Heterogeneous Multi-task Learning with Expert Diversity

Predicting multiple heterogeneous biological and medical targets is a challenge for traditional deep learning models. In contrast to single-task learning, in which a separate model is trained for each target, multi-task learning (MTL) optimizes a single model to predict multiple related targets simultaneously. To address this challenge, we propose the Multi-gate Mixture-of-Experts with Exclusivity (MMoEEx). Our work aims to tackle the heterogeneous MTL setting, in which the same model optimizes multiple tasks with different characteristics. Such a scenario can overwhelm current MTL approaches due to the challenges in balancing shared and task-specific representations and the need to optimize tasks with competing optimization paths. Our method makes two key contributions: first, we introduce an approach to induce more diversity among experts, thus creating representations more suitable for highly imbalanced and heterogenous MTL learning; second, we adopt a two-step optimization [6, 11] approach to balancing the tasks at the gradient level. We validate our method on three MTL benchmark datasets, including Medical Information Mart for Intensive Care (MIMIC-III) and PubChem BioAssay (PCBA).Comment: 10 pages, 7 figures, BIOKDD, IEEE/AC

Finding the perfect match between nanoparticles and microfluidics to respond to cancer challenges

The clinical translation of new cancer theranostic has been delayed by inherent cancerâ s heterogeneity. Additionally, this delay has been enhanced by the lack of an appropriate in vitro model, capable to produce accurate data. Nanoparticles and microfluidic devices have been used to obtain new and more efficient strategies to tackle cancer challenges. On one hand, nanoparticles-based therapeutics can be modified to target specific cells, and/or molecules, and/or modified with drugs, releasing them over time. On the other hand, microfluidic devices allow the exhibition of physiologically complex systems, incorporation of controlled flow, and control of the chemical environment. Herein, we review the use of nanoparticles and microfluidic devices to address different cancer challenges, such as detection of CTCs and biomarkers, point-of-care devices for early diagnosis and improvement of therapies. The future perspectives of cancer challenges are also addressed herein.F.R. Maia acknowledges Portuguese Foundation for Scienceand Technology (FCT) for her work contract under theTransitional Rule DL 57/2016 (CTTI-57/18-I3BS5). J. M.Oliveira thanks FCT for his distinction attributed under theFCT Investigator program (IF/01285/2015)

Combinatory approach for developing silk fibroin-based scaffolds seeded with human adipose-derived stem cells for a cartilage tissue engineering applications

Several processing technologies have been combined to create scaffolds for different tissue engineering (TE) applications. Hydrogels have been extensively used for cartilage TE applications, presenting several structural similarities to the natural extracellular matrix of cartilage tissue environment[1]. From the different biodegradable materials proposed as matrices for cartilage scaffolding[2], silk fibroin (SF) presents high versatility, processability and tailored mechanical properties, which make this protein attractive for the development of innovative matrices for cartilage TE purposes[3]. In a previous study, we proposed fast formed SF hydrogels produced through a horseradish peroxidase (HRP) and hydrogen peroxide (H2O2) crosslinking reaction, taking advantage of the presence of tyrosine groups[4]. In this work, macro-/micro-porous SF scaffolds derived from enzymatically cross- linked SF hydrogels by a HRP/H2O2 complex were produced in combination with salt-leaching and freeze-drying methodologies. The scaffolds morphology, mechanical properties and chemical characterization were assessed by mean of different characterization techniques (SEM, micro-CT, Instron, FTIR and XRD). The scaffolds structural integrity was evaluated by swelling ratio and degradation profile studies. The in vitro ability to support the adhesion, proliferation and differentiation into the chondrogenic lineage was tested using human adipose-derived stem cells (hASCs) cultured over 28 days in basal and chondrogenic conditions. Cell behaviour in the presence of the SF scaffolds was evaluated through different quantitative (GAGs/DNA and RT-PCR) and qualitative (live/dead, SEM, histology and immunocytochemistry) assays. The in vivo biocompatibility of the SF-based scaffolds was also assessed by subcutaneous implantation in mice for 2 and 4 weeks and analysed by means of hematoxylin & eosin (H&E) staining and immunohistochemical analysis of CD31 angiogenic marker. The results showed highly porous and interconnected SF structures that allowed cell adhesion and infiltration into the scaffolds. In vitro cell viability and proliferation were also observed over the 28 days of culturing in basal conditions and a significant increase of GAGs content was detected on constructs cultured in chondrogenic differentiation medium. In vivo results showed that the implanted scaffolds allowed tissue ingrowthâ s and blood vessels formation/infiltration. The obtained results demonstrated that the innovative approach of combining enzymatically cross-linked SF hydrogels with the salt- leaching and freeze-drying methodologies allowed to produce more versatile scaffold architectures with appropriate mechanical properties and large swelling ability. The positive influence over in vitro chondrogenic differentiation and in vivo response, revealed by the new tissue formation and angiogenesis within the porous scaffolds, validates the proposed macro-/micro-porous SF scaffolds for being used in cartilage TE applications. Moreover, the versatility of these combinatory approach can allow for further applications in other musculoskeletal TE strategies.Investigator FCT program IF/00423/2012 and IF/00411/2013 are also greatly acknowledged. Financial support from FCT/MCTES (Fundação para a Ciência e a Tecnologia/ Ministério da Ciência, Tecnologia, e Ensino Superior) and Fundo Social Europeu através do Programa Operacional do Capital Humano (FSE/POCH), PD/59/2013, PD/BD/113806/2015.info:eu-repo/semantics/publishedVersio

Engineering of extracellular matrix-like biomaterials at nano- and macroscale toward fabrication of hierarchical scaffolds for bone tissue engineering

The increasing rate of musculoskeletal pathologies has compelled the development of improved and novel treatment strategies in order to address unmet clinical needs. Tissue engineering approaches comprising the use of scaffolds for bone regeneration have been showing to be a promising alternative to conventional bone repair/substitution approaches. In particular, hierarchical scaffolds as methods of structural support and osteogenic differentiation promoters are among the most used tools in bone tissue engineering (BTE). In this reasoning, hierarchical scaffolds have sparked the field, striving toward mimicking the natural bone tissue in both, its complex 3D structure and composition. A recent and promising trend has been the merging of nanotechnology and tissue engineering concepts. As such the incorporation of nanoparticles and nanocomposites into micro- or macroscaffold systems can result in an improvement of scaffoldsâ biofunctionality at different levels. These tools are versatile in nature and can be used for multiple purposes such as drug delivery, thermal conductors, and mechanical reinforcement. Taking into consideration multidisciplinary approaches, several strategies have been pursued. The recent reports dealing with the approaches pursued in the hierarchical scaffolds production and enhancement, ranging from the nanoscale to the macroscale, are overviewed herein.The authors thank the funds provided by the project FROnTHERA (NORTE-01-0145-FEDER-000023), supported by Norte Portugal Regional Operational Programme (NORTE 2020), under the PORTUGAL 2020 Partnership Agreement, through the European Regional Development Fund (ERDF), the project 3BioMeD (FCT/4773/ 4/5/2017/S) supported by Fundação para a Ciência e a Tecnologia (FCT) and the R&D Project KOAT PTDC/BTMMAT/29760/2017 (POCI 01-0145-FEDER-029760) financed by FCT and cofinanced by FEDER and POCI. F.R.M. acknowledges FCT for her contract under the Transitional Rule DL 57/2016 (CTTI-57/18-I3BS (5))

The protective effect of endogenous melatonin on gilthead seabream sperm during cryopreservation

Cryopreservation is widely used for artificial reproduction techniques (ART) but requires good gamete quality to succeed. Considering the endogenously produced melatonin by the fish and its protective role in the organism, the objective of this experiment was to search for the best moment of the day to collect gilthead seabream (Sparus aurata) sperm with better quality and, at the same time, to test the potential protective effect of the exogenous melatonin during sperm freezing and thawing processes. Fish were first sampled every 6 h, corresponding to the beginning of the light period (6 h), mid-light (12h), beginning of the dark period (18 h), and mid-dark (24 h) to determine melatonin concentration in blood plasma by radioimmunoassay (RIA). The analysis showed higher values at 24 h (244 pg/mL) compared with 12 h (99 pg/mL), which allowed the selection of those moments for the next experiment. After, fish were sampled for sperm collection at mid-light (ML, 12 h) and mid-dark (MD, 24 h), and fresh sperm was used to assess gamete quality and for the cryopreservation assay. Sperm samples were cryopreserved to test supplementation of different melatonin concentrations (0.001 mM, 0.01 mM and 0.1 mM) together with a control group without added melatonin. Gamete quality was assessed through spermatozoa concentration and motility (CASA system), cell viability (PI/SYBR-green) and DNA fragmentation (Comet assay). Despite cell viability that was higher at ML, most of the fresh sperm motility parameters did not differ between ML and MD, only linearity (LIN) was enhanced at MD. Nevertheless, in cryopreserved samples, total motility (TM) was significantly higher at MD in all melatonin treatments, control, and fresh samples, revealing an endogenous night-effect. Moreover, spermatozoa concentration was also higher at MD (28.9 x 109/mL) than at ML (20.7 x 109/mL). Supplemented melatonin did not confer extra protection to gilthead seabream sperm during cryopreservation since the tested concentrations did not differ between the control in any sperm quality test. It is here suggested that endogenously produced melatonin may contribute to the improvement of some gamete quality parameters at mid-dark, allowing the aquaculture sector to select better sperm quality in a noninvasive way by choosing it as the best moment of the day for sperm collection.LA/P/0101/2020info:eu-repo/semantics/publishedVersio

Investigation of Dendrimer-based nanoparticles cellular uptake and cell tracking in a semiautomated microfluidic platform

A microfluidic device such as Kima Pump and Vena8 biochip is able to realize functions that are not easily imaginable in conventional biological analysis, such as highly parallel, sophisticated high-throughput analysis and single-cell analysis in a well-defined manner [1]. Cancer cell tracking within the microfluidic model will be achieved by grafting fluorescent label probe Fluorescein-5(6)-isothiocyanate (FITC) to dendrimer nanoparticles allowing cell visualization by immunofluorescent staining followed by fluorescence microscopy. In this study, synthesis and physicochemical characterization of Carboxymethyl-chitosan/poly(amidoamine) dendrimer nanoparticles (CMCht/PAMAM NPâ s) were performed[2].  Several cancer cell lines such as a HeLA (cervical carcinoma cell line), HTTC-116 (Colon Carcinoma) and Glioblastome cell line (GBM) were exposed to different concentrations of CMCht/PAMAM dendrimer nanoparticles over a period of 7d. After finding the adequate NP concentration, the internalization efficiency was tested, as well as cellular trafficking, in static and dynamic conditions (Kima Pump bioreactor).Portuguese Foundation for Science and Technology (FCT) through the project PEst­C/SAU/LA0026/20

Characterization of antioxidants activity in a microfluidic channel

Antioxidant is the common designation for substances that have a potential action in the prevention of oxidative stress. The characterization of the reactivity of these substances has attracted the attention of many researchers, with the aim to establish correlations between the intake of antioxidants and health maintenance or to detect early stages of diseases associated with oxidative stress. The measurement of antioxidant capacity of physiological fluids (blood serum, saliva or urine) or foodstuff is currently performed by means of different methods, mostly based on spectrophotometric detection. Voltammetry has gained popularity in this context.[1] Whereas peak potentials are used to characterize the reactivity of the antioxidant, the peak currents (or the area under voltammograms) are used for the antioxidant capacity evaluation. Although voltammetric methods constitute one of the most effective means to monitor the antioxidant electron-transfer reactions, quantitative information is not directly obtained from voltammograms of antioxidants mixtures. The antioxidant capacity is usually evaluated by relative parameters defined towards a reference substance. The significance of this result is limited and cannot be translated in the effective protection degree provided by the antioxidant. In a recent work, we have proposed an analytical method for the evaluation of the reducing antioxidant capacity of antioxidants evaluated by electrolysis (RACE). [2] The oxidation of antioxidants is analyzed in large scale controlled potential electrolysis and its consumption is monitored at the anode by the current decrease. The monitored charge for the complete oxidation of active antioxidants provides a quantitative measure of their ability to eliminate a given reactive oxygen species, according to the selected potential used in the electrolysis. In order to transfer the RACE methodology to a sensor design, electrochemical microfluidic devices were built and tested. Experimental variables such as device geometry and flow rate were optimised in order to achieve a thin-layer regime in mass transport [3]. The chronoamperometric response of antioxidants was analyzed to evaluate its reducing power at selected potentials, according to the nature of the reactive oxygen species whose action is simulated. These results demonstrated the validity of the concept

Sugarcane straw polyphenols as potential food and nutraceutical ingredient

The sugarcane processing industry generates a large amount of straw, which has a negative environmental impact, and high costs are associated with their elimination, wasting their potential bioactive value attributed to their richness in polyphenols. In this study, an ethanolic extract produced from sugarcane straw was screened for its phenolic compounds content, and the potential use of this extract in the development of a food ingredient was further evaluated. Fifty different secondary metabolites belonging to the hydroxybenzoic acids, hydroxycinnamic acids, and flavonoids were identified by liquid chromatography–electrospray ionization–ultrahigh-resolution—quadrupole time of flight–mass spectrometry (LC-ESI-UHR-QqTOF-MS). The predominant phenolic compounds found were 4-hydroxybenzaldehyde, chlorogenic acid, and 5-O-feruloylquinic acid. The obtained extracts showed strong potential as food preservatives by exhibiting (a) antioxidant activity using both 2.2′-azino-bis (3-ethylbenzothiazoline-6-sulphonic acid) diammonium salt radical cation (ABTS) and 2,2-diphenyl-1-picrylhydrazyl (DPPH) methods; and (b) antimicrobial capacity, with a minimum inhibitory concentration of 50 mg/mL for Staphylococcus aureus, 74% inhibition for Bacillus cereus, and 44% for Salmonella enterica; and (c) the capacity to inhibit a food browning enzyme, tyrosinase (28–73% for 1–8 mg/ mL). Moreover, the extracts showed antidiabetic potential by inhibiting the enzymes α-glucosidase (15–38% for 1.25–5.00 mg/mL) and dipeptidyl peptidase-IV (DPP-IV) (62–114% for 0.31–5.00 mg/mL). The extract (0.625 mg/mL) also exhibited the capacity to reduce proinflammatory mediators (i.e., interleukins 6 and 8, and tumor necrosis factor alpha) when Caco-2 cells were stimulated with interleukin 1 beta. Thus, sugarcane straw extract, which is rich in phenolic compounds, showed high potential to be used in the development of food-preservative ingredients owing to its antioxidant and antimicrobial potential, and to be explored as a food supplement in diabetes prevention and as coadjuvant to reduce intestinal inflammation by reducing proinflammatory mediators.info:eu-repo/semantics/publishedVersio

Bioengineered nanoparticles loaded-hydrogels to target TNF Alpha in inflammatory diseases

Rheumatoid Arthritis (RA) is an incurable autoimmune disease that promotes the chronic impairment of patientsâ mobility. For this reason, it is vital to develop therapies that target early inflammatory symptoms and act before permanent articular damage. The present study offers two novel therapies based in advanced drug delivery systems for RA treatment: encapsulated chondroitin sulfate modified poly(amidoamine) dendrimer nanoparticles (NPs) covalently bonded to monoclonal anti-TNF α antibody in both Tyramine-Gellan Gum and Tyramine-Gellan Gum/Silk Fibroin hydrogels. Using pro-inflammatory THP-1 (i.e., human monocytic cell line), the therapy was tested in an inflammation in vitro model under both static and dynamic conditions. Firstly, we demonstrated effective NP-antibody functionalization and TNF-α capture. Upon encapsulation, the NPs were released steadily over 21 days. Moreover, in static conditions, the approaches presented good anti-inflammatory activity over time, enabling the retainment of a high percentage of TNF α. To mimic the physiological conditions of the human body, the hydrogels were evaluated in a dual-chamber bioreactor. Dynamic in vitro studies showed absent cytotoxicity in THP-1 cells and a significant reduction of TNF-α in suspension over 14 days for both hydrogels. Thus, the developed approach showed potential for use as personalized medicine to obtain better therapeutic outcomes and decreased adverse effects.The authors thank the financial support provided under the Norte2020 project (NORTE-08-5369-FSE000044). D.C.F. acknowledges the Portuguese Foundation for Science and Technology (FCT) for her PhD scholarship (PD/BD/143081/2018) and F.R.M. for her contract under the Transitional Rule DL 57/2016 (CTTI-57/18-I3BS(5)). The FCT distinction attributed to J.M.O. under the Investigator FCT program (number IF/01285/2015) is also greatly acknowledged