Efficacy of marbofloxacin against respiratory infections of lambs

The trial was carried out in a sheep flock with mixed Mannheimia haemolytica/Mycoplasma spp. respiratory infection; 60 lambs were included therein and allocated as follows: lambs in group MH were subcutaneously injected with marbofloxacin (3.0 mg/kg bodyweight) on two occasions, once daily 2 days apart – lambs in group ML3 were given marbofloxacin (2.0 mg/kg) on three occasion, once daily for three consecutive days – lambs in group ML2 were given marbofloxacin (2.0 mg/kg) on two occasions, 2 days apart – lambs in group T were subcutaneously injected with tilmicosin (15 mg/kg) on two occasions, 4 days apart – lambs in group C were untreated controls. The lambs were monitored before and after treatment and the clinical findings were scored; they were euthanatised 42 days after treatment for pathological examination of the lungs. Groups were similar at the start of a field trial with respect to all parameters (general clinical condition, presence of nasal discharge, presence of ophthalmic discharge, results of lung auscultation) evaluated (P > 0.05). After treatment, no systemic or local adverse reactions were observed in any lamb. Forty-two days after treatment, the median general clinical assessment score of groups MH, ML3 and T was 0, that of group ML2 was 1 and that of group C lambs was 2 (P < 0.01). Treatment with marbofloxacin was associated with improved clinical scores; the results were similar for all evaluations 14 days after treatment and subsequently. Clinical cure rate 42 days after treatment was 100, 100, 42, 100 and 0% for group MH, ML3, ML2, T and C lambs, respectively (P < 0.01). After controlling for initial weight, treatment was found to have a significant effect on carcass weight (P < 0.01). Pairwise differences in lung lesion scores between any of the four treated groups and the untreated controls were significant (P < 0.02). It is concluded that marbofloxacin is effective against respiratory infections of lambs at a dose rate of 3.0 mg/kg bodyweight given on two occasions, once daily 2 days apart or at a dose rate of 2.0 mg/kg given on three occasions for three consecutive days.     

Contributions of MIR to soundscape ecology. Part 3: Tagging and classifying audio features using a multi-labeling k-nearest neighbor approach

Scientists are using acoustic monitoring to assess the impact of altered soundscapes on wildlife communities and human systems. In the soundscape ecology field, monitoring and analyses approaches rely on the interdisciplinary intersection of ecology, acoustics, and computer science. Combining theory and practice of each field in the context of Knowledge Discovery in Databases (KDD), soundscape ecologists provide innovative monitoring solutions for ecologically-driven research questions. We propose a soundscape content analysis framework for improved knowledge outcome with assistance of the new multi-label (ML) concept.Here, we investigated the effectiveness of a ML k-nearest neighbor algorithm (ML-kNN) for labeling concurrent soundscape components within a single recording. We manually labeled 1200 field recordings for the presence of soundscape components and extracted ecological acoustic features, audio profile features, and Gaussian-mixture model features for each recording. Then, we tested the ML-kNN algorithm accuracy with well-established metrics adapted to ML learning.We found that seventeen unique acoustic features could predict a set of biophonic, geophonic, and anthrophonic labels for a single field recording with average precision of 0.767. However, certain labels were predicted incorrectly depending on the time of day and co-occurrence of that label with another label, suggesting further refinement is needed to improve the accuracy of predicted labels.Overall, this ML classification approach could enable researchers to label field recordings more quickly and generate an “alert” system for monitoring changes in a specific sound class. Ultimately, the adaptation of the ML algorithm may provide soundscape ecologists with new metadata labels that are searchable in large databases of soundscape field recordings.     

Inheritance, biochemical abnormalities, and clinical features of feline mucolipidosis II: the first animal model of human I-cell disease

Mucolipidosis II (ML II), also called I-cell disease, is a unique lysosomal storage disease caused by deficient activity of the enzyme N-acetylglucosamine-1-phosphotransferase, which leads to a failure to internalize enzymes into lysosomes. We report on a colony of domestic shorthair cats with ML II that was established from a half-sibling male of an affected cat. Ten male and 9 female kittens out of 89 kittens in 26 litters born to clinically normal parents were affected; this is consistent with an autosomal recessive mode of inheritance. The activities of three lysosomal enzymes from affected kittens, compared to normal adult control cats, were high in serum (11-73 times normal) but low in cultured fibroblasts (9-56% of normal range) that contained inclusion bodies (I-cells), reflecting the unique enzyme defect in ML II. Serum lysosomal enzyme activities of adult obligate carriers were intermediate between normal and affected values. Clinical features in affected kittens were observed from birth and included failure to thrive, behavioral dullness, facial dysmorphia, and ataxia. Radiographic lesions included metaphyseal flaring, radial bowing, joint laxity, and vertebral fusion. In contrast to human ML II, diffuse retinal degeneration leading to blindness by 4 months of age was seen in affected kittens. All clinical signs were progressive and euthanasia or death invariably occurred within the first few days to 7 months of life, often due to upper respiratory disease or cardiac failure. The clinical and radiographic features, lysosomal enzyme activities, and mode of inheritance are homologous with ML II in humans. Feline ML II is currently the only animal model in which to study the pathogenesis of and therapeutic interventions for this unique storage disease.     

Facial Structure Alterations and Abnormalities of the Paranasal Sinuses on Multidetector Computed Tomography Scans of Patients with Treated Mucosal Leishmaniasis

Background/Objectives

Mucosal leishmaniasis (ML) is a progressive disease that affects cartilage and bone structures of the nose and other upper respiratory tract structures. Complications associated with ML have been described, but there is a lack of studies that evaluate the structural changes of the nose and paranasal sinuses in ML using radiological methods. In this study, we aimed to assess the opacification of the paranasal sinuses in patients with treated ML and any anatomical changes in the face associated with ML using multidetector computed tomography scans (MDCT) of the sinuses. We compared the findings with a control group.

Methodology/Principal Findings

We evaluated 54 patients with treated ML who underwent CT scans of the sinuses and compared them with a control group of 40 patients who underwent orbital CT scans. The degree of sinus disease was assessed according to the Lund-Mackay criteria. Forty of the 54 patients with a history of ML (74.1%) had a tomographic score compatible with chronic sinusitis (Lund-Mackay ≥4). CT scans in the leishmaniasis and control groups demonstrated significant differences in terms of facial structure alterations. Patients from the ML group showed more severe levels of partial opacification and pansinus mucosal thickening (42.6%) and a greater severity of total opacification. Patients from the ML group with a Lund-Mackay score ≥4 presented longer durations of disease before treatment and more severe presentations of the disease at diagnosis.

Conclusion/Significance

CT scans of the sinuses of patients with ML presented several structural alterations, revealing a prominent destructive feature of the disease. The higher prevalence in this study of chronic rhinosinusitis observed in CT scans of patients with treated ML than in those of the control group suggests that ML can be considered a risk factor for chronic rhinosinusitis in this population (p<0.05).     

α2-Macroglobulin-like protein 1 can conjugate and inhibit proteases through their hydroxyl groups,because of an enhanced reactivity of its thiol ester

Proteins in the α-macroglobulin (αM) superfamily use thiol esters to form covalent conjugation products upon their proteolytic activation. αM protease inhibitors use theirs to conjugate proteases and preferentially react with primary amines (e.g. on lysine side chains), whereas those of αM complement components C3 and C4B have an increased hydroxyl reactivity that is conveyed by a conserved histidine residue and allows conjugation to cell surface glycans. Human α₂-macroglobulin–like protein 1 (A2ML1) is a monomeric protease inhibitor but has the hydroxyl reactivity–conveying histidine residue. Here, we have investigated the role of hydroxyl reactivity in a protease inhibitor by comparing recombinant WT A2ML1 and the A2ML1 H1084N mutant in which this histidine is removed. Both of A2ML1s'' thiol esters were reactive toward the amine substrate glycine, but only WT A2ML1 reacted with the hydroxyl substrate glycerol, demonstrating that His-1084 increases the hydroxyl reactivity of A2ML1''s thiol ester. Although both A2ML1s conjugated and inhibited thermolysin, His-1084 was required for the conjugation and inhibition of acetylated thermolysin, which lacks primary amines. Using MS, we identified an ester bond formed between a thermolysin serine residue and the A2ML1 thiol ester. These results demonstrate that a histidine-enhanced hydroxyl reactivity can contribute to protease inhibition by an αM protein. His-1084 did not improve A2ML1''s protease inhibition at pH 5, indicating that A2ML1''s hydroxyl reactivity is not an adaption to its acidic epidermal environment.     

An open real-time tele-stethoscopy system

ABSTRACT: BACKGROUND: Acute respiratory infections are the leading cause of childhood mortality. The lack of physicians in rural areas of developing countries makes difficult their correct diagnosis and treatment. The staff of rural health facilities (health-care technicians) may not be qualified to distinguish respiratory diseases by auscultation. For this reason, the goal of this project is the development of a tele-stethoscopy system that allows a physician to receive real-time cardio-respiratory sounds from a remote auscultation, as well as video images showing where the technician is placing the stethoscope on the patient's body. METHODS: A real-time wireless stethoscopy system was designed. The initial requirements were: 1) The system must send audio and video synchronously over IP networks, not requiring an Internet connection; 2) It must preserve the quality of cardiorespiratory sounds, allowing to adapt the binaural pieces and the chestpiece of standard stethoscopes, and; 3) Cardiorespiratory sounds should be recordable at both sides of the communication. In order to verify the diagnostic capacity of the system, a clinical validation with eight specialists has been designed. In a preliminary test, twelve patients have been auscultated by all the physicians using the tele-stethoscopy system, versus a local auscultation using traditional stethoscope. The system must allow listen the cardiac (systolic and diastolic murmurs, gallop sound, arrhythmias) and respiratory (rhonchi, rales and crepitations, wheeze, diminished and bronchial breath sounds, pleural friction rub) sounds. RESULTS: The design, development and initial validation of the real-time wireless tele-stethoscopy system are described in detail. The system was conceived from scratch as open-source, low-cost and designed in such a way that many universities and small local companies in developing countries may manufacture it. Only free open-source software has been used in order to minimize manufacturing costs and look for alliances to support its improvement and adaptation. The microcontroller firmware code, the computer software code and the PCB schematics are available for free download in a subversion repository hosted in SourceForge. CONCLUSIONS: It has been shown that real-time tele-stethoscopy, together with a videoconference system that allows a remote specialist to oversee the auscultation, may be a very helpful tool in rural areas of developing countries.     

A mantle length structured stock assessment model for the jumbo squid,Dosidicus gigas,fishery of the Ecuadorian Pacific: a limited data approach

The jumbo squid Dosidicus gigas is a new fishery resource in Ecuador; the species is harvested from January to December every year. Biological sampling was carried out each month during March–December (2013) and January–December (2014) in different coastal zones off Ecuador, and the monthly mantle length (ML) composition was obtained from field data in the coastal areas. The catch-at-mantle length data were analysed based on the mantle length structured model (CAMLA). The results showed that the biomass of D. gigas in Pacific Ecuadorian waters was 641,915 t (2013) and 1,866,857 t (2014). For 2013, for squid smaller than 30?cm ML the biomass was greater than 30,000 t, while individuals between 35 and 48?cm ML had an estimated biomass varying between 35,000 and 45,000 t. During 2014, the biomass estimated for squid smaller than 30?cm ML was low (40,000 t or less); however, squid between 38 and 48?cm ML showed a change in biomass compared with the previous fishing season, varying from 100,000 to 190,000 t. The harvested rate-at-mantle length for squid larger than 35?cm ML was higher than for individuals between 12 and 30?cm ML. The CAMLA model was found to be appropriate for modelling catch-at-mantle length of jumbo squid in Ecuadorian waters, and the model can be used to obtain harvest management quantities, as well as quantitative outputs useful for Ecuadorian stakeholders.     

Walking variability during continuous pseudo-random oscillations of the support surface and visual field

Walking on uneven surfaces or while undergoing perturbations has been associated with increased gait variability in both modeling and human studies. Previous gait research involving continuous perturbations has focused on sinusoidal oscillations, which can result in individuals predicting the perturbation and/or entraining to it. Therefore, we examined the effects of continuous, pseudo-random support surface and visual field oscillations on 12 healthy, young participants. Participants walked in a virtual reality environment under no perturbation (NOP), anterior–posterior (AP) walking surface and visual oscillation and mediolateral (ML) walking surface and visual oscillation conditions. Participants exhibited shorter (p≤0.005), wider (p<0.001) and faster (p<0.001) steps relative to NOP during ML perturbations and shorter (p≤0.005) and wider (p<0.001) steps during AP perturbations. Step length variability and step width variability both increased relative to NOP during all perturbation conditions (p<0.001) but exhibited greater increases for the ML perturbations (p<0.001). Participants exhibited greater trunk position variability and trunk velocity variability in the ML direction than in the AP direction during ML perturbations relative to NOP (p<0.001). Significantly greater variability in the ML direction indicates that to maintain stability, participants needed to exert greater control in the ML direction. This observation is consistent with prior modeling predictions. The large and consistent responses observed during ML visual and walking surface perturbations suggest potential for application during gait training and patient assessment.     

Machine learning in bioprocess development: from promise to practice

Fostered by novel analytical techniques, digitalization, and automation, modern bioprocess development provides large amounts of heterogeneous experimental data, containing valuable process information. In this context, data-driven methods like machine learning (ML) approaches have great potential to rationally explore large design spaces while exploiting experimental facilities most efficiently. Herein we demonstrate how ML methods have been applied so far in bioprocess development, especially in strain engineering and selection, bioprocess optimization, scale-up, monitoring, and control of bioprocesses. For each topic, we will highlight successful application cases, current challenges, and point out domains that can potentially benefit from technology transfer and further progress in the field of ML.     

A decision tree--based method for the differential diagnosis of Aortic Stenosis from Mitral Regurgitation using heart sounds

Background  

New technologies like echocardiography, color Doppler, CT, and MRI provide more direct and accurate evidence of heart disease than heart auscultation. However, these modalities are costly, large in size and operationally complex and therefore are not suitable for use in rural areas, in homecare and generally in primary healthcare set-ups. Furthermore the majority of internal medicine and cardiology training programs underestimate the value of cardiac auscultation and junior clinicians are not adequately trained in this field. Therefore efficient decision support systems would be very useful for supporting clinicians to make better heart sound diagnosis. In this study a rule-based method, based on decision trees, has been developed for differential diagnosis between "clear" Aortic Stenosis (AS) and "clear" Mitral Regurgitation (MR) using heart sounds.     

Multiple maxima of likelihood in phylogenetic trees: an analytic approach

Maximum likelihood (ML) is a widely used criterion for selecting optimal evolutionary trees. However, the nature of the likelihood surface for trees is still not sufficiently understood, especially with regard to the frequency of multiple optima. Here, we initiate an analytic study for identifying sequences that generate multiple optima. We concentrate on the problem of optimizing edge weights for a given tree or trees (as opposed to searching through the space of all trees). We report a new approach to computing ML directly, which we have used to find large families of sequences that have multiple optima, including sequences with a continuum of optimal points. Such data sets are best supported by different (two or more) phylogenies that vary significantly in their timings of evolutionary events. Some standard biological processes can lead to data with multiple optima, and consequently the field needs further investigation. Our results imply that hill-climbing techniques as currently implemented in various software packages cannot guarantee that one will find the global ML point, even if it is unique.     

Parsimony, likelihood, and the role of models in molecular phylogenetics

Methods such as maximum parsimony (MP) are frequently criticized as being statistically unsound and not being based on any "model." On the other hand, advocates of MP claim that maximum likelihood (ML) has some fundamental problems. Here, we explore the connection between the different versions of MP and ML methods, particularly in light of recent theoretical results. We describe links between the two methods--for example, we describe how MP can be regarded as an ML method when there is no common mechanism between sites (such as might occur with morphological data and certain forms of molecular data). In the process, we clarify certain historical points of disagreement between proponents of the two methodologies, including a discussion of several forms of the ML optimality criterion. We also describe some additional results that shed light on how much needs to be assumed about underlying models of sequence evolution in order to successfully reconstruct evolutionary trees.     

Biochemical,Cellular, and Biophysical Characterization of a Potent Inhibitor of Mutant Isocitrate Dehydrogenase IDH1

Two mutant forms (R132H and R132C) of isocitrate dehydrogenase 1 (IDH1) have been associated with a number of cancers including glioblastoma and acute myeloid leukemia. These mutations confer a neomorphic activity of 2-hydroxyglutarate (2-HG) production, and 2-HG has previously been implicated as an oncometabolite. Inhibitors of mutant IDH1 can potentially be used to treat these diseases. In this study, we investigated the mechanism of action of a newly discovered inhibitor, ML309, using biochemical, cellular, and biophysical approaches. Substrate binding and product inhibition studies helped to further elucidate the IDH1 R132H catalytic cycle. This rapidly equilibrating inhibitor is active in both biochemical and cellular assays. The (+) isomer is active (IC₅₀ = 68 nm), whereas the (−) isomer is over 400-fold less active (IC₅₀ = 29 μm) for IDH1 R132H inhibition. IDH1 R132C was similarly inhibited by (+)-ML309. WT IDH1 was largely unaffected by (+)-ML309 (IC₅₀ >36 μm). Kinetic analyses combined with microscale thermophoresis and surface plasmon resonance indicate that this reversible inhibitor binds to IDH1 R132H competitively with respect to α-ketoglutarate and uncompetitively with respect to NADPH. A reaction scheme for IDH1 R132H inhibition by ML309 is proposed in which ML309 binds to IDH1 R132H after formation of the IDH1 R132H NADPH complex. ML309 was also able to inhibit 2-HG production in a glioblastoma cell line (IC₅₀ = 250 nm) and had minimal cytotoxicity. In the presence of racemic ML309, 2-HG levels drop rapidly. This drop was sustained until 48 h, at which point the compound was washed out and 2-HG levels recovered.     

The effects of location and design on the diffusion of respiratory gases in mammal burrows

To investigate the constraints placed on the location and design of mammal burrows by the resident mammal's need for an adequate exchange of respiratory gases with the free atmosphere, we constructed several simple mathematical models for the steady-state diffusion of these gases in sterile burrow-soil systems. In this exchange, diffusion through the soil is of prime importance. Openings of narrow tunnels further than three body lengths from a mammal have a negligible effect on its respiratory microenvironment. Since only a short length of a narrow tunnel around the mammal is of importance in this exchange we may confine attention to design and siting criteria for a discrete chamber containing the mammal.The porosity of the soil in which a burrow chamber is sited and the volume of the burrow chamber have strong and moderate effects respectively on the rate of gas exchange between a resident mammal and the free atmosphere. The depth of the burrow chamber, beyond two chamber diameters, has only a weak effect on this transfer. Soil temperature within the thermoneutral zone of the resident mammal has a weak effect on this transfer, but below the thermoneutral zone, where temperature modifies the rate of consumption (production) of respiratory gas, the effect is strong. Concentrations of respiratory gas in the burrow chamber approach free-atmosphere values when soil porosity, soil temperature, and chamber volume increase and burrow depth decreases.Large mammals are more restricted in the design and siting of burrows than small mammals. Our models indicate that normothermic eutherian mammals with masses much in excess of 0·5 kg are precluded from an indefinite occupation of deep burrows in most field situations. In considering the limitations to our models, several avenues for expanding a mammal's respiratory space are suggested.     

Advances in application of machine learning to life cycle assessment: a literature review

Purpose

Life Cycle Assessment (LCA) is the process of systematically assessing impacts when there is an interaction between the environment and human activity. Machine learning (ML) with LCA methods can help contribute greatly to reducing impacts. The sheer number of input parameters and their uncertainties that contribute to the full life cycle make a broader application of ML complex and difficult to achieve. Hence a systems engineering approach should be taken to apply ML in isolation to aspects of the LCA. This study addresses the challenge of leveraging ML methods to deliver LCA solutions. The overarching hypothesis is that: LCA underpinned by ML methods and informed by dynamic data paves the way to more accurate LCA while supporting life cycle decision making.

Methods

In this study, previous research on ML for LCA were considered, and a literature review was undertaken.

Results

The results showed that ML can be a useful tool in certain aspects of the LCA. ML methods were shown to be applied efficiently in optimization scenarios in LCA. Finally, ML methods were integrated as part of existing inventory databases to streamline the LCA across many use cases.

Conclusions

The conclusions of this article summarise the characteristics of existing literature and provide suggestions for future work in limitations and gaps which were found in the literature.

     

Clinical criteria for Mucosal Leishmaniasis diagnosis in rural South America: A systematic literature review

BackgroundMucosal Leishmaniasis (ML), a neglected tropical disease caused by Leishmania parasites, impairs the quality of life of under-resourced populations in South America. If not treated promptly, this disease progresses to facial deformities and death. The low sensitivity of microscopy results and the unavailability of other accurate tests hamper the diagnosis. As clinical criteria are readily available in any setting, these may be combined in a syndromic algorithm, which in turn can be used as a diagnostic tool. We explore potential clinical criteria for a syndromic diagnostic algorithm for ML in rural healthcare settings in South America.Methodology/Principal findingsThe protocol for this systematic review was pre-registered in PROSPERO with the number: CRD42017074148. In patients with ML, described in case series identified through a systematic retrieval process, we explored the cumulative ML detection rates of clinical criteria. Participants: all patients with active mucosal disease from an endemic area in South America. Any original, non-treatment study was eligible, and case reports were excluded. PUBMED, EMBASE, Web of Science, SCIELO, and LILACS databases were searched without restrictions. The risk of bias was assessed with the JBI checklist for case series. We included 10 full texts describing 192 ML patients. Male gender had the highest detection rate (88%), followed by ulcer of the nasal mucosa (77%), age >15 (69%), and symptom duration >4 months (63%).SignificanceWithin this selection of patients, we found that the male gender, ulcer of the nasal mucosa, age >15, and symptom duration >4 months lead to the highest detection rates. However, higher detection comes -naturally- with a higher rate of false positives as well. As we only included ML patients, this could not be verified. Therefore, the criteria that we found to be most promising should be validated in a well-designed prospective study.     

Covariation of GC content and the silent site substitution rate in rodents: implications for methodology and for the evolution of isochores

Many attempts to test selectionist and neutralist models employ estimates of synonymous (Ks) and non-synonymous (Ka) substitution rates of orthologous genes. For example, a stronger Ka-Ks correlation than expected under neutrality has been argued to indicate a role for selection and the absence of a Ks-GC4 correlation has been argued to be inconsistent with neutral models for isochore evolution. However, both of these results, we have shown previously, are sensitive to the method by which Ka and Ks are estimated. Using a maximum likelihood (ML) estimator (GY94) we found a positive correlation between Ks and GC4 and only a weak correlation between Ka and Ks, lower than expected under neutral expectations. This ML method is computationally slow. Recently, a new ad hoc approximation of this ML method has been provided (YN00). This is effectively an extension of Li's protocol but that also allows for codon usage bias. This method is computationally near-instantaneous and therefore potentially of great utility for analysis of large datasets. Here we ask whether this method might have such applicability. To this end we ask whether it too recovers the two unusual results. We report that when the ML and earlier ad hoc methods disagree, YN00 recovers the results described by the ML methods, i.e. a positive correlation between GC4 and Ks and only a weak correlation between Ks and Ka. If the ML method can be trusted, then YN00 can also be considered an adequately reliable method for analysis of large datasets. Assuming this to be so we also analyze further the patterns. We show, for example, that the positive correlation between GC4 and Ks is probably in part a mutational bias, there being more methyl induced CpG-->TpG mutations in GC rich regions. As regards the evolution of isochores, it seems inappropriate to use the claimed lack of a correlation between GC and Ks as definitive evidence either against or for any model. If the positive correlation is real then, we argue, this is hard to reconcile with the biased gene conversion model for isochore formation as this predicts a negative correlation.     

Regression-based quantitative trait loci mapping: robust, efficient and effective

Regression has always been an important tool for quantitative geneticists. The use of maximum likelihood (ML) has been advocated for the detection of quantitative trait loci (QTL) through linkage with molecular markers, and this approach can be very effective. However, linear regression models have also been proposed which perform similarly to ML, while retaining the many beneficial features of regression and, hence, can be more tractable and versatile than ML in some circumstances. Here, the use of linear regression to detect QTL in structured outbred populations is reviewed and its perceived shortfalls are revisited. It is argued that the approach is valuable now and will remain so in the future.