Position representations of moving objects align with real-time position in the early visual response

When interacting with the dynamic world, the brain receives outdated sensory information, due to the time required for neural transmission and processing. In motion perception, the brain may overcome these fundamental delays through predictively encoding the position of moving objects using information from their past trajectories. In the present study, we evaluated this proposition using multivariate analysis of high temporal resolution electroencephalographic data. We tracked neural position representations of moving objects at different stages of visual processing, relative to the real-time position of the object. During early stimulus-evoked activity, position representations of moving objects were activated substantially earlier than the equivalent activity evoked by unpredictable flashes, aligning the earliest representations of moving stimuli with their real-time positions. These findings indicate that the predictability of straight trajectories enables full compensation for the neural delays accumulated early in stimulus processing, but that delays still accumulate across later stages of cortical processing

Predictive coding of visual motion in both monocular and binocular human visual processing

Neural processing of sensory input in the brain takes time, and for that reason our awareness of visual events lags behind their actual occurrence. One way the brain might compensate to minimize the impact of the resulting delays is through extrapolation. Extrapolation mechanisms have been argued to underlie perceptual illusions in which moving and static stimuli are mislocalised relative to one another (such as the flash-lag and related effects). However, where in the visual hierarchy such extrapolation processes take place remains unknown. Here, we address this question by identifying monocular and binocular contributions to the flash-grab illusion. In this illusion, a brief target is flashed on a moving background that reverses direction. As a result, the perceived position of the target is shifted in the direction of the reversal. We show that the illusion is attenuated, but not eliminated, when the motion reversal and the target are presented dichoptically to separate eyes. This reveals extrapolation mechanisms at both monocular and binocular processing stages contribute to the illusion. We interpret the results in a hierarchical predictive coding framework, and argue that prediction errors in this framework manifest directly as perceptual illusions

Kinome profiling of myxoid liposarcoma reveals NF-kappaB-pathway kinase activity and Casein Kinase II inhibition as a potential treatment option

<p>Abstract</p> <p>Background</p> <p>Myxoid liposarcoma is a relatively common malignant soft tissue tumor, characterized by a (12;16) translocation resulting in a FUS-DDIT3 fusion gene playing a pivotal role in its tumorigenesis. Treatment options in patients with inoperable or metastatic myxoid liposarcoma are relatively poor though being developed and new hope is growing.</p> <p>Results</p> <p>Using kinome profiling and subsequent pathway analysis in two cell lines and four primary cultures of myxoid liposarcomas, all of which demonstrated a FUS-DDIT3 fusion gene including one new fusion type, we aimed at identifying new molecular targets for systemic treatment. Protein phosphorylation by activated kinases was verified by Western Blot and cell viability was measured before and after treatment of the myxoid liposarcoma cells with kinase inhibitors. We found kinases associated with the atypical nuclear factor-kappaB and Src pathways to be the most active in myxoid liposarcoma. Inhibition of Src by the small molecule tyrosine kinase inhibitor dasatinib showed only a mild effect on cell viability of myxoid liposarcoma cells. In contrast, inhibition of the nuclear factor-kappaB pathway, which is regulated by the FUS-DDIT3 fusion product, in myxoid liposarcoma cells using casein kinase 2 inhibitor 4,5,6,7-tetrabromobenzotriazole (TBB) showed a significant decrease in cell viability, decreased phosphorylation of nuclear factor-kappaB pathway proteins, and caspase 3 mediated apoptosis. Combination of dasatinib and TBB showed an enhanced effect.</p> <p>Conclusion</p> <p>Kinases associated with activation of the atypical nuclear factor-kappaB and the Src pathways are the most active in myxoid liposarcoma <it>in vitro </it>and inhibition of nuclear factor-kappaB pathway activation by inhibiting casein kinase 2 using TBB, of which the effect is enhanced by Src inhibition using dasatinib, offers new potential therapeutic strategies for myxoid liposarcoma patients with advanced disease.</p

Presence of chemotherapy-induced toxicity predicts improved survival in patients with localised extremity osteosarcoma treated with doxorubicin and cisplatin: a report from the European Osteosarcoma Intergroup.

Chemotherapy-induced toxicity is an independent prognostic indicator in several cancers. We aimed to determine whether toxicity was related to survival and histological response in high-grade localised extremity osteosarcoma. We undertook a retrospective analysis of patients treated within three consecutive randomised controlled trials (RCTs) of the European Osteosarcoma Intergroup

Thromboembolic involvement and its possible pathogenesis in COVID-19 mortality: lesson from post-mortem reports

The emergence of Coronavirus Disease 19 (COVID-19) as a pandemic has claimed hundreds of thousands of lives worldwide since its initial breakout. With increasing reports from clinical observations and autopsy findings, it became clear that the disease causes acute respiratory distress syndrome (ARDS), as well as a broad spectrum of systemic and multiorgan pathologies, including angiopathy, endothelialitis, and thrombosis. Coagulopathy is associated with the activity of megakaryocytes, which play crucial roles in modulating the platelet homeostasis. Only a few autopsy reports include findings on thrombosis formation and the presence of megakaryocytes. Here we review and summarize the possible involvement and the pathophysiology of the thromboembolic events in COVID-19 patients based on post-mortem reports. We reviewed post-mortem reports from March 2020 to September 2020. Eleven autopsy reports that demonstrated thromboembolic involvement findings, either macroscopically or microscopically, were included in this review. All studies reported similar pulmonary gross findings. Not all studies described thrombi formation and megakaryocyte findings. Pulmonary embolism, coagulopathy, severe endothelial injury, and widespread thrombosis are frequent in COVID-19 patients, following many patients with high-level D-Dimer, increased fibrinogen, abnormal prothrombic coagulation, and thrombocytopenia. Reports showed that thrombus was also found in the lower extremities' deep veins and the prostatic venous plexus. In conclusion, a complex interaction of SARS-CoV-2 virus invasion with platelets, leukocytes, endothelial cells, inflammation, immune response, and the possible involvement of megakaryocytes may increase the cumulative risk of thrombosis by a yet unclear cellular and humoral interaction.Orthopaedics, Trauma Surgery and Rehabilitatio

The thermoacidophilic methanotroph Methylacidiphilum fumariolicum SolV oxidizes subatmospheric H₂ with a high-affinity, membrane-associated [NiFe] hydrogenase

The trace amounts (0.53 ppmv) of atmospheric hydrogen gas (H2) can be utilized by microorganisms to persist during dormancy. This process is catalyzed by certain Actinobacteria, Acidobacteria, and Chloroflexi, and is estimated to convert 75 × 1012 g H2 annually, which is half of the total atmospheric H2. This rapid atmospheric H2 turnover is hypothesized to be catalyzed by high-affinity [NiFe] hydrogenases. However, apparent high-affinity H2 oxidation has only been shown in whole cells, rather than for the purified enzyme. Here, we show that the membrane-associated hydrogenase from the thermoacidophilic methanotroph Methylacidiphilum fumariolicum SolV possesses a high apparent affinity (Km(app) = 140 nM) for H2 and that methanotrophs can oxidize subatmospheric H2. Our findings add to the evidence that the group 1h [NiFe] hydrogenase is accountable for atmospheric H2 oxidation and that it therefore could be a strong controlling factor in the global H2 cycle. We show that the isolated enzyme possesses a lower affinity (Km = 300 nM) for H2 than the membrane-associated enzyme. Hence, the membrane association seems essential for a high affinity for H2. The enzyme is extremely thermostable and remains folded up to 95 °C. Strain SolV is the only known organism in which the group 1h [NiFe] hydrogenase is responsible for rapid growth on H2 as sole energy source as well as oxidation of subatmospheric H2. The ability to conserve energy from H2 could increase fitness of verrucomicrobial methanotrophs in geothermal ecosystems with varying CH4 fluxes. We propose that H2 oxidation can enhance growth of methanotrophs in aerated methane-driven ecosystems. Group 1h [NiFe] hydrogenases could therefore contribute to mitigation of global warming, since CH4 is an important and extremely potent greenhouse gas.</p

Adjuvant Zoledronic Acid in High-Risk Giant Cell Tumor of Bone: A Multicenter Randomized Phase II Trial

LESSONS LEARNED:Adjuvant treatment with zoledronic acid did not decrease the recurrence rate of giant cell tumor of bone (GCTB) in this study. The efficacy could not be determined because of the small sample size.GCTB recurrences, even in the denosumab era, are still an issue; therefore, a randomized study exploring the efficacy of zoledronic acid in the adjuvant setting in GCTB is still valid.BACKGROUND:Bisphosphonates are assumed to inhibit giant cell tumor of bone (GCTB)-associated osteoclast activity and have an apoptotic effect on the neoplastic mononuclear cell population. The primary objective of this study was to determine the 2-year recurrence rate of high-risk GCTB after adjuvant zoledronic acid versus standard care.METHODS:In this multicenter randomized open-label phase II trial, patients with high-risk GCTB were included (December 2008 to October 2013). Recruitment was stopped because of low accrual after the introduction of denosumab. In the intervention group, patients received adjuvant zoledronic acid (4 mg) intravenously at 1, 2, 3, 6, 9, and 12 months after surgery.RESULTS:Fourteen patients were included (intervention n = 8, controls n = 6). Median follow-up was long: 93.5 months (range, 48-111). Overall 2-year recurrence rate was 38% (3/8) in the intervention versus 17% (1/6) in the control group (p = .58). All recurrences were seen within the first 15 months after surgery.CONCLUSION:Adjuvant treatment with zoledronic acid did not decrease the recurrence rate of GCTB in this study. The efficacy could not be determined because of the small sample size. Because recurrences, even in the denosumab era, are still an issue, a randomized study exploring the efficacy of zoledronic acid in the adjuvant setting in GCTB is still valid.Experimentele farmacotherapi

Method to measure the mismatch between target and achieved received dose intensity of chemotherapy in cancer trials: a retrospective analysis of the MRC BO06 trial in osteosarcoma

OBJECTIVES: In cancer studies, the target received dose intensity (tRDI) for any regimen, the intended dose and time for the regimen, is commonly taken as a proxy for achieved RDI (aRDI), the actual individual dose and time for the regimen. Evaluating tRDI/aRDI mismatches is crucial to assess study results whenever patients are stratified on allocated regimen. The manuscript develops a novel methodology to highlight and evaluate tRDI/aRDI mismatches. DESIGN: Retrospective analysis of a randomised controlled trial, MRC BO06 (EORTC 80931). SETTING: Population-based study but proposed methodology can be applied to other trial designs. PARTICIPANTS: A total of 497 patients with resectable high-grade osteosarcoma, of which 19 were excluded because chemotherapy was not started or the estimated dose was abnormally high (>1.25 × prescribed dose). INTERVENTIONS: Two regimens with the same anticipated cumulative dose (doxorubicin 6×75 mg/m2/week; cisplatin 6×100 mg/m2/week) over different time schedules: every 3 weeks in regimen-C and every 2 weeks in regimen-DI. PRIMARY AND SECONDARY OUTCOME MEASURES: tRDI distribution was measured across groups of patients derived from k-means clustering of treatment data. K-means creates groups of patients who are aRDI-homogeneous. The main outcome is the proportion of tRDI values in groups of homogeneous aRDI. RESULTS: For nearly half of the patients, there is a mismatch between tRDI and aRDI; for 21%, aRDI was closer to the tRDI of the other regimen. CONCLUSIONS: For MRC BO06, tRDI did not predict well aRDI. The manuscript offers an original procedure to highlight the presence of and quantify tRDI/aRDI mismatches. Caution is required to interpret the effect of chemotherapy-regimen intensification on survival outcome at an individual level where such a mismatch is present.The study relevance lies in the use of individual realisation of the intended treatment, which depends on individual delays and/or dose reductions reported throughout the treatment. TRIAL REGISTRATION NUMBER: ISRCTN86294690