On characterisations of the input to state stability properties for conformable fractional order bilinear systems

This paper proposes for the first time the theoretical requirements that a fractional-order bilinear system with conformable derivative has to fulfil in order to satisfy different input-to-state stability (ISS) properties. Variants of ISS, namely ISS itself, integral ISS, exponential integral ISS, small-gain ISS, and strong integral ISS for the general class of conformable fractional-order bilinear systems are investigated providing a set of necessary and sufficient conditions for their existence and then compared. Finally, the correctness of the obtained theoretical results is verified by numerical example

Understanding the Matrix:The Role of Extracellular DNA in Oral Biofilms

Dental plaque is the key etiological agent in caries formation and the development of the prevalent chronic oral inflammatory disease, periodontitis. The dental plaque biofilm comprises a diverse range of microbial species encased within a rich extracellular matrix, of which extracellular DNA (eDNA) has been identified as an important component. The molecular mechanisms of eDNA release and the structure of eDNA have yet to be fully characterized. Nonetheless, key functions that have been proposed for eDNA include maintaining biofilm structural integrity, initiating adhesion to dental surfaces, acting as a nutrient source, and facilitating horizontal gene transfer. Thus, eDNA is a potential therapeutic target for the management of oral disease–associated biofilm. This review aims to summarize advances in the understanding of the mechanisms of eDNA release from oral microorganisms and in the methods of eDNA detection and quantification within oral biofilms

Whole-organism phenotypic screening methods used in early-phase anthelmintic drug discovery

Diseases caused by parasitic helminths (worms) represent a major global health burden in both humans and animals. As vaccines against helminths have yet to achieve a prominent role in worm control, anthelmintics are the primary tool to limit production losses and disease due to helminth infections in both human and veterinary medicine. However, the excessive and often uncontrolled use of these drugs has led to widespread anthelmintic resistance in these worms - particularly of animals - to almost all commercially available anthelmintics, severely compromising control. Thus, there is a major demand for the discovery and development of new classes of anthelmintics. A key component of the discovery process is screening libraries of compounds for anthelmintic activity. Given the need for, and major interest by the pharmaceutical industry in, novel anthelmintics, we considered it both timely and appropriate to re-examine screening methods used for anthelmintic discovery. Thus, we reviewed current literature (1977-2021) on whole-worm phenotypic screening assays developed and used in academic laboratories, with a particular focus on those employed to discover nematocides. This review reveals that at least 50 distinct phenotypic assays with low-, medium- or high-throughput capacity were developed over this period, with more recently developed methods being quantitative, semi-automated and higher throughput. The main features assessed or measured in these assays include worm motility, growth/development, morphological changes, viability/lethality, pharyngeal pumping, egg hatching, larval migration, CO2- or ATP-production and/or enzyme activity. Recent progress in assay development has led to the routine application of practical, cost-effective, medium- to high-throughput whole-worm screening assays in academic or public-private partnership (PPP) contexts, and major potential for novel high-content, high-throughput platforms in the near future. Complementing this progress are major advances in the molecular data sciences, computational biology and informatics, which are likely to further enable and accelerate anthelmintic drug discovery and development

Critical illness polyneuropathy, myopathy and neuronal biomarkers in COVID-19 patients: A prospective study

OBJECTIVE: The aim was to characterize the electrophysiological features and plasma biomarkers of critical illness polyneuropathy (CIN) and myopathy (CIM) in coronavirus disease 2019 (COVID-19) patients with intensive care unit acquired weakness (ICUAW). METHODS: An observational ICU cohort study including adult patients admitted to the ICU at Uppsala University Hospital, Uppsala, Sweden, from March 13th to June 8th 2020. We compared the clinical, electrophysiological and plasma biomarker data between COVID-19 patients who developed CIN/CIM and those who did not. Electrophysiological characteristics were also compared between COVID-19 and non-COVID-19 ICU patients. RESULTS: 111 COVID-19 patients were included, 11 of whom developed CIN/CIM. Patients with CIN/CIM had more severe illness; longer ICU stay, more thromboembolic events and were more frequently treated with invasive ventilation for longer than 2 weeks. In particular CIN was more frequent among COVID-19 patients with ICUAW (50%) compared with a non-COVID-19 cohort (0%, p = 0.008). Neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAp) levels were higher in the CIN/CIM group compared with those that did not develop CIN/CIM (both p = 0.001) and correlated with nerve amplitudes. CONCLUSIONS: CIN/CIM was more prevalent among COVID-19 ICU patients with severe illness. SIGNIFICANCE: COVID-19 patients who later developed CIN/CIM had significantly higher NfL and GFAp in the early phase of ICU care, suggesting their potential as predictive biomarkers for CIN/CIM

The extent of neuroradiological findings in COVID-19 shows correlation with blood biomarkers, Glasgow coma scale score and days in intensive care

Background and purpose: A wide range of neuroradiological findings has been reported in patients with coronavirus disease 2019 (COVID-19), ranging from subcortical white matter changes to infarcts, haemorrhages and focal contrast media enhancement. These have been descriptively but inconsistently reported and correlations with clinical findings and biomarkers have been difficult to extract from the literature. The purpose of this study was to quantify the extents of neuroradiological findings in a cohort of patients with COVID-19 and neurological symptoms, and to investigate correlations with clinical findings, duration of intensive care and biomarkers in blood. Material and methods: Patients with positive SARS-CoV-2 and at least one new-onset neurological symptom were included from April until July 2020. Nineteen patients were examined regarding clinical symptoms, biomarkers in blood and MRI of the brain. In order to quantify the MRI findings, a semi-quantitative neuroradiological severity scale was constructed a priori, and applied to the MR images by two specialists in neuroradiology. Results and conclusions: The score from the severity scale correlated significantly with blood biomarkers of CNS injury (glial fibrillary acidic protein, total-tau, ubiquitin carboxyl-terminal hydrolase L1) and inflammation (C-reactive protein), Glasgow Coma Scale score, and the number of days spent in intensive care. The underlying radiological assessments had inter-rater agreements of 90.5%/86% (for assessments with 2/3 alternatives). Total intraclass correlation was 0.80. Previously reported neuroradiological findings in COVID-19 have been diverse and heterogenous. In this study, the extent of findings in MRI examination of the brain, quantified using a structured report, shows correlation with relevant biomarkers

Biomarkers for CNS injury in CSF are elevated in COVID-19 and associated with neurological symptoms and disease severity

BACKGROUND: Neurological symptoms have been frequently reported in hospitalized patients with coronavirus disease 2019 (COVID-19) and biomarkers of CNS injury are reported to be increased in plasma but not extensively studied in CSF. This study examines CSF for biomarkers of CNS injury and other pathology in relation to neurological symptoms and disease severity in patients with neurological manifestations of COVID-19. METHODS: Nineteen patients with neurological symptoms and mild to critical COVID-19 were prospectively included. Extensive analysis of CSF, including measurement of biomarkers of CNS injury (neurofilament light chain protein (NfL) glial fibrillary acidic protein (GFAp) and total tau) was performed and related to neurological features and disease severity. RESULTS: Neurological symptoms included altered mental status (42%), headache (42%), central (21%) and peripheral weakness (32%). Two patients demonstrated minor pleocytosis and four patients had increased immunoglobulin G levels in CSF. Neuronal autoantibody testing using commercial tests was negative in all patients. Increased CSF levels of NfL, GFAp and total-tau protein were seen in 63%, 37%, and 16% of patients, respectively. Increased NfL correlated with disease severity, time in intensive care and level of consciousness. NfL in CSF was higher in patients with central neurological symptoms. CONCLUSION: Although limited by small sample size, our data suggest that levels of NfL, GFAp and total tau in CSF are commonly elevated in patients with COVID-19 with neurological symptoms. This is in contrast to the standard CSF work-up where pathological findings are scarce. NfL in particular, is associated with central neurological symptoms and disease severity

Interspecies competition in oral biofilms mediated by Streptococcus gordonii extracellular deoxyribonuclease SsnA

Abstract Extracellular DNA (eDNA) is a key component of many microbial biofilms including dental plaque. However, the roles of extracellular deoxyribonuclease (DNase) enzymes within biofilms are poorly understood. Streptococcus gordonii is a pioneer colonizer of dental plaque. Here, we identified and characterised SsnA, a cell wall-associated protein responsible for extracellular DNase activity of S. gordonii. The SsnA-mediated extracellular DNase activity of S. gordonii was suppressed following growth in sugars. SsnA was purified as a recombinant protein and shown to be inactive below pH 6.5. SsnA inhibited biofilm formation by Streptococcus mutans in a pH-dependent manner. Further, SsnA inhibited the growth of oral microcosm biofilms in human saliva. However, inhibition was ameliorated by the addition of sucrose. Together, these data indicate that S. gordonii SsnA plays a key role in interspecies competition within oral biofilms. Acidification of the medium through sugar catabolism could be a strategy for cariogenic species such as S. mutans to prevent SsnA-mediated exclusion from biofilms

Quantification of Extracellular DNA Network Abundance and Architecture within Streptococcus gordonii Biofilms Reveals Modulatory Factors

Extracellular DNA (eDNA) is an important component of biofilm matrix that serves to maintain biofilm structural integrity, promotes genetic exchange within the biofilm, and provides protection against antimicrobial compounds. Advances in microscopy techniques have provided evidence of the cobweb- or lattice-like structures of eDNA within biofilms from a range of environmental niches. However, methods to reliably assess the abundance and architecture of eDNA remain lacking. This study aimed to address this gap by development of a novel, high-throughput image acquisition and analysis platform for assessment of eDNA networks in situ within biofilms. Utilizing Streptococcus gordonii as the model, the capacity for this imaging system to reliably detect eDNA networks and monitor changes in abundance and architecture (e.g., strand length and branch number) was verified. Evidence was provided of a synergy between glucans and eDNA matrices, while it was revealed that surface-bound nuclease SsnA could modify these eDNA structures under conditions permissive for enzymatic activity. Moreover, cross talk between the competence and hexaheptapeptide permease systems was shown to regulate eDNA release by S. gordonii. This novel imaging system can be applied across the wider field of biofilm research, with potential to significantly advance interrogation of the mechanisms by which the eDNA network architecture develops, how it can influence biofilm properties, and how it may be targeted for therapeutic benefit. IMPORTANCE Extracellular DNA (eDNA) is critical for maintaining the structural integrity of many microbial biofilms, making it an attractive target for the management of biofilms. However, our knowledge and targeting of eDNA are currently hindered by a lack of tools for the quantitative assessment of eDNA networks within biofilms. Here, we demonstrate use of a novel image acquisition and analysis platform with the capacity to reliably monitor the abundance and architecture of eDNA networks. Application of this tool to Streptococcus gordonii biofilms has provided new insights into how eDNA networks are stabilized within the biofilm and the pathways that can regulate eDNA release. This highlights how exploitation of this novel imaging system across the wider field of biofilm research has potential to significantly advance interrogation of the mechanisms by which the eDNA network architecture develops, how it can influence biofilm properties, and how it may be targeted for therapeutic benefit

Special Section on Pediatric Drug Disposition and Pharmacokinetics-Minireview Ontogeny of Hepatic Drug Transporters and Relevance to Drugs Used in Pediatrics

ABSTRACT Most of the pharmacokinetic studies conducted to calculate pediatric drug doses are based on scaling from adult data using various allometric parameters related to body size. However, these uniform scaling methods cannot account for all physiologic changes occurring during maturation, which influence various drugs in different ways. The ontogeny of physiologic and biologic functions accompanying the progression from infancy to childhood to adulthood does not proceed in a simple monotonic rate with body size for various elimination pathways. The transporters and their interplay with enzymes have a substantial role in drug metabolism and disposition. Although much is known about enzymes and their ontogeny, there is a scarcity of information on the ontogenic profile of drug transporters, particularly during the early years of human life. These ontogeny data are required for the enhancement of physiologically based pharmacokinetic models, and consequently for the prediction of pharmacokinetic profiles of new therapeutic compounds in pediatric populations. This review points to the relative ontogeny rate for enzymes and transporters and how these may confound our understanding of the role that transporters may or may not play in childhood compared with adulthood