Pyridine-based small-molecule drugs, vitamins, and cofactors are vital for many cellular processes, but little is known about their interactions with membrane interfaces. These specific membrane ...interactions of these small molecules or ions can assist in diffusion across membranes or reach a membrane-bound target. This study explores how minor differences in small molecules (isoniazid, benzhydrazide, isonicotinamide, nicotinamide, picolinamide, and benzamide) can affect their interactions with model membranes. Langmuir monolayer studies of dipalmitoylphosphatidylcholine (DPPC) or dipalmitoylphosphatidylethanolamine (DPPE), in the presence of the molecules listed, show that isoniazid and isonicotinamide affect the DPPE monolayer at lower concentrations than the DPPC monolayer, demonstrating a preference for one phospholipid over the other. The Langmuir monolayer studies also suggest that nitrogen content and stereochemistry of the small molecule can affect the phospholipid monolayers differently. To determine the molecular interactions of the simple N-containing aromatic pyridines with a membrane-like interface,
H one-dimensional NMR and
H-
H two-dimensional NMR techniques were utilized to obtain information about the position and orientation of the molecules of interest within aerosol-OT (AOT) reverse micelles. These studies show that all six of the molecules reside near the AOT sulfonate headgroups and ester linkages in similar positions, but nicotinamide and picolinamide tilt at the water-AOT interface to varying degrees. Combined, these studies demonstrate that small structural changes of small N-containing molecules can affect their specific interactions with membrane-like interfaces and specificity toward different membrane components.
In March 2020, the United Kingdom Primary Immunodeficiency Network (UKPIN) established a registry of cases to collate the outcomes of individuals with PID and SID following SARS-CoV-2 infection and ...treatment. A total of 310 cases of SARS-CoV-2 infection in individuals with PID or SID have now been reported in the UK. The overall mortality within the cohort was 17.7% (n=55/310). Individuals with CVID demonstrated an infection fatality rate (IFR) of 18.3% (n=17/93), individuals with PID receiving IgRT had an IFR of 16.3% (n=26/159) and individuals with SID, an IFR of 27.2% (n=25/92). Individuals with PID and SID, had higher inpatient mortality and died at a younger age than the general population. Increasing age, low pre-SARS-CoV-2 infection lymphocyte count and the presence of common co-morbidities increased the risk of mortality in PID. Access to specific COVID-19 treatments in this cohort was limited: only 22.9% (n=33/144) of patients admitted to hospital received dexamethasone, remdesivir, an anti-SARS-CoV-2 antibody-based therapeutic (e.g. REGN-COV2 or convalescent plasma) or tocilizumab as a monotherapy or in combination. Dexamethasone, remdesivir and anti-SARS-CoV-2 antibody-based therapeutics appeared efficacious in PID and SID. Compared to the general population, individuals with PID or SID are at high risk of mortality following SARS-CoV-2 infection. Increasing age, low baseline lymphocyte count and the presence of co-morbidities are additional risk factors for poor outcome in this cohort.
OBJECTIVES
To describe a technique for transurethral tumour inoculation, bioluminescence imaging (BLI) and validation of this approach using ex vivo magnetic resonance imaging (MRI), as a ...reproducible and quantifiable model of orthotopic bladder cancer is required to enable preclinical pharmacological studies of intravesically administered anticancer agents and the use of BLI provides a sensitive method to monitor tumour growth over time.
MATERIALS AND METHODS
Human KU‐7 bladder tumour cells were transduced with a lentiviral construct to stably express the firefly luciferase gene. These cells were then inoculated in female nude mice by intravesical instillation. BLI was performed weekly and the mice were killed after 4 weeks. Ex vivo MRI and whole‐mount step‐sections were obtained to assess bladder tumour volume.
RESULTS
KU‐7 tumour cells were highly tumorigenic and were successfully inoculated in 96% of mice. After 4 weeks, all tumours were confined to the mucosa and submucosa (≤pT1). There was an excellent correlation between tumour volume and BLI for both ex vivo bladder MRI (R2 = 0.929) and end‐point histological measurements (R2 = 0.836).
CONCLUSIONS
We have established and validated a reliable model of orthotopic bladder cancer that can be used to evaluate various methods of intravesical therapy. BLI allows excellent longitudinal surveillance and quantification of tumour burden.
Serial measurements of respiration in infants from birth to 7 months have revealed a changing pattern of response with age to spontaneous transient disturbances (e.g. deep sighs). These responses may ...be interpreted in terms of changing stability of the respiratory control system. The simplest possible model of respiratory control is analysed here. The control system is described by a feedback loop comprising a lung compartment, central and peripheral CO2 detectors and a circulatory delay. The differential equations representing this model are analysed in terms of the phase portrait. First we define the bounds of the solutions in the phase space and the equilibrium points. Next we discuss the local stability and damping of the system under small displacements from these equilibrium points. This local stability can be described in terms of the solution of a linear approximation about the equilibrium points. The trajectories of the solution vector under larger displacements from the equilibrium points are discussed in terms of Taylor expansions. It is shown by this analyses that this simple model can account qualitatively for the observed patterns of respiration following a deep sigh and the changes in that response from birth to 7 months.
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