Positive-unlabeled learning for binary and multi-class cell detection in histopathology images with incomplete annotations

Cell detection in histopathology images is of great interest to clinical practice and research, and convolutional neural networks (CNNs) have achieved remarkable cell detection results. Typically, to train CNN-based cell detection models, every positive instance in the training images needs to be annotated, and instances that are not labeled as positive are considered negative samples. However, manual cell annotation is complicated due to the large number and diversity of cells, and it can be difficult to ensure the annotation of every positive instance. In many cases, only incomplete annotations are available, where some of the positive instances are annotated and the others are not, and the classification loss term for negative samples in typical network training becomes incorrect. In this work, to address this problem of incomplete annotations, we propose to reformulate the training of the detection network as a positive-unlabeled learning problem. Since the instances in unannotated regions can be either positive or negative, they have unknown labels. Using the samples with unknown labels and the positively labeled samples, we first derive an approximation of the classification loss term corresponding to negative samples for binary cell detection, and based on this approximation we further extend the proposed framework to multi-class cell detection. For evaluation, experiments were performed on four publicly available datasets. The experimental results show that our method improves the performance of cell detection in histopathology images given incomplete annotations for network training.Comment: Accepted for publication at the Journal of Machine Learning for Biomedical Imaging (MELBA) https://melba-journal.org/2022:027. arXiv admin note: text overlap with arXiv:2106.1591

Metabolomics and physio-chemical analyses of mulberry plants leaves response to manganese deficiency and toxicity reveal key metabolites and their pathways in manganese tolerance

IntroductionManganese (Mn) plays a pivotal role in plant growth and development. Aside aiding in plant growth and development, Mn as heavy metal (HM) can be toxic in soil when applied in excess. Morus alba is an economically significant plant, capable of adapting to a range of environmental conditions and possessing the potential for phytoremediation of contaminated soil by HMs. The mechanism by which M. alba tolerates Mn stresses remains obscure.MethodsIn this study, Mn concentrations comprising sufficiency (0.15 mM), higher regimes (1.5 mM and 3 mM), and deficiency (0 mM and 0.03 mM), were applied to M. alba in pot treatment for 21 days to understand M. alba Mn tolerance. Mn stress effects on the net photosynthetic rate (Pn), stomatal conductance (Gs), transpiration rate (Tr), intercellular CO2 concentration (Ci), chlorophyll content, plant morphological traits, enzymatic and non-enzymatic parameters were analyzed as well as metabolome signatures via non-targeted LC-MS technique.ResultsMn deficiency and toxicity decrease plant biomass, Pn, Ci, Gs, Tr, and chlorophyll content. Mn stresses induced a decline in the activities of catalase (CAT) and superoxide dismutase (SOD), while peroxidase (POD) activity, and leaf Mn content, increased. Soluble sugars, soluble proteins, malondialdehyde (MDA) and proline exhibited an elevation in Mn deficiency and toxicity concentrations. Metabolomic analysis indicates that Mn concentrations induced 1031 differentially expressed metabolites (DEMs), particularly amino acids, lipids, carbohydrates, benzene and derivatives and secondary metabolites. The DEMs are significantly enriched in alpha-linolenic acid metabolism, biosynthesis of unsaturated fatty acids, galactose metabolism, pantothenate and CoA biosynthesis, pentose phosphate pathway, carbon metabolism, etc.Discussion and conclusionThe upregulation of Galactinol, Myo-inositol, Jasmonic acid, L-aspartic acid, Coproporphyrin I, Trigonelline, Pantothenol, and Pantothenate and their significance in the metabolic pathways makes them Mn stress tolerance metabolites in M. alba. Our findings reveal the fundamental understanding of DEMs in M. alba’s response to Mn nutrition and the metabolic mechanisms involved, which may hold potential significance for the advancement of M. alba genetic improvement initiatives and phytoremediation programs

A universal optical modulator for synthetic topologically tuneable structured matter

Topologically structured matter, such as metasurfaces and metamaterials, have given rise to impressive photonic functionality, fuelling diverse applications from microscopy and holography to encryption and communication. Presently these solutions are limited by their largely static nature and preset functionality, hindering applications that demand dynamic photonic systems with reconfigurable topologies. Here we demonstrate a universal optical modulator that implements topologically tuneable structured matter as virtual pixels derived from cascading low functionality tuneable devices, altering the paradigm of phase and amplitude control to encompass arbitrary spatially varying retarders in a synthetic structured matter device. Our approach opens unprecedented functionality that is user-defined with high flexibility, allowing our synthetic structured matter to act as an information carrier, beam generator, analyser, and corrector, opening an exciting path to tuneable topologies of light and matter

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival

Clinical significance of the detection of serum IgG4 and IgG4/IgG ratio in patients with thyroid-associated ophthalmopathy

To evaluate the clinical significance of detecting serum IgG4 and the IgG4/IgG ratio in patients with thyroid-associated ophthalmopathy (TAO) and to explore whether high serum IgG4 levels and the IgG4/IgG ratio are associated with the severity and activity of TAO, we retrospectively assessed the records of 78 TAO patients and 32 controls collected in our hospital from July 2020 to July 2022. The TAO patients were divided into TAO inactive and TAO active phase groups according to the clinical activity score (CAS), and we evaluated the association between the serum IgG4 levels, the IgG4/IgG ratio, and the clinical data of the participants. The levels of IgG4 significantly increased in the TAO active group compared to those in the inactive and control groups (P < 0.05). Additionally, the number of patients with increased IgG4 levels (≥135 mg/dL) in the TAO active group was markedly higher than that in the inactive and control groups (P < 0.05). The IgG4/IgG ratio was also significantly enhanced in the TAO active group compared to the inactive and control groups (P < 0.05). CAS was identified as an independent factor influencing IgG4 levels in patients with TAO. The levels of serum IgG4, as well as the IgG4/IgG ratio, were significantly increased in some patients with active TAO, and they were related to the CAS, suggesting that the pathogenesis of TAO may be heterogeneous

An Efficient Design of TaOx‐Based Memristor by Inserting an Ultrathin Al2O3 Layer with High Stability for Neuromorphic Computing and Logic Operation

Abstract New computing‐in‐memory architecture based on memristors can achieve in situ storage and computing of data, which greatly improves the computing efficiency of the hardware system. Here, a reliable bilayer structured TaOx/Al2O3 memristor with a 2 nm Al2O3 insertion layer is demonstrated. This device exhibits stable and gradual switching behavior with a low set/reset voltage (0.61 V/−0.49 V) and multilevel conductance characteristics. It is further indicated that the device has a larger ON/Off ratio (≈148×) and better nonlinearity of conductance modulation by inserting an Al2O3 layer. Various forms of synaptic plasticity are mimicked, such as long‐term potentiation/depression (LTP/LTD), paired‐pulse facilitation (PPF), and spike‐timing‐dependent plasticity (STDP). Based on the quasi‐linear conductance modulation characteristics, excellent classification accuracy (90.4%) is achieved for the applications of handwritten digit recognition. Moreover, the logic operations (intersection, union, and complement) are implemented on a 3 × 5 memristor array, which shows an efficient way to design versatile and reliable devices and provides a novel idea for neuromorphic computing and in‐memory logic operation

Einstein Probe discovery of EP240408a: a peculiar X-ray transient with an intermediate timescale

International audienceWe report the discovery of a peculiar X-ray transient, EP240408a, by Einstein Probe (EP) and follow-up studies made with EP, Swift, NICER, GROND, ATCA and other ground-based multi-wavelength telescopes. The new transient was first detected with Wide-field X-ray Telescope (WXT) on board EP on April 8th, 2024, manifested in an intense yet brief X-ray flare lasting for 12 seconds. The flare reached a peak flux of 3.9x10^(-9) erg/cm2/s in 0.5-4 keV, about 300 times brighter than the underlying X-ray emission detected throughout the observation. Rapid and more precise follow-up observations by EP/FXT, Swift and NICER confirmed the finding of this new transient. Its X-ray spectrum is non-thermal in 0.5-10 keV, with a power-law photon index varying within 1.8-2.5. The X-ray light curve shows a plateau lasting for about 4 days, followed by a steep decay till becoming undetectable about 10 days after the initial detection. Based on its temporal property and constraints from previous EP observations, an unusual timescale in the range of 7-23 days is found for EP240408a, which is intermediate between the commonly found fast and long-term transients. No counterparts have been found in optical and near-infrared, with the earliest observation at 17 hours after the initial X-ray detection, suggestive of intrinsically weak emission in these bands. We demonstrate that the remarkable properties of EP240408a are inconsistent with any of the transient types known so far, by comparison with, in particular, jetted tidal disruption events, gamma-ray bursts, X-ray binaries and fast blue optical transients. The nature of EP240408a thus remains an enigma. We suggest that EP240408a may represent a new type of transients with intermediate timescales of the order of about 10 days. The detection and follow-ups of more of such objects are essential for revealing their origin