JURNAL AGROTEKNOLOGI
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Genotypic and phenotypic characterization of Staphylococcus aureus isolates from the respiratory tract in mechanically-ventilated patients
No full textStaphylococcus aureus is a commensal and frequent colonizer of the upper respiratory tract. When mechanical ventilation disrupts natural defenses, S. aureus is frequently isolated from the lower airways, but distinguishing between colonization and infection is difficult. The objectives of this study were (1) to investigate the bacterial genome sequence in consecutive isolates in order to identify changes related to the pathological adaptation to the lower respiratory tract and (2) to explore the relationship between specific phenotypic and genotypic features with the patient’s study group, persistence of the clinical isolate and clinical outcome. A set of 94 clinical isolates were selected and corresponded to 34 patients that were classified as having pneumonia (10), tracheobronchitis (11) and bronchial colonization (13). Clinical strains were phenotypically characterized by conventional identification and susceptibility testing methods. Isolates underwent whole genome sequencing using Illumina HiSeq4000. Genotypic characterization was performed with an in-house pipeline (BacterialTyper). Genomic variation arising within-host was determined by comparing mapped sequences and de novo assemblies. Virulence factors important in staphylococcal colonization and infection were characterized using previously established functional assays. (1) Toxin production was assessed using a THP-1 cytotoxicity assay, which reports on the gross cytotoxicity of individual isolates. In addition, we investigated the expression of the major virulence factor, alpha-toxin (Hla) by Western blot. (2) Adhesion to the important extracellular matrix molecule, fibronectin, was determined using a standardized microtitre plate assay. Finally, invasion experiments using THP-1 and A539 cell lines and selected clinical strains were also performed. Repeated isolation of S. aureus from endotracheal aspirate usually reflects persistence of the same strain. Within-host variation is detectable in this setting, but it shows no evidence of pathological adaptation related to virulence, resistance or niche adaptations. Cytotoxicity was variable among isolates with 14 strains showing no cytotoxicity, with these latter presenting an unaltered Fn binding capacity. No changes on cytotoxicity were reported when comparing study groups. Fn binding capacity was reported for almost all strains, with the exception of two strains that presented the lowest values. Strains isolated from patients with pneumonia presented a lower capacity of adhesion in comparison to those isolated during tracheobronchitis (p = 0.002). Hla was detected in 71 strains (75.5%), with most of the producer strains in pneumonia and bronchial colonization group (p = 0.06). In our cohort, Hla expression (presence or absence) in sequential isolates was usually preserved (70%) although in seven cases the expression varied over time. No relationship was found between low cytotoxicity and intracellular persistence in invasion experiments. In our study population, persistent S. aureus isolation from airways in ventilated patients does not reflect pathological adaptation. There is an important diversity of sequence types. Cytotoxicity is variable among strains, but no association with study groups was found, whereas isolates from patients with pneumonia had lower adhesion capability. Favorable clinical outcome correlated with increased bacterial adhesion in vitro. Most of the strains isolated from the lower airways were Hla producers and no correlation with an adverse outcome was reported. The identification of microbial factors that contribute to virulence is relevant to optimize patient management during lower respiratory tract infections
Railways as patient capital
No full textWhy are railways mostly in the public sector? Interest rates define a time limit for markets. Projects with longer break-evens cannot be funded by business alone. Corporate ‘franchise’ arrangements overcome the limit by means of revenue guarantees which transfer risks to government. Innovations originate bottom-up in private enterprise. Positive externalities create demand for universal provision but scaling up cannot be financed commercially. In the British railway manias of the 1830s and 1840s speculative fever overwhelmed prudence. Overinvestment left an excessive infrastructure legacy and wiped out windfall profits. In other countries railways required external support. Expanding access give rise to stand-offs with investors which ended up in government regulation or takeover. The tramway boom of 1870 to 1914 followed this pattern, initially with horse power and then electricity. In the UK railway privatisation of the 1990s, the free market delusion was confounded by the infrastructure requirement for long-term commitment
Specific body mass index trajectories were related to musculoskeletal pain and mortality: 19-year follow-up cohort
No full textObjective
We aimed to study 19-year body mass index (BMI) patterns and their (1) bidirectional relationship with musculoskeletal pain and (2) mortality risk.
Study design and Setting
We used data from the Chingford study and group-based trajectory modelling to define 19-year BMI patterns. We investigated whether baseline back, hand, hip, and knee pain (as single- and multi-site) predicted 19-year BMI trajectory, and whether 19-year BMI patterns predicted pain in year 20. We explored BMI trajectories and mortality risk over 25 years (life expectancy).
Results
We included 938 women (mean age: year-1=54, year-20=72) and found seven distinct 19-year BMI trajectories: two normal-weighted (reference), slightly overweight, lower and upper overweight-to-obese, lower and upper obese. BMI patterns capturing the increase overweight-to-obese (BMI 27-34 overtime) were bidirectionally related to knee and multi-site pain. The lower obese pattern (BMI 33-38) was unidirectionally associated with lower limb pain. Women with BMI above 40 had an increased all-cause and cardiovascular mortality risk.
Conclusions
For most postmenopausal women, the overweight WHO category was a transition. Two patterns capturing increase overweight-to-obese were mutually related to musculoskeletal pain, i.e., knee and multi-site pain contributed to becoming obese, and trajectories of becoming obese increased the odds of experiencing pain later
KCNK18 biallelic variants associated with intellectual disability and neurodevelopmental disorders alter TRESK channel activity
No full textThe TWIK-related spinal cord potassium channel (TRESK) is encoded by KCNK18, and variants in this gene have previously been associated with susceptibility to familial migraine with aura (MIM #613656). A single amino acid substitution in the same protein, p.Trp101Arg, has also been associated with intellectual disability (ID), opening the possibility that variants in this gene might be involved in different disorders. Here, we report the identification of KCNK18 biallelic missense variants (p.Tyr163Asp and p.Ser252Leu) in a family characterized by three siblings affected by mild-to-moderate ID, autism spectrum disorder (ASD) and other neurodevelopment-related features. Functional characterization of the variants alone or in combination showed impaired channel activity. Interestingly, Ser252 is an important regulatory site of TRESK, suggesting that alteration of this residue could lead to additive downstream effects. The functional relevance of these mutations and the observed co-segregation in all the affected members of the family expand the clinical variability associated with altered TRESK function and provide further insight into the relationship between altered function of this ion channel and human disease
An assay to investigate factors influencing initial orientation in nocturnally fledging seabirds
No full textThe first solitary migration of juvenile birds is difficult to study because of a low juvenile survival rates and sometimes long delays in return to the breeding grounds. Consequently, little is known about this crucial life event for many bird species, in particular the sensory guidance mechanisms facilitating the first migratory journey. Initial orientation during the first migration is a key measure to investigate these mechanisms. Here, we developed an assay to measure initial orientation as flight direction upon first take‐off in nocturnally fledging juvenile seabirds. We dorsally deployed a coloured LED on juvenile birds to allow researchers to observe the vanishing bearings of individuals as they flew out to sea. Additionally, we co‐deployed either a small Neodymium magnet or glass bead (control) on top of the bird's head to investigate the use of magnetoreception, previously unexplored in this early life stage.
We used this assay to observe the first flight of Manx shearwaters (Puffinus puffinus) and found that they did not orient towards their wintering ground straight after taking off. Further, we did not find an effect of the magnetic treatment on juveniles’ flight direction, though whether this is due to the birds not using magnetoreception, other salient cues being available or a lack of motivation to orient to the migratory beeline is unclear. We were, however, able to identify wind direction and topography as drivers of first flight direction in Manx shearwaters, which fledged with wind component between a crosswind and a tailwind and directed their maiden flight towards the sea and away from the land.
This novel assay will facilitate the study of the maiden flight of nocturnally fledging birds and will help advance the study of sensory guidance mechanisms underpinning migratory orientation in a wide range of taxa, including species which are traditionally challenging to study
Is psychosis a syndemic manifestation of historical and contemporary adversity? findings from UKBioBank
No full textAims: Psychosis is associated with many forms of adversity, deprivation, and living in urban areas. This paper tests if psychosis may be a part of a syndemic of multiple adversities.
Methods: Drawing on UK Biobank data (UKBB) (access ID: 57601), we sought to understand mechanisms by which childhood, recent/contemporary and place-based adversities might cluster and interact to be implicated in pathways by which psychoses evolves. We investigated the associations between adversities,
potential mediating inflammatory markers, and ICD-10 diagnoses (F20-F31) of psychotic disorders. We fitted logistic regression models initially including all relevant candidate variables and used backwards deletion to retain theoretically plausible and statistically significant (p<0.05) associations with psychotic disorders. The candidate variables were entered in a partial least square structural equation model (PLSSEM) to test for syndemic interactions between risk factors. We tested whether the findings were
sensitive to demographics; sex and ethnicity.
Results: We fitted a PLS-SEM model with including psychosis as a syndemic outcome, and identified three latent constructs: Life-time Adversity, Current Adversity and Biomarkers. Factor loadings were above 0.30, and all structural paths were significant (p<0.05). There were moderate associations between Life-time
Adversity and Current Adversity (standardised coefficient (sc) = 0.178), Current Adversity and Biomarkers (sc = 0.227). All three latent constructs showed small but significant associations with psychosis (sc<0.04). Life-time Adversity and Current Adversity were more strongly associated among ethnic minorities (combined) than White British people in the model.
Conclusions: Our findings stress the importance of interactions between childhood and contemporary adversities in preventive and therapeutic interventions for psychotic disorders, especially among ethnic minorities
Reward sensitivity and action in Parkinson’s disease patients with and without apathy
No full textClinical apathy results in dysfunction of goal directed behaviour, a key component of which is the initiation of action. Previous work has suggested that blunting of reward sensitivity is an important mechanism underlying apathy. However, an additional component might be impoverished initiation of action itself. This study aims to investigate the link between motivation and motor output and its association with apathy and dopamine. An oculomotor task that measures pupillary and saccadic response to monetary incentives was used to assess reward sensitivity, first in 23 young and 18 elderly controls, and then in 22 patients with Parkinson’s disease tested ON and OFF dopaminergic medication. To distinguish between pupillary responses to anticipated reward alone versus responses associated with motor preparation, a saccadic ‘go/no-go’ task was performed. Half of the trials required a saccade to be initiated to receive a reward and in the remaining trials no action was required but reward was still obtained. No significant difference in pupil response was demonstrated between the two conditions in all groups tested, suggesting pupillary responses to rewards are not contingent upon motor preparation in Parkinson’s disease. Being ON or OFF dopamine did not influence this response either. Previous work demonstrated associations between apathy and pupillary reward insensitivity in Parkinson’s disease. Here we observed this effect only when an action was required to receive a reward, and only in the ON state. These findings suggest that apathy in Parkinson’s disease is linked to reduced reward sensitivity and that this is most prominently observed when actions have to be initiated to rewarding goals, with the effect modulated by being ON dopaminergic medication. OFF medication, there was no such strong relationship, and similarly in the ‘no-go’ conditions, either ON or OFF dopaminergic drugs. The results provide preliminary data which suggest that apathy in Parkinson’s disease is associated with a reduction in reward sensitivity and this is most evident when associated with initiation of goal directed actions in the presence of adequate dopamine
Kinetics of abacavir-induced remodelling of the major histocompatibility complex class I peptide repertoire
No full textAbacavir hypersensitivity syndrome can occur in individuals expressing the HLA-B*57:01 major histocompatibility complex class I allotype when utilising the drug abacavir as a part of their anti-retroviral regimen. The drug is known to bind within the HLA-B*57:01 antigen binding cleft, leading to the selection of novel self-peptide ligands, thus provoking life-threatening immune responses. However, the sub-cellular location of abacavir binding and the mechanics of altered peptide selection are not well understood. Here, we probed the impact of abacavir on the assembly of HLA-B*57:01 peptide complexes. We show that whilst abacavir had minimal impact on the maturation or average stability of HLA-B*57:01 molecules, abacavir was able to differentially enhance the formation, selectively decrease the dissociation, and alter tapasin loading dependency of certain HLA-B*57:01-peptide complexes. Our data reveals a spectrum of abacavir mediated effects on the immunopeptidome which reconciles the heterogeneous functional T cell data reported in the literature
Unsupervised learning of 3D object categories from videos in the wild
No full textOur goal is to learn a deep network that, given a small number of images of an object of a given category, reconstructs it in 3D. While several recent works have obtained analogous results using synthetic data or assuming the availability of 2D primitives such as keypoints, we are interested in working with challenging real data and with no manual annotations. We thus focus on learning a model from multiple views of a large collection of object instances. We contribute with a new large dataset of object centric videos suitable for training and benchmarking this class of models. We show that existing techniques leveraging meshes, voxels, or implicit surfaces, which work well for reconstructing isolated objects, fail on this challenging data. Finally, we propose a new neural network design, called warp-conditioned ray embedding (WCR), which significantly improves reconstruction while obtaining a detailed implicit representation of the object surface and texture, also compensating for the noise in the initial SfM reconstruction that bootstrapped the learning process. Our evaluation demonstrates performance improvements over several deep monocular reconstruction baselines on existing benchmarks and on our novel dataset. For additional material please visit: https://henzler. github.io/publication/unsupervised_videos/
Updates to the Oxford Space Environment Goniometer to measure visible wavelength bidirectional reflectance distribution functions in ambient conditions
No full textUnderstanding how the surfaces of airless planetary bodies—such as the Moon—scatter visible light enables constraints to be placed on their surface properties and top boundary layer inputs to be set within thermal models. Remote sensing instruments—such as Diviner onboard the Lunar Reconnaissance Orbiter—measure thermal emission and visible light scattering functions across visible (∼0.38–0.7 µm) to thermal infrared (TIR) wavelengths (∼0.7–350 μm). To provide ground support measurements for such instruments, the Oxford Space Environment Goniometer (OSEG) was built. Initially, the OSEG focused on measuring TIR directional emissivity functions for regolith and regolith simulant samples in a simulated space environment, but it has recently been modified to measure visible wavelength Bidirectional Reflectance Distribution Functions (BRDFs) of samples in ambient conditions. Laboratory-measured BRDFs can be used (1) to test and to help interpret models—such as the Hapke photometric model—and (2) as visible scattering function inputs for thermal models. This paper describes the modifications to and initial calibration measurements taken by the Visible Oxford Space Environment Goniometer with a 532 nm laser, and details how this setup can be used to measure BRDFs of regolith and regolith simulant samples of airless planetary bodies