Discovery and structure–activity relationships of 6-(benzoylamino)benzoxaboroles as orally active anti-inflammatory agents

Structure–activity relationships of 6-(benzoylamino)benzoxaborole analogs were investigated for the inhibition of TNF-α, IL-1β, and IL-6 from lipopolysaccharide stimulated peripheral blood mononuclear cells. Compound 1q showed potent activity against all three cytokines with IC₅₀ values between 0.19 and 0.50 μM, inhibited LPS-induced TNF-α and IL-6 elevation in mice and improved collagen-induced arthritis in mice. Compound 1q (AN4161) is considered to be a promising lead for novel anti-inflammatory agent with an excellent pharmacokinetic profile.     

Bronchodilator Responsiveness and Reported Respiratory Symptoms in an Adult Population

Background

The relationship between patient-reported symptoms and objective measures of lung function is poorly understood.

Aim

To determine the association between responsiveness to bronchodilator and respiratory symptoms in random population samples.

Methods

4669 people aged 40 years and older from 8 sites in Canada completed interviewer-administered respiratory questionnaires and performed spirometry before and after administration of 200 ug of inhaled salbutamol. The effect of anthropometric variables, smoking exposure and doctor-diagnosed asthma (DDA) on bronchodilator responsiveness in forced expiratory volume in 1 second (FEV₁) and in forced vital capacity (FVC) were evaluated. Multiple logistic regression was used to test for association between quintiles of increasing changes in FEV₁ and in FVC after bronchodilator and several respiratory symptoms.

Results

Determinants of bronchodilator change in FEV₁ and FVC included age, DDA, smoking, respiratory drug use and female gender [p<0.005 to p<0.0001 ]. In subjects without doctor-diagnosed asthma or COPD, bronchodilator response in FEV₁ was associated with wheezing [p for trend<0.0001], while bronchodilator response for FVC was associated with breathlessness. [p for trend <0.0001].

Conclusions

Bronchodilator responsiveness in FEV₁ or FVC are associated with different respiratory symptoms in the community. Both flow and volume bronchodilator responses are useful parameters which together can be predictive of both wheezing and breathlessness in the general population.     

Left Atrial Structure and Function in Heart Failure with Preserved Ejection Fraction: A RELAX Substudy

Given the emerging recognition of left atrial structure and function as an important marker of disease in heart failure with preserved ejection fraction (HF-pEF), we investigated the association between left atrial volume and function with markers of disease severity and cardiac structure in HF-pEF. We studied 100 patients enrolled in the PhosphdiesteRasE-5 Inhibition to Improve CLinical Status and EXercise Capacity in Diastolic Heart Failure (RELAX) trial who underwent cardiac magnetic resonance (CMR), cardiopulmonary exercise testing, and blood collection before randomization. Maximal left atrial volume index (LAVi; N = 100), left atrial emptying fraction (LAEF; N = 99; including passive and active components (LAEF_P, LAEF_A; N = 80, 79, respectively) were quantified by CMR. After adjustment for multiple testing, maximal LAVi was only associated with age (ρ = 0.39), transmitral filling patterns (medial E/e’ ρ = 0.43), and N-terminal pro-BNP (NT-proBNP; ρ = 0.65; all p<0.05). Lower LAEF was associated with older age, higher transmitral E/A ratio and higher NT-proBNP. Peak VO₂ and V_E/VCO₂ slope were not associated with left atrial structure or function. After adjustment for age, sex, transmitral E/A ratio, CMR LV mass, LV ejection fraction, and creatinine clearance, NT-proBNP remained associated with maximal LAVi (β = 0.028, p = 0.0007) and total LAEF (β = -0.033, p = 0.001). Passive and active LAEF were most strongly associated with age and NT-proBNP, but not gas exchange or other markers of ventricular structure or filling properties. Left atrial volume and emptying function are associated most strongly with NT-proBNP and diastolic filling properties, but not significantly with gas exchange, in HFpEF. Further research to explore the relevance of left atrial structure and function in HF-pEF is warranted.     

Population attenuation in zooplankton communities during transoceanic transfer in ballast water

Successful biological invasion requires introduction of a viable population of a nonindigenous species (NIS). Rarely have ecologists assessed changes in populations while entrained in invasion pathways. Here, we investigate how zooplankton communities resident in ballast water change during transoceanic voyages. We used next‐generation sequencing technology to sequence a nuclear small subunit ribosomal DNA fragment of zooplankton from ballast water during initial, middle, and final segments as a vessel transited between Canada and Brazil. Operational taxonomic unit (OTU) diversity decreased as voyage duration increased, indicating loss of community‐based genetic diversity and development of bottlenecks for zooplankton taxa prior to discharge of ballast water. On average, we observed 47, 26, and 24 OTUs in initial, middle, and final samples, respectively. Moreover, a comparison of genetic diversity within taxa indicated likely attenuation of OTUs in final relative to initial samples. Abundance of the most common taxa (copepods) declined in all final relative to initial samples. Some taxa (e.g., Copepoda) were represented by a high number of OTUs throughout the voyage, and thus had a high level of intraspecific genetic variation. It is not clear whether genotypes that were most successful in surviving transit in ballast water will be the most successful upon introduction to novel environments. This study highlights that population bottlenecks may be common prior to introduction of NIS to new ecosystems.     

Mean Recency Period for Estimation of HIV-1 Incidence with the BED-Capture EIA and Bio-Rad Avidity in Persons Diagnosed in the United States with Subtype B

HIV incidence estimates are used to monitor HIV-1 infection in the United States. Use of laboratory biomarkers that distinguish recent from longstanding infection to quantify HIV incidence rely on having accurate knowledge of the average time that individuals spend in a transient state of recent infection between seroconversion and reaching a specified biomarker cutoff value. This paper describes five estimation procedures from two general statistical approaches, a survival time approach and an approach that fits binomial models of the probability of being classified as recently infected, as a function of time since seroconversion. We compare these procedures for estimating the mean duration of recent infection (MDRI) for two biomarkers used by the U.S. National HIV Surveillance System for determination of HIV incidence, the Aware BED EIA HIV-1 incidence test (BED) and the avidity-based, modified Bio-Rad HIV-1/HIV-2 plus O ELISA (BRAI) assay. Collectively, 953 specimens from 220 HIV-1 subtype B seroconverters, taken from 5 cohorts, were tested with a biomarker assay. Estimates of MDRI using the non-parametric survival approach were 198.4 days (SD 13.0) for BED and 239.6 days (SD 13.9) for BRAI using cutoff values of 0.8 normalized optical density and 30%, respectively. The probability of remaining in the recent state as a function of time since seroconversion, based upon this revised statistical approach, can be applied in the calculation of annual incidence in the United States.     

Aging Dogs Manifest Myopia as Measured by Autorefractor

Objective

Dogs, like humans, experience eye changes with aging: hardening and clouding of the lens and accumulated oxidative damage from UV sunlight. It has been debated whether such changes could be affecting the visual function of dogs. The objective of this study was to determine if autorefractometry could be used to measure visual function in dogs.

Animals and Methods

Nine Beagle dogs (ages 1 to 14 years) were examined by a veterinary ophthalmologist and their eyes determined to be free of cataracts. Spherical equivalent refractive error was measured by handheld autorefractor (Welch Allyn SureSight) under both indirect and direct lighting conditions with five measurements per condition, per eye. Measures were repeated on three different days for each dog within six weeks. Nonparametric statistics were used to detect differences among lighting conditions and test days, and between eyes. Spearmen correlation assessed the visual measurement outcomes’ association with age.

Results

There was no difference for day-to-day or between-eye measurements. Significantly, the Beagles showed a myopic shift with aging (average spherical equivalent ranged from plano to -3.00 diopters), suggesting that dogs become more near-sighted as they age (r = -0.48 and -0.73 under direct and indirect lights; p<0.05 both). Younger dogs were able to make larger accommodation changes from indirect light to direct light conditions, indicating a more flexible lens (r = -0.50, p<0.05).

Conclusions

Although designed for humans, the hand-held autorefractor technique is applicable to dogs and sensitive to light conditions. The age-associated myopic shift could be expected to compromise dogs’ visual functions.     

First Report of Peronospora belbahrii on Sweet Basil in Baja California Sur,México

In Baja California Sur, Mexico, a foliar disease occurred on sweet basil which seriously affected its quality and yield. The most common symptoms were yellowing and necrosis on leaves, caused by a downy mycelium growth on the lower leaf surface. Symptomatic leaves from two sampling sites were collected for morphological studies and molecular analysis of pathogen DNA. Based on morphological characteristics (sporangiophore size of 240–530 × 7–11 μm, branches of 5–8 order and a sporangia size of 27–31 × 21–25 μm) and molecular analysis (the GenBank blast of the PCR assays showed unique rDNA sequence data with 99% similarity to P. belbahrii), the pathogen was identified as Peronospora belbahrii, the causal agent of basil downy mildew. This is the first report of P. belbahrii affecting sweet basil in Mexico.     

Lateral impacts correlate with falx cerebri displacement and corpus callosum trauma in sports-related concussions

Corpus callosum trauma has long been implicated in mild traumatic brain injury (mTBI), yet the mechanism by which forces penetrate this structure is unknown. We investigated the hypothesis that coronal and horizontal rotations produce motion of the falx cerebri that damages the corpus callosum. We analyzed previously published head kinematics of 115 sports impacts (2 diagnosed mTBI) measured with instrumented mouthguards and used finite element (FE) simulations to correlate falx displacement with corpus callosum deformation. Peak coronal accelerations were larger in impacts with mTBI (8592 rad/s² avg.) than those without (1412 rad/s² avg.). From FE simulations, coronal acceleration was strongly correlated with deep lateral motion of the falx center (r = 0.85), while horizontal acceleration was correlated with deep lateral motion of the falx periphery (r > 0.78). Larger lateral displacement at the falx center and periphery was correlated with higher tract-oriented strains in the corpus callosum body (r = 0.91) and genu/splenium (r > 0.72), respectively. The relationship between the corpus callosum and falx was unique: removing the falx from the FE model halved peak strains in the corpus callosum from 35% to 17%. Consistent with model results, we found indications of corpus callosum trauma in diffusion tensor imaging of the mTBI athletes. For a measured alteration of consciousness, depressed fractional anisotropy and increased mean diffusivity indicated possible damage to the mid-posterior corpus callosum. Our results suggest that the corpus callosum may be sensitive to coronal and horizontal rotations because they drive lateral motion of a relatively stiff membrane, the falx, in the direction of commissural fibers below.

     

Tooth and consequences: Heterodonty and dental replacement in piranhas and pacus (Serrasalmidae)

Tooth replacement in piranhas is unusual: all teeth on one side of the head are lost as a unit, then replaced simultaneously. We used histology and microCT to examine tooth‐replacement modes across carnivorous piranhas and their herbivorous pacu cousins (Serrasalmidae) and then mapped replacement patterns onto a molecular phylogeny. Pacu teeth develop and are replaced in a manner like piranhas. For serrasalmids, unilateral tooth replacement is not an “all or nothing” phenomenon; we demonstrate that both sides of the jaws have developing tooth rows within them, albeit with one side more mineralized than the other. All serrasalmids (except one) share unilateral tooth replacement, so this is not an adaptation for carnivory. All serrasalmids have interlocking teeth; piranhas interdigitate lateral tooth cusps with adjacent teeth, forming a singular saw‐like blade, whereas lateral cusps in pacus clasp together. For serrasalmids to have an interlocking dentition, their teeth need to develop and erupt at the same time. We propose that interlocking mechanisms prevent tooth loss and ensure continued functionality of the feeding apparatus. Serrasalmid dentitions are ubiquitously heterodont, having incisiform and molariform dentitions reminiscent of mammals. Finally, we propose that simultaneous tooth replacement be considered as a synapomorphy for the family.