julilili42/papers huggingface dataset:
The Naturality of Natural Deduction (II): On Atomic Polymorphism and Generalized Propositional Connectives
2021-10-29

Abstract In a previous paper (of which this is a prosecution) we investigated the extraction of proof-theoretic properties of natural deduction derivations from their impredicative translation into System F. Our key idea was to introduce an extended equational theory for System F codifying at a syntactic level some properties found in parametric models of polymorphic type theory. A different approach to extract proof-theoretic properties of natural deduction derivations was proposed in a recent series of papers on the basis of an embedding of intuitionistic propositional logic into a predicative fragment of System F, called atomic System F. In this paper we show that this approach finds a general explanation within our equational study of second-order natural deduction, and a clear semantic justification in terms of parametricity.
Empagliflozin Improves Insulin Sensitivity of the Hypothalamus in Humans With Prediabetes: A Randomized, Double-Blind, Placebo-Controlled, Phase 2 Trial
2021-10-29

&lt;b&gt;Objective:&lt;/b&gt; Insulin action in the human brain reduces food intake, improves whole-body insulin sensitivity, and modulates body fat mass and its’ distribution. Obesity and type 2 diabetes are often associated with brain insulin resistance, resulting in impaired brain-derived modulation of peripheral metabolism. So far, no pharmacological treatment for brain insulin resistance has been established. Since SGLT2 inhibitors lowers glucose levels and modulate energy metabolism, we hypothesized that SGLT2 inhibition may be a pharmacological approach to reverse brain insulin resistance. &lt;p&gt;&lt;b&gt;Research Design and Methods:&lt;/b&gt; In this randomized, double-blind, placebo-controlled clinical trial, 40 patients (mean ± SD; age: 60 ± 9 years; BMI: 31.5 ± 3.8 kg/m2) with prediabetes were randomized to receive 25 mg empagliflozin qd or placebo. Before and after 8 weeks of treatment, brain insulin sensitivity was assessed by functional MRI combined with intranasal administration of insulin to the brain.&lt;/p&gt; &lt;p&gt;&lt;b&gt;Results:&lt;/b&gt; We identified a significant interaction between time and treatment in the hypothalamic response to insulin. Post hoc analyses revealed that only empagliflozin treated patients experienced increased hypothalamic insulin responsiveness. Hypothalamic insulin action significantly mediated empagliflozin-induced decrease in fasting glucose and liver fat.&lt;/p&gt; &lt;p&gt;&lt;b&gt;Conclusions:&lt;/b&gt; Our results corroborate insulin resistance of the hypothalamus in humans with prediabetes. Treatment with empagliflozin for 8 weeks was able to restore hypothalamic insulin sensitivity; a favorable response that could contribute to the beneficial effects of SGLT2 inhibitors. Our findings position SGLT2 inhibition as the first pharmacological approach to reverse brain insulin resistance, with potential benefits for adiposity and whole-body metabolism.&lt;/p&gt;
Artifacts in EEG-based BCI therapies: friend or foe?
2021-10-29

Abstract EEG-based brain-computer interfaces (BCI) have promising therapeutic potential beyond traditional neurofeedback training, such as enabling personalized and optimized virtual reality (VR) neurorehabilitation paradigms where the timing and parameters of the visual experience is synchronized with specific brain-states. While BCI algorithms are often designed to focus on whichever portion of a signal is most informative, in these brain-state-synchronized applications, it is of critical importance that the resulting decoder is sensitive to physiological brain activity representative of various mental states, and not to artifacts, such as those arising from naturalistic movements. In this study, we compare the relative classification accuracy with which different motor tasks can be decoded from both extracted brain activity and artifacts contained in the EEG signal. EEG data was collected from 17 chronic stroke patients while performing six different head, hand, and arm movements in a realistic VR-based neurorehabilitation paradigm. Results show that the artifactual component of the EEG signal is significantly more informative than brain activity with respect to classification accuracy. This finding is consistent across different feature extraction methods and classification pipelines. While informative brain signals can be recovered with suitable cleaning procedures, we recommend that features should not be designed solely to maximize classification accuracy, as this could select for remaining artifactual components. We also propose the use of machine learning approaches that are interpretable to verify that classification is driven by physiological brain-states. In summary, whereas informative artifacts are a helpful friend in BCI-based communication applications, they can be a problematic foe in the estimation of physiological brain states.
Probing the nature of black holes: Deep in the mHz gravitational-wave sky
2021-10-30

Black holes are unique among astrophysical sources: they are the simplest macroscopic objects in the Universe, and they are extraordinary in terms of their ability to convert energy into electromagnetic and gravitational radiation. Our capacity to probe their nature is limited by the sensitivity of our detectors. The LIGO/Virgo interferometers are the gravitational-wave equivalent of Galileo's telescope. The first few detections represent the beginning of a long journey of exploration. At the current pace of technological progress, it is reasonable to expect that the gravitational-wave detectors available in the 2035-2050s will be formidable tools to explore these fascinating objects in the cosmos, and space-based detectors with peak sensitivities in the mHz band represent one class of such tools. These detectors have a staggering discovery potential, and they will address fundamental open questions in physics and astronomy. Are astrophysical black holes adequately described by general relativity? Do we have empirical evidence for event horizons? Can black holes provide a glimpse into quantum gravity, or reveal a classical breakdown of Einstein's gravity? How and when did black holes form, and how do they grow? Are there new long-range interactions or fields in our Universe, potentially related to dark matter and dark energy or a more fundamental description of gravitation? Precision tests of black hole spacetimes with mHz-band gravitational-wave detectors will probe general relativity and fundamental physics in previously inaccessible regimes, and allow us to address some of these fundamental issues in our current understanding of nature.
Activation and Identification of a Griseusin Cluster in Streptomyces sp. CA-256286 by Employing Transcriptional Regulators and Multi-Omics Methods
2021-10-30

Streptomyces are well-known producers of a range of different secondary metabolites, including antibiotics and other bioactive compounds. Recently, it has been demonstrated that “silent” biosynthetic gene clusters (BGCs) can be activated by heterologously expressing transcriptional regulators from other BGCs. Here, we have activated a silent BGC in Streptomyces sp. CA-256286 by overexpression of a set of SARP family transcriptional regulators. The structure of the produced compound was elucidated by NMR and found to be an N-acetyl cysteine adduct of the pyranonaphtoquinone polyketide 3′-O-α-d-forosaminyl-(+)-griseusin A. Employing a combination of multi-omics and metabolic engineering techniques, we identified the responsible BGC. These methods include genome mining, proteomics and transcriptomics analyses, in combination with CRISPR induced gene inactivations and expression of the BGC in a heterologous host strain. This work demonstrates an easy-to-implement workflow of how silent BGCs can be activated, followed by the identification and characterization of the produced compound, the responsible BGC, and hints of its biosynthetic pathway.
The Antiproliferative and Apoptosis-Inducing Effects of the Red Macroalgae Gelidium latifolium Extract against Melanoma Cells
2021-10-30

The red macroalga Gelidium latifolium is widely distributed in the coastal areas of Indonesia. However, current knowledge on its potential biological activities is still limited. In this study, we investigated the potential bioactive compounds in Gelidium latifolium ethanol extract (GLE), and its cytotoxic effects against the murine B16-F10 melanoma cell line. GLE shows high total phenolic content (107.06 ± 17.42 mg GAE/g) and total flavonoid content (151.77 ± 3.45 mg QE/g), which potentially contribute to its potential antioxidant activity (DPPH = 650.42 ± 2.01 μg/mL; ABTS = 557.01 ± 1.94 μg/mL). ESI-HR-TOF-MS analysis revealed large absorption in the [M-H]- of 327.2339 m/z, corresponding to the monoisotopic molecular mass of brassicolene. The presence of this compound potentially contributes to GLE’s cytotoxic activity (IC50 = 84.29 ± 1.93 μg/mL). Furthermore, GLE significantly increased the number of apoptotic cells (66.83 ± 3.06%) compared to controls (18.83 ± 3.76%). Apoptosis was also confirmed by changes in the expression levels of apoptosis-related genes (i.e., p53, Bax, Bak, and Bcl2). Downregulated expression of Bcl2 indicates an intrinsic apoptotic pathway. Current results suggest that components of Gelidium latifolium should be further investigated as possible sources of novel antitumor drugs.
mTOR inhibition via Rapamycin treatment partially reverts the deficit in energy metabolism caused by FH loss in RPE cells
2021-10-30

Abstract Age-related macular degeneration (AMD) is a complex degenerative disease of the retina with multiple risk-modifying factors, including ageing, genetics and lifestyle choices. The combination of these factors leads to oxidative stress, inflammation and metabolic failure in the retinal pigment epithelium (RPE) with subsequent degeneration of photoreceptors in the retina. The alternative complement pathway is tightly linked to AMD. In particular, the genetic variant in the complement factor H gene ( CFH ), that leads to the Y402H polymorphism in the factor H protein (FH), confers the second highest risk for the development and progression of AMD. While the association between the FH Y402H variant and increased complement system activation is known, recent studies have uncovered novel FH functions not tied to this activity and highlighted functional relevance for intracellular FH. In our previous studies, we show that loss of CFH expression in RPE cells causes profound disturbances in cellular metabolism, increases the vulnerability towards oxidative stress and modulates the activation of pro-inflammatory signaling pathways, most importantly the NF-kB pathway. Here, we silenced CFH in hTERT-RPE1 cells to investigate the mechanism by which intracellular FH regulates RPE cell homeostasis. We found that silencing of CFH results in hyperactivation of mTOR signaling along with decreased mitochondrial respiration and that mTOR inhibition via rapamycin can partially rescue these metabolic defects. To obtain mechanistic insight into the function of intracellular FH in hTERT-RPE1 cells, we analyzed the interactome of FH via immunoprecipitation followed by Mass spectrometry-based analysis. We found that FH interacts with essential components of the ubiquitin-proteasomal pathway (UPS) as well as with factors associated with RB1/E2F signalling in a complement-pathway independent manner. Moreover, we found, that FH silencing affects mRNA levels of the E3 Ubiquitin-Protein Ligase Parkin and PTEN induced putative kinase (Pink1), both of them are associated with UPS. As inhibition of mTORC1 has been previoulsy shown to result in increased overall protein degradation via UPS and as FH mRNA and protein levels were shown to be affected by inhibition of UPS, our data stress a potential regulatory link between endogenous FH activity and the UPS.
Mitral Valve Surgery via Upper Ministernotomy: Single-Centre Experience in More than 400 Patients
2021-10-30

Background: Minimally invasive mitral valve (MV) surgery has emerged as an alternative to conventional sternotomy aiming to decrease surgical trauma. The aim of the study was to describe our experience with minimally invasive MV surgery through partial upper sternotomy (PUS) regarding short- and long-term outcomes. Methods: From January 2004 through March 2014, 419 patients with a median age of 58.9 years (interquartile range 18.7; 31.7% females) underwent isolated primary MV surgery using PUS. Myxomatous degenerative MV disease was the predominant pathology (77%). The patients’ mean EuroSCORE II risk profile was 3.9 ± 3.6%. Results: Mitral valve repair was performed in 384 patients (91.6%) and replacement in 35 patients (8.4%). Thirty-day mortality was 3.1%. In total, 29 (6.9%) deaths occurred during the follow-up. The overall estimated survival at 1, 5, and 10 years was 93.1 ± 1.3%, 87.1 ± 1.9%, and 81.1 ± 3.4%. Reoperation was necessary in 14 (3.3%) patients. The overall freedom from MV reoperation at 1, 5, and 10 years was 98.2 ± 0.7%, 96.1 ± 1.2%, and 86.7 ± 6.7% and the overall freedom from recurrent MV regurgitation &gt; grade 2 in repaired valves at 1, 5, and 10 years was 98.8 ± 0.6%, 98.8 ± 0.6%, and 94.6 ± 3.3%. Conclusions: Minimally invasive MV surgery via PUS can be performed with particularly good early and late results. Thus, the PUS approach with the use of standard surgical instruments and cannulation techniques can be a valuable option for the MV surgery either in patients contraindicated or not suitable to minithoracotomy.
Attitudes of Company Executives toward a Comprehensive Workplace Health Management—Results of an Exploratory Cross-Sectional Study in Germany
2021-10-31

Workplace health management (WHM) in Germany aims at maintaining and increasing the health and well-being of employees. Little is known about company executives’ attitudes toward WHM. To gain more insight, we conducted a large-scale survey in companies in the German county of Reutlingen in 2017. We sent a standardized questionnaire to 906 companies, containing inter alia 26 self-constructed declarative statements depicting company executives’ opinions on various WHM aspects; 222 questionnaires could be evaluated. By exploratory factor analysis we assigned the 26 items to six factors reflecting different attitudes toward WHM. Factor values were standardized to a scale from 0 to 10. The attitude ‘positive view of general health services in the company’, for example, achieved by far the lowest mean agreement (3.3 points). For the attitude ‘general skepticism toward WHM’, agreement and disagreement were balanced (5.0 points). Using multiple regression analyses, we searched for variables that could partially explain respondents’ agreement with attitudes. In conclusion, a general WHM skepticism was widespread, but not dominant. The idea that general health services should be offered in companies was predominantly rejected. Older respondents and respondents from smaller companies and craft enterprises were more skeptical than average about WHM and its possible extensions.
Risk perception and optimism during the early stages of the COVID-19 pandemic
2021-11-01

Slowing the spread of COVID-19 requires people to actively change their lives by following protective practices, such as physical distancing and disinfecting their hands. Perceptions about the personal risk of COVID-19 may affect compliance with these practices. In this study, we assessed risk perception and optimism about COVID-19 in a multinational (UK, USA and Germany), longitudinal design during the early stages of the pandemic (16 March 2020; 1 April 2020; 20 May 2020). Our main findings are that (i) people showed a comparative optimism bias about getting infected and infecting others, but not for getting severe symptoms, (ii) this optimism bias did not change over time, (iii) optimism bias seemed to relate to perceived level of control over the action, (iv) risk perception was linked to publicly available information about the disorder, (v) people reported adhering closely to protective measures but these measures did not seem to be related to risk perception, and (vi) risk perception was related to questions about stress and anxiety. In additional cross-sectional samples, we replicated our most important findings. Our open and partly preregistered results provide detailed descriptions of risk perceptions and optimistic beliefs during the early stages of the COVID-19 pandemic in three Western countries.
Effects of exergaming on hippocampal volume and brain‐derived neurotrophic factor levels in Parkinson’s disease
2021-11-01

Abstract Background and objective Cognitive impairment is among the most burdensome non‐motor symptoms in Parkinson's disease (PD) and has been associated with hippocampal atrophy. Exercise has been reported to enhance neuroplasticity in the hippocampus in correlation with an improvement of cognitive function. We present data from the Training‐PD study, which was designed to evaluate effects of an “” training protocol on neuronal plasticity in PD. Methods We initiated a 6‐week exergaming training program, combining visually stimulating computer games with physical exercise in 17 PD patients and 18 matched healthy controls. Volumetric segmentation of hippocampal subfields on T1‐ and T2‐weighted magnetic resonance imaging and brain‐derived neurotrophic factor (BDNF) serum levels were analyzed before and after the training protocol. Results The PD group showed a group‐dependent significant volume increase of the left hippocampal subfields CA1, CA4/dentate gyrus (DG) and subiculum after the 6‐week training protocol. The effect was most pronounced in the left DG of PD patients, who showed a significantly smaller percentage volume compared to healthy controls at baseline, but not at follow‐up. Both groups had a significant increase in serum BDNF levels after training. Conclusions The results of the present study indicate that exergaming might be a suitable approach to induce hippocampal volume changes in PD patients. Further and larger studies are needed to verify our findings.
Fractures of the femoral head: a narrative review
2021-11-01

Fractures of the femoral head are rare injuries, which typically occur after posterior hip dislocation. The Pipkin classification, developed in 1957, is the most commonly used classification scheme to date. The injury is mostly caused by high-energy trauma, such as motor vehicle accidents or falls from a significant height. Emergency treatment consists of urgent closed reduction of the hip joint, followed by non-operative or operative treatment of the femoral head fracture and any associated injuries. There is an ongoing controversy about the suitable surgical approach (anterior vs. posterior) for addressing fractures of the femoral head. Fracture location, degree of displacement, joint congruity and the presence of loose fragments, as well as concomitant injuries are crucial factors in choosing the adequate surgical approach. Long-term complications such as osteonecrosis of the femoral head, posttraumatic osteoarthritis and heterotopic ossification can lead to a relatively poor functional outcome. Cite this article: EFORT Open Rev 2021;6:1122-1131. DOI: 10.1302/2058-5241.6.210034
A Machine learning model trained on dual-energy CT radiomics significantly improves immunotherapy response prediction for patients with stage IV melanoma
2021-11-01

Background To assess the additive value of dual-energy CT (DECT) over single-energy CT (SECT) to radiomics-based response prediction in patients with metastatic melanoma preceding immunotherapy. Material and methods A total of 140 consecutive patients with melanoma (58 female, 63±16 years) for whom baseline DECT tumor load assessment revealed stage IV and who were subsequently treated with immunotherapy were included. Best response was determined using the clinical reports (81 responders: 27 complete response, 45 partial response, 9 stable disease). Individual lesion response was classified manually analogous to RECIST 1.1 through 1291 follow-up examinations on a total of 776 lesions (6.7±7.2 per patient). The patients were sorted chronologically into a study and a validation cohort (each n=70). The baseline DECT was examined using specialized tumor segmentation prototype software, and radiomic features were analyzed for response predictors. Significant features were selected using univariate statistics with Bonferroni correction and multiple logistic regression. The area under the receiver operating characteristic curve of the best subset was computed (AUROC). For each combination (SECT/DECT and patient response/lesion response), an individual random forest classifier with 10-fold internal cross-validation was trained on the study cohort and tested on the validation cohort to confirm the predictive performance. Results We performed manual RECIST 1.1 response analysis on a total of 6533 lesions. Multivariate statistics selected significant features for patient response in SECT (min. brightness, R2=0.112, padj. ≤0.001) and DECT (textural coarseness, R2=0.121, padj. ≤0.001), as well as lesion response in SECT (mean absolute voxel intensity deviation, R2=0.115, padj. ≤0.001) and DECT (iodine uptake metrics, R2≥0.12, padj. ≤0.001). Applying the machine learning models to the validation cohort confirmed the additive predictive power of DECT (patient response AUROC SECT=0.5, DECT=0.75; lesion response AUROC SECT=0.61, DECT=0.85; p&lt;0.001). Conclusion The new method of DECT-specific radiomic analysis provides a significant additive value over SECT radiomics approaches for response prediction in patients with metastatic melanoma preceding immunotherapy, especially on a lesion-based level. As mixed tumor response is not uncommon in metastatic melanoma, this lends a powerful tool for clinical decision-making and may potentially be an essential step toward individualized medicine.
Vitamins as Possible Cancer Biomarkers: Significance and Limitations
2021-11-01

The Western-style diet, which is common in developed countries and spreading into developing countries, is unbalanced in many respects. For instance, micronutrients (vitamins A, B complex, C, D, E, and K plus iron, zinc, selenium, and iodine) are generally depleted in Western food (causing what is known as ‘hidden hunger’), whereas some others (such as phosphorus) are added beyond the daily allowance. This imbalance in micronutrients can induce cellular damage that can increase the risk of cancer. Interestingly, there is a large body of evidence suggesting a strong correlation between vitamin intake as well as vitamin blood concentrations with the occurrence of certain types of cancer. The direction of association between the concentration of a given vitamin and cancer risk is tumor specific. The present review summarized the literature regarding vitamins and cancer risk to assess whether these could be used as diagnostic or prognostic markers, thus confirming their potential as biomarkers. Despite many studies that highlight the importance of monitoring vitamin blood or tissue concentrations in cancer patients and demonstrate the link between vitamin intake and cancer risk, there is still an urgent need for more data to assess the effectiveness of vitamins as biomarkers in the context of cancer. Therefore, this review aims to provide a solid basis to support further studies on this promising topic.