Accurate and robust pathological image analysis for colorectal cancer (CRC) diagnosis is time-consuming and knowledge-intensive, but is essential for CRC patients' treatment. The current heavy ...workload of pathologists in clinics/hospitals may easily lead to unconscious misdiagnosis of CRC based on daily image analyses.
Based on a state-of-the-art transfer-learned deep convolutional neural network in artificial intelligence (AI), we proposed a novel patch aggregation strategy for clinic CRC diagnosis using weakly labeled pathological whole-slide image (WSI) patches. This approach was trained and validated using an unprecedented and enormously large number of 170,099 patches, > 14,680 WSIs, from > 9631 subjects that covered diverse and representative clinical cases from multi-independent-sources across China, the USA, and Germany.
Our innovative AI tool consistently and nearly perfectly agreed with (average Kappa statistic 0.896) and even often better than most of the experienced expert pathologists when tested in diagnosing CRC WSIs from multicenters. The average area under the receiver operating characteristics curve (AUC) of AI was greater than that of the pathologists (0.988 vs 0.970) and achieved the best performance among the application of other AI methods to CRC diagnosis. Our AI-generated heatmap highlights the image regions of cancer tissue/cells.
This first-ever generalizable AI system can handle large amounts of WSIs consistently and robustly without potential bias due to fatigue commonly experienced by clinical pathologists. It will drastically alleviate the heavy clinical burden of daily pathology diagnosis and improve the treatment for CRC patients. This tool is generalizable to other cancer diagnosis based on image recognition.
An efficient, diastereoselective synthesis of densely functionalized pyrroloindolines is reported. The reaction proceeds via cycloaddition of a vinylaziridine-derived Pd-stabilized 1,3-dipole to ...electron-deficient 3-nitroindoles. The reactions give the trans diastereoisomer with high selectivity; however, when a 4-substituent is present on the indole ring, a reversal of diastereoselectivity is observed.
Microglia are the resident macrophages of the CNS, and are in charge of maintaining a healthy microenvironment to ensure neuronal survival. Microglia carry out a non-stop patrol of the CNS, make ...contact with neurons and look for abnormalities, all of which requires a vast amount of energy. This non-signaling energy demand increases after activation by pathogens, neuronal damage or other kinds of stimulation. Of the three major energy substrates – glucose, fatty acids and glutamine – glucose is crucial for microglia survival and several glucose transporters are expressed to supply sufficient glucose influx. Fatty acids are another source of energy for microglia and have also been shown to strongly influence microglial immune activity. Glutamine, although possibly suitable for use as an energy substrate by microglia, has been shown to have neurotoxic effects when overloaded. Microglial fuel metabolism might be associated with microglial reactivity under different pathophysiological conditions and a microglial fuel switch may thus be the underlying cause of hypothalamic dysregulation, which is associated with obesity.
•Microglia express proteins involved in metabolism of the main energy substrates.Activated microglia might meet their increased energy demand by a metabolic switch.•Such a switch could generate metabolites harmful to neighboring neurons.
A new methodology is developed to determine spatial location and properties of traps generated by electrical stressing of AlGaN/GaN high-electron mobility transistors, based on integrated optical and ...electrical analysis. Mild off-state stress increases irreversibly the number of traps located in the near-surface AlGaN region at the gate edge. A deep level with 0.45-eV activation energy in fresh devices changes its nature to interacting defect after the off-state stress, accompanied by an activation energy change. These results are consistent with trap generation in the near-surface AlGaN region at the gate edge related to high electric field and gate leakage current, as stressing does not result in the generation of cracks in the AlGaN layer.
Polyomaviruses are nonenveloped icosahedral viruses with a double-stranded circular DNA containing approximately 5000 bp and 5–6 open reading frames. In contrast to mammalian polyomaviruses (MPVs), ...avian polyomaviruses (APVs) exhibit high lethality and multipathogenicity, causing severe infections in birds without oncogenicity. APVs are classified into 10 major species: Adélie penguin polyomavirus, budgerigar fledgling disease virus, butcherbird polyomavirus, canary polyomavirus, cormorant polyomavirus, crow polyomavirus, Erythrura gouldiae polyomavirus, finch polyomavirus, goose hemorrhagic polyomavirus, and Hungarian finch polyomavirus under the genus Gammapolyomavirus. This paper briefly reviews the genomic structure and pathogenicity of the 10 species of APV and some of their differences in terms of virulence from MPVs. Each gene’s genomic size, number of amino acid residues encoding each gene, and key biologic functions are discussed. The rationale for APV classification from the Polyomavirdae family and phylogenetic analyses among the 10 APVs are also discussed. The clinical symptoms in birds caused by APV infection are summarized. Finally, the strategies for developing an effective vaccine containing essential epitopes for preventing virus infection in birds are discussed. We hope that more effective and safe vaccines with diverse protection will be developed in the future to solve or alleviate the problems of viral infection.
•Prrrt2−/− mice exhibit paroxysmal dystonia with face validity.•Prrt2 transcripts reside in granule cells but not Purkinje cells or interneurons within cerebellar cortex.•In the cerebellar molecular ...layer, Prrt2−/− mice have increased numbers of docked vesicles but decreased total vesicles.•In Prrt2−/− mice, we found reduced parallel fiber facilitation at parallel fiber-Purkinje cell synapses.
PRRT2 loss-of-function mutations have been associated with familial paroxysmal kinesigenic dyskinesia (PKD), infantile convulsions and choreoathetosis, and benign familial infantile seizures. Dystonia is the foremost involuntary movement disorder manifest by patients with PKD. Using a lacZ reporter and quantitative reverse-transcriptase PCR, we mapped the temporal and spatial distribution of Prrt2 in mouse brain and showed the highest levels of expression in cerebellar cortex. Further investigation into PRRT2 localization within the cerebellar cortex revealed that Prrt2 transcripts reside in granule cells but not Purkinje cells or interneurons within cerebellar cortex, and PRRT2 is presynaptically localized in the molecular layer. Analysis of synapses in the cerebellar molecular layer via electron microscopy showed that Prrt2−/− mice have increased numbers of docked vesicles but decreased vesicle numbers overall. In addition to impaired performance on several motor tasks, approximately 5% of Prrt2−/− mice exhibited overt PKD with clear face validity manifest as dystonia. In Prrt2 mutants, we found reduced parallel fiber facilitation at parallel fiber-Purkinje cell synapses, reduced Purkinje cell excitability, and normal cerebellar nuclear excitability, establishing a potential mechanism by which altered cerebellar activity promotes disinhibition of the cerebellar nuclei, driving motor abnormalities in PKD. Overall, our findings replicate, refine, and expand upon previous work with PRRT2 mouse models, contribute to understanding of paroxysmal disorders of the nervous system, and provide mechanistic insight into the role of cerebellar cortical dysfunction in dystonia.
Background
Patients with locally advanced basal cell carcinoma (laBCC) or metastatic BCC (mBCC), two difficult‐to‐treat populations, have had limited treatment options. Sonidegib, a hedgehog pathway ...inhibitor (HPI), was approved in laBCC based on results from the BOLT trial.
Objective
To evaluate long‐term efficacy and safety of sonidegib in laBCC and mBCC in the BOLT 18‐ and 30‐month analyses.
Methods
BOLT (NCT01327053, ClinicalTrials.gov), a double‐blind phase 2 study, enrolled patients from July 2011 until January 2013. Eligible HPI‐treatment–naïve patients with laBCC not amenable to curative surgery/radiotherapy or mBCC were randomized 1 : 2 to sonidegib 200 mg (laBCC, n = 66; mBCC, n = 13) or 800 mg (laBCC, n = 128; mBCC, n = 23). Tumour response was assessed per central and investigator review.
Results
With 30 months of follow‐up, among patients treated with sonidegib 200 mg (approved dose), objective response rates were 56.1% (central) and 71.2% (investigator) in laBCC and 7.7% (central) and 23.1% (investigator) in mBCC. Tumour responses were durable as follows: median duration of response was 26.1 months (central) and 15.7 months (investigator) in laBCC and 24.0 months (central) and 18.1 months (investigator) in mBCC. Five patients with laBCC and three with mBCC in the 200‐mg arm died. Median overall survival was not reached in either population; 2‐year overall survival rates were 93.2% (laBCC) and 69.3% (mBCC). In laBCC, efficacy was similar regardless of aggressive or non‐aggressive histology. Sonidegib 200 mg continued to have a better safety profile than 800 mg, with lower rates of grade 3/4 adverse events (43.0% vs. 64.0%) and adverse events leading to discontinuation (30.4% vs. 40.0%).
Conclusion
Sonidegib continued to demonstrate long‐term efficacy and safety in these populations. These data support the use of sonidegib 200 mg per local treatment guidelines.
A trans-diastereoselective Pd-catalyzed dearomative 3 + 2 cycloaddition between vinylcyclopropane dicarboxylates and 3-nitroindoles has been developed. The reaction provides densely functionalized ...cyclopentabindolines with versatile vinyl and nitro-groups. The addition of a halide additive was found to be critical for the diastereoselectivity of the reaction, which is proposed to be a result of a rapid π-σ-π interconversion between the intermediates allowing for Curtin–Hammett control. A switch in diastereoselectivity to afford products with the vinyl and nitro groups cis to each other is observed with a 4-substituted 3-nitroindole.
This paper presents the results of an experimental study on the interfacial bond strength of glass fiber reinforced polymer (GFRP) bars in high-strength concrete cube. The experimental program ...consisted of testing 54 concrete cube specimens prepared according to CSA S802-02 standard. Two main parameters were considered in the experimental investigation: the compressive strength of concrete (from 25.6
MPa to 92.4
MPa) and the type of rebar (steel, sand-coated GFRP, and helically wrapped GFRP). The test results showed that the interfacial bond strength of the GFRP bars increased as the compressive strength of concrete increased. However, the increasing rate of the bond strength of the GFRP bars with respect to the concrete strength was much smaller than that of the steel bars. The concrete specimens were sawn in half after the test for a closer investigation of the actual mode of bond failure. Visual examination of the specimens showed that bond failure of the steel bar was caused by concrete crushing against the face of the ribs, while bond failure of the GFRP bars occurred not only in the concrete but also in the bars by delamination of the resin-rich outer layer from the fiber core. The average area of the delaminated resin-rich layer of the GFRP bar increased with increasing compressive strength of concrete.
Precipitation suppression due to an increase of aerosol number concentration in stratiform cloud is well‐known. It is not certain whether the suppression applies for deep convection. Recent studies ...have suggested increasing precipitation from deep convection with increasing aerosols under some, but not all, conditions. Increasing precipitation with increasing aerosols can result from strong interactions in deep convection between dynamics and microphysics. High cloud liquid, due to delayed autoconversion, provides more evaporation, leading to more active downdrafts, convergence fields, condensation, collection of cloud liquid by precipitable hydrometeors, and precipitation. Evaporation of cloud liquid is a primary determinant of the intensity of the interactions. It is partly controlled by wind shear modulating the entrainment of dry air into clouds and transport of cloud liquid into unsaturated areas. Downdraft‐induced convergence, crucial to the interaction, is weak for shallow clouds, generally associated with low convective available potential energy (CAPE). Aerosol effects on cloud and precipitation can vary with CAPE and wind shear. Pairs of idealized numerical experiments for high and low aerosol cases were run for five different environmental conditions to investigate the dependence of aerosol effect on stability and wind shear. In the environment of high CAPE and strong wind shear, cumulonimbus‐ and cumulus‐type clouds were dominant. Transport of cloud liquid to unsaturated areas was larger at high aerosol, leading to stronger downdrafts. Because of the large vertical extent of those clouds, strong downdrafts and convergence developed for strong interactions between dynamics and microphysics. These led to larger precipitation at high aerosol. Detrainment of cloud liquid and associated evaporation were less with lower CAPE and wind shear, where dynamically weaker clouds dominated. Transport of cloud liquid to unsaturated areas was not as active as in the environment of high CAPE and strong shear. Also, evaporatively driven differences in downdrafts at their level of initial descent were not magnified in clouds with shallow depth as much as in deep convective clouds as they accelerated to the surface over shorter distances. Hence the interaction between dynamics and microphysics was reduced, leading to precipitation suppression at high aerosol. These results demonstrate that increasing aerosol can either decrease or increase precipitation for an imposed large‐scale environment supporting cloud development. The implications for larger‐scale aspects of the hydrological cycle will require further study with larger‐domain models and cumulus parameterizations with advanced microphysics.
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