Miracle-dz/UniFAR-FTUs huggingface dataset:
Karyopherin abnormalities in neurodegenerative proteinopathies

Abstract Neurodegenerative proteinopathies are characterized by progressive cell loss that is preceded by the mislocalization and aberrant accumulation of proteins prone to aggregation. Despite their different physiological functions, disease-related proteins like tau, α-synuclein, TAR DNA binding protein-43, fused in sarcoma and mutant huntingtin, all share low complexity regions that can mediate their liquid-liquid phase transitions. The proteins’ phase transitions can range from native monomers to soluble oligomers, liquid droplets and further to irreversible, often-mislocalized aggregates that characterize the stages and severity of neurodegenerative diseases. Recent advances into the underlying pathogenic mechanisms have associated mislocalization and aberrant accumulation of disease-related proteins with defective nucleocytoplasmic transport and its mediators called karyopherins. These studies identify karyopherin abnormalities in amyotrophic lateral sclerosis, frontotemporal dementia, Alzheimer’s disease, and synucleinopathies including Parkinson’s disease and dementia with Lewy bodies, that range from altered expression levels to the subcellular mislocalization and aggregation of karyopherin α and β proteins. The reported findings reveal that in addition to their classical function in nuclear import and export, karyopherins can also act as chaperones by shielding aggregation-prone proteins against misfolding, accumulation and irreversible phase-transition into insoluble aggregates. Karyopherin abnormalities can, therefore, be both the cause and consequence of protein mislocalization and aggregate formation in degenerative proteinopathies. The resulting vicious feedback cycle of karyopherin pathology and proteinopathy identifies karyopherin abnormalities as a common denominator of onset and progression of neurodegenerative disease. Pharmacological targeting of karyopherins, already in clinical trials as therapeutic intervention targeting cancers such as glioblastoma and viral infections like COVID-19, may therefore represent a promising new avenue for disease-modifying treatments in neurodegenerative proteinopathies.
The cost-effectiveness of atezolizumab in first-line for metastatic triple negative breast cancer is heavily linked to PD-L1 level

The present analysis was conducted to assess the pharmacological costs of atezolizumab as first-line treatment in triple negative metastatic breast cancer (mBC). Pivotal phase III randomized controlled trial (RCT) was considered. Nine hundred and two patients were included. Differences in costs between the 2 arms (atezolizumab plus nabpaclitaxel versus placebo plus nab-paclitaxel) was 17 398 €, with a cost of 7564 €per month of OS-gain in the overall population and 2485 €per month of OS-gain in PD-L1-positive (≥1) population. Combining pharmacological costs of drugs with the measure of efficacy represented by the OS, atezolizumab could be considered cost-effective in first-line treatment for triple-negative mBC only in PD-L1-positive population, but a reduction of costs is mandatory.
Study on the earth pressure of a foundation pit adjacent to a composite foundation with rigid-flexible and long-short piles

Model tests were performed to investigate the lateral earth pressure acting on the retaining structure adjacent to both natural ground (NG) and composite foundation (CFRLP), which were supported with rigid-flexible and long-short piles. Two testing procedures, namely, applying a load to the foundation and rotating the retaining structure along its toe, were considered. The results indicate that the additional lateral earth pressure acting on the retaining structure adjacent to the CFRLP is less than that of the NG in the depth of the reinforcement area strengthened by flexible piles. Compared with NG, the CFRLP yielded a smaller normalized height of application of the lateral earth pressure, suggesting that the CFRLP blocked the horizontal diffusion of the load and had a strong ability to transfer the surcharge load to the deep soil. When rotating the retaining structure, the lateral earth pressure acting on the upper part of the retaining structure experienced limited reduction once the displacement at the top of the retaining structure was greater than 8 mm, whereas the pressure acting on the lower part of the retaining structure continued to decrease with increasing displacement. In addition, a three-dimensional finite element model (FEM) was used to investigate the influence of the pile parameter and the wall-soil friction angle on the additional lateral earth pressure.
British Association of Sexual Health and HIV national guideline on the management of sexually acquired reactive arthritis 2021

These guidelines update the 2008 UK guideline for the management of sexually acquired reactive arthritis. The guideline is aimed at those over the age of 16 years, presenting to healthcare professionals working in sexual health services. The recommendations are primarily aimed at services offering level 3 care in sexually transmitted infection management within the United Kingdom. However, the principles will apply to those presenting to level 1 and 2 services, and appropriate local referral pathways will need to be developed.
Disorder, networks, and cognition: do social networks buffer the influence of neighborhood and household disorder on cognitive functioning?

Abstract Objectives To examine whether neighborhood and household disorder matter for cognitive functioning among middle-aged and older adults and whether the disorder-cognition link is moderated by social network resources. Method Data are drawn from National Social Life, Health, and Aging Project (NSHAP) Wave 2 (N = 3198). Both neighborhood and household were considered as key residential contexts that shape one’s social life and health. Exposure to neighborhood and household disorder was measured using interviewer assessments of signs of disorder and decay, including the presence of disrepair, trash, noise, and unpleasant smells such as air pollution, in the buildings and streets in which the respondent lives. Cognitive function was measured using the survey-adapted Montreal Cognitive Assessment (MoCA-SA). Network size, network range, and frequency of interaction among network members were assessed as moderators. Results Neighborhood and household disorder were independently associated with cognitive function. However, disorder in the household appeared to have more direct associations with cognitive function than did the neighborhood when both were present. The association between household disorder and cognitive function was mitigated by network size, such that poor housing conditions were associated with lower cognitive function only for those with small social networks. Conclusion This study suggests a larger network may play a role in minimizing the negative influence of household disorder on cognitive function for middle-aged and older adults. Social policy and intervention aimed at promoting network ties may help reduce further disparities in cognitive function, especially for those vulnerable groups living in a poor-quality household.
Compositionality in a Parallel Architecture for Language Processing

Compositionality has been a central concept in linguistics and philosophy for decades, and it is increasingly prominent in many other areas of cognitive science. Its status, however, remains contentious. Here, I reassess the nature and scope of the principle of compositionality (Partee, 1995) from the perspective of psycholinguistics and cognitive neuroscience. First, I review classic arguments for compositionality and conclude that they fail to establish compositionality as a property of human language. Next, I state a new competence argument, acknowledging the fact that any competent user of a language L can assign to most expressions in L at least one meaning which is a function only of the meanings of the expression's parts and of its syntactic structure. I then discuss selected results from cognitive neuroscience, indicating that the human brain possesses the processing capacities presupposed by the competence argument. Finally, I outline a language processing architecture consistent with the neuroscience results, where semantic representations may be generated by a syntax-driven stream and by an "asyntactic" processing stream, jointly or independently. Compositionality is viewed as a constraint on computation in the former stream only.
The Mitogen-Activated Protein Kinase Kinase TaMKK5 Mediates Immunity via the TaMKK5-TaMPK3-TaERF3 Module.

Sharp eyespot disease, caused by the soil-borne fungus Rhizoctonia cerealis, seriously threatens production of wheat (Triticum aestivum). Despite considerable advances in understanding the mechanisms of mitogen-activated protein kinase (MAPK) cascades in innate immunity in model plant species, the roles of MAPK cascades in wheat are unknown. In this study, we identified a wheat MAPK kinase TaMKK5, located on chromosome 6B, and deciphered its functional role in the innate immune responses to R. cerealis attack. The TaMKK5-6B transcript level was elevated after R. cerealis infection and was higher in resistant wheat genotypes compared to susceptible genotypes. Overexpressing TaMKK5-6B increased resistance to sharp eyespot and up-regulated the expression of multiple defense-related genes in wheat, including the MAPK gene TaMPK3, the ethylene response factor gene TaERF3, the calcium-dependent protein kinase gene TaCPK7-D, the glutathione s-transferase-1 gene TaGST1, Defensin, and Chitinase 2, while TaMKK5 knock-down compromised the resistance and repressed the expression of these defense-related genes. Bimolecular fluorescence complementation, yeast two-hybrid, pull-down, and phosphorylation assays showed that TaMKK5 physically interacted with TaMPK3, and phosphorylated and activated TaMPK3, and that TaMPK3 interacted with and phosphorylated TaERF3. The TaMKK5-TaMPK3 cascade modulates the expression of TaGST1, Defensin, and Chitinase 2 through TaERF3. Collectively, TaMKK5 mediates resistance to sharp eyespot through the TaMKK5-TaMPK3-TaERF3 module and by up-regulating the expression of defense-related genes in wheat. This study provides insights into the role of the wheat MAPK cascades in innate immunity. TaMKK5-6B is a promising gene for breeding wheat cultivars that are resistant to sharp eyespot.
Deleterious and Protective Psychosocial and Stress-Related Factors Predict Risk of Spontaneous Preterm Birth

Abstract Objectives The aim of the study was to: (1) Identify (early in pregnancy) psychosocial and stress-related factors that predict risk of spontaneous preterm birth (PTB, gestational age <37 weeks); (2) Investigate whether “protective” factors (e.g., happiness/social support) decrease risk; (3) Use the Dhabhar Quick-Assessment Questionnaire for Stress and Psychosocial Factors™ (DQAQ-SPF™) to rapidly quantify harmful or protective factors that predict increased or decreased risk respectively, of PTB. Study Design This is a prospective cohort study. Relative risk (RR) analyses investigated association between individual factors and PTB. Machine learning-based interdependency analysis (IDPA) identified factor clusters, strength, and direction of association with PTB. A nonlinear model based on support vector machines was built for predicting PTB and identifying factors that most strongly predicted PTB. Results Higher levels of deleterious factors were associated with increased RR for PTB: General anxiety (RR = 8.9; 95% confidence interval or CI = 2.0,39.6), pain (RR = 5.7; CI = 1.7,17.0); tiredness/fatigue (RR = 3.7; CI = 1.09,13.5); perceived risk of birth complications (RR = 4; CI = 1.6,10.01); self-rated health current (RR = 2.6; CI = 1.0,6.7) and previous 3 years (RR = 2.9; CI = 1.1,7.7); and divorce (RR = 2.9; CI = 1.1,7.8). Lower levels of protective factors were also associated with increased RR for PTB: low happiness (RR = 9.1; CI = 1.25,71.5); low support from parents/siblings (RR = 3.5; CI = 0.9,12.9), and father-of-baby (RR = 3; CI = 1.1,9.9). These factors were also components of the clusters identified by the IDPA: perceived risk of birth complications (p < 0.05 after FDR correction), and general anxiety, happiness, tiredness/fatigue, self-rated health, social support, pain, and sleep (p < 0.05 without FDR correction). Supervised analysis of all factors, subject to cross-validation, produced a model highly predictive of PTB (AUROC or area under the receiver operating characteristic = 0.73). Model reduction through forward selection revealed that even a small set of factors (including those identified by RR and IDPA) predicted PTB. Conclusion These findings represent an important step toward identifying key factors, which can be assessed rapidly before/after conception, to predict risk of PTB, and perhaps other adverse pregnancy outcomes. Quantifying these factors, before, or early in pregnancy, could identify women at risk of delivering preterm, pinpoint mechanisms/targets for intervention, and facilitate the development of interventions to prevent PTB. Key Points Newly designed questionnaire used for rapid quantification of stress and psychosocial factors early during pregnancy. Deleterious factors predict increased preterm birth (PTB) risk. Protective factors predict decreased PTB risk.
Constraining the Phrase-Based, Joint Probability Statistical Translation Model

The Joint Probability Model proposed by Marcu and Wong (2002) provides a probabilistic framework for modeling phrase-based statistical machine transla- tion (SMT). The model’s usefulness is, however, limited by the computational complexity of estimating parameters at the phrase level. We present a method of constraining the search space of the Joint Probability Model based on statistically and linguistically motivated word align- ments. This method reduces the complexity and size of the Joint Model and allows it to display performance superior to the standard phrase-based models for small amounts of training material.
Direct evidence of acid-base interactions in gecko adhesion

Direct investigation of gecko setae-substrate contact provides clear evidence for acid-base interactions in gecko adhesion. While it is generally accepted that van der Waals (vdW) forces govern gecko adhesion, several studies indicate contributions from non-vdW forces and highlight the importance of understanding the adhesive contact interface. Previous work hypothesized that the surface of gecko setae is hydrophobic, with nonpolar lipid tails exposed on the surface. However, direct experimental evidence supporting this hypothesis and its implications on the adhesion mechanism is lacking. Here, we investigate the sapphire-setae contact interface using interface-sensitive spectroscopy and provide direct evidence of the involvement of acid-base interactions between polar lipid headgroups exposed on the setal surface and sapphire. During detachment, a layer of unbound lipids is left as a footprint due to cohesive failure within the lipid layer, which, in turn, reduces wear to setae during high stress sliding. The absence of this lipid layer enhances adhesion, despite a small setal-substrate contact area. Our results show that gecko adhesion is not exclusively a vdW-based, residue-free system.
Searching for Success Factors of Agritourism: The Case of Kleve County (Germany)

Abstract Agritourism is increasing in popularity as more urban residents appreciate the slower paced rural environment and its authenticity. External influences (political crises and pandemics) have recently reduced mobility which makes agritourism an attractive alternative to former more distant holiday destinations. Agritourists are interested in working farms, local production and animal husbandry. Some European regions (e.g., Bavaria and South Tyrol) have successfully developed agritourism whereas the majority of rural regions are left behind. Agritourism diversifies farmers’ business model and increases their income. For our study, we chose Kleve County (Lower Rhine Area, Germany) as an exemplary region for a touristically unknown rural area. Regional opinion leaders, farmers and industry experts were interviewed to share their experiences about factors that could further and contribute to successful development of agritourism. The results of our case study and supplementary market interviews suggest that its success in less known rural regions depends on the geographic location, mutual efforts of local visionary entrepreneurs, regional beneficial networks and on committed political stakeholders to develop a sustainable business model. The results may be useful for other comparable European rural regions to diversify their farming and develop their own business model.
High purity alumina by controlled precipitation from aluminum sulfate solutions

Des echantillons d'alumine-α a haute purete et haute densite ont ete produits a partir de poudres precipitees de solutions aqueuses de sulfate d'alumine, calcinees a 900°C, pressees isostatiquement et frittees a 900°C, pressees isostatiquement et frittees a 1550°C. Il n'est pas possible de fritter directement la poudre de sulfate d'alumine hydrate precipitee du fait qu'une microstructure vermiculaire a gros grain se developpe lors de la transformation de γ−Al 2 O 3 en α−Al 2 O 3
The Disparate Approaches of General Practitioners to the Pharmaceuticalisation of Cardiovascular Disease Prevention

In the context of current clinical practice guidance, this paper will analyse the role of GPs in decision-making about the primary prevention of cardiovascular disease (CVD) using the concept of pharmaceuticalisation. Drawing on thematic analysis of semi-structured interviews with 20 GPs, the paper argues that the way GPs approach CVD pharmaceuticalisation is shaped by their understandings of and use of guidelines (and the knowledge they embody), existing treatment perspectives and the moral qualities of preventative treatment, and professional evaluations of ‘relevant’ information. The analysis indicates that there exist disparate and distinct approaches to and understandings of CVD pharmaceuticalisation amongst GPs. Depending on how knowledge, treatment perspectives and values variously combine, GPs sit somewhere on a spectrum of how pharmaceuticalised they are in terms of the approaches to and understandings of the prevention of CVD.
Human Microglia Extensively Reconstitute in Humanized-BLT Mice With Human Interleukin-34 Transgene and Support HIV-1 Brain Infection

Humanized bone marrow-liver-thymic (hu-BLT) mice develop a functional immune system in periphery, nevertheless, have a limited reconstitution of human myeloid cells, especially microglia, in CNS. Further, whether bone marrow derived hematopoietic stem and progenitor cells (HSPCs) can enter the brain and differentiate into microglia in adults remains controversial. To close these gaps, in this study we unambiguously demonstrated that human microglia in CNS were extensively reconstituted in adult NOG mice with human interleukin-34 transgene (hIL34 Tg) from circulating CD34+ HSPCs, nonetheless not in hu-BLT NOG mice, providing strong evidence that human CD34+ HSPCs can enter adult brain and differentiate into microglia in CNS in the presence of hIL34. Further, the human microglia in the CNS of hu-BLT-hIL34 NOG mice robustly supported HIV-1 infection reenforcing the notion that microglia are the most important target cells of HIV-1 in CNS and demonstrating its great potential as an in vivo model for studying HIV-1 pathogenesis and evaluating curative therapeutics in both periphery and CNS compartments.
Towards a Framework for Data Enhanced Process Models in Process Mining

Understanding and improving business processes have become important steps towards success for organizations. Getting insights about a process is not only based on the control flow, but also on the data generated within the process. Today, almost every process step generates data, especially in the health care domain. So far, most analyzes inside a process model are limited to time analyzes and identification of decision logic. However, various attributes can be linked to events, such as the number of abnormal lab values derived from a lab test, which could be displayed in the process model. This can help to explore the process with domain experts, where they can choose the attributes of interest for each event and observe their influence on the process, i.e. the influence of abnormal lab values on the treatment process. Therefore, the interplay of event attributes and the control flow can be observed directly in the process model.
An Unsupervised Learning Approach to Text Line Detection in Complex Illuminated Medieval Manuscripts

This paper outlines a simple and effective clustering and ﬁltering approach for text line detection in challenging illuminated medieval manuscripts from Western Europe. As illuminated medieval manuscripts were copied and illustrated by hand and do not have regular formats, they pose particular difﬁcul-ties for traditional methods of text line extraction, which have been designed for printed books. This paper introduces an unsupervised learning approach to text line detection in challenging manuscripts based on clustering, using a k-means algorithm with a combination of three salient features that are well-suited for image processing. These are: the gradient in the y-direction, mean values of rows, and grayscale values. The strength of the method lies in its reduced number of features, its computational lightness, low-memory use, transparency at every step of the process, and versatility. It can also be used on a single image, being per-page based, unlike supervised learning approaches which require large training datasets. This stands as an alternative to computationally-heavy algorithms such as neural networks, which have been increasingly used in recent years to solve such tasks.
Data Augmentation Using Many-To-Many RNNs for Session-Aware Recommender Systems

The ACM WSDM WebTour 2021 Challenge organized by Booking.com focuses on applying Session-Aware recommender systems in the travel domain. Given a sequence of travel bookings in a user trip, we look to recommend the user's next destination. To handle the large dimensionality of the output's space, we propose a many-to-many RNN model, predicting the next destination chosen by the user at every sequence step as opposed to only the final one. We show how this is a computationally efficient alternative to doing data augmentation in a many-to-one RNN, where we consider every subsequence of a session starting from the first element. Our solution achieved 4th place in the final leaderboard, with an accuracy@4 of 0.5566.
A protein-truncating mutation in CCNB3 in a patient with recurrent miscarriages and failure of meiosis I

To cite: Rezaei M, Buckett W, Bareke E, et al. J Med Genet Epub ahead of print: [please include Day Month Year]. doi:10.1136/ jmedgenet-2021-107875 Human Genetics, Research Institute of the McGill University Health Centre, Montréal, Québec, Canada Obstetrics and Gynecology, McGill University Health Centre, Montréal, Québec, Canada McGill University and Génome Québec Innovation Centre, Montréal, Québec, Canada Department of Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA