Miracle-dz/UniFAR-FTUs huggingface dataset:
Mitosis detection in breast cancer pathology images by combining handcrafted and convolutional neural network features

Abstract. Breast cancer (BCa) grading plays an important role in predicting disease aggressiveness and patient outcome. A key component of BCa grade is the mitotic count, which involves quantifying the number of cells in the process of dividing (i.e., undergoing mitosis) at a specific point in time. Currently, mitosis counting is done manually by a pathologist looking at multiple high power fields (HPFs) on a glass slide under a microscope, an extremely laborious and time consuming process. The development of computerized systems for automated detection of mitotic nuclei, while highly desirable, is confounded by the highly variable shape and appearance of mitoses. Existing methods use either handcrafted features that capture certain morphological, statistical, or textural attributes of mitoses or features learned with convolutional neural networks (CNN). Although handcrafted features are inspired by the domain and the particular application, the data-driven CNN models tend to be domain agnostic and attempt to learn additional feature bases that cannot be represented through any of the handcrafted features. On the other hand, CNN is computationally more complex and needs a large number of labeled training instances. Since handcrafted features attempt to model domain pertinent attributes and CNN approaches are largely supervised feature generation methods, there is an appeal in attempting to combine these two distinct classes of feature generation strategies to create an integrated set of attributes that can potentially outperform either class of feature extraction strategies individually. We present a cascaded approach for mitosis detection that intelligently combines a CNN model and handcrafted features (morphology, color, and texture features). By employing a light CNN model, the proposed approach is far less demanding computationally, and the cascaded strategy of combining handcrafted features and CNN-derived features enables the possibility of maximizing the performance by leveraging the disconnected feature sets. Evaluation on the public ICPR12 mitosis dataset that has 226 mitoses annotated on 35 HPFs (400× magnification) by several pathologists and 15 testing HPFs yielded an F-measure of 0.7345. Our approach is accurate, fast, and requires fewer computing resources compared to existent methods, making this feasible for clinical use.
Measurement of shear stress-mediated intracellular calcium dynamics in human dermal lymphatic endothelial cells

The shear stress applied to lymphatic endothelial cells (LEC) by lymph flow changes dramatically under normal conditions as well as in response to disease conditions and immune reactions. In general, LEC are known to regulate the contraction frequency and strength of lymphatic pumping in response to shear stress. Intracellular calcium concentration ([Ca2+]i) is an important factor that regulates lymphatic contraction characteristics. In this study, we measured changes in the [Ca2+]i under different shear stress levels and determined the source of this calcium signal. Briefly, human dermal LEC were cultured in custom-made microchannels for 3 days before loading with 2 µM fura-2 AM, a ratiometric calcium dye to measure [Ca2+]i. Step changes in shear stress resulted in a rapid increase in [Ca2+]i followed by a gradual return to the basal level and sometimes below the initial baseline (45.2 ± 2.2 nM). The [Ca2+]i reached a peak at 126.2 ± 5.6 nM for 10 dyn/cm2 stimulus, whereas the peak was only 71.8 ± 5.4 nM for 1 dyn/cm2 stimulus, indicating that the calcium signal depends on the magnitude of shear stress. Removal of the extracellular calcium from the buffer or pharmocological blockade of calcium release-activated calcium (CRAC) channels significantly reduced the peak [Ca2+]i, demonstrating a role of extracellular calcium entry. Inhibition of endoplasmic reticulum (ER) calcium pumps showed the importance of intracellular calcium stores in the initiation of this signal. In conclusion, we demonstrated that the shear-mediated calcium signal is dependent on the magnitude of the shear and involves ER store calcium release and extracellular calcium entry.
Modulation of Face-sensitive Event-related Potentials by Canonical and Distorted Human Faces: The Role of Vertical Symmetry and Up-Down Featural Arrangement

This study examined the sensitivity of early face-sensitive event-related potential (ERP) components to the disruption of two structural properties embedded in faces, namely, updown featural arrangement and vertical symmetry. Behavioral measures and ERPs were recorded as adults made an orientation judgment for canonical faces and distorted faces that had been manipulated for either or both of the mentioned properties. The P1, the N170, and the vertex positive potential (VPP) exhibited a similar gradient in sensitivity to the two investigated properties, in that they all showed a linear increase in amplitude or latency as the properties were selectively disrupted in the order of (1) up-down featural arrangement, (2) vertical symmetry, and (3) both up-down featural arrangement and vertical symmetry. Exceptions to this finding were seen for the amplitudes of the N170 and VPP, which were largest for the stimulus in which solely vertical symmetry was disrupted. Interestingly, the enhanced amplitudes of the N170 and VPP are consistent with a drop in behavioral performance on the orientation judgment for this stimulus.
Accelerated Cell Death in Podospora Autophagy Mutants

ABSTRACT Although autophagy is characteristic of type II programmed cell death (PCD), its role in cell death is currently debated. Both cell death-promoting and prosurvival roles of autophagy have been reported depending on the organism and the cell type. In filamentous fungi, a cell death reaction known as an incompatibility reaction occurs when cells of unlike genotype fuse. Cell death by incompatibility is characterized by a dramatic vacuolar enlargement and cell lysis. In Podospora anserina, autophagy is induced early during this cell death reaction. Cell death by incompatibility in Podospora is a model of type II PCD used here to assess the role of autophagy in this type of cell death. We have inactivated PaATG1, the Podospora ortholog of the Saccharomyces cerevisiae ATG1 gene involved in the early steps of autophagy in yeast. The ΔPaATG1 mutant displays developmental defects characteristic of abrogated autophagy in Podospora. Using the green fluorescent protein-PaATG8 autophagosome marker, we show that autophagy is abolished in this mutant. Neither cell death by incompatibility nor vacuolization are suppressed in ΔPaATG1 and ΔPaATG8 autophagy mutants, indicating that a vacuolar cell death reaction without autophagy occurs in Podospora. Our results thus provide a novel example of a type II PCD reaction in which autophagy is not the cause of cell death. In addition, we found that cell death is accelerated in ΔPaATG null mutants, suggesting that autophagy has a protective role in this type II PCD reaction.
Re-evaluation and modification of the Stuivenberg Hospital Acute Renal Failure (SHARF) scoring system for the prognosis of acute renal failure: an independent multicentre, prospective study.

BACKGROUND A prognostic scoring system for hospital mortality in acute renal failure (Stuivenberg Hospital Acute Renal Failure, SHARF score) was developed in a single-centre study. The scoring system consists of two scores, for the time of diagnosis of acute renal failure (ARF) and for 48 h later, each originally based on four parameters (age, serum albumin, prothrombin time and heart failure). The scoring system was now tested and adapted in a prospective study. METHODS The study involved eight intensive care units. We studied 293 consecutive patients with ARF in 6 months. Their mortality was 50.5%. The causes of ARF were medical in 184 (63%) patients and surgical in 108 (37%). In the latter group, 74 (69%) patients underwent cardiac and 19 (18%) vascular surgery. RESULTS As the performance of the original SHARF scores was much lower in the multicentre study than in the original single-centre study, we re-analysed the multicentre data to customize the original model for the population studied. The independent variables were the score developed in the original study plus all additonal parameters that were significant on univariate analysis. The new multivariate analysis revealed an additional subset of three parameters for inclusion in the model (serum bilirubin, sepsis and hypotension). For the modified SHARF II score, r(2) was 0.27 at 0 and 0.33 at 48 h, respectively, the receiver operating characteristic (ROC) values were 0.82 and 0.83, and the Hosmer-Lemeshow goodness-of-fit P values were 0.19 and 0.05. CONCLUSION After customizing and by using two scoring moments, this prediction model for hospital mortality in ARF is useful in different settings for comparing groups of patients and centres, quality assessment and clinical trials. We do not recommend its use for individual patient prognosis.
Identification of a Novel Mode of Complement Activation on Stimulated Platelets Mediated by Properdin and C3(H2O)

Elevated numbers of activated platelets circulate in patients with chronic inflammatory diseases, including atherosclerosis and coronary disease. Activated platelets can activate the complement system. Although complement activation is essential for immune responses and removal of spent cells from circulation, it also contributes to inflammation and thrombosis, especially in patients with defective complement regulation. Proinflammatory activated leukocytes, which interact directly with platelets in response to vascular injury, are among the main sources of properdin, a positive regulator of the alternative pathway. The role of properdin in complement activation on stimulated platelets is unknown. Our data show that physiological forms of human properdin bind directly to human platelets after activation by strong agonists in the absence of C3, and bind nonproportionally to surface CD62P expression. Activation of the alternative pathway on activated platelets occurs when properdin is on the surface and recruits C3b or C3(H2O) to form C3b,Bb or a novel cell-bound C3 convertase [C3(H2O),Bb], which normally is present only in the fluid phase. Alternatively, properdin can be recruited by C3(H2O) on the platelet surface, promoting complement activation. Inhibition of factor H–mediated cell surface complement regulation significantly increases complement deposition on activated platelets with surface properdin. Finally, properdin released by activated neutrophils binds to activated platelets. Altogether, these data suggest novel molecular mechanisms for alternative pathway activation on stimulated platelets that may contribute to localization of inflammation at sites of vascular injury and thrombosis.
Preclinical Efficacy and Immunological Safety of FR104, an Antagonist Anti‐CD28 Monovalent Fab′ Antibody

Antagonist anti‐CD28 antibodies prevent T cell costimulation and differentiate from CTLA4Ig since they cannot block CTLA‐4 and PDL‐1 coinhibitory signals. They demonstrated efficacy in suppressing effector T cells while enhancing regulatory T cells function and immune tolerance. However, anti‐CD28 antibodies devoid of immunotoxicity and with a good pharmacokinetic profile have not yet been developed. Here, we describe FR104, a novel humanized pegylated anti‐CD28 Fab′ antibody fragment presenting a long elimination half‐life in monkeys. In vitro, FR104 failed to induce human T cell proliferation and cytokines secretion, even in the presence of anti‐CD3 antibodies or when cross‐linked with secondary antibodies. Furthermore, in humanized NOD/SCID mice adoptively transferred with human PBMC, whereas superagonist and divalent antibodies elicited rapid cytokines secretion and human T cell activation, FR104 did not. These humanized mice developed a florid graft‐versus‐host disease, which was prevented by administration of FR104 in a CTLA4‐dependent manner. Interestingly, administration of high doses of CTLA4‐Ig was ineffective to prevent GVHD, whereas administration of low doses was partially effective. In conclusion, we demonstrated that FR104 is devoid of agonist activity on human T cells and thus compatible with a clinical development that might lead to higher therapeutic indexes, by sparing CTLA‐4, as compared to CD80/CD86 antagonists.
Flow Model of the Protein-protein Interaction Network for Finding Credible Interactions

Large-scale protein-protein interactions (PPIs) detected by yeast-two-hybrid (Y2H) systems are known to contain many false positives. The separation of credible interactions from background noise is still an unavoidable task. In the present study, we propose the relative reliability score for PPI as an intrinsic characteristic of global topology in the PPI networks. Our score is calculated as the dominant eigenvector of an adjacency matrix and represents the steady state of the network flow. By using this reliability score as a cut-off threshold from noisy Y2H PPI data, the credible interactions were extracted with better or comparable performance of previously proposed methods which were also based on the network topology. The result suggests that the application of the network-flow model to PPI data is useful for extracting credible interactions from noisy experimental data.
Multi-walled Сarbon Nanotubes Penetrate into Plant Cells and Affect the Growth of Onobrychis arenaria Seedlings

Engineered nanoparticles (ENPs) are now being used in many sectors of industry; however, the impact of ENPs on the environment still requires further study, since their use, recycling, and accidental spill can result in the accumulation of nanoparticles in the atmosphere, soil, and water. Plants are an integral part of ecosystems; hence their interaction with ENPs is inevitable. It is important to understand the consequences of this interaction and assess its potential effects. The present research is focused on studying the effects of the industrial material Taunit, containing multi-walled carbon nanotubes (MWNTs), on plants, and testing of its ability to penetrate into plant cells and tissues. Taunit has been found to stimulate the growth of roots and stems and cause an increase in peroxidase activity inOnobrychis arenariaseedlings. Peroxidase activity increases with decreasing concentration of Taunit from 1,000 to 100 mg/l. MWNTs from Taunit were detected in the cells and tissues of seedling roots and leaves, implying the ability of MWNTs to penetrate into roots and accumulate there, as well as their ability to be transported into seedling leaves. Thus, the changes in the physiological parameters of plants are associated not only with MWNT adsorption on the root surface, as previously believed, but also with their penetration, uptake and accumulation in the plant cells and tissues.
CD4+ cell-dependent granuloma formation in humanized mice infected with mycobacteria

We have used humanized mice, in which human immune cells differentiate de novo from transplanted cord blood progenitor cells, to study the human immune responses to infection with Mycobacterium bovis bacillus Calmette–Guérin and Mycobacterium tuberculosis. Granulomas with a core containing giant cells, human CD68+ macrophages, and high bacilli numbers surrounded by a layer of CD3+ T cells and a fibrotic response encapsulating the lesions were observed in livers and lungs from bacillus Calmette–Guérin-infected humanized mice but not in nonhumanized infected controls. Paradoxically, humanized mice contained higher mycobacterial numbers in organs than nonhumanized controls. The enhancement of bacterial load was mediated by human CD4+ cells and associated to an increased expression of Programmed Death-1 protein and CD57 on T cells, molecules associated with inhibition and senescence. The lesions from mice depleted of CD4+ cells were scarcer, minimal, and irregular compared with those from mice depleted of CD8+ cells or nondepleted controls. Granulomas of bacillus Calmette–Guérin-infected humanized mice administered with a TNF-neutralizing TNF receptor fusion molecule preserved their structure, but contained higher levels of intracellular bacilli. Extended necrosis was observed in granulomas from M. tuberculosis- but not bacillus Calmette–Guérin-infected humanized mice. Our data indicate that humanized mice can be used as a model to study the formation and maintenance of human granuloma in tuberculosis and other infectious or noninfectious diseases.
Understanding Cultural Conflicts using Metaphors and Sociolinguistic Measures of Influence

In this article, we outline a novel approach to the automated analysis of cross-cultural conflicts through the discovery and classification of the metaphors used by the protagonist parties involved in the conflict. We demonstrate the feasibility of this approach on a prototypical conflict surrounding the appropriate management and oversight of gun-ownership in the United States. In addition, we present a way of incorporating sociolinguistic measures of influence in discourse to draw further insights from complex data. The results presented in this article should be considered as illustrative of the types of analyses that can be obtained using our methodology; however, no attempt was made to rigorously validate the specific findings reported here. We address open issues such as how our approach could be generalized to analyze cross-cultural conflicts around the world.
Legionella pneumophila Persists within Biofilms Formed by Klebsiella pneumoniae, Flavobacterium sp., and Pseudomonas fluorescens under Dynamic Flow Conditions

Legionella pneumophila, the agent of Legionnaires' disease pneumonia, is transmitted to humans following the inhalation of contaminated water droplets. In aquatic systems, L. pneumophila survives much of time within multi-organismal biofilms. Therefore, we examined the ability of L. pneumophila (clinical isolate 130b) to persist within biofilms formed by various types of aquatic bacteria, using a bioreactor with flow, steel surfaces, and low-nutrient conditions. L. pneumophila was able to intercalate into and persist within a biofilm formed by Klebsiella pneumoniae, Flavobacterium sp. or Pseudomonas fluorescens. The levels of L. pneumophila within these biofilms were as much as 4×104 CFU per cm2 of steel coupon and lasted for at least 12 days. These data document that K. pneumoniae, Flavobacterium sp. , and P. fluorescens can promote the presence of L. pneumophila in dynamic biofilms. In contrast to these results, L. pneumophila 130b did not persist within a biofilm formed by Pseudomonas aeruginosa, confirming that some bacteria are permissive for Legionella colonization whereas others are antagonistic. In addition to colonizing certain mono-species biofilms, L. pneumophila 130b persisted within a two-species biofilm formed by K. pneumoniae and Flavobacterium sp. Interestingly, the legionellae were also able to colonize a two-species biofilm formed by K. pneumoniae and P. aeruginosa, demonstrating that a species that is permissive for L. pneumophila can override the inhibitory effect(s) of a non-permissive species.
Indole-3-Carbinol Triggers Aryl Hydrocarbon Receptor-dependent Estrogen Receptor (ER)α Protein Degradation in Breast Cancer Cells Disrupting an ERα-GATA3 Transcriptional Cross-Regulatory Loop

We have established in human breast cancer cells that indole-3-carbinol (I3C), a promising anti-cancer phytochemical from Brassica vegetables, ablates ERα expression by stimulating the Rbx-1 E3 ligase mediated degradation of ERα protein and disruption of a cross-regulatory positive feedback loop involving ERα and the GATA3 transcription factor.
Increasing Connectivity in Wireless Sensor-Actuator Networks Using Dynamic Actuator Cooperation

Distributed systems based on networked sensors and actuators with embedded computation capabilities are commonly used to monitor and control the physical world. To provide a meaningful service such as disaster and emergency surveillance, meeting real-time-and-energy constraints and the stability of transmit queues are the basic requirements of communication protocols in such networks. In settings with sparse distribution of actuator nodes, multi-hop routing is traditionally used to relay information to a remote sink. A problem with this approach is that the loss of connectivity of actuator nodes may lead to partitioning of the network. In this paper, we address the problem of minimizing power consumption at each actuator node and minimizing assignment overhead at each sensor node while ensuring network connectivity. We propose that each actuator is enabled with two wireless interfaces: one to communicate with its assigned sensor network, and the other to communicate with the network of neighboring actuators. At any instant of time, an actuator can adjust its transmit power level to ensure connectivity and pro-actively inform its attached sensor network in case of mobility. These strategies have an associated cost. We show in this paper that at any instant of time, the strategy chosen by an actuator to adjust power and control-overhead due to mobility are optimal subject to constraints. The proposal is validated by means of analysis and simulations.
The Pupillary Light Response Reveals the Focus of Covert Visual Attention

The pupillary light response is often assumed to be a reflex that is not susceptible to cognitive influences. In line with recent converging evidence, we show that this reflexive view is incomplete, and that the pupillary light response is modulated by covert visual attention: Covertly attending to a bright area causes a pupillary constriction, relative to attending to a dark area under identical visual input. This attention-related modulation of the pupillary light response predicts cuing effects in behavior, and can be used as an index of how strongly participants attend to a particular location. Therefore, we suggest that pupil size may offer a new way to continuously track the focus of covert visual attention, without requiring a manual response from the participant. The theoretical implication of this finding is that the pupillary light response is neither fully reflexive, nor under complete voluntary control, but is instead best characterized as a stereotyped response to a voluntarily selected target. In this sense, the pupillary light response is similar to saccadic and smooth pursuit eye movements. Together, eye movements and the pupillary light response maximize visual acuity, stabilize visual input, and selectively filter visual information as it enters the eye.
The Velocity Field Predicted by the Optical Redshift Survey

We have used the Optical Redshift Survey (ORS) of Santiago et al. to construct the gravity field due to fluctuations in the galaxy density field out to distances of 8000 km s-1. At large scales where linear theory applies, the comparison of this gravity field with the observed peculiar velocity field offers a powerful cosmological probe because the predicted flow field is proportional to the parameter Ω0. 6/b, where Ω is the matter density and b is the bias of the galaxy distribution. The more densely sampled ORS gravity field, to excellent approximation, matches that of the earlier IRAS 1.2 Jy redshift survey of Fisher et al., provided β is reduced by a factor of bopt/bIRAS ≈ 1.4. Apart from this scaling, the most significant difference between the ORS and IRAS fields is induced by differing estimates of the overdensity of the Virgo cluster. Neither of these gravity fields is consistent with the peculiar velocity field constructed from the full Mark III sample. We find that a simple but plausible nonlinear bias algorithm for the galaxy distribution relative to the mass has a negligible effect on the derived fields. We conclude that the substitution of optical for IRAS catalogs cannot alone resolve the discrepancies between the IRAS gravity field and the Mark III peculiar velocity field.