Miracle-dz/UniFAR-FTUs huggingface dataset:
BoNT-A for Post-Stroke Spasticity: Guidance on Unmet Clinical Needs from a Delphi Panel Approach

There is extensive literature supporting the efficacy of botulinum toxin (BoNT-A) for the treatment of post-stroke spasticity, however, there remain gaps in the routine management of patients with post-stroke spasticity. A panel of 21 Italian experts was selected to participate in this web-based survey Delphi process to provide guidance that can support clinicians in the decision-making process. There was a broad consensus among physicians that BoNT-A intervention should be administered as soon as the spasticity interferes with the patients’ clinical condition. Patients monitoring is needed over time, a follow-up of 4–6 weeks is considered necessary. Furthermore, physicians agreed that treatment should be offered irrespective of the duration of the spasticity. The Delphi consensus also stressed the importance of patient-centered goals in order to satisfy the clinical needs of the patient regardless of time of onset or duration of spasticity. The findings arising from this Delphi process provide insights into the unmet needs in managing post-stroke spasticity from the clinician’s perspective and provides guidance for physicians for the utilization of BoNT-A for the treatment of post-stroke spasticity in daily practice.
Blood Pressure Monitoring System Using a Two-Channel Ballistocardiogram and Convolutional Neural Networks

Hypertension is a chronic disease that kills 7.6 million people worldwide annually. A continuous blood pressure monitoring system is required to accurately diagnose hypertension. Here, a chair-shaped ballistocardiogram (BCG)-based blood pressure estimation system was developed with no sensors attached to users. Two experimental sessions were conducted with 30 subjects. In the first session, two-channel BCG and blood pressure data were recorded for each subject. In the second session, the two-channel BCG and blood pressure data were recorded after running on a treadmill and then resting on the newly developed system. The empirical mode decomposition algorithm was used to remove noise in the two-channel BCG, and the instantaneous phase was calculated by applying a Hilbert transform to the first intrinsic mode functions. After training a convolutional neural network regression model that predicts the systolic and diastolic blood pressures (SBP and DBP) from the two-channel BCG phase, the results of the first session (rest) and second session (recovery) were compared. The results confirmed that the proposed model accurately estimates the rapidly rising blood pressure in the recovery state. Results from the rest sessions satisfied the Association for the Advancement of Medical Instrumentation (AAMI) international standards. The standard deviation of the SBP results in the recovery session exceeded 0.7.
The Importance of Appropriate Diagnosis in the Practical Management of Chronic Obstructive Pulmonary Disease

Chronic obstructive pulmonary disease (COPD) is projected to continue to contribute to an increase in the overall worldwide burden of disease until 2030. Therefore, an accurate assessment of the risk of airway obstruction in patients with COPD has become vitally important. Although the Global Initiative for Chronic Obstructive Lung Disease (GOLD), the American Thoracic Society (ATS) and European Respiratory Society (ERS), and the Japanese Respiratory Society (JRS) provide the criteria by which to diagnose COPD, many studies suggest that it is in fact underdiagnosed. Its prevalence increases, while the impact of COPD-related systemic comorbidities is also increasingly recognized in clinical aspects of COPD. Although a recent report suggests that spirometry should not be used to screen for airflow limitation in individuals without respiratory symptoms, the early detection of COPD in patients with no, or few, symptoms is an opportunity to provide appropriate management based on COPD guidelines. Clinical advances have been made in pharmacotherapeutic approaches to COPD. This article provides a current understanding of the importance of an appropriate diagnosis in the real-world management of COPD.
Newcastle Disease Virus Induced Pathologies Severely Affect the Exocrine and Endocrine Functions of the Pancreas in Chickens

Newcastle disease virus (NDV) causes a highly contagious and devastating disease in poultry. ND causes heavy economic losses to the global poultry industry by decreasing the growth rate, decrease in egg production high morbidity and mortality. Although significant advances have been made in the vaccine development, outbreaks are reported in vaccinated birds. In this study, we report the damage caused by NDV infection in the pancreatic tissues of vaccinated and specific-pathogen-free chickens. The histopathological examination of the pancreas showed severe damage in the form of partial depletion of zymogen granules, acinar cell vacuolization, necrosis, apoptosis, congestion in the large and small vessels, sloughing of epithelial cells of the pancreatic duct, and mild perivascular edema. Increased plasma levels of corticosterone and somatostatin were observed in NDV-infected chicken at three- and five- days post infection (DPI). A slight decrease in the plasma concentrations of insulin was noticed at 5 DPI. Significant changes were not observed in the plasma levels of glucagon. Furthermore, NDV infection decreased the activity and mRNA expression of amylase, lipase, and trypsin from the pancreas. Taken together, our findings highlight that NDV induces extensive tissue damage in the pancreas, decreases the activity and expression of pancreatic enzymes, and increases plasma corticosterone and somatostatin. These findings provide new insights that a defective pancreas may be one of the reasons for decreased growth performance after NDV infection in chickens.
Diphenyl-Methane Based Thyromimetic Inhibitors for Transthyretin Amyloidosis

Thyromimetics, whose physicochemical characteristics are analog to thyroid hormones (THs) and their derivatives, are promising candidates as novel therapeutics for neurodegenerative and metabolic pathologies. In particular, sobetirome (GC-1), one of the initial halogen-free thyromimetics, and newly synthesized IS25 and TG68, with optimized ADME-Tox profile, have recently attracted attention owing to their superior therapeutic benefits, selectivity, and enhanced permeability. Here, we further explored the functional capabilities of these thyromimetics to inhibit transthyretin (TTR) amyloidosis. TTR is a homotetrameric transporter protein for THs, yet it is also responsible for severe amyloid fibril formation, which is facilitated by tetramer dissociation into non-native monomers. By combining nuclear magnetic resonance (NMR) spectroscopy, computational simulation, and biochemical assays, we found that GC-1 and newly designed diphenyl-methane-based thyromimetics, namely IS25 and TG68, are TTR stabilizers and efficient suppressors of TTR aggregation. Based on these observations, we propose the novel potential of thyromimetics as a multi-functional therapeutic molecule for TTR-related pathologies, including neurodegenerative diseases.
Forces between Polymer Surfaces and Self-Assembled Monolayers

Gold-coated atomic force microscope (AFM) tips functionalized with amine-, hydroxyl-, carboxylic acid-, and methyl-terminated alkanethiol molecules were used to probe the adhesive forces of polystyrene and poly(acrylic acid) films in dry air (relative humidity < 0.5%). X-ray photoelectron spectroscopy (XPS) and contact angle measurements confirmed the quality and uniformity of similarly treated gold surfaces and the polymer films. XPS indicated that the amine-functionalized thiol films were protonated and comprised of multilayers. Contact angle data were used to calculate surface free energies, and DMT theory yielded the works of adhesion and interfacial free energies for the tip-substrate combinations. In the case of polystyrene, the work of adhesion followed the order methyl > carboxylic acid > hydroxyl > amine. For poly(acrylic acid), the observed order was hydroxyl > amine > carboxylic acid > methyl.
Selective Activation of CNS and Reference PPARGC1A Promoters Is Associated with Distinct Gene Programs Relevant for Neurodegenerative Diseases

The transcriptional regulator peroxisome proliferator activated receptor gamma coactivator 1A (PGC-1α), encoded by PPARGC1A, has been linked to neurodegenerative diseases. Recently discovered CNS-specific PPARGC1A transcripts are initiated far upstream of the reference promoter, spliced to exon 2 of the reference gene, and are more abundant than reference gene transcripts in post-mortem human brain samples. The proteins translated from the CNS and reference transcripts differ only at their N-terminal regions. To dissect functional differences between CNS-specific isoforms and reference proteins, we used clustered regularly interspaced short palindromic repeats transcriptional activation (CRISPRa) for selective endogenous activation of the CNS or the reference promoters in SH-SY5Y cells. Expression and/or exon usage of the targets was ascertained by RNA sequencing. Compared to controls, more differentially expressed genes were observed after activation of the CNS than the reference gene promoter, while the magnitude of alternative exon usage was comparable between activation of the two promoters. Promoter-selective associations were observed with canonical signaling pathways, mitochondrial and nervous system functions and neurological diseases. The distinct N-terminal as well as the shared downstream regions of PGC-1α isoforms affect the exon usage of numerous genes. Furthermore, associations of risk genes of amyotrophic lateral sclerosis and Parkinson’s disease were noted with differentially expressed genes resulting from the activation of the CNS and reference gene promoter, respectively. Thus, CNS-specific isoforms markedly amplify the biological functions of PPARGC1A and CNS-specific isoforms and reference proteins have common, complementary and selective functions relevant for neurodegenerative diseases.
Defining the Human-Biota Thresholds of Toxicological Concern for Organic Chemicals in Freshwater: The Proposed Strategy of the LIFE VERMEER Project Using VEGA Tools

Several tons of chemicals are released every year into the environment and it is essential to assess the risk of adverse effects on human health and ecosystems. Risk assessment is expensive and time-consuming and only partial information is available for many compounds. A consolidated approach to overcome this limitation is the Threshold of Toxicological Concern (TTC) for assessment of the potential health impact and, more recently, eco-TTCs for the ecological aspect. The aim is to allow a safe assessment of substances with poor toxicological characterization. Only limited attempts have been made to integrate the human and ecological risk assessment procedures in a “One Health” perspective. We are proposing a strategy to define the Human-Biota TTCs (HB-TTCs) as concentrations of organic chemicals in freshwater preserving both humans and ecological receptors at the same time. Two sets of thresholds were derived: general HB-TTCs as preliminary screening levels for compounds with no eco- and toxicological information, and compound-specific HB-TTCs for chemicals with known hazard assessment, in terms of Predicted No effect Concentration (PNEC) values for freshwater ecosystems and acceptable doses for human health. The proposed strategy is based on freely available public data and tools to characterize and group chemicals according to their toxicological profiles. Five generic HB-TTCs were defined, based on the ecotoxicological profiles reflected by the Verhaar classes, and compound-specific thresholds for more than 400 organic chemicals with complete eco- and toxicological profiles. To complete the strategy, the use of in silico models is proposed to predict the required toxicological properties and suitable models already available on the VEGAHUB platform are listed.
Recent Advances in Electrical Doping of 2D Semiconductor Materials: Methods, Analyses, and Applications

Two-dimensional materials have garnered interest from the perspectives of physics, materials, and applied electronics owing to their outstanding physical and chemical properties. Advances in exfoliation and synthesis technologies have enabled preparation and electrical characterization of various atomically thin films of semiconductor transition metal dichalcogenides (TMDs). Their two-dimensional structures and electromagnetic spectra coupled to bandgaps in the visible region indicate their suitability for digital electronics and optoelectronics. To further expand the potential applications of these two-dimensional semiconductor materials, technologies capable of precisely controlling the electrical properties of the material are essential. Doping has been traditionally used to effectively change the electrical and electronic properties of materials through relatively simple processes. To change the electrical properties, substances that can donate or remove electrons are added. Doping of atomically thin two-dimensional semiconductor materials is similar to that used for silicon but has a slightly different mechanism. Three main methods with different characteristics and slightly different principles are generally used. This review presents an overview of various advanced doping techniques based on the substitutional, chemical, and charge transfer molecular doping strategies of graphene and TMDs, which are the representative 2D semiconductor materials.
Therapeutic Evaluation of Antibody-Based Targeted Delivery of Interleukin 9 in Experimental Pulmonary Hypertension

Background and Aims: Pulmonary hypertension (PH) is a heterogeneous disorder associated with poor prognosis. For the majority of patients, only limited therapeutic options are available. Thus, there is great interest to develop novel treatment strategies focusing on pulmonary vascular and right ventricular remodeling. Interleukin 9 (IL9) is a pleiotropic cytokine with pro- and anti-inflammatory functions. The aim of this study was to evaluate the therapeutic activity of F8IL9F8 consisting of IL9 fused to the F8 antibody, specific to the alternatively-spliced EDA domain of fibronectin, which is abundantly expressed in pulmonary vasculature and right ventricular myocardium in PH. Methods: The efficacy of F8IL9F8 in attenuating PH progression in the monocrotaline mouse model was evaluated in comparison to an endothelin receptor antagonist (ERA) or an IL9 based immunocytokine with irrelevant antibody specificity (KSFIL9KSF). Treatment effects were assessed by right heart catheterization, echocardiography as well as histological and immunohistochemical tissue analyses. Results: Compared to controls, systolic right ventricular pressure (RVPsys) was significantly elevated and a variety of right ventricular echocardiographic parameters were significantly impaired in all MCT-induced PH groups except for the F8IL9F8 group. Both, F8IL9F8 and ERA treatments lead to a significant reduction in RVPsys and an improvement of echocardiographic parameters when compared to the MCT group not observable for the KSFIL9KSF group. Only F8IL9F8 significantly reduced lung tissue damage and displayed a significant decrease of leukocyte and macrophage accumulation in the lungs and right ventricles. Conclusions: Our study provides first pre-clinical evidence for the use of F8IL9F8 as a new therapeutic agent for PH in terms of a disease-modifying concept addressing cardiovascular remodeling.
Integrated in Silico and Experimental Approach towards the Design of a Novel Recombinant Protein Containing an Anti-HER2 scFv

Biological therapies, such as recombinant proteins, are nowadays amongst the most promising approaches towards precision medicine. One of the most innovative methodologies currently available aimed at improving the production yield of recombinant proteins with minimization of costs relies on the combination of in silico studies to predict and deepen the understanding of the modified proteins with an experimental approach. The work described herein aims at the design and production of a biomimetic vector containing the single-chain variable domain fragment (scFv) of an anti-HER2 antibody fragment as a targeting motif fused with HIV gp41. Molecular modeling and docking studies were performed to develop the recombinant protein sequence. Subsequently, the DNA plasmid was produced and HEK-293T cells were transfected to evaluate the designed vector. The obtained results demonstrated that the plasmid construction is robust and can be expressed in the selected cell line. The multidisciplinary integrated in silico and experimental strategy adopted for the construction of a recombinant protein which can be used in HER2+-targeted therapy paves the way towards the production of other therapeutic proteins in a more cost-effective way.
Quality of life of women living with metastatic breast cancer and receiving palliative care: A systematic review

Abstract The quality of life (QoL) of women living with metastatic breast cancer and receiving palliative care needs more attention. We reviewed published studies (1992–2019) examining QoL of women receiving palliative care. The findings were interpreted according to the World Health Organization’s (WHO) definition of palliative care. Four themes emerged: (1) the impact of medical treatment on pain relief; (2) the need for psychosocial attention and support; (3) the necessity of an interdisciplinary approach; (4) ambiguous understanding of the term palliative care. A common understanding of the term palliative care and more research is needed to enhance the QoL of women living with metastatic breast cancer.
Impact of a telephone triage service for non-critical emergencies in Switzerland: A cross-sectional study

Introduction Telephone triage services (TTS) play an increasing role in the delivery of healthcare. The objective of this study was to characterize the adult users of a TTS for non-critical emergencies, describe the types of advice given and their subsequent observation, and assess the influence of TTS on the use of the healthcare system in a sanitary region of Switzerland. Methods Data from a TTS based in the French part of Switzerland were analyzed. This service consists of a medical contact center for non-critical emergencies, with trained nurses available 24/7. A random selection of 2,034 adult calls was performed between July and December 2018. Research students contacted users 2 to 4 weeks after the initial call and assessed sociodemographic and clinical data, as well as the impact of the advice received on the use of the healthcare system. Results A sample of 412 users was included in the analyses. The average age was 49.0 (SD 20.4) years; 68.5% were women and 72.8% of Swiss origin. The two main recommendations provided by nurses were to consult the emergency department (ED) (44.6%, n = 184) and to contact a physician on duty (33.2%, n = 137). The majority of users followed the advice given by the nurses (substantial agreement [k = 0.79] with consulting the ED and perfect agreement [k = 0.87] with contacting a physician on duty). We calculated that calling the TTS could decrease the intention to visit the ED by 28.1%. Conclusion TTS for non-critical emergencies have the potential to decrease the use of ED services.
CRISPRi-Library-Guided Target Identification for Engineering Carotenoid Production by Corynebacterium glutamicum

Corynebacterium glutamicum is a prominent production host for various value-added compounds in white biotechnology. Gene repression by dCas9/clustered regularly interspaced short palindromic repeats (CRISPR) interference (CRISPRi) allows for the identification of target genes for metabolic engineering. In this study, a CRISPRi-based library for the repression of 74 genes of C. glutamicum was constructed. The chosen genes included genes encoding enzymes of glycolysis, the pentose phosphate pathway, and the tricarboxylic acid cycle, regulatory genes, as well as genes of the methylerythritol phosphate and carotenoid biosynthesis pathways. As expected, CRISPRi-mediated repression of the carotenogenesis repressor gene crtR resulted in increased pigmentation and cellular content of the native carotenoid pigment decaprenoxanthin. CRISPRi screening identified 14 genes that affected decaprenoxanthin biosynthesis when repressed. Carotenoid biosynthesis was significantly decreased upon CRISPRi-mediated repression of 11 of these genes, while repression of 3 genes was beneficial for decaprenoxanthin production. Largely, but not in all cases, deletion of selected genes identified in the CRISPRi screen confirmed the pigmentation phenotypes obtained by CRISPRi. Notably, deletion of pgi as well as of gapA improved decaprenoxanthin levels 43-fold and 9-fold, respectively. The scope of the designed library to identify metabolic engineering targets, transfer of gene repression to stable gene deletion, and limitations of the approach were discussed.
The Antithrombotic Agent Pterostilbene Interferes with Integrin αIIbβ3-Mediated Inside-Out and Outside-In Signals in Human Platelets

Platelets play a crucial role in the physiology of primary hemostasis and pathological processes such as arterial thrombosis; thus, developing a therapeutic target that prevents platelet activation can reduce arterial thrombosis. Pterostilbene (PTE) has remarkable pharmacological activities, including anticancer and neuroprotection. Few studies have reported the effects of pterostilbene on platelet activation. Thus, we examined the inhibitory mechanisms of pterostilbene in human platelets and its role in vascular thrombosis prevention in mice. At low concentrations (2–8 μM), pterostilbene strongly inhibited collagen-induced platelet aggregation. Furthermore, pterostilbene markedly diminished Lyn, Fyn, and Syk phosphorylation and hydroxyl radical formation stimulated by collagen. Moreover, PTE directly hindered integrin αIIbβ3 activation through interfering with PAC-1 binding stimulated by collagen. In addition, pterostilbene affected integrin αIIbβ3-mediated outside-in signaling, such as integrin β3, Src, and FAK phosphorylation, and reduced the number of adherent platelets and the single platelet spreading area on immobilized fibrinogen as well as thrombin-stimulated fibrin clot retraction. Furthermore, pterostilbene substantially prolonged the occlusion time of thrombotic platelet plug formation in mice. This study demonstrated that pterostilbene exhibits a strong activity against platelet activation through the inhibition of integrin αIIbβ3-mediated inside-out and outside-in signaling, suggesting that pterostilbene can serve as a therapeutic agent for thromboembolic disorders.
The Role of Cholesterol and Fatty Acids in the Etiology and Diagnosis of Autism Spectrum Disorders

Autism spectrum disorders (ASDs) are a group of neurodevelopmental disorders whose pathogenesis seems to be related to an imbalance of excitatory and inhibitory synapses, which leads to disrupted connectivity during brain development. Among the various biomarkers that have been evaluated in the last years, metabolic factors represent a bridge between genetic vulnerability and environmental aspects. In particular, cholesterol homeostasis and circulating fatty acids seem to be involved in the pathogenesis of ASDs, both through the contribute in the stabilization of cell membranes and the modulation of inflammatory factors. The purpose of the present review is to summarize the available data about the role of cholesterol and fatty acids, mainly long-chain ones, in the onset of ASDs. A bibliographic research on the main databases was performed and 36 studies were included in our review. Most of the studies document a correlation between ASDs and hypocholesterolemia, while the results concerning circulating fatty acids are less univocal. Even though further studies are necessary to confirm the available data, the metabolic biomarkers open to new treatment options such as the modulation of the lipid pattern through the diet.