Miracle-dz/UniFAR-FTUs huggingface dataset:
PathoFusion: An Open-Source AI Framework for Recognition of Pathomorphological Features and Mapping of Immunohistochemical Data

Simple Summary We present an open-source AI framework for marking, training, and automated recognition of pathological features in whole-slide scans of diagnostic tissue sections. The integrated system permits high-resolution qualitative as well as quantitative morphological analyses of entire histological slides and harbors significant potential to facilitate the microscopic analysis of complex pathomorphological problems and the simultaneous mapping of immunohistochemical markers in routine slide diagnostics. Abstract We have developed a platform, termed PathoFusion, which is an integrated system for marking, training, and recognition of pathological features in whole-slide tissue sections. The platform uses a bifocal convolutional neural network (BCNN) which is designed to simultaneously capture both index and contextual feature information from shorter and longer image tiles, respectively. This is analogous to how a microscopist in pathology works, identifying a cancerous morphological feature in the tissue context using first a narrow and then a wider focus, hence bifocal. Adjacent tissue sections obtained from glioblastoma cases were processed for hematoxylin and eosin (H&E) and immunohistochemical (CD276) staining. Image tiles cropped from the digitized images based on markings made by a consultant neuropathologist were used to train the BCNN. PathoFusion demonstrated its ability to recognize malignant neuropathological features autonomously and map immunohistochemical data simultaneously. Our experiments show that PathoFusion achieved areas under the curve (AUCs) of 0.985 ± 0.011 and 0.988 ± 0.001 in patch-level recognition of six typical pathomorphological features and detection of associated immunoreactivity, respectively. On this basis, the system further correlated CD276 immunoreactivity to abnormal tumor vasculature. Corresponding feature distributions and overlaps were visualized by heatmaps, permitting high-resolution qualitative as well as quantitative morphological analyses for entire histological slides. Recognition of more user-defined pathomorphological features can be added to the system and included in future tissue analyses. Integration of PathoFusion with the day-to-day service workflow of a (neuro)pathology department is a goal. The software code for PathoFusion is made publicly available.
Differential Sensitivity of Wild-Type and BRAF-Mutated Cells to Combined BRAF and Autophagy Inhibition

BRAF inhibitors are insufficient monotherapies for BRAF-mutated cancer; therefore, we investigated which inhibitory pathway would yield the most effective therapeutic approach when targeted in combination with BRAF inhibition. The oncogenic BRAF inhibitor, PLX4720, increased basal autophagic flux in BRAF-mutated cells compared to wild-type (WT) BRAF cells. Interestingly, early autophagy inhibition improved the effectiveness of PLX4720 regardless of BRAF mutation, whereas late autophagy inhibition did not. Although ATG5 knockout led to PLX4720 resistance in both WT and BRAF-mutated cells, the MEK inhibitor trametinib exhibited a synergistic effect on PLX4720 sensitivity in WT BRAF cells but not in BRAF-mutated cells. Conversely, the prolonged inhibition of endoplasmic reticulum (ER) stress reduced basal autophagy in BRAF-mutated cells, thereby increasing PLX4720 sensitivity. Taken together, our results suggest that the combined inhibition of ER stress and BRAF may simultaneously suppress both pro-survival ER stress and autophagy, and may therefore be suitable for treatment of BRAF-mutated tumors whose autophagy is increased by chronic ER stress. Similarly, for WT BRAF tumors, therapies targeting MEK signaling may be a more effective treatment strategy. Together, this study presents a rational combination treatment strategy to improve the efficacy of BRAF inhibitors depending on BRAF mutation status.
Human T-cell leukemia virus type 1 infection among Japanese immigrants and their descendants living in Southeast Brazil: A call for preventive and control responses

Human T-cell leukemia virus type 1 (HTLV-1) has worldwide distribution and is considered endemic in southwestern Japan. HTLV-1 infection has been associated with adult T-cell leukemia/lymphoma (ATL) and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) besides other diseases. This cross-sectional study aimed to investigate the prevalence, risk factors and molecular characterization of HTLV-1, among the world’s largest population of Japanese immigrants and their descendants outside of Japan, in São Paulo, Southeast Brazil, as well as to analyze the phylogenetic relationship among isolates of HTLV-1. From July to December 2017, 2,139 individuals from five Japanese associations were interviewed and submitted to blood collection. All serum samples were first tested for the presence of anti-HTLV-1/2 antibodies by ELISA and then peripheral blood from individuals with positive serological results were analyzed for the presence of HTLV-1 5’LTR proviral DNA. Partial sequencing of the 5’LTR region of HTLV-1 proviral DNA was performed by Sanger. The prevalence of HTLV-1 infection was 5.1% (CI 95%: 4.2–6.0). In the multiple logistic regression model, HTLV-1 infection was associated with age ≥ 45 years, female sex, being first and second-generation Japanese immigrants, and having sexual partners with history of blood transfusion. The phylogenetic analysis revealed that all HTLV-1 were classified as Cosmopolitan (1a) subtype. Of them, 47.8% were classified as Transcontinental (A) subgroup and 52.2% as belonging to the Japanese (B) subgroup. Although most HTLV-1-infected patients were asymptomatic (97.3%), blurred vision was associated with HTLV-1 infection. The high prevalence of HTLV-1 infection found in this studied population and especially the intra- and interfamily HTLV-1 transmission presents an urgent call for preventive and control responses of this infection in Brazil.
The Role of DJ-1 in Cellular Metabolism and Pathophysiological Implications for Parkinson’s Disease

DJ-1 is a multifunctional protein associated with pathomechanisms implicated in different chronic diseases including neurodegeneration, cancer and diabetes. Several of the physiological functions of DJ-1 are not yet fully understood; however, in the last years, there has been increasing evidence for a potential role of DJ-1 in the regulation of cellular metabolism. Here, we summarize the current knowledge on specific functions of DJ-1 relevant to cellular metabolism and their role in modulating metabolic pathways. Further, we illustrate pathophysiological implications of the metabolic effects of DJ-1 in the context of neurodegeneration in Parkinson´s disease.
Green Deep Eutectic Solvents for Microwave-Assisted Biomass Delignification and Valorisation

Aiming to fulfil the sustainability criteria of future biorefineries, a novel biomass pretreatment combining natural deep eutectic solvents (NaDESs) and microwave (MW) technology was developed. Results showed that NaDESs have a high potential as green solvents for lignin fractionation/recovery and sugar release in the following enzymatic hydrolysis. A new class of lignin derived NaDESs (LigDESs) was also investigated, showing promising effects in wheat straw delignification. MW irradiation enabled a fast pretreatment under mild condition (120 °C, 30 min). To better understand the interaction of MW with these green solvents, the dielectric properties of NaDESs were investigated. Furthermore, a NaDES using the lignin recovered from biomass pretreatment as hydrogen bond donor was prepared, thus paving the way for a “closed-loop” biorefinery process.
Work-Time Compositions of Physical Behaviors and Trajectories of Sick Leave Due to Musculoskeletal Pain

We aimed to investigate the association between work-time compositions of physical behavior and sick leave trajectories due to musculoskeletal pain over one year. We conducted a secondary analysis using the data of 981 workers in a Danish prospective cohort (DPHACTO 2012–2014). At baseline, we assessed physical behaviors (sitting, standing, light physical activity (LIPA), and moderate-to-vigorous physical activity (MVPA)) at work and during leisure, using accelerometers. Over 1 year follow-up, workers reported sick-leave days due to musculoskeletal pain at 4-week intervals. Four distinct trajectories of sick leave were previously identified in this cohort (“no sick leave”, “few days—increasing trajectory”, “some days—decreasing trajectory”, “some days—increasing trajectory”), and used as an outcome in multinomial regression models with work-time compositions as predictors, adjusted for compositions of behavior during leisure, age, sex, body mass index, and smoking habits. More time spent sitting relative to the other behaviors was negatively associated with the trajectory of few days—increasing sick leave (p = 0.004), while time in LIPA was positively associated with the trajectory of some days—increasing sick leave (p = 0.009). Standing and MVPA were not significantly associated with sick leave trajectories. In conclusion, work-time compositions with more sitting relative to the other behaviors had lower risk for an increasing trajectory of sick leave due to pain, while compositions with more LIPA had higher risk. This may have implications for prevention of pain-related sick leave in blue-collar workers.
An FTIR linear dichroism study of lipid membranes

Infrared linear dichroism (LD) was measured for bilayers of 1,2-dioleoyl-sn-glycero-3-phosphocholine/water, l-octanoylsn-glycerol/water, and 1-oleoyl-sn-glycerol in H20 and D20. Order parameters were determined for vibrational modes in the acyl chain region of the bilayer (symmetric CH2 stretch and olefinic CH=CH stretch), the interface region (C=O stretch), and the head group region (antisymmetric PO, stretch). The results show no significant difference between the order parameters calculated for 1-oleoyl-sn-glycerol in H 2 0 as compared with D20. However, the two acyl chains in 1,2-dioleoyl-snglycero-3-phosphocholine seem to be more ordered than the single chains in 1-octanoyl-sn-glycerol and I-oleoyl-sn-glycerol. We conclude that FTIR LD spectroscopy is a sensitive method for studying lipid lamellar liquid crystalline phases.
Bioelectrical impedance analysis for assessment of body composition in infants and young children‐A systematic literature review

Bioelectrical impedance analysis (BIA) is an easy to use, portable tool, but the accuracy of the technique in infants and young children (<24 months) remains unclear. A systematic literature review was conducted to identify studies that have developed and validated BIA equations in this age group. MEDLINE, Scopus, EMBASE, and CENTRAL were searched for relevant literature published up until June 30, 2020, using terms related to bioelectrical impedance, body composition, and paediatrics. Two reviewers independently screened studies for eligibility, resulting in 15 studies that had developed and/or validated equations. Forty‐six equations were developed and 34 validations were conducted. Most equations were developed in young infants (≤6 months), whereas only seven were developed among older infants and children (6‐24 months). Most studies were identified as having a high risk of bias, and only a few included predominantly healthy children born at term. Using the best available evidence, BIA appears to predict body composition at least as well as other body composition tools; however, among younger infants BIA may provide little benefit over anthropometry‐based prediction equations. Currently, none of the available equations can be recommended for use in research or in clinical practice.
A global phylogeny of turtles reveals a burst of climate-associated diversification on continental margins

Significance Biodiversity is unevenly distributed across the tree of life. Understanding the factors that led to this unevenness can illuminate how macroevolutionary processes have interacted with changing global environments to shape patterns of biodiversity. By developing a comprehensive phylogeny for extant turtles and analyzing the diversification dynamics of the group, we show that species-level diversity is strongly associated with historical climate shifts. Our findings indicate that newly exposed continental margins created during a period of cooling and drying are important evolutionary cradles for turtle speciation, explain why turtle biodiversity is orders of magnitude more depauperate than the remaining major lineages of amniotes, and reconcile the seemingly contradictory insights that fossils and extant species suggest into a single picture of evolutionary diversification. Living turtles are characterized by extraordinarily low species diversity given their age. The clade’s extensive fossil record indicates that climate and biogeography may have played important roles in determining their diversity. We investigated this hypothesis by collecting a molecular dataset for 591 individual turtles that, together, represent 80% of all turtle species, including representatives of all families and 98% of genera, and used it to jointly estimate phylogeny and divergence times. We found that the turtle tree is characterized by relatively constant diversification (speciation minus extinction) punctuated by a single threefold increase. We also found that this shift is temporally and geographically associated with newly emerged continental margins that appeared during the Eocene−Oligocene transition about 30 million years before present. In apparent contrast, the fossil record from this time period contains evidence for a major, but regional, extinction event. These seemingly discordant findings appear to be driven by a common global process: global cooling and drying at the time of the Eocene−Oligocene transition. This climatic shift led to aridification that drove extinctions in important fossil-bearing areas, while simultaneously exposing new continental margin habitat that subsequently allowed for a burst of speciation associated with these newly exploitable ecological opportunities.
Soluble epoxide hydrolase inhibitor trifluoromethoxyphenyl‐3‐(1‐propionylpiperidin‐4‐yl)urea prevents hyperalgesia through regulating NLRC4 inflammasome‐related pro‐inflammatory and anti‐inflammatory signaling pathways in the lipopolysaccharide‐induced pain mouse model

Epoxyeicosatrienoic acids (EETs) have anti‐inflammatory effects and soluble epoxide hydrolase (sEH) inhibition might be a useful therapeutic approach to manage inflammatory disorders. The purpose of the study was to investigate whether nucleotide‐binding and oligomerization domain‐like receptor (NLR) C4 inflammasome‐related pro‐inflammatory and anti‐inflammatory signaling pathways in the central nervous system (CNS) participates in the effect of trifluoromethoxyphenyl‐3‐(1‐propionylpiperidin‐4‐yl)urea (TPPU), a potent sEH inhibitor, to prevent hyperalgesia in the LPS‐induced pain mouse model. The latency of pain within 30 s was measured by the hot plate test in male mice injected with saline, lipopolysaccharide (LPS) (10 mg/kg), and/or TPPU (0.3, 0.5, or 1 mg/kg) after 6 h. Hyperalgesia induced by LPS was associated with decreased 14,15‐dihydroxyeicosatrienoic acid and interleukin (IL)‐1β levels and enhanced expression of NLRC4, apoptosis‐associated speck‐like protein containing a caspase activation and recruitment domain (ASC), caspase‐1 p20, IL‐1β, and caspase‐11 p20 in the brains and spinal cords of the animals. Besides the increased expression of nicotinamide adenine dinucleotide phosphate oxidase (NOX) subunits (gp91phox and p47phox) and nitrotyrosine, a decrease in NLRC3, inducible nitric oxide synthase (iNOS), and neuronal NOS (nNOS) expression was also observed in the tissues of LPS‐treated mice. TPPU at 0.5 mg/kg dose prevented the changes induced by LPS. Likely, decreased activity of pro‐inflammatory NLRC4/ASC/pro‐caspase‐1 and caspase‐11 inflammasomes and NOX in addition to enhanced levels of anti‐inflammatory EETs and expression of NLRC3, iNOS, and nNOS in the CNS of mice participates in the protective effect of TPPU against LPS‐induced hyperalgesia.
Population Density and Driving Factors of North China Leopards in Tie Qiao Shan Nature Reserve

Simple Summary The North China leopard is a subspecies of leopard distributed in China, but little is known about its population status. This study selected the most active areas of North China leopards to determine the population density and distribution of North China leopards. We found that different prey had different effects on the density distribution of North China leopards. Environmental factors and human factors are also important factors affecting the population density distribution of North China leopards. These results provided an effective basis for the protection of North China leopard population and management evaluation of the reserve. It also provided effective methods for the protection and management of other endangered species. Abstract The North China leopard (Panthera pardus japonesis) is a rare leopard subspecies distributed only in China. In this study, we conducted camera-trap surveys of a North China Leopard population in Tie Qiao Shan Nature Reserve, Shanxi Province, China. We estimated population abundance and density distribution, and explored the effects of distribution of different prey populations, habitat, and anthropogenic factors on the spatial distribution of North China leopard density. Our results suggested that the North China leopard density was 4.23 individuals/100 km2, and that 17.98 individuals might live within the study area. The population density of the North China leopard increased with the distribution of wild boars, and, on the contrary, decreased with the distribution of roe deer. We found that habitat environmental factors and anthropogenic interference also significantly affected the population density and spatial distribution of the North China leopard. These insights informed us that in order to protect this predator, which is only distributed in China, we should adopt a comprehensive customized adaptive landscape protection strategy.
Difference-Education Improves First-Generation Students’ Grades Throughout College and Increases Comfort With Social Group Difference

Difference-education interventions teach people a contextual theory of difference: that social group difference comes from participating in and adapting to diverse sociocultural contexts. At two universities, we delivered difference-education interventions during the college transition and examined long-term academic and intergroup outcomes. Nearly 4 years later, first-generation students who received a difference-education intervention earned higher grades and were more likely to attain honors standing than those in the control condition. Based on an end-of-college survey with students at one of the two universities, both first-generation and continuing-generation students showed greater comfort with social group difference compared with students in the control condition. Our results demonstrate for the first time that teaching first-generation students a contextual theory of difference can lead to long-term academic benefits that persist until graduation. This work also provides new evidence that difference-education can improve comfort with social group difference.
Does exercise therapy improve patient-reported outcomes in rheumatoid arthritis? - A systematic review and meta-analysis for the update of the 2020 JCR guidelines for the management of rheumatoid arthritis.

OBJECTIVE This study aimed to evaluate the impact of exercise therapy on patient-reported outcomes (PROs) in rheumatoid arthritis (RA) as part of the process of updating the 2020 Japanese Guidelines for the management of RA according to the Grading of Recommendations, Assessment, Development, and Evaluation system. METHODS We searched PubMed, Japana Centra Revuo Medicina Web, and the Cochrane Library (from 2009 to 2018) to identify articles that evaluated PROs of exercise therapy and RA disease activity. RESULTS A total of 662 articles were identified, including nine RCTs, and meta-analyses were performed on six RCTs on systemic exercise therapy and three RCTs on upper extremity exercise therapy. Analyzed exercise therapies were diverse, differing in target population, intervention method, and duration. Significant improvements were observed in the Health Assessment Questionnaire Disability Index (mean difference -0.35, 95% confidence interval [CI]: -0.60 - -0.10), pain (standardized mean difference -2.04, 95% CI: -3.77 - -0.32), and SF-36. For upper extremity exercise therapy, significant improvements in PROs (Disabilities of the Arm, Shoulder, and Hand Questionnaire, Michigan Hand Outcome Questionnaire) were observed. CONCLUSION Exercise therapy in RA treatment improves patient subjective assessment of pain, physical function, and quality of life.
Outdoor Inverse Rendering From a Single Image Using Multiview Self-Supervision

In this paper we show how to perform scene-level inverse rendering to recover shape, reflectance and lighting from a single, uncontrolled image using a fully convolutional neural network. The network takes an RGB image as input, regresses albedo, shadow and normal maps from which we infer least squares optimal spherical harmonic lighting coefficients. Our network is trained using large uncontrolled multiview and timelapse image collections without ground truth. By incorporating a differentiable renderer, our network can learn from self-supervision. Since the problem is ill-posed we introduce additional supervision. Our key insight is to perform offline multiview stereo (MVS) on images containing rich illumination variation. From the MVS pose and depth maps, we can cross project between overlapping views such that Siamese training can be used to ensure consistent estimation of photometric invariants. MVS depth also provides direct coarse supervision for normal map estimation. We believe this is the first attempt to use MVS supervision for learning inverse rendering. In addition, we learn a statistical natural illumination prior. We evaluate performance on inverse rendering, normal map estimation and intrinsic image decomposition benchmarks.