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Glanders is a highly contagious and life-threatening zoonotic disease caused by Burkholderia mallei ( B. mallei ). Without an effective vaccine or treatment, early diagnosis has been regarded as the most effective method to prevent glanders transmission. Currently, the diagnosis of glanders is heavily reliant on serological tests. However, given that markedly different host immune responses can be elicited by genetically different strains of the same bacterial species, infection by B. mallei , whose genome is unstable and plastic, may result in various immune responses. This variability can make the serodiagnosis of glanders challenging. Therefore, there is a need for a comprehensive understanding and assessment of how B. mallei genomic variations impact the appropriateness of specific target antigens for glanders serodiagnosis. In this study, we investigated how genomic variations in the B. mallei genome affect gene content (gene presence/absence) and expression, with a special focus on antigens used or potentially used in serodiagnosis. In all the genome sequences of B. mallei isolates available in NCBI's RefSeq database (accessed in July 2023) and in-house sequenced samples, extensive small and large variations were observed when compared to the type strain ATCC 23344. Further pan-genome analysis of those assemblies revealed variations of gene content among all available genomes of B. mallei . Specifically, differences in gene content ranging from 31 to 715 genes with an average of 334 gene presence-absence variations were found in strains with complete or chromosome-level genome assemblies, using the ATCC 23344 strain as a reference. The affected genes included some encoded proteins used as serodiagnostic antigens, which were lost due mainly to structural variations. Additionally, a transcriptomic analysis was performed using the type strain ATCC 23344 and strain Zagreb which has been widely utilized to produce glanders antigens. In total, 388 significant differentially expressed genes were identified between these two strains, including genes related to bacterial pathogenesis and virulence, some of which were associated with genomic variations, particularly structural variations. To our knowledge, this is the first comprehensive study to uncover the impacts of genetic variations of B. mallei on its gene content and expression. These differences would have significant impacts on host innate and adaptive immunity, including antibody production, during infection. This study provides novel insights into B. mallei genetic variants, knowledge which will help to improve glanders serodiagnosis., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Charron, Gao, Chmara, Hoover, Nadin-Davis, Chauvin, Hazelwood, Makondo, Duceppe and Kang.)

Passively administered monoclonal antibodies (mAbs) given before or after viral infection can prevent or blunt disease. Here, we examine the efficacy of aerosol mAb delivery to prevent infection and disease in rhesus macaques inoculated with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Delta variant via intranasal and intratracheal routes. SARS-CoV-2 human mAbs or a human mAb directed to respiratory syncytial virus (RSV) are nebulized and delivered using positive airflow via facemask to sedated macaques pre- and post-infection. Nebulized human mAbs are detectable in nasal, oropharyngeal, and bronchoalveolar lavage (BAL) samples. SARS-CoV-2 mAb treatment significantly reduces levels of SARS-CoV-2 viral RNA and infectious virus in the upper and lower respiratory tracts relative to controls. Reductions in lung and BAL virus levels correspond to reduced BAL inflammatory cytokines and lung pathology. Aerosolized antibody therapy for SARS-CoV-2 could be effective for reducing viral burden and limiting disease severity., (© 2023. The Author(s).)

The accurate, rapid, and specific detection of DNA strands in solution is becoming increasingly important, especially in biomedical applications such as the trace detection of COVID-19 or cancer diagnosis. In this work we present the design, elaboration and characterization of an optofluidic sensor based on a polymer-based microresonator which shows a quick response time, a low detection limit and good sensitivity. The device is composed of a micro-racetrack waveguide vertically coupled to a bus waveguide and embedded within a microfluidic circuit. The spectral response of the microresonator, in air or immersed in deionised water, shows quality factors up to 72,900 and contrasts up to 0.9. The concentration of DNA strands in water is related to the spectral shift of the microresonator transmission function, as measured at the inflection points of resonance peaks in order to optimize the signal-over-noise ratio. After functionalization by a DNA probe strand on the surface of the microresonator, a specific and real time measurement of the complementary DNA strands in the solution is realized. Additionally, we have inferred the dissociation constant value of the binding equilibrium of the two complementary DNA strands and evidenced a sensitivity of 16.0 pm/µM and a detection limit of 121 nM.

Compared to open-field crops, the influence of the surrounding landscape on insect diversity in greenhouse crops has been poorly studied. Due to growing evidence of insect influx in greenhouses, identifying the landscape properties influencing the protected crop colonization by insect pests and their natural enemies would promote the improvement of both pest prevention and conservation biological control methods. Here, we present a field study on the effect of the surrounding landscape on the colonization of greenhouse crops by insect pests and associated natural enemies. By monitoring 32 greenhouse strawberry crops in the South West of France, we surveyed crop colonization by four insect pests and four natural enemy groups over two cultivation periods. Our results showed that the landscape structure and composition could have contrasting effects on insect colonization of greenhouse crops so there could be species-specific effects and not general ones. While the degree of openness of greenhouses and the pest management practices modulated insect diversity marginally, we also showed that seasonality represented a key factor in insect crop colonization. The various responses of insect pests and natural enemy groups to the landscape support the idea that pest management methods must involve the surrounding environment.

Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) marks the third novel β-coronavirus to cause significant human mortality in the last two decades. Although vaccines are available, too few have been administered worldwide to keep the virus in check and to prevent mutations leading to immune escape. To determine if antibodies could be identified with universal coronavirus activity, plasma from convalescent subjects was screened for IgG against a stabilized pre-fusion SARS-CoV-2 spike S2 domain, which is highly conserved between human β-coronavirus. From these subjects, several S2-specific human monoclonal antibodies (hmAbs) were developed that neutralized SARS-CoV-2 with recognition of all variants of concern (VoC) tested (Beta, Gamma, Delta, Epsilon, and Omicron). The hmAb 1249A8 emerged as the most potent and broad hmAb, able to recognize all human β-coronavirus and neutralize SARS-CoV and MERS-CoV. 1249A8 demonstrated significant prophylactic activity in K18 hACE2 mice infected with SARS-CoV-2 lineage A and lineage B Beta, and Omicron VoC. 1249A8 delivered as a single 4 mg/kg intranasal (i.n.) dose to hamsters 12 hours following infection with SARS-CoV-2 Delta protected them from weight loss, with therapeutic activity further enhanced when combined with 1213H7, an S1-specific neutralizing hmAb. As little as 2 mg/kg of 1249A8 i.n. dose 12 hours following infection with SARS-CoV Urbani strain, protected hamsters from weight loss and significantly reduced upper and lower respiratory viral burden. These results indicate in vivo cooperativity between S1 and S2 specific neutralizing hmAbs and that potent universal coronavirus neutralizing mAbs with therapeutic potential can be induced in humans and can guide universal coronavirus vaccine development., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: M.S.P., J.-G.P., A.D., F.S.O., M.B., S.S., N.B.E., P.A.G., M.R.W., L.M.-S., and J.J.K. are co-inventors on patents that include claims related to the hmAbs described. A.L., D.C., J.W., P.L., and V.L.T. are employees of Aridis Pharmaceuticals.

Virulence gene expression can represent a substantial fitness cost to pathogenic bacteria. In the model entero-pathogen Salmonella Typhimurium (S.Tm), such cost favors emergence of attenuated variants during infections that harbor mutations in transcriptional activators of virulence genes (e.g., hilD and hilC). Therefore, understanding the cost of virulence and how it relates to virulence regulation could allow the identification and modulation of ecological factors to drive the evolution of S.Tm toward attenuation. In this study, investigations of membrane status and stress resistance demonstrate that the wild-type (WT) expression level of virulence factors embedded in the envelope increases membrane permeability and sensitizes S.Tm to membrane stress. This is independent from a previously described growth defect associated with virulence gene expression in S.Tm. Pretreating the bacteria with sublethal stress inhibited virulence expression and increased stress resistance. This trade-off between virulence and stress resistance could explain the repression of virulence expression in response to harsh environments in S.Tm. Moreover, we show that virulence-associated stress sensitivity is a burden during infection in mice, contributing to the inherent instability of S.Tm virulence. As most bacterial pathogens critically rely on deploying virulence factors in their membrane, our findings could have a broad impact toward the development of antivirulence strategies., Competing Interests: The authors have declared that no competing interests exist.

Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) marks the third novel β-coronavirus to cause significant human mortality in the last two decades. Although vaccines are available, too few have been administered worldwide to keep the virus in check and to prevent mutations leading to immune escape. To determine if antibodies could be identified with universal coronavirus activity, plasma from convalescent subjects was screened for IgG against a stabilized pre-fusion SARS-CoV-2 spike S2 domain, which is highly conserved between human β-coronavirus. From these subjects, several S2-specific human monoclonal antibodies (hmAbs) were developed that neutralized SARS-CoV-2 with recognition of all variants of concern (VoC) tested (Beta, Gamma, Delta, Epsilon, and Omicron). The hmAb 1249A8 emerged as the most potent and broad hmAb, able to recognize all human β-coronavirus and neutralize SARS-CoV and MERS-CoV. 1249A8 demonstrated significant prophylactic activity in K18 hACE2 mice infected with SARS-CoV-2 lineage A and lineage B Beta, and Omicron VoC. 1249A8 delivered as a single 4 mg/kg intranasal (i.n.) dose to hamsters 12 hours following infection with SARS-CoV-2 Delta protected them from weight loss, with therapeutic activity further enhanced when combined with 1213H7, an S1-specific neutralizing hmAb. As little as 2 mg/kg of 1249A8 i.n. dose 12 hours following infection with SARS-CoV Urbani strain, protected hamsters from weight loss and significantly reduced upper and lower respiratory viral burden. These results indicate in vivo cooperativity between S1 and S2 specific neutralizing hmAbs and that potent universal coronavirus neutralizing mAbs with therapeutic potential can be induced in humans and can guide universal coronavirus vaccine development.

Aspergillosis remains a difficult disease to diagnose antemortem in many species, especially avian species. In the present study, banked plasma samples from various avian species were examined for gliotoxin (GT), which is a recognized key virulence factor produced during the replication of Aspergillus species hyphae and a secondary metabolite bis(methyl)gliotoxin (bmGT). Initially, liquid chromatography-tandem mass spectrometry methods for detecting GT and bmGT were validated in a controlled model using sera obtained from rats experimentally infected with Aspergillus fumigatus . The minimum detection level for both measurements was determined to be 3 ng/ml, and the assay was found to be accurate and reliable. As proof of concept, GT was detected in 85.7% (30/35) of the samples obtained from birds with confirmed aspergillosis and in 60.7% (17/28) of samples from birds with probable infection but only in one of those from clinically normal birds (1/119). None of the birds were positive for bmGT. Repeated measures from birds under treatment suggests results may have prognostic value. Further studies are needed to implement quantitative methods and to determine the utility of this test in surveillance screening in addition to its use as a diagnostic test in birds with suspected aspergillosis.

Although it is well appreciated that gene expression is inherently noisy and that transcriptional noise is encoded in a promoter's sequence, little is known about the extent to which noise levels of individual promoters vary across growth conditions. Using flow cytometry, we here quantify transcriptional noise in Escherichia coli genome-wide across 8 growth conditions and find that noise levels systematically decrease with growth rate, with a condition-dependent lower bound on noise. Whereas constitutive promoters consistently exhibit low noise in all conditions, regulated promoters are both more noisy on average and more variable in noise across conditions. Moreover, individual promoters show highly distinct variation in noise across conditions. We show that a simple model of noise propagation from regulators to their targets can explain a significant fraction of the variation in relative noise levels and identifies TFs that most contribute to both condition-specific and condition-independent noise propagation. In addition, analysis of the genome-wide correlation structure of various gene properties shows that gene regulation, expression noise, and noise plasticity are all positively correlated genome-wide and vary independently of variations in absolute expression, codon bias, and evolutionary rate. Together, our results show that while absolute expression noise tends to decrease with growth rate, relative noise levels of genes are highly condition-dependent and determined by the propagation of noise through the gene regulatory network., Competing Interests: The authors have declared that no competing interests exist.

Radiology is participating in the recent consolidation trend. Larger practices can invest in the infrastructure and teams to help improve the clinical value of the services they deliver. An example of national practice is provided that leverages its scale to promote clinical best practices aimed at reducing variability in the recommendations radiologists make for common imaging findings. This is accomplished by promoting the culture of learning and collaboration. In some initiatives, developing a machine learning tool to facilitate the application of clinical algorithms at the point of dictation facilitates the adoption of the recommendations. Regular feedback on practice and individual performance promotes improvement in performance and personal satisfaction of the clinicians. Cost savings through the reduction of unnecessary imaging studies or invasive procedures as well as improved outcomes through evidence-based follow-up have been achieved. In some cases, reductions in the rupture rate of abdominal aortic aneurysms have been realized through clinical follow-up programs. Embracing a culture of continuous learning through peer learning can lay the foundation for sharing clinical best practices. Having access to the benefits of scale in the form of investment in data, analytics, project management, and machine learning tools can facilitate the process of creating clinical value for our patients., (Copyright © 2019 American College of Radiology. Published by Elsevier Inc. All rights reserved.)

Aspergillus fumigatus is an airborne opportunistic fungal pathogen responsible for severe infections. Among them, invasive pulmonary aspergillosis has become a major concern as mortality rates exceed 50% in immunocompromised hosts. In parallel, allergic bronchopulmonary aspergillosis frequently encountered in cystic fibrosis patients, is also a comorbidity factor. Current treatments suffer from high toxicity which prevents their use in weakened subjects, resulting in impaired prognostic. Because of their low toxicity and high specificity, anti-infectious therapeutic antibodies could be a new alternative to conventional therapeutics. In this study, we investigated the potential of Chitin Ring Formation cell wall transglycosylases of A. fumigatus to be therapeutic targets for therapeutic antibodies. We demonstrated that the Crf target was highly conserved, regardless of the pathophysiological context; whereas the CRF1 gene was found to be 100% conserved in 92% of the isolates studied, Crf proteins were expressed in 98% of the strains. In addition, we highlighted the role of Crf proteins in fungal growth, using a deletion mutant for CRF1 gene, for which a growth decrease of 23.6% was observed after 48 h. It was demonstrated that anti-Crf antibodies neutralized the enzymatic activity of recombinant Crf protein, and delayed fungal growth by 12.3% in vitro when added to spores. In a neutropenic rat model of invasive pulmonary aspergillosis, anti-Crf antibodies elicited a significant recruitment of neutrophils, macrophages and T CD4 lymphocytes but it was not correlated with a decrease of fungal burden in lungs and improvement in survival. Overall, our study highlighted the potential relevance of targeting Crf cell wall protein (CWP) with therapeutic antibodies.

Wendelstein 7-X aims at quasi-steady state operation with up to 10 MW of heating power for 30 min. Power exhaust will be handled predominantly via 10 actively water cooled CFC (carbon-fiber-reinforced carbon) based divertor units designed to withstand power loads of 10 MW/m 2 locally in steady state. If local loads exceed this value, a risk of local delamination of the CFC and failure of entire divertor modules arises. Infrared endoscopes to monitor all main plasma facing components are being prepared, and near real time software tools are under development to identify areas of excessive temperature rise, to distinguish them from non-critical events, and to trigger alarms. Tests with different cameras were made in the recent campaign. Long pulse operation enforces additional diagnostic design constraints: for example, the optics need to be thermally decoupled from the endoscope housing. In the upcoming experimental campaign, a graphite scraper element, in front of the island divertor throat, will be tested as a possible means to protect the divertor pumping gap edges during the transient discharge evolution.

Aspergillosis is a fungal disease due to Aspergillus molds that can affect both humans and animals. As routine diagnosis remains difficult, improvement of basic knowledge with respect to its pathophysiology is critical to search for new biomarkers of infection and new therapeutic targets. Large-scale proteomics allows assessment of protein changes during various disease processes. In the present study, mass spectrometry iTRAQ® (isobaric tags for relative and absolute quantitation) protocol was used for direct identification and relative quantitation of host proteins in diseased fluids and tissues collected from an experimental rat model challenged with Aspergillus, as well as in blood obtained from naturally-infected penguins. In all, mass spectrometry analysis revealed that proteome during aspergillosis was mostly represented by proteins that usually express role in metabolic processes and biological process regulation. Ten and 17 proteins were significantly ≥4.0-fold overrepresented in blood of Aspergillus-diseased rats and penguins, respectively, while five and 39 were negatively ≥4.0-fold depleted within the same samples. In rat lungs, 33 proteins were identified with positive or negative relative changes versus controls and were quite different from those identified in the blood. Except for some zinc finger proteins, kinases, and histone transferases, and while three pathways were common (Wnt, cadherin and FGF), great inter-species variabilities were observed regarding the identity of the differentially-represented proteins. Thus, this finding confirmed how difficult it is to define a unique biomarker of infection. iTRAQ® protocol appears as a convenient proteomic tool that is greatly suited to ex vivo exploratory studies and should be considered as preliminary step before validation of new diagnostic markers and new therapeutic targets in humans., Competing Interests: The authors have declared that no competing interests exist.

Background: Hypoxia continues to present risks in military aviation. Hypoxia symptoms include sensory and cognitive effects; of these, it is important to identify which components of operator performance are most vulnerable to hypoxia-induced decline in order to determine which sensory modality is most effective for alerting an impaired aviator of an imminent hypoxic episode., Methods: A study was performed in a hypobaric chamber to characterize deterioration of cognitive performance under moderate (MH) and severe (SH) hypoxia conditions, culminating in subjects' inability to perform tasks. Subjects operated a synthetic workstation, performing multiple simultaneous tasks during hypobaric exposures equivalent to 5486 m (18,000 ft) MH and 7620 m (25,000 ft) SH ascents. Performance was compared across baseline, altitude exposure, and recovery periods within MH vs. SH altitude profiles. Ascents lasted until at least one of a list of termination criteria was met, at which point the chamber was returned to ground level pressure and the subject resumed workstation performance during recovery., Results: SH conditions generated greater deficits than MH conditions, and these more severe effects hastened the termination of exposures (5 vs. 18 min mean duration, respectively). Workstation performance collapsed rapidly on SH exposure, with Mathematics and Auditory Monitoring tasks proving vulnerable to breakdown. In MH exposures, these tasks exhibited impaired accuracy (declining 11% and 9%, respectively) and speed, with declines in Auditory Monitoring lingering into recovery., Discussion: The relative robustness of memory and visual monitoring vs. the vulnerability of mathematical and auditory processing suggest that care should be taken designing purely auditory cockpit hypoxia warning alerts.Beer JMA, Shender BS, Chauvin D, Dart TS, Fischer J. Cognitive deterioration in moderate and severe hypobaric hypoxia conditions. Aerosp Med Hum Perform. 2017; 88(7):617-626.

Here we report the conception, synthesis and evaluation of new hydrophilic rhodamine-based enzymatic substrates for detection of peptidase activity compatible with high-throughput screening using droplet-based microfluidics.

Cerebrotendinous xanthomatosis (CTX) is a rare inborn disorder of sterol storage with autosomal recessive inheritance and a variable clinical presentation. We describe two siblings with an early psychiatric presentation of CTX-associated attention-deficit/hyperactivity disorder and oppositional defiant disorder, also associated with a mild intellectual disability and major behavioral impairments. In both cases, treatment with chenodeoxycholic acid improved externalized symptoms and a partial recovery of cognitive impairments was observed. This suggests that CTX is potentially reversible, demonstrating the need for early diagnosis and treatment of this disorder before irreversible neurological lesions can occur.

Reading therapy has been shown to be effective in treating reading disabilities (RD) in dyslexic children, but little is known of its use in subjects with mild mental retardation (MR). Twenty adult volunteers, with both RD and mild MR, underwent 60 consecutive weeks in a cognitive remediation program, and were compared with 32 untreated control subjects. The experimental group showed a significant improvement in word identification, as measured by oral production (p=0.0004) or silent reading (p=0.023), and sentence comprehension (p=0.0002). Adults with MR appear to benefit from new approaches in the field of RD.

Objective: To assess the relationship between word identification and intelligence in adults with mild mental retardation (IQ < 80)., Method: A standardized evaluation was administered to 67 adults with mild mental retardation. The evaluation included a psychiatric interview, the WAIS-R, and a 2-h interview with a speech therapist and reading tests., Results: Causes of mental retardation were diverse in the sample, and IQ scores ranged from 43 to 79 (mean score = 64). All subjects exhibited reading impairment, including 69% with severe impairment. No subject with an IQ score under 65 was able to perform adequately in the word identification tasks. Word identification was correlated with total and verbal IQ, but not with performance IQ., Conclusion: Our results suggest that, in contrast to subjects with normal intelligence, IQ score is correlated with reading in subjects with mild mental retardation. Finally, remediation should be preferentially implemented for subjects with IQ score greater than 65.

Clinicians and parents are familiar with the fact that adolescents have a special vocabulary, but very few studies have examined this. Linguists describe it as deeply metaphoric, creative and lively, thus showing that young people have a deep knowledge of language and truly experience pleasure using words. This contrasts with teachers' complaints about the little taste adolescents show for oral school activities and how poorly they express themselves. Some of them link this to the use of this polysemic and all purpose vocabulary. The context of locution is probably the explanation for these diverging opinions. Using this hypothesis, we have realised a quantitative study of the lexical variations depending on the person the adolescent is talking to in two groups (20 and 19 subjects), from very different social and educational backgrounds. Each teen-ager had to perform the same linguistic task: the description of a photograph on two occasions, once with an adult examiner and once with a friend. We studied the lexical differences between the two narratives. When adolescents are together they use their particular vocabulary four times more than when with an adult. But this qualitative difference is not a quantitative one, such as the length of the narrative or the number and repetition of whole words, and isn't correlated with the lexical stock. The use of this vocabulary runs across gender and social class categories. It can equally be found in high performance and upper class students as well as in underprivileged youngsters of technical schooling. It is the only variable that does not change between the two high schools. Thus this special vocabulary would not be connected to the subject's lexical competence, nor to gender or social background. It is the psychological function of this language that seems to be prominent.