Pyrethroid resistance in the Sudan Savannah Region in Nigeria: a study of the resistance profile and resistance mechanism of Anopheles populations from Hadejia Town in Jigawa State

Insecticide-based control measures are key strategies against malaria vectors, and pyrethroid is the only recommended class of insecticide for public health use. The work aimed at determining the pyrethroid resistance in Anopheline mosquitoes and the frequency of the knockdown resistance (kdr) gene determinant. Larval samples were collected from two sites in Hadejia Town, Jigawa State in April 2020 and November/December 2020, and reared to adulthood in Bayero University Kano Biochemistry's insectary. Samples were identified by morphological and molecular techniques. Three to five-day-old adult mosquitoes were exposed to standard concentrations of 0.75% permethrin and 0.05% deltamethrin according to WHO criteria. Kdr mutations were investigated using PCR. Results of morphological identification showed an abundance (100%) of the Anopheles gambiae complex. However, molecular identification showed varying percentages of An. gambiae s.s (15% and 35%), An. coluzzii (80% and 45%), and An. arabiensis (5% and 20%) each for agricultural and industrial sites, respectively. The result also revealed relatively higher KT50 and KT50 in the agricultural site and was relatively higher with permethrin based on the KT50. Higher insecticide resistance of Anopheles mosquitoes observed in the agricultural site suggests that the practice may affect resistance development. The frequency of negative (homozygous) L1014F kdr mutation genotype was 70% in the resistant (alive) mosquito population and 50% in the susceptible (dead) mosquito population. The frequency of kdr mutation for agricultural and industrial sites was 35% and 15%, respectively. This finding suggests that the kdr gene determinant may not be the only mechanism involved in the resistance of the Anopheline mosquito to pyrethroid

Predictors of influenza severity among hospitalized adults with laboratory confirmed influenza: Analysis of nine influenza seasons from the Valencia region, Spain

Purpose Influenza hospitalizations contribute substantially to healthcare disruption. We explored the impact of ageing, comorbidities and other risk factors to better understand associations with severe clinical outcomes in adults hospitalized with influenza. Methods We analysed multi-season data from adults ≥18 years, hospitalized with laboratory-confirmed influenza in Valencia, Spain. Severity was defined as intensive care unit (ICU) admission, assisted ventilation and/or death. Generalized estimating equations were used to estimate associations between risk factors and severity. Rate of hospital discharge was analysed with a cumulative incidence function. Results Only 26% of influenza patients had their primary discharge diagnosis coded as influenza. Comorbidities were associated with severity among adults aged 50–79 years, with the highest odds ratio (OR) in patients with ≥3 comorbidities aged 50–64 years (OR = 6.7; 95% CI: 1.0–44.6). Morbid obesity and functional dependencies were also identified risk factors (ORs varying from 3 to 5 depending on age). The presence of increasing numbers of comorbidities was associated with prolonged hospital stay. Conclusions Influenza clinical outcomes are aggravated by the presence of comorbidities and ageing. Increased awareness of influenza among hospitalized patients could prompt clinical and public health interventions to reduce associated burden

Molecular characterization of porcine circovirus 2 isolated from diseased pigs co-infected with porcine reproductive and respiratory syndrome virus

In this study, we isolated a porcine circovirus 2 (PCV2) strain from piglets co-infected with porcine reproductive and respiratory syndrome virus (PRRSV). The complete genome of this strain was sequenced, phylogenetic and polymorphic analyses were carried out. BLAST searches revealed the highest sequence identity (99.5% nt and 99.3% aa) to Guangxi strain EF675230. The phylogenetic tree showed that clustering of the isolates didn't strongly correlate to geographical distribution. Polymorphic analyses demonstrated that the amino acids at most of the polymorphic sites in Open Reading Frame 1(ORF1) and 2 (ORF2)belong to the same amino acid group according to chemical or structural properties, and revealed that highly polymorphic regions overlapped with the known immunoreactive epitopes of ORF2

Context-specific regulation of surface and soluble IL7R expression by an autoimmune risk allele.

IL-7 is a key factor in T cell immunity and common variants at IL7R, encoding its receptor, are associated with autoimmune disease susceptibility. IL7R mRNA is induced in stimulated monocytes, yet a function for IL7R in monocyte biology remains unexplored. Here we characterize genetic regulation of IL7R at the protein level in healthy individuals, and find that monocyte surface and soluble IL7R (sIL7R) are markedly induced by lipopolysaccharide. In monocytes, both surface IL7R and sIL7R expression strongly associate with allelic carriage of rs6897932, a disease-associated IL7R polymorphism. Monocytes produce more sIL7R than CD4 + T cells, and the amount is additionally correlated with the expression of DDX39A, encoding a splicing factor. Synovial fluid-derived monocytes from patients with spondyloarthritis are enriched for IL7R+ cells with a unique transcriptional profile that overlaps with IL-7-induced gene sets. Our data thus suggest a previously unappreciated function for monocytes in IL-7 biology and IL7R-associated diseases

Effect of β2-adrenergic receptor stimulation on lung fluid in stable heart failure patients

Introduction: The purpose of this study was to determine 1) if stable heart-failure patients with reduced ejection fraction (HFrEF) have elevated extravascular lung water (EVLW) versus healthy control subjects, and 2) the effect of acute β2AR agonist inhalation on lung fluid balance. Methods: Twenty-two stable HFrEF patients and 18 age- and sex-matched healthy subjects were studied. Lung diffusing capacity for carbon monoxide (DLCO), alveolar-capillary conductance (DmCO), pulmonary capillary blood volume (Vc) (via rebreathe) and lung tissue volume (Vtis) (via computed tomography) were assessed before and within 30 min of administration of nebulized albuterol. EVLW was derived as Vtis – Vc. Results: Pre-albuterol, Vtis and EVLW were greater in HFrEF vs. control (998 ± 200 vs. 884 ± 123 ml, P = 0.041; 943 ± 202 vs. 802 ± 133 ml, P = 0.015, respectively). Albuterol decreased Vtis and EVLW in HFrEF (−4.6 ± 7.8%, P = 0.010; −4.6 ± 8.8%, P = 0.018) and control (−2.8 ± 4.9%, P = 0.029; −3.0 ± 5.7%, P = 0.045). There was an inverse relationship between pre-albuterol values and the pre- to post-albuterol change for EVLW (r2 = −0.264, P = 0.015) and DmCO (r2 = −0.343, P = 0.004) in HFrEF only. Conclusion: Lung fluid is elevated in stable HFrEF patients relative to healthy subjects. Stimulation of the β2ARs may cause fluid removal in HFrEF, especially in patients who exhibit greater evidence for increased lung water at baseline

Characterizing preclinical sub-phenotypic models of acute respiratory distress syndrome:An experimental ovine study

Abstract The acute respiratory distress syndrome (ARDS) describes a heterogenous population of patients with acute severe respiratory failure. However, contemporary advances have begun to identify distinct sub‐phenotypes that exist within its broader envelope. These sub‐phenotypes have varied outcomes and respond differently to several previously studied interventions. A more precise understanding of their pathobiology and an ability to prospectively identify them, may allow for the development of precision therapies in ARDS. Historically, animal models have played a key role in translational research, although few studies have so far assessed either the ability of animal models to replicate these sub‐phenotypes or investigated the presence of sub‐phenotypes within animal models. Here, in three ovine models of ARDS, using combinations of oleic acid and intravenous, or intratracheal lipopolysaccharide, we investigated the presence of sub‐phenotypes which qualitatively resemble those found in clinical cohorts. Principal Component Analysis and partitional clustering identified two clusters, differentiated by markers of shock, inflammation, and lung injury. This study provides a first exploration of ARDS phenotypes in preclinical models and suggests a methodology for investigating this phenomenon in future studies

A constructive approach for discovering new drug leads: Using a kernel methodology for the inverse-QSAR problem

<p>Abstract</p> <p>Background</p> <p>The inverse-QSAR problem seeks to find a new molecular descriptor from which one can recover the structure of a molecule that possess a desired activity or property. Surprisingly, there are very few papers providing solutions to this problem. It is a difficult problem because the molecular descriptors involved with the inverse-QSAR algorithm must adequately address the forward QSAR problem for a given biological activity if the subsequent recovery phase is to be meaningful. In addition, one should be able to construct a feasible molecule from such a descriptor. The difficulty of recovering the molecule from its descriptor is the major limitation of most inverse-QSAR methods.</p> <p>Results</p> <p>In this paper, we describe the reversibility of our previously reported descriptor, the vector space model molecular descriptor (VSMMD) based on a vector space model that is suitable for kernel studies in QSAR modeling. Our inverse-QSAR approach can be described using five steps: (1) generate the VSMMD for the compounds in the training set; (2) map the VSMMD in the input space to the kernel feature space using an appropriate kernel function; (3) design or generate a new point in the kernel feature space using a kernel feature space algorithm; (4) map the feature space point back to the input space of descriptors using a pre-image approximation algorithm; (5) build the molecular structure template using our VSMMD molecule recovery algorithm.</p> <p>Conclusion</p> <p>The empirical results reported in this paper show that our strategy of using kernel methodology for an inverse-Quantitative Structure-Activity Relationship is sufficiently powerful to find a meaningful solution for practical problems.</p

Mitotic chromosome binding predicts transcription factor properties in interphase

Mammalian transcription factors (TFs) differ broadly in their nuclear mobility and sequence-specific/non-specific DNA binding. How these properties affect their ability to occupy specific genomic sites and modify the epigenetic landscape is unclear. The association of TFs with mitotic chromosomes observed by fluorescence microscopy is largely mediated by non-specific DNA interactions and differs broadly between TFs. Here we combine quantitative measurements of mitotic chromosome binding (MCB) of 501 TFs, TF mobility measurements by fluorescence recovery after photobleaching, single molecule imaging of DNA binding, and mapping of TF binding and chromatin accessibility. TFs associating to mitotic chromosomes are enriched in DNA-rich compartments in interphase and display slower mobility in interphase and mitosis. Remarkably, MCB correlates with relative TF on-rates and genome-wide specific site occupancy, but not with TF residence times. This suggests that non-specific DNA binding properties of TFs regulate their search efficiency and occupancy of specific genomic sites