Miracle-dz/UniFAR-FTUs huggingface dataset:
Rating scales for rare neurological diseases

We are living in exciting times. Effective treatments are emerging for devastating disorders that were completely intractable until the very recent past, including a growing number of the thousands of mostly genetic rare diseases that overall account for a significant portion of neurology and child neurology. This has been made possible by spectacular advances in genetics, the generation of relevant animal and cellular models, progress in molecular and cell biology leading to the identification of therapeutic targets, and the development of novel therapeutic agents, including small molecules, oligonucleotides, monoclonal antibodies, and gene therapy.
Zona Incerta GABAergic Output Controls a Signaled Locomotor Action in the Midbrain Tegmentum

Abstract The zona incerta is a subthalamic nucleus proposed to link sensory stimuli with motor responses to guide behavior, but its functional role is not well established. Using mice of either sex, we studied the effect of manipulating zona incerta GABAergic cells on the expression of a signaled locomotor action, known as signaled active avoidance. We found that modulation of GABAergic zona incerta cells, but not of cells in the adjacent thalamic reticular nucleus (NRT), fully controls the expression of signaled active avoidance responses. Inhibition of zona incerta GABAergic cells drives active avoidance responses, while excitation of these cells blocks signaled active avoidance mainly by inhibiting cells in the midbrain pedunculopontine tegmental nucleus (PPT). The zona incerta regulates signaled locomotion in the midbrain.
Hepatoid adenocarcinoma of the lung and the review of the literature

Introduction Hepatoid adenocarcinoma of the lung is an extremely rare type of the non-small cell lung cancer. Treatment principles and prognosis are similar to that of lung adenocarcinoma. Case report A 62-year-old female smoker presented with a huge mass in the left upper lobe. After diagnostic biopsy, she underwent left pneumonectomy and mediastinal lymph node dissection. A diagnosis of stage T4N1M0 hepatoid adenocarcinoma of the lung with positive surgical margins was made. Management and outcome After the operation, the level of serum alpha fetoprotein was 9010 ng/ml (N: <10). The level of serum alpha fetoprotein was decreased with concurrent chemoradiotherapy and chemotherapy. Disease progression was detected at 11 months after diagnosis. No response was obtained to other therapies. The patient died at 14 months from the time of diagnosis. Discussion Usually, patients with hepatoid adenocarcinoma of the lung are male smokers. Hepatoid adenocarcinoma tends to settle in the upper lobes of the lung. The most important prognostic factor of the hepatoid adenocarcinoma of the lung is the disease stage at the diagnosis and patients with metastatic disease have poor survival.
Effect of S-Allyl –L-Cysteine on MCF-7 Cell Line 3-Mercaptopyruvate Sulfurtransferase/Sulfane Sulfur System, Viability and Apoptosis

The S-Allyl-L-cysteine (SAC) component of aged garlic extract (AGE) is proven to have anticancer, antihepatotoxic, neuroprotective and neurotrophic properties. γ-Cystathionase (CTH), cystathionine β-synthase (CBS) and 3-mercaptopyruvate sulfurtransferase (MPST) are involved in H2S/sulfane sulfur endogenous formation from L-cysteine. The aim of the study was to determine the effect of SAC on MCF-7 cells survival and apoptosis, which is a widely known approach to reduce the number of cancer cells. An additional goal of this paper was to investigate the effect of SAC on the activity and expression of enzymes involved in H2S production. The experiments were carried out in the human breast adenocarcinoma cell line MCF-7. Changes in the cell viability were determined by MTT assay. Cell survival was determined by flow cytometry (FC). Changes in enzymes expression were analyzed using Western blot. After 24 h and 48 h incubation with 2245 µM SAC, induction of late apoptosis was observed. A decrease in cell viability was observed with increasing SAC concentration and incubation time. SAC had no significant cytotoxic effect on the MCF-7 cells upon all analyzed concentrations. CTH, MPST and CBS expression were confirmed in non-treated MCF-7 cells. Significant decrease in MPST activity at 2245 µM SAC after 24 h and 48 h incubation vs. 1000 µM SAC was associated with decrease in sulfane sulfur levels. The presented results show promising SAC effects regarding the deterioration of the MCF-7 cells’ condition in reducing their viability through the downregulation of MPST expression and sulfate sulfur level reduction.
Increased risk of osteoporosis following commonly used first-line treatments for lymphoma: a Danish Nationwide Cohort Study

Abstract High-dose prednisolone is used in first-line treatment for lymphoma, but the potential adverse impact on bone health is unclear. Danish patients with diffuse large B-cell lymphoma or follicular lymphoma diagnosed between 2000 and 2012 were matched to the background population. Osteoporotic events (osteoporosis treatment or low-energy fracture) were identified using the Danish National Patient Registry and Prescription Registry. In total, 2589 patients and 12,945 controls were included. Lymphoma patients had increased risk of osteoporotic events compared to the matched population (hazard ratio 1.61 [95% confidence interval 1.40;1.84]). The 5- and 10-year cumulative risks of osteoporotic events for lymphoma patients were 10.0% [8.6;11.4] and 16.3% [13.8;18.7], whereas corresponding risks in the background population were 6.8% [6.3;7.3] and 13.5% [12.4;14.6]. Patients without osteoporotic event in the first two years after treatment were not at higher risk of osteoporotic events in subsequent years. Risk factors for osteoporotic events were female sex and age >70 years.
Selection-Driven Gene Inactivation in Salmonella.

Bacterial genes are sometimes found to be inactivated by mutation. This inactivation may be observable simply because selection for function is intermittent or too weak to eliminate inactive alleles quickly. Here I investigate cases in Salmonella enterica where inactivation is instead positively selected. These are identified by a rate of introduction of premature stop codons to a gene that is higher than expected under selective neutrality, as assessed by comparison to the rate of synonymous changes. I identify 84 genes that meet this criterion at a 10% false discovery rate. Many of these genes are involved in virulence, motility and chemotaxis, biofilm formation, and resistance to antibiotics or other toxic substances. It is hypothesized that most of these genes are subject to an ongoing process in which inactivation is favored under rare conditions, but the inactivated allele is deleterious under most other conditions and is subsequently driven to extinction by purifying selection.
Sensorimotor Induction of Auditory Misattribution in Early Psychosis.

Dysfunction of sensorimotor predictive processing is thought to underlie abnormalities in self-monitoring producing passivity symptoms in psychosis. Experimentally induced sensorimotor conflict can produce a failure in bodily self-monitoring (presence hallucination [PH]), yet it is unclear how this is related to auditory self-monitoring and psychosis symptoms. Here we show that the induction of sensorimotor conflict in early psychosis patients induces PH and impacts auditory-verbal self-monitoring. Participants manipulated a haptic robotic system inducing a bodily sensorimotor conflict. In experiment 1, the PH was measured. In experiment 2, an auditory-verbal self-monitoring task was performed during the conflict. Fifty-one participants (31 early psychosis patients, 20 matched controls) participated in the experiments. The PH was present in all participants. Psychosis patients with passivity experiences (PE+) had reduced accuracy in auditory-verbal self-other discrimination during sensorimotor stimulation, but only when sensorimotor stimulation involved a spatiotemporal conflict (F(2, 44) = 6.68, P = . 002). These results show a strong link between robotically controlled alterations in sensorimotor processing and auditory misattribution in psychosis and provide evidence for the role of sensorimotor processes in altered self-monitoring in psychosis.
Does BERT need domain adaptation for clinical negation detection?

INTRODUCTION Classifying whether concepts in an unstructured clinical text are negated is an important unsolved task. New domain adaptation and transfer learning methods can potentially address this issue. OBJECTIVE We examine neural unsupervised domain adaptation methods, introducing a novel combination of domain adaptation with transformer-based transfer learning methods to improve negation detection. We also want to better understand the interaction between the widely used bidirectional encoder representations from transformers (BERT) system and domain adaptation methods. MATERIALS AND METHODS We use 4 clinical text datasets that are annotated with negation status. We evaluate a neural unsupervised domain adaptation algorithm and BERT, a transformer-based model that is pretrained on massive general text datasets. We develop an extension to BERT that uses domain adversarial training, a neural domain adaptation method that adds an objective to the negation task, that the classifier should not be able to distinguish between instances from 2 different domains. RESULTS The domain adaptation methods we describe show positive results, but, on average, the best performance is obtained by plain BERT (without the extension). We provide evidence that the gains from BERT are likely not additive with the gains from domain adaptation. DISCUSSION Our results suggest that, at least for the task of clinical negation detection, BERT subsumes domain adaptation, implying that BERT is already learning very general representations of negation phenomena such that fine-tuning even on a specific corpus does not lead to much overfitting. CONCLUSION Despite being trained on nonclinical text, the large training sets of models like BERT lead to large gains in performance for the clinical negation detection task.
Evaluating phone camera and cloud service-based 3D imaging and printing of human bones for anatomical education

Objective To evaluate the feasibility of a phone camera and cloud service-based workflow to image bone specimens and print their three-dimensional (3D) models for anatomical education. Design The images of four typical human bone specimens, photographed by a phone camera, were aligned and converted into digital images for incorporation into a digital model through the Get3D website and submitted to an online 3D printing platform to obtain the 3D printed models. The fidelity of the 3D digital, printed models relative to the original specimens, was evaluated through anatomical annotations and 3D scanning. Setting The Morphologic Science Experimental Center, Central South University, China. Participants Specimens of four typical bones—the femur, rib, cervical vertebra and skull—were used to evaluate the feasibility of the workflow. Outcome measures The gross fidelity of anatomical features within the digital models and 3D printed models was evaluated first using anatomical annotations in reference to Netter’s Atlas of Human Anatomy. The measurements of the deviation were quantised and visualised for analysis in Geomagic Control 2015. Results All the specimens were reconstructed in 3D and printed using this workflow. The overall morphology of the digital and 3D printed models displayed a large extent of similarity to the corresponding specimens from a gross anatomical perspective. A high degree of similarity was also noticed in the quantitative analysis, with distance deviations ≤2 mm present among 99% of the random sampling points that were tested. Conclusion The photogrammetric digitisation workflow adapted in the present study demonstrates fairly high precision with relatively low cost and fewer equipment requirements. This workflow is expected to be used in morphological/anatomical science education, particularly in institutions and schools with limited funds or in certain field research projects involving the fast acquisition of 3D digital data on human/animal bone specimens or on other remains.
Salivary biomarkers for diagnosis of systemic diseases and malignant tumors. A systematic review

Background Saliva evaluation could be a possible alternative to blood and/or tissue analyses, for researching specific molecules associated to the presence of systemic diseases and malignancies. The present systematic review has been designed in order to answer to the question “are there significant associations between specific salivary biomarkers and diagnosis of systemic diseases or malignancies? ”. Material and Methods The Preferred Reporting Item for Systematic Reviews and Meta-analysis (PRISMA) statement was used to guide the review. The combinations of “saliva” and “systemic diseases” or “diagnosis” or “biomarkers” or “cancers” or “carcinoma” or “tumors”, were used to search Medline, Scopus and Web of Science databases. Endpoint of research has been set at May 2019. Studies were classified into 3 groups according to the type of disease investigated for diagnosis: 1) malignant tumors; 2) neurologic diseases and 3) inflammatory/metabolic/cardiovascular diseases. Assessment of quality has been assigned according to a series of questions proposed by the National Institute of Health. Level of evidence was assessed using the categories proposed in the Oxford Center for Evidence-Based medicine (CEMB) levels for diagnosis (2011). Results Seventy-nine studies met the inclusion and exclusion criteria. Fifty-one (64%) investigated malignant tumors, 14 (17.5%) neurologic and 14 (18.5%) inflammatory/cardiovascular/metabolic diseases. Among studies investigating malignant tumors, 12 (23.5%) were scored as “good” and 11 of these reported statistically significant associations between salivary molecules and pathology. Two and 5 studies were found to have a good quality, among those evaluating the association between salivary biomarkers and neurologic and inflammatory/metabolic/cardiovascular diseases, respectively. Conclusions The present systematic review confirms the existence of some “good” quality evidence to support the role of peculiar salivary biomarkers for diagnosis of systemic diseases (e.g. lung cancer and EGFR). Key words:Salivary diagnostics, biomarkers, systemic diseases, malignant tumors, early diagnosis.
HilD, HilC, and RtsA Form Homodimers and Heterodimers To Regulate Expression of the Salmonella Pathogenicity Island I Type III Secretion System

The SPI1 type three secretion system is a key virulence factor required for Salmonella to both cause gastroenteritis and initiate serious systemic disease. The system responds to numerous environmental signals in the intestine, integrating this information via a complex regulatory network. Here, we show that the primary regulatory proteins in the network function as both homodimers and heterodimers, providing information regarding both regulation of virulence in this important pathogen and general signal integration to control gene expression. ABSTRACT Salmonella enterica serovar Typhimurium colonizes and invades host intestinal epithelial cells using the type three secretion system (T3SS) encoded on Salmonella pathogenicity island 1 (SPI1). The level of SPI1 T3SS gene expression is controlled by the transcriptional activator HilA, encoded on SPI1. Expression of hilA is positively regulated by three homologous transcriptional regulators, HilD, HilC, and RtsA, belonging to the AraC/XylS family. These regulators also activate the hilD, hilC, and rtsA genes by binding to the same DNA sequences upstream of these promoters, forming a complex feed-forward loop to control SPI1 expression. Despite the apparent redundancy in function, HilD has a unique role in SPI1 regulation because the majority of external regulatory inputs act exclusively through HilD. To better understand SPI1 regulation, the nature of interaction between HilD, HilC, and RtsA has been characterized using biochemical and genetic techniques. Our results showed that HilD, HilC, and RtsA can form heterodimers as well as homodimers in solution. Comparison with other AraC family members identified a putative α-helix in the N-terminal domain, which acts as the dimerization domain. Alanine substitution in this region results in reduced dimerization of HilD and HilC and also affects their ability to activate hilA expression. The dimer interactions of HilD, HilC, and RtsA add another layer of complexity to the SPI1 regulatory circuit, providing a more comprehensive understanding of SPI1 T3SS regulation and Salmonella pathogenesis. IMPORTANCE The SPI1 type three secretion system is a key virulence factor required for Salmonella to both cause gastroenteritis and initiate serious systemic disease. The system responds to numerous environmental signals in the intestine, integrating this information via a complex regulatory network. Here, we show that the primary regulatory proteins in the network function as both homodimers and heterodimers, providing information regarding both regulation of virulence in this important pathogen and general signal integration to control gene expression.
New Horizons in the use of routine data for ageing research

Abstract The past three decades have seen a steady increase in the availability of routinely collected health and social care data and the processing power to analyse it. These developments represent a major opportunity for ageing research, especially with the integration of different datasets across traditional boundaries of health and social care, for prognostic research and novel evaluations of interventions with representative populations of older people. However, there are considerable challenges in using routine data at the level of coding, data analysis and in the application of findings to everyday care. New Horizons in applying routine data to investigate novel questions in ageing research require a collaborative approach between clinicians, data scientists, biostatisticians, epidemiologists and trial methodologists. This requires building capacity for the next generation of research leaders in this important area. There is a need to develop consensus code lists and standardised, validated algorithms for common conditions and outcomes that are relevant for older people to maximise the potential of routine data research in this group. Lastly, we must help drive the application of routine data to improve the care of older people, through the development of novel methods for evaluation of interventions using routine data infrastructure. We believe that harnessing routine data can help address knowledge gaps for older people living with multiple conditions and frailty, and design interventions and pathways of care to address the complex health issues we face in caring for older people.
Multidimensional entanglement transport through single-mode fiber

This work suggests a new approach to multidimensional entanglement transport through conventional single-mode fiber. The global quantum network requires the distribution of entangled states over long distances, with substantial advances already demonstrated using polarization. While Hilbert spaces with higher dimensionality, e.g., spatial modes of light, allow higher information capacity per photon, such spatial mode entanglement transport requires custom multimode fiber and is limited by decoherence-induced mode coupling. Here, we circumvent this by transporting multidimensional entangled states down conventional single-mode fiber (SMF). By entangling the spin-orbit degrees of freedom of a biphoton pair, passing the polarization (spin) photon down the SMF while accessing multiple orbital angular momentum (orbital) subspaces with the other, we realize multidimensional entanglement transport. We show high-fidelity hybrid entanglement preservation down 250 m SMF across multiple 2 × 2 dimensions, confirmed by quantum state tomography, Bell violation measures, and a quantum eraser scheme. This work offers an alternative approach to spatial mode entanglement transport that facilitates deployment in legacy networks across conventional fiber.
Pharmacokinetics, Pharmacodynamics and Immunogenicity of Infliximab in Paediatric Inflammatory Bowel Disease; a Systematic Review and Revised Dosing Considerations.

OBJECTIVES Infliximab (IFX), a monoclonal antibody directed against TNF-α is a potent treatment option for inflammatory bowel disease (IBD). Dosing regimens in children are extrapolated from adult data using a fixed, weight-based dose, which is often not adequate. While clinical trials have focused on safety and efficacy, there is limited data on pharmacokinetic (PK) characteristics and immunogenicity of IFX in children. The objective was to provide a systematic overview of current literature on PK and immunogenicity of IFX in children with IBD, in order to assess the validity of current adult to paediatric dosing extrapolation. METHODS A literature search identified publications up to October 2018. Eligibility criteria were (1) study population consisting of children and/or adolescents with IBD, (2) report of IFX trough levels (TLs) and/or antibodies-to infliximab (ATI), (3) full text article or abstract, (4) article in English, and (5) original data. RESULTS Initial electronic search yielded 2360 potentially relevant articles, with 1831 remaining after removal of duplicates. An additional search yielded another 202 potentially relevant articles. Of the 2033 retrieved articles, 2000 articles were excluded based on title, abstract or eligibility criteria. Clearance of infliximab was increased in young children and children with extensive disease, leading to lower TLs after extrapolated dosing of 5 mg/kg, ATI emergence and subsequent reduced efficacy. CONCLUSIONS Adult to paediatric weight-based dosing extrapolation is often inadequate. We provide several considerations for optimal dosing of IFX in children and adolescents with IBD.
Ficus deltoidea extract down-regulates protein tyrosine phosphatase 1B expression in a rat model of type 2 diabetes mellitus: a new insight into its antidiabetic mechanism

Ficus deltoidea var. deltoidea Jack (FD) is a well-known plant used in Malay folklore medicine to lower blood glucose in diabetic patients. For further research of the antihyperglycemic mechanisms, the protein tyrosine phosphatase 1B (PTP1B)-inhibitory effect of FD was analysed both in vitro and in vivo. To optimise a method for FD extraction, water, 50, 70, 80, 90 and 95 % ethanol extracts were prepared and determined for their total phenolic and triterpene contents, and PTP1B-inhibition capacity. Among the tested extracts, 70 % ethanol FD extract showed a significant PTP1B inhibition (92·0 % inhibition at 200 µg/ml) and high phenolic and triterpene contents. A bioassay-guided fractionation of the 70 % ethanol extract led to the isolation of a new triterpene (3β,11β-dihydroxyolean-12-en-23-oic acid; F3) along with six known compounds. In vivo, 4 weeks’ administration of 70 % ethanol FD extract (125, 250 and 500 mg/kg/d) to streptozotocin–nicotinamide-induced type 2 diabetic rats reversed the abnormal changes of blood glucose, insulin, total Hb, GLUT2, lipid profile, and oxidative stress in liver and pancreas. Moreover, FD reduced the mRNA expression of the key gluconeogenic enzymes (phosphoenolpyruvate carboxykinase and glucose 6-phosphatase) and restored insulin receptor and GLUT2 encoding gene (Slc2a2) expression. In addition, FD significantly down-regulated the hepatic PTP1B gene expression. These results revealed that FD could potentially improve insulin sensitivity, suppress hepatic glucose output and enhance glucose uptake in type 2 diabetes mellitus through down-regulation of PTP1B. Together, our findings give scientific evidence for the traditional use of FD as an antidiabetic agent.