supported by dynamic and flexible beliefs abstracted away from our immediate sensory milieu. How this real-world flexibility is instantiated in neural circuits remains unknown. Here we have macaques navigate in a virtual environment by primarily leveraging sensory (optic flow) signals, or by more heavily relying on acquired internal models. We record single-unit spiking activity simultaneously from the dorsomedial superior temporal area (MSTd), parietal area 7a, and the dorso-lateral prefrontal cortex (dlPFC). Results show that while animals were able to maintain adaptive task-relevant beliefs regardless of sensory context, the fine-grain statistical dependencies between neurons, particularly in 7a and dlPFC, dynamically remapped with the changing computational demands. In dlPFC, but not 7a, destroying these statistical dependencies abolished the area's ability for cross-context decoding. Lastly, correlation analyses suggested that the more unit-to-unit couplings remapped in dlPFC, and the less they did so in MSTd, the less were population codes and behavior impacted by the loss of sensory evidence. We conclude that dynamic functional connectivity between prefrontal cortex neurons maintains a stable population code and context-invariant beliefs during naturalistic behavior with closed action-perception loops.

Human primary motor cortex indexes the onset of subjective intention in brain-machine-interface mediated actions.

Self-initiated behavior is accompanied by the experience of willing our actions. Here, we leverage the unique opportunity to examine the full intentional chain - from will (W) to action (A) to environmental effects (E) - in a tetraplegic person fitted with a primary motor cortex (M1) brain machine interface (BMI) generating hand movements via neuromuscular electrical stimulation (NMES). This combined BMI-NMES approach allowed us to selectively manipulate each element of the intentional chain (W, A, and E) while performing extra-cellular recordings and probing subjective experience. Our results reveal single-cell, multi-unit, and population-level dynamics in human M1 that encode W and may predict its subjective onset. Further, we show that the proficiency of a neural decoder in M1 reflects the degree of W-A binding, tracking the participant's subjective experience of intention in (near) real time. These results point to M1 as a critical node in forming the subjective experience of intention and demonstrate the relevance of intention-related signals for translational neuroprosthetics.

Causal inference during closed-loop navigation: parsing of self- and object-motion.

A key computation in building adaptive internal models of the external world is to ascribe sensory signals to their likely cause(s), a process of causal inference (CI). CI is well studied within the framework of two-alternative forced-choice tasks, but less well understood within the cadre of naturalistic action-perception loops. Here, we examine the process of disambiguating retinal motion caused by self- and/or object-motion during closed-loop navigation. First, we derive a normative account specifying how observers ought to intercept hidden and moving targets given their belief about (i) whether retinal motion was caused by the target moving, and (ii) if so, with what velocity. Next, in line with the modelling results, we show that humans report targets as stationary and steer towards their initial rather than final position more often when they are themselves moving, suggesting a putative misattribution of object-motion to the self. Further, we predict that observers should misattribute retinal motion more often: (i) during passive rather than active self-motion (given the lack of an efference copy informing self-motion estimates in the former), and (ii) when targets are presented eccentrically rather than centrally (given that lateral self-motion flow vectors are larger at eccentric locations during forward self-motion). Results support both of these predictions. Lastly, analysis of eye movements show that, while initial saccades toward targets were largely accurate regardless of the self-motion condition, subsequent gaze pursuit was modulated by target velocity during object-only motion, but not during concurrent object- and self-motion. These results demonstrate CI within action-perception loops, and suggest a protracted temporal unfolding of the computations characterizing CI. This article is part of the theme issue 'Decision and control processes in multisensory perception'.

Life History Traits and Longevity of the Invasive Asian Common Toad Duttaphrynus melanostictus (Schneider, 1799) in Madagascar.

We analyzed the body length, age structure, and age at sexual maturity of the invasive Asian common toad Duttaphrynus melanostictus from different sites in Toamasina, east Madagascar. We used skeletochronology as a proxy for age estimation, while gonads were histologically analyzed to determine the age of sexual maturity. The analysis of pooled age data from three sites investigated in 2016 showed that both sexes were larger, although not older, than those of native populations. For the individuals from Madagascar, the males were significantly smaller and younger (mean ± SD, SVL: 71.4 ± 1.6 mm; age: 1.8 ± 0.7 years) than the females (SVL: 78.42 ± 1.9 mm; age: 2.7 ± 1.3 years), when the data were pooled, but when the data were analyzed separately for each of the three sites, similar results were obtained only for one site. The oldest recorded male and female were 3 and 6 years old, respectively. Gonadal histology showed that the males and females reach sexual maturity after the first and second years of age, respectively. Further studies are needed to understand if the larger size and faster growth rates observed in the invasive population of D. melanostictus in Madagascar are a consequence of more favorable environmental conditions with respect to the native range (e.g., the availability of larger trophic niches, a lack of competitors, and lower predatory pressure), and we suggest to extend the monitoring of these life history traits to understand how they might influence the invasion.

Metal Core-Shell Nanoparticle Supercrystals: From Photoactivation of Hydrogen Evolution to Photocorrosion.

Gas nanobubbles are directly linked to many important chemical reactions. While they can be detrimental to operational devices, they also reflect the local activity at the nanoscale. Here, supercrystals made of highly monodisperse Ag@Pt core-shell nanoparticles are first grown onto a solid support and fully characterized by electron microscopies and X-ray scattering. Supercrystals are then used as a plasmonic photocatalytic platform for triggering the hydrogen evolution reaction. The catalytic activity is measured operando at the single supercrystal level by high-resolution optical microscopy, which allows gas nanobubble nucleation to be probed at the early stage with high temporal resolution and the amount of gas molecules trapped inside them to be quantified. Finally, a correlative microscopy approach and high-resolution electron energy loss spectroscopy help to decipher the mechanisms at the origin of the local degradation of the supercrystals during catalysis, namely nanoscale erosion and corrosion.

Fuelling electrocatalysis at a single nanoparticle by ion flow in a nanoconfined electrolyte layer.

We explore the possibility of coupling the transport of ions and water in a nanochannel with the chemical transformation of a reactant at an individual catalytic nanoparticle (NP). Such configuration could be interesting for constructing artificial photosynthesis devices coupling the asymmetric production of ions at the catalytic NP, with the ion selectivity of the nanochannels acting as ion pumps. Herein we propose to observe how such ion pumping can be coupled to an electrochemical reaction operated at the level of an individual electrocatalytic Pt NP. This is achieved by confining a (reservoir) droplet of electrolyte to within a few micrometres away from an electrocatalytic Pt NP on an electrode. While the region of the electrode confined by the reservoir and the NP are cathodically polarised, operando optical microscopy reveals the growth of an electrolyte nanodroplet on top of the NP. This suggests that the electrocatalysis of the oxygen reduction reaction operates at the NP and that an electrolyte nanochannel is formed - acting as an ion pump - between the reservoir and the NP. We have described here the optically imaged phenomena and their relevance to the characterization of the electrolyte nanochannel linking the NPs to the electrolyte microreservoir. Additionally, we have addressed the capacity of the nanochannel to transport ions and solvent flow to the NP.

A theory of autism bridging across levels of description.

Autism impacts a wide range of behaviors and neural functions. As such, theories of autism spectrum disorder (ASD) are numerous and span different levels of description, from neurocognitive to molecular. We propose how existent behavioral, computational, algorithmic, and neural accounts of ASD may relate to one another. Specifically, we argue that ASD may be cast as a disorder of causal inference (computational level). This computation relies on marginalization, which is thought to be subserved by divisive normalization (algorithmic level). In turn, divisive normalization may be impaired by excitatory-to-inhibitory imbalances (neural implementation level). We also discuss ASD within similar frameworks, those of predictive coding and circular inference. Together, we hope to motivate work unifying the different accounts of ASD.

Imaging the Footprint of Nanoscale Electrochemical Reactions for Assessing Synergistic Hydrogen Evolution.

This work proposes a novel method for measuring the intrinsic activity of single metal-based nanoparticles towards water reduction in neutral media at industrially relevant current densities. Instead of using gas nanobubbles as proxy, the method uses optical microscopy to track the local footprint of the reaction through the precipitation of metal hydroxide, which is associated to the local pH increase during electrocatalysis. The results show the electrocatalytic activities of different types of metal nanoparticles and bifunctionnal core-shell nanostructures made of Ni and Pt, and demonstrate the importance of metal hydroxide nano-shells in enhancing electrocatalysis. This method should be generalizable to any electrocatalytic reaction involving pH changes such as nitrate or CO2 reduction.

HER2 Amplification in p53-Mutated Endometrial Carcinomas.

p53-mutated endometrial carcinomas tend to recur and develop distant metastases. Therefore, the detection of new potential therapeutic targets such as HER2 is particularly interesting. In this retrospective study, which considered over 118 endometrial carcinomas, the p53 mutation was detected in 29.6% of cases. In these cases, the HER2 protein profile was studied via immunohistochemistry, and an overexpression of HER2 protein (++ or +++) was noted in 31.4%. The CISH technique was used in these cases to determine if gene amplification was present. In 18% of cases, the technique was not conclusive. Amplification of the HER2 gene was observed in 36.3% of cases and 36.3% of cases showed a polysomal-like aneusomy for centromere 17. Amplification was found in serous carcinomas, clear cell carcinomas and carcinosarcomas, highlighting the future potentiality of HER2-targeted therapies in these variants of aggressive carcinomas.

Causal inference during closed-loop navigation: parsing of self- and object-motion.

A key computation in building adaptive internal models of the external world is to ascribe sensory signals to their likely cause(s), a process of Bayesian Causal Inference (CI). CI is well studied within the framework of two-alternative forced-choice tasks, but less well understood within the cadre of naturalistic action-perception loops. Here, we examine the process of disambiguating retinal motion caused by self- and/or object-motion during closed-loop navigation. First, we derive a normative account specifying how observers ought to intercept hidden and moving targets given their belief over (i) whether retinal motion was caused by the target moving, and (ii) if so, with what velocity. Next, in line with the modeling results, we show that humans report targets as stationary and steer toward their initial rather than final position more often when they are themselves moving, suggesting a misattribution of object-motion to the self. Further, we predict that observers should misattribute retinal motion more often: (i) during passive rather than active self-motion (given the lack of an efference copy informing self-motion estimates in the former), and (ii) when targets are presented eccentrically rather than centrally (given that lateral self-motion flow vectors are larger at eccentric locations during forward self-motion). Results confirm both of these predictions. Lastly, analysis of eye-movements show that, while initial saccades toward targets are largely accurate regardless of the self-motion condition, subsequent gaze pursuit was modulated by target velocity during object-only motion, but not during concurrent object- and self-motion. These results demonstrate CI within action-perception loops, and suggest a protracted temporal unfolding of the computations characterizing CI.

Three Types of Endometriosis: Pathogenesis, Diagnosis and Treatment. State of the Art.

At present, there is no curative treatment for endometriosis. Medical management and surgical treatment do not provide long-term relief. A detailed understanding of its pathophysiology is mandatory in order to facilitate both the diagnosis and treatment. The delay that typically precedes proper diagnosis (6 to 7 years) is probably one of the most challenging aspects of endometriosis management. In 2012, the total cost per woman due to endometriosis was estimated to be 9579€ per year in a multicenter study across the USA and Europe. According to their physiopathology and their localization, ectopic endometrial lesions, consisting of endometrial glands and stroma, can be divided into three different types: superficial peritoneal endometriosis (SPE), ovarian endometrioma (OMA), and deep infiltrating endometriosis (DIE). The following paper aims to review the available data in the literature on the pathogenesis, diagnosis, and treatment of different types of endometriosis.