Critical Role of Hemopexin Mediated Cytoprotection in the Pathophysiology of Sickle Cell Disease

Circulating hemopexin is the primary protein responsible for the clearance of heme; therefore, it is a systemic combatant against deleterious inflammation and oxidative stress induced by the presence of free heme. This role of hemopexin is critical in hemolytic pathophysiology. In this review, we outline the current research regarding how the dynamic activity of hemopexin is implicated in sickle cell disease, which is characterized by a pathological aggregation of red blood cells and excessive hemolysis. This pathophysiology leads to symptoms such as acute kidney injury, vaso-occlusion, ischemic stroke, pain crises, and pulmonary hypertension exacerbated by the presence of free heme and hemoglobin. This review includes in vivo studies in mouse, rat, and guinea pig models of sickle cell disease, as well as studies in human samples. In summary, the current research indicates that hemopexin is likely protective against these symptoms and that rectifying depleted hemopexin in patients with sickle cell disease could improve or prevent the symptoms. The data compiled in this review suggest that further preclinical and clinical research should be conducted to uncover pathways of hemopexin in pathological states to evaluate its potential clinical function as both a biomarker and therapy for sickle cell disease and related hemoglobinopathies.     

An Unbalanced Synaptic Transmission: Cause or Consequence of the Amyloid Oligomers Neurotoxicity?

Amyloid-β (Aβ) 1-40 and 1-42 peptides are key mediators of synaptic and cognitive dysfunction in Alzheimer’s disease (AD). Whereas in AD, Aβ is found to act as a pro-epileptogenic factor even before plaque formation, amyloid pathology has been detected among patients with epilepsy with increased risk of developing AD. Among Aβ aggregated species, soluble oligomers are suggested to be responsible for most of Aβ’s toxic effects. Aβ oligomers exert extracellular and intracellular toxicity through different mechanisms, including interaction with membrane receptors and the formation of ion-permeable channels in cellular membranes. These damages, linked to an unbalance between excitatory and inhibitory neurotransmission, often result in neuronal hyperexcitability and neural circuit dysfunction, which in turn increase Aβ deposition and facilitate neurodegeneration, resulting in an Aβ-driven vicious loop. In this review, we summarize the most representative literature on the effects that oligomeric Aβ induces on synaptic dysfunction and network disorganization.     

Clinical Characteristics of POC1B-Associated Retinopathy and Assignment of Pathogenicity to Novel Deep Intronic and Non-Canonical Splice Site Variants

Mutations in POC1B are a rare cause of inherited retinal degeneration. In this study, we present a thorough phenotypic and genotypic characterization of three individuals harboring putatively pathogenic variants in the POC1B gene. All patients displayed a similar, slowly progressive retinopathy (cone dystrophy or cone-rod dystrophy) with normal funduscopy but disrupted outer retinal layers on optical coherence tomography and variable age of onset. Other symptoms were decreased visual acuity and photophobia. Whole genome sequencing revealed a novel homozygous frameshift variant in one patient. Another patient was shown to harbor a novel deep intronic variant in compound heterozygous state with a previously reported canonical splice site variant. The third patient showed a novel nonsense variant and a novel non-canonical splice site variant. We aimed to validate the effect of the deep intronic variant and the non-canonical splice site variant by means of in vitro splice assays. In addition, direct RNA analysis was performed in one patient. Splicing analysis revealed that the non-canonical splice site variant c.561-3T>C leads to exon skipping while the novel deep intronic variant c.1033-327T>A causes pseudoexon activation. Our data expand the genetic landscape of POC1B mutations and confirm the benefit of genome sequencing in combination with downstream functional validation using minigene assays for the analysis of putative splice variants. In addition, we provide clinical multimodal phenotyping of the affected individuals.     

Association of mid-infrared-predicted milk and blood constituents with early-lactation disease,removal, and production outcomes in Holstein cows

Partial least squares regression estimates of milk and blood constituents using Fourier-transform mid-infrared (FTIR) analysis have shown promise as a tool for monitoring early-lactation excessive energy deficit in dairy herds. Our objective was to analyze milk via FTIR to determine the association of early-lactation predicted milk β-hydroxybutyrate (BHB) concentrations, predicted blood nonesterified fatty acid (NEFA) concentrations, and predicted milk de novo fatty acid (FA) percentages relative to total FA concentrations, with the risk of disease or removal in early lactation (hyperketonemia, displaced abomasum, metritis, culling, or death) and average daily milk yield during the first 15 wk of lactation. We enrolled 517 multiparous Holstein cows from 2 dairy farms in New York. Composite milk samples were collected twice weekly from 3 to 18 DIM for a total of 4 timepoints (T1, T2, T3, T4) and analyzed using FTIR spectrometry for milk BHB and FA composition and predicted blood NEFA. Blood samples were collected for hyperketonemia determination (BHB ≥ 1.2 mmol/L) using a handheld meter, and farm-diagnosed occurrence of disease or removal during the first 30 DIM and average daily milk yield during the first 15 wk of lactation were collected from herd management software. The incidence of disease or removal between 3 and 18 DIM was 20.2%. Explanatory models for disease or removal were developed for each predicted constituent of interest at each timepoint using fixed-effect multivariable Poisson regression. Repeated measures ANOVA models were developed for each predicted constituent to assess differences in average daily milk yield. For all timepoints, increased risk of disease or removal was associated with higher predicted milk BHB [relative risk (RR)_T1 = 2.0; RR_T2 = 3.4; RR_T3 = 5.2; RR_T4 = 9.1], higher predicted blood NEFA (RR_T1 = 2.7; RR_T2 = 2.5; RR_T3 = 3.8; RR_T4 = 10.0), and lower predicted milk de novo FA relative percentages (RR_T1 = 2.9; RR_T2 = 3.3; RR_T3 = 5.8; RR_T4 = 7.2). Average daily milk yield was increased for cows above the cut point for predicted milk BHB (2.1 kg/d) and predicted blood NEFA (3.5 kg/d) and below the cut point for de novo FA relative percentages (2.3 kg/d). Our results suggest that FTIR-predicted milk BHB, blood NEFA, and milk de novo FA relative percentages are promising indicators of subsequent disease or removal in early lactation; their positive relationship with milk yield warrants further exploration.     

Engineering biodegradable polymer blends containing flame retardant-coated starch/nanoparticles

We have shown that the addition of resorcinol di(phenyl phosphate) (RDP)-coated starch can improve the compatibility to either Ecoflex or poly(lactic acid) (PLA). The increased compatibilization enhanced the tensile properties such as yield strength and impact toughness. In particular, we examined the effect of addition of RDP-coated starch on thermal responses of a blend of Ecoflex/PLA. We found that the combination of RDP-coated starches with nanoclays could render the blends self-extinguishing since they are formed as a shell-like chars on the exposure surface against heat, which can prevent the melt polymers against dripping. With an examination on the scanning transmission X-ray microscopy (STXM) images of the blends, the Ecoflex domains were well dispersed in the PLA matrix, while the domains became smaller when the RDP-coated starch was added. Moreover, we demonstrated that the introduction of either flat-like or tube-like clays could provide an increase of interfacial area on the RDP-coated starch surfaces, where each polymer chain preferentially segregates to either the starch or the clay surface. Thus, large complex in-situ grafts with polymers can be formed at the interfaces. Additionally, the complex in-situ grafts could influence flammability of the blends. We have shown that the addition of RDP-coated clays can decrease the mass loss rate of Ecoflex/Starch blends, while a lot of nanofiber are formed on the chars surface, which are entangled each other with the clay platelets. The mechanical properties of the chars structures were examined by nano-indentation, where a good elastic chars formation could keep the internal pressures built up with decomposed gases from melt polymers as well as ductility of the chars could play an important role on releasing the internal gases through small vents on its surface, steadily where a good elastic and ductile chars formation could require keeping the internal pressures built up with decomposed gases from melt polymers.     

High fat feeding exacerbates endoplasmic reticulum stress and beta cell demise

A growing body of evidence suggests that the insulin‐producing beta cells in the pancreas are susceptible to saturated fatty acid‐induced endoplasmic reticulum (ER) stress and apoptosis, and that this may contribute to the development of diabetes. In this issue of the European Journal of Lipid Science and Technology, Guo et al. [p. 233–234] report on accelerated beta cell dysfunction and death induced by high fat feeding of the Ncb5or knockout mouse, which lacks the ER‐associated NADH‐cytochrome b5 oxidoreductase and has impaired fatty acid desaturation.     

Mitigation strategies to reduce pesticide inputs into ground- and surface water and their effectiveness; a review

In this paper, the current knowledge on mitigation strategies to reduce pesticide inputs into surface water and groundwater, and their effectiveness when applied in practice is reviewed. Apart from their effectiveness in reducing pesticide inputs into ground- and surface water, the mitigation measures identified in the literature are evaluated with respect to their practicability. Those measures considered both effective and feasible are recommended for implementing at the farm and catchment scale. Finally, recommendations for modelling are provided using the identified reduction efficiencies. Roughly 180 publications directly dealing with or being somehow related to mitigation of pesticide inputs into water bodies were examined. The effectiveness of grassed buffer strips located at the lower edges of fields has been demonstrated. However, this effectiveness is very variable, and the variability cannot be explained by strip width alone. Riparian buffer strips are most probably much less effective than edge-of-field buffer strips in reducing pesticide runoff and erosion inputs into surface waters. Constructed wetlands are promising tools for mitigating pesticide inputs via runoff/erosion and drift into surface waters, but their effectiveness still has to be demonstrated for weakly and moderately sorbing compounds. Subsurface drains are an effective mitigation measure for pesticide runoff losses from slowly permeable soils with frequent waterlogging. For the pathways drainage and leaching, the only feasible mitigation measures are application rate reduction, product substitution and shift of the application date. There are many possible effective measures of spray drift reduction. While sufficient knowledge exists for suggesting default values for the efficiency of single drift mitigation measures, little information exists on the effect of the drift reduction efficiency of combinations of measures. More research on possible interactions between different drift mitigation measures and the resulting overall drift reduction efficiency is therefore indicated. Point-source inputs can be mitigated against by increasing awareness of the farmers with regard to pesticide handling and application, and encouraging them to implement loss-reducing measures of "best management practice". In catchments dominated by diffuse inputs at least in some years, mitigation of point-source inputs alone may not be sufficient to reduce pesticide loads/concentrations in water bodies to an acceptable level.     

Shedding of escherichia coli O157:H7 by cattle fed diets containing monensin or tylosin

Monensin and tylosin have activity against gram-positive bacteria, and it has been theorized that their effects on the intestinal environment may promote proliferation of gram-negative bacteria such as Escherichia coli. Effects of these antibiotics on the shedding of E. coli O157:H7 were studied in a feedlot environment, using 32 finishing steers. A diet containing 85% barley grain, 10% barley silage, and 5% supplement was amended with 33 ppm monensin, 11 ppm tylosin, both of these additives, or no additives (control). All steers were orally inoculated with 10(10) CFU of a mixture of four strains of nalidixic acid-resistant E. coli O157:H7. Fecal (grab), oral (mouth swab) and water, water-water bowl interface, feed, and pen floor fecal pat samples were collected weekly for 12 weeks. Prevalence of E. coli O157:H7-positive fecal grab samples did not differ (P = 0.26) among treatments, nor did the rate (P = 0.81) or duration (P = 0.85) of shedding of the organism. Fecal grab samples were positive for E. coli O157:H7 more frequently (P < 0.001) than were oral swabs. More (P = 0.02) E. coli O157:H7-positive oral swabs were recovered from the tylosin group than from controls. E. coli O157:H7 was not detected in any of 47 water samples, but was present in 1 of 47 water bowl swabs, 7 of 48 feed samples, and 36 of 48 fecal pats. Pulsed-field gel electrophoresis suggested that differences existed among inoculated strains in their ability to persist in animals and in the environment. However, this study revealed no evidence that dietary inclusion of monensin or tylosin, alone or in combination, increased fecal shedding of E. coli O157:H7 or its persistence in the environment.     

Anti-neuroinflammatory effects of geranium oil in microglial cells

Microglial cells are major immune cells in the brain, and their activation is involved in neurodegenerative diseases such as Alzheimer’s disease. Activated microglial cells secrete proinflammatory factors including nitric oxide (NO), which is an important mediator of neuroinflammation and neuronal cell death. In the present study, we demonstrated that geranium oil inhibited NO production, as well as the expression of the proinflammatory enzymes cyclooxygenase-2 (COX-2) and induced nitric oxide synthase (iNOS) in primary cultures of activated microglial cells. When tested at their natural relative concentrations in the oil, none of the major constituents of the oil could inhibit NO production. However, at higher concentrations, citronellol exhibited an inhibitory activity. The results suggest a possible synergistic interaction between these components. Thus, geranium oil might be beneficial in the prevention/treatment of neurodegenerative diseases where neuroinflammation is part of the pathophysiology.