Miracle-dz/UniFAR-FTUs huggingface dataset:
Increased retinal neovascularization in Fas ligand-deficient mice.

PURPOSE To investigate whether the absence of the Fas-Fas ligand system of apoptosis regulation affects hyperoxia-induced retinal vaso-obliteration and retinal neovascularization in a mouse model of oxygen-induced retinopathy. METHODS C57BL/6 (B6) and congenic Fas ligand-deficient generalized lymphoproliferative disease (gld) mice were exposed to 75% oxygen from postnatal day (P)7 to P12 and then allowed to recover in room air. Eyes obtained from P7, P8, P10, P12, P14, P17, and P21, from both hyperoxia-injured and room air control animals were processed for histopathologic examination. Retinopathy was also qualitatively assessed in FITC-dextran perfused retinas by fluorescence microscopy. TUNEL assays were used to compare apoptosis in B6 and gld mice. Intraretinal blood vessel formation was quantitated by immunolabeling with an anti-type-IV collagen antibody. Retinopathy was further assessed by quantitation of preretinal neovascular nuclei on P17. RT-PCR was used to examine retinal expression of Fas and Fas ligand (FasL) over a time course of hyperoxia-induced retinopathy. RESULTS In hyperoxia-injured mice, the same degree of vaso-obliteration was apparent on P8, P10, and P12 in B6 and gld mice. By P17, the hyperoxia-exposed FITC-perfused retinas of both strains exhibited preretinal neovascular tufts. However, P17 gld hyperoxia-exposed retinas exhibited approximately a 50% increase in preretinal neovascular nuclei compared with B6 mice. In addition, a subset of apoptotic cells located solely within the neovascular tufts on P17 were significantly decreased in hyperoxia-exposed gld retinas, compared with B6 control animals. RT-PCR showed an increase in the expression levels of Fas in both strains of mice as a result of hyperoxia-induced injury. CONCLUSIONS These data suggest that the Fas-FasL interaction plays an important role in retinal neovascularization after hyperoxia-induced injury. The absence of functional FasL leads to an increased incidence of preretinal neovascular nuclei and decreased retinal apoptosis suggesting that this pathway may serve as a means of regulating endogenous endothelial cell populations in pathologic angiogenesis.
Molecular phylogeny, 3D-structural insights, docking and mechanisms of action of plant beta-galactosidases

Beta-galactosidase BGAL is an exoglycosidase that catalyses the hydrolysis of terminal β-linked galactose residues. To better understand the molecular characteristics and structural insights of mango BGAL MiBGAL, we performed the sequence analyses, reconstruction of the evolutionary tree, homology modelling and molecular docking. BGALs are widely distributed enzymes that evolved from a common bacterial ancestor. Plant BGALs pBGALs belong to glycosyl hydrolase-35GH35 family and had close similarities with fungi BGALs. Three conserved motifs and GH35 putative active site with a consensus sequence G-G-P-[LIVM]2-x2-Q-x-E-N-E-[FY] were identified in 67 BGAL sequences. Modelled 3D structure of MiBGAL is composed of a catalytic TIM barrel domain domain-I and three other β-domains, II, III & IV. Structural studies identified the residues Glu182 and Glu251 as the proton donor and nucleophile, respectively in pBGALs that could function through retaining mechanism. p-nitrophenyl-β-D-galactopyranoside and 2-[4-2-hydroxyethylpiperazin-1-yl]ethanesulfonic acid could be potential substrate and inhibitor, respectively among the docked-ligands for both tomato BGAL4 and MiBGAL.
Molecular immunology profiles of monkeys following xenografting with the islets and heart of α‐1,3‐galactosyltransferase knockout pigs

Effective immunosuppression strategies and genetically modified animals have been used to prevent hyperacute and acute xenograft rejection; however, the underlying mechanisms remain unknown. In this study, we evaluated the expression of a comprehensive set of immune system‐related genes (89 genes, including five housekeeping genes) in the blood of cynomolgus monkeys (~5 yr old) used as graft recipients, before and after the xenografting of the islets and heart from single and double α‐1,3‐galactosyltransferase (GalT) knockout (KO) pigs (<6 weeks old). The immunosuppressive regimen included administration of cobra venom factor, anti‐thymocyte globulin, rituximab, and anti‐CD154 monoclonal antibodies to recipients before and after grafting. Islets were xenografted into the portal vein in type 1 diabetic monkeys, and the heart was xenografted by heterotopic abdominal heart transplantation. Genes from recipient blood were analyzed using RT2 profiler PCR arrays and the web‐based RT2 profiler PCR array software v.3. 5. Recipients treated with immunosuppressive agents without grafting showed significant downregulation of CCL5, CCR4, CCR6, CD4, CD40LG, CXCR3, FASLG, CXCR3, FOXP3, GATA3, IGNG, L10, IL23A, TRAF6, MAPK8, MIF, STAT4, TBX21, TLR3, TLR7, and TYK2 and upregulation of IFNGR1; thus, genes involved in protection against viral and bacterial infection were downregulated, confirming the risk of infection. Notably, C3‐level control resulted in xenograft failure within 2 days because of a 7‐ to 11‐fold increase in all xenotransplanted models. Islet grafting using single GalT‐KO pigs resulted in upregulation of CXCL10 and MX1, early inflammation, and acute rejection‐associated signals at 2 days after xenografting. We observed at least 5‐fold upregulation in recipients transplanted with islets grafts from single (MX1) or double (C3, CCR8, IL6, IL13, IRF6, CXCL10, and MX1) GalT‐KO pigs after 77 days; single GalT‐KO incurred early losses owing to immune attacks. Our results suggest that this novel, simple, non‐invasive, and time‐efficient procedure (requiring only 1.5 ml blood) for evaluating graft success, minimizing immune rejection, and blocking infection.
Incomplete Recovery of Pneumococcal CD4 T Cell Immunity after Initiation of Antiretroviral Therapy in HIV-Infected Malawian Adults

HIV-infected African adults are at a considerably increased risk of life-threatening invasive pneumococcal disease (IPD) which persists despite antiretroviral therapy (ART). Defects in naturally acquired pneumococcal-specific T-cell immunity have been identified in HIV-infected adults. We have therefore determined the extent and nature of pneumococcal antigen-specific immune recovery following ART. HIV-infected adults were followed up at 3, 6 and 12 months after initiating ART. Nasopharyngeal swabs were cultured to determine carriage rates. Pneumococcal-specific CD4 T-cell immunity was assessed by IFN-γ ELISpot, proliferation assay, CD154 expression and intracellular cytokine assay. S. pneumoniae colonization was detected in 27% (13/48) of HIV-infected patients prior to ART. The rates remained elevated after 12 months ART, 41% (16/39) (p = 0.17) and significantly higher than in HIV-uninfected individuals (HIVneg 14%(4/29); p = 0.0147). CD4+ T-cell proliferative responses to pneumococcal antigens increased significantly to levels comparable with HIV-negative individuals at 12 months ART (p = 0.0799). However, recovery of the pneumococcal-specific CD154 expression was incomplete (p = 0.0015) as were IFN-γ ELISpot responses (p = 0.0040) and polyfunctional CD4+ T-cell responses (TNF-α, IL-2 and IFN-γ expression) (p = 0.0040) to a pneumolysin-deficient mutant strain. Impaired control of pneumococcal colonisation and incomplete restoration of pneumococcal-specific immunity may explain the persistently higher risk of IPD amongst HIV-infected adults on ART. Whether vaccination and prolonged ART can overcome this immunological defect and reduce the high levels of pneumococcal colonisation requires further evaluation.
Transformerless active power decoupling topologies for grid connected PV applications

Active power decoupling (APD) topologies are well known for improving the reliability of a single-phase inverter by eliminating the need for electrolytic capacitors at the DC-link. In this paper, several APD topologies are analysed for grid connected PV application, where, the common mode leakage currents are one of the main concerns. It is found that few APD topologies can minimize these leakage currents without any modification in the original circuits. The performance of these APD topologies in minimising the leakage currents are analysed and evaluated using the simulation studies. Further, a new transformerless APD topology is derived and its performance is analysed in minimising the leakage current.
Novel cationic lipid nanoparticles as an ophthalmic delivery system for multicomponent drugs: development, characterization, in vitro permeation, in vivo pharmacokinetic, and molecular dynamics studies

The purpose of this study was to prepare, optimize, and characterize a cationic lipid nanoparticle (CLN) system containing multicomponent drugs using a molecular dynamics model as a novel method of evaluating formulations. Puerarin (PUE) and scutellarin (SCU) were used as model drugs. CLNs were successfully prepared using melt-emulsion ultrasonication and low temperature-solidification technique. The properties of CLNs such as morphology, particle size, zeta potential, entrapment efficiency (EE), drug loading (DL), and drug release behavior were investigated. The CLNs were evaluated by corneal permeation, preocular retention time, and pharmacokinetics in the aqueous humor. Additionally, a molecular dynamics model was used to evaluate the formulation. Electron microscopy results showed that the nanoparticles were approximately spherical in shape. The EE (%) and DL (%) values of PUE and SCU in the optimal formulation were 56.60±3.73, 72.31±1.96 and 1.68±0.17, 2.44±1.14, respectively. The pharmacokinetic study in the aqueous humor showed that compared with the PUE and SCU solution, the area under the concentration–time curve (AUC) value of PUE was enhanced by 2.33-fold for PUE-SCU CLNs (p<0.01), and the SCU AUC was enhanced by 2.32-fold (p<0.01). In the molecular dynamics model, PUE and SCU passed through the POPC bilayer, with an obvious difference in the free energy well depth. It was found that the maximum free energy required for PUE and SCU transmembrane movement was ~15 and 88 kJ·mol−1, respectively. These findings indicated that compared with SCU, PUE easily passed through the membrane. The diffusion coefficient for PUE and SCU were 4.1×10−3±0.0027 and 1.0×10−3±0.0006 e−5cm2·s−1, respectively. Data from the molecular dynamics model were consistent with the experimental data. All data indicated that CLNs have a great potential for ocular administration and can be used as an ocular delivery system for multicomponent drugs. Moreover, the molecular dynamics model can also be used as a novel method for evaluating formulations.
Dipole Localization Errors due to not Incorporating Compartments with Anisotropic Conductivities: Simulation Study in a Spherical Head Model

EEG source localisation has proven to be a valuable tool in the presurgical evaluation of patients with epilepsy. However, the typical volume conductor models used for this purpose do not take into account the anistropic properties of the skull and white matter in the brain. We investigated the dipole localisation error due to not taking into account the anisotropic conductivities of the skull and white matter. We found that only neglecting skull anisotropy causes an error of on average 20.16 mm for cortical test dipoles and 4.14 mm for test dipoles in the thalamic shell. Neglecting only white matter anisotropy causes an error of on average 4.23 mm for cortical dipoles and 17.05 mm for test dipoles in the thalamic shell. Neglecting both white matter anisotropy and skull anisotropy causes a dipole localisation error of 22.54 mm in the cortical region, while in the thalamic shell the error is on average 7.62 mm. The error caused by not taking into account the anisotropic conductivity is not negligible. Therefore, one must incorporate the anisotropic conductivities in the volume conductor for EEG dipole source localization.
The Protein Feature Ontology: a tool for the unification of protein feature annotations

MOTIVATION The advent of sequencing and structural genomics projects has provided a dramatic boost in the number of uncharacterized protein structures and sequences. Consequently, many computational tools have been developed to help elucidate protein function. However, such services are spread throughout the world, often with standalone web pages. Integration of these methods is needed and so far this has not been possible as there was no common vocabulary available that could be used as a standard language. RESULTS The Protein Feature Ontology has been developed to provide a structured controlled vocabulary for features on a protein sequence or structure and comprises approximately 100 positional terms, now integrated into the Sequence Ontology (SO) and 40 non-positional terms which describe features relating to the whole-protein sequence. In addition, post-translational modifications are described by using a pre-existing ontology, the Protein Modification Ontology (MOD). This ontology is being used to integrate over 150 distinct annotations provided by the BioSapiens Network of Excellence, a consortium comprising 19 partner sites in Europe. AVAILABILITY The Protein Feature Ontology can be browsed by accessing the ontology lookup service at the European Bioinformatics Institute (http://www.ebi.ac.uk/ontology-lookup/browse.do? ontName=BS).
Imbalance of synaptic actin dynamics as a key to fragile X syndrome?

Our experiences and memories define who we are, and evidence has accumulated that memory formation is dependent on functional and structural adaptations of synaptic structures in our brain. Especially dendritic spines, the postsynaptic compartments of synapses show a strong structure‐to‐function relationship and a high degree of structural plasticity. Although the molecular mechanisms are not completely understood, it is known that these modifications are highly dependent on the actin cytoskeleton, the major cytoskeletal component of the spine. Given the crucial involvement of actin in these mechanisms, dysregulations of spine actin dynamics (reflected by alterations in dendritic spine morphology) can be found in a variety of neurological disorders ranging from schizophrenia to several forms of autism spectrum disorders such as fragile X syndrome (FXS). FXS is caused by a single mutation leading to an inactivation of the X‐linked fragile X mental retardation 1 gene and loss of its gene product, the RNA‐binding protein fragile X mental retardation protein 1 (FMRP), which normally can be found both pre‐ and postsynaptically. FMRP is involved in mRNA transport as well as regulation of local translation at the synapse, and although hundreds of FMRP‐target mRNAs could be identified only a very few interactions between FMRP and actin‐regulating proteins have been reported and validated. In this review we give an overview of recent work by our lab and others providing evidence that dysregulated actin dynamics might indeed be at the very base of a deeper understanding of neurological disorders ranging from cognitive impairment to the autism spectrum.
Evaluation of elephant grass silage with the addition of cassava scrapings

Objetivou-se com este experimento avaliar os efeitos da adicao de raspa de mandioca na ensilagem sobre as perdas por gases e efluentes, a recuperacao da materia seca, o pH, os teores de N-NH3, acidos orgânicos e acidos graxos volateis e a composicao bromatologica de silagens de capim-elefante. Utilizou-se um delineamento inteiramente casualizado, com quatro niveis de raspa de mandioca (0, 7, 15 ou 30% da materia natural), cada um com quatro repeticoes. O capim foi cortado aos 50 dias de rebrota e ensilado em silos de 15 litros de capacidade, com valvula de bunsen para escape dos gases. A adicao de raspa de mandioca ocasionou reducao quadratica nas perdas por gases e reducao linear nas perdas por efluente. A recuperacao de materia seca aumentou de forma quadratica com a adicao de raspa de mandioca. O teor de materia seca aumentou, enquanto os de proteina bruta, fibra em detergente neutro, fibra em detergente acido (FDA) e hemicelulose diminuiram linearmente com a adicao de raspa de mandioca. O valor de pH e o teor de acido latico aumentaram de forma quadratica com a adicao de raspa de mandioca. Os teores de N-NH3 e de acido butirico diminuiram de forma quadratica com a adicao de raspa de mandioca, enquanto o teor de acido acetico diminuiu linearmente. A inclusao de raspa de mandioca na ensilagem reduz as perdas por gases e efluentes e melhora o perfil fermentativo de silagens de capim-elefante e o nivel de 7% da materia natural e suficiente para assegurar essa melhora.
Germline CDH1 deletions in hereditary diffuse gastric cancer families

Germline CDH1 point or small frameshift mutations can be identified in 30–50% of hereditary diffuse gastric cancer (HDGC) families. We hypothesized that CDH1 genomic rearrangements would be found in HDGC and identified 160 families with either two gastric cancers in first-degree relatives and with at least one diffuse gastric cancer (DGC) diagnosed before age 50, or three or more DGC in close relatives diagnosed at any age. Sixty-seven carried germline CDH1 point or small frameshift mutations. We screened germline DNA from the 93 mutation negative probands for large genomic rearrangements by Multiplex Ligation-Dependent Probe Amplification. Potential deletions were validated by RT–PCR and breakpoints cloned using a combination of oligo-CGH-arrays and long-range-PCR. In-silico analysis of the CDH1 locus was used to determine a potential mechanism for these rearrangements. Six of 93 (6.5%) previously described mutation negative HDGC probands, from low GC incidence populations (UK and North America), carried genomic deletions (UK and North America). Two families carried an identical deletion spanning 193 593 bp, encompassing the full CDH3 sequence and CDH1 exons 1 and 2. Other deletions affecting exons 1, 2, 15 and/or 16 were identified. The statistically significant over-representation of Alus around breakpoints indicates it as a likely mechanism for these deletions. When all mutations and deletions are considered, the overall frequency of CDH1 alterations in HDGC is ∼46% (73/160). CDH1 large deletions occur in 4% of HDGC families by mechanisms involving mainly non-allelic homologous recombination in Alu repeat sequences. As the finding of pathogenic CDH1 mutations is useful for management of HDGC families, screening for deletions should be offered to at-risk families.
Non‐uniform displacement and strain between the soleus and gastrocnemius subtendons of rat Achilles tendon

Achilles tendon (AT) comprises of 3 subtendons arising from the soleus (SOL) and the lateral (LG) and medial (MG) heads of the gastrocnemius muscle. While recent human studies show differential displacement within AT, these displacements have not been attributed to specific subtendons. We tested the hypothesis that the SOL and LG subtendons show differential displacement and strain during various combinations of SOL, LG, and MG excitations. Movement of knots, sutured onto SOL and LG subtendons of 12 Wistar rats, was videotaped, while the muscles were stimulated intramuscularly and ankle torque was assessed. When SOL only was stimulated, the plantar flexion torque was the smallest among the different conditions (P < .001). In this condition, from passive to active state, the displacement (0.57 vs 0.47 mm, P = .002) and strain (8.4% vs 2.4%, P < .001) in the SOL subtendon were greater than in LG subtendon. When LG only was stimulated, a higher ankle torque was measured as compared to SOL stimulation (P < .001); the displacement was similar in both subtendons (~0.6 mm), while the strain was greater in LG than in SOL (4.7% vs 1.7%, P < .001). When all 3 muscles were stimulated simultaneously, ankle torque was highest and the displacement (0.79 vs 0.74 mm, P = .002) and strain (7.7% vs 4.4%, P = .003) were greater in SOL than in LG. These data show that the different subtendons of AT can experience relative displacement and differential strains. Together with anatomical dissections, the results revealed that such uniformities may be due to a lower stiffness of SOL subtendon compared to LG.
Attribute-based Decision Graphs for multiclass data classification

Graph-based representation has been successfully used to support various machine learning and data mining algorithms. The learning algorithms strongly rely on the algorithm employed for constructing the graph from input data, given as a set of vector-based patterns. A popular way to build such graphs is to treat each data pattern as a vertex; vertices are then connected according to some similarity measure, resulting in an structure known as data graph. In this paper we propose a new type of data graph, focused on data attributes, named Attribute-based Decision Graph - AbDG, suitable for supervised multiclass classification tasks. The input data for constructing an AbDG is a set of data-vectors (patterns), that can be described by either type of attributes (numeric, categorical or both). Also, algorithms for constructing such graphs and using them in classification tasks are described. An AbDG can be associated to a classifying procedure approached as a graph matching process, where the sub-graph representing a new pattern is matched against the AbDG. The proposed approach has been experimentally evaluated on classification tasks in twenty knowledge domains and the results are competitive when compared to those of two well-known classification methods (C4.5 and Multi-Interval ID3).
Power MOSFET Linearizer of a High-Voltage Power Amplifier for High-Frequency Pulse-Echo Instrumentation

A power MOSFET linearizer is proposed for a high-voltage power amplifier (HVPA) used in high-frequency pulse-echo instrumentation. The power MOSFET linearizer is composed of a DC bias-controlled series power MOSFET shunt with parallel inductors and capacitors. The proposed scheme is designed to improve the gain deviation characteristics of the HVPA at higher input powers. By controlling the MOSFET bias voltage in the linearizer, the gain reduction into the HVPA was compensated, thereby reducing the echo harmonic distortion components generated by the ultrasonic transducers. In order to verify the performance improvement of the HVPA implementing the power MOSFET linearizer, we measured and found that the gain deviation of the power MOSFET linearizer integrated with HVPA under 10 V DC bias voltage was reduced (−1.8 and −0.96 dB, respectively) compared to that of the HVPA without the power MOSFET linearizer (−2.95 and −3.0 dB, respectively) when 70 and 80 MHz, three-cycle, and 26 dBm input pulse waveforms are applied, respectively. The input 1-dB compression point (an index of linearity) of the HVPA with power MOSFET linearizer (24.17 and 26.19 dBm at 70 and 80 MHz, respectively) at 10 V DC bias voltage was increased compared to that of HVPA without the power MOSFET linearizer (22.03 and 22.13 dBm at 70 and 80 MHz, respectively). To further verify the reduction of the echo harmonic distortion components generated by the ultrasonic transducers, the pulse-echo responses in the pulse-echo instrumentation were compared when using HVPA with and without the power MOSFET linearizer. When three-cycle 26 dBm input power was applied, the second, third, fourth, and fifth harmonic distortion components of a 75 MHz transducer driven by the HVPA with power MOSFET linearizer (−48.34, −44.21, −48.34, and −46.56 dB, respectively) were lower than that of the HVPA without the power MOSFET linearizer (−45.61, −41.57, −45.01, and −45.51 dB, respectively). When five-cycle 20 dBm input power was applied, the second, third, fourth, and fifth harmonic distortions of the HVPA with the power MOSFET linearizer (−41.54, −41.80, −48.86, and −46.27 dB, respectively) were also lower than that of the HVPA without the power MOSFET linearizer (−25.85, −43.56, −49.04, and −49.24 dB, respectively). Therefore, we conclude that the power MOSFET linearizer could reduce gain deviation of the HVPA, thus reducing the echo signal harmonic distortions generated by the high-frequency ultrasonic transducers in pulse-echo instrumentation.