The influence of dietary fatty acids (FA) on mania-like behavior and brain oxidative damage were evaluated in rats. First generation of rats born and maintained under supplementation with soybean-oil ...(SO), fish-oil (FO) or hydrogenated-vegetable-fat (HVF), which are rich in n−6, n−3 and trans (TFA) FA, respectively, until adulthood, were exposed to an amphetamine (AMPH)-induced mania animal model to behavioral and biochemical evaluations.
While AMPH caused hyperlocomotion in HVF and, to a less extent, in SO- and FO-groups, a better memory performance was observed in FO group. Among vehicle-groups, HVF increased reactive species (RS) generation and protein-carbonyl (PC) levels in cortex; FO reduced RS generation in hippocampus and decreased PC levels in hippocampus and striatum. Among AMPH-treated animals, HVF exacerbated RS generation in all evaluated brain areas and increased PC levels in cortex and striatum; FO reduced RS generation in hippocampus and decreased PC levels in hippocampus and striatum. FO was related to higher percentage of polyunsaturated fatty acids (PUFA) and docosahexaenoic acid (DHA) in cortex and striatum, while HVF was associated to higher incorporation of TFA in cortex, hippocampus and striatum, besides increased n−6/n−3 FA ratio in striatum. While a continuous exposure to TFA may intensify oxidative events in brain, a prolonged FO consumption may prevent mania-like-behavior; enhance memory besides decreasing brain oxidative markers. A substantial inclusion of processed foods, instead of foods rich in omega-3, in the long term is able to influence the functionality of brain structures related to behavioral disturbances and weaker neuroprotection, whose impact should be considered by food safety authorities and psychiatry experts.
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•Intake of foods rich in trans fatty acids (TFA) is growing in Western countries.•TFA can facilitate responses to amphetamine in rats of the first generation.•Brain incorporation of TFA was related to oxidative and behavioral disturbances.•Brain incorporation of omega-3 improved memory and reduced oxidative damages.•Processed foods increase vulnerability to develop neuropsychiatric diseases.
Alpha-1 antitrypsin deficiency (A1ATD) is an autosomal recessive disease characterized by low plasma levels of A1AT, a serine protease inhibitor representing the most abundant circulating ...antiprotease normally present at plasma levels of 1–2 g/L. The dominant clinical manifestations include predispositions to early onset emphysema due to protease/antiprotease imbalance in distal lung parenchyma and liver disease largely due to unsecreted polymerized accumulations of misfolded mutant A1AT within the endoplasmic reticulum of hepatocytes. Since 1987, the only FDA licensed specific therapy for the emphysema component has been infusions of A1AT purified from pooled human plasma at the 2020 cost of up to US $200,000/year with the risk of intermittent shortages. In the past three decades various, potentially less expensive, recombinant forms of human A1AT have reached early stages of development, one of which is just reaching the stage of human clinical trials. The focus of this review is to update strategies for the treatment of the pulmonary component of A1ATD with some focus on perspectives for therapeutic production and regulatory approval of a recombinant product from plants. We review other competitive technologies for treating the lung disease manifestations of A1ATD, highlight strategies for the generation of data potentially helpful for securing FDA Investigational New Drug (IND) approval and present challenges in the selection of clinical trial strategies required for FDA licensing of a New Drug Approval (NDA) for this disease.
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•Oxidants and proteases play interacting roles in COPD & A1AT biology.•CHO and plant cell recombinant oxidant resistant therapies are here.•Transformative small molecule and gene/base editing therapies are emerging.•FDA approval processes for A1AT therapies present challenges.
Purpose
The complement system is a crucial part of innate immunity. Recent work demonstrated an unexpected contribution to tissue homeostasis and degeneration. This study investigated for the first ...time, in human disc tissues, the deposition profile of the complement activation product terminal complement complex (TCC), an inflammatory trigger and inducer of cell lysis, and its inhibitor CD59, and their correlation with the degree of disc degeneration (DD).
Methods
Disc biopsies were collected from patients diagnosed with DD (
n
= 39, age 63 ± 12) and adolescent idiopathic scoliosis (AIS,
n
= 10, age 17 ± 4) and compared with discs from healthy Young (
n
= 11, age 7 ± 7) and Elder (
n
= 10, age 65 ± 15) donors. Immunohistochemical detection of TCC and CD59 in nucleus pulposus (NP), annulus fibrosus (AF) and endplate (EP) was correlated with age, Pfirrmann grade and Modic changes.
Results
Higher percentage of TCC+ cells was detected in the NP and EP of DD compared to Elder (
P
< 0.05), and in the EP of Young versus Elder (
P
< 0.001). In DD, TCC deposition was positively correlated with Pfirrmann grade, but not with Modic changes, whereas for Young donors, a negative correlation was found with age, indicating TCC’s involvement not only in DD, but also in early stages of skeletal development. Higher CD59 positivity was found in AIS and DD groups compared to Young (
P
< 0.05), and it was negatively correlated with the age of the patients.
Conclusion
TCC deposition positively correlated with the degree of disc degeneration. A functional relevance of TCC may exist in DD, representing a potential target for new therapeutics.
In 2019 there were 490,000 children under five living with HIV. Understanding the dynamics of HIV suppression and rebound in this age group is crucial to optimizing treatment strategies and ...increasing the likelihood of infants achieving and sustaining viral suppression. Here we studied data from a cohort of 122 perinatally-infected infants who initiated antiretroviral treatment (ART) early after birth and were followed for up to four years. These data included longitudinal measurements of viral load (VL) and CD4 T cell numbers, together with information regarding treatment adherence. We previously showed that the dynamics of HIV decline in 53 of these infants who suppressed VL within one year were similar to those in adults. However, in extending our analysis to all 122 infants, we find that a deterministic model of HIV infection in adults cannot explain the full diversity in infant trajectories. We therefore adapt this model to include imperfect ART adherence and natural CD4 T cell decline and reconstitution processes in infants. We find that individual variation in both processes must be included to obtain the best fits. We also find that infants with faster rates of CD4 reconstitution on ART were more likely to experience resurgences in VL. Overall, our findings highlight the importance of combining mathematical modeling with clinical data to disentangle the role of natural immune processes and viral dynamics during HIV infection.
Arctic and boreal lake greenhouse gas emissions (GHG) are an important component of regional carbon (C) budgets. Yet the magnitude and seasonal patterns of lake GHG emissions are poorly constrained, ...because sampling is limited in these remote landscapes, particularly during winter and shoulder seasons. To better define patterns of under ice GHG content (and emissions potential at spring thaw), we surveyed carbon dioxide (CO2) and methane (CH4) concentrations and stable isotopic composition during winter of 2017 in 13 lakes in the arid Yukon Flats Basin of interior Alaska, USA. Partial pressures of CO2 and CH4 ranged over three orders of magnitude, were positively correlated, and CO2 exceeded CH4 at all but one site. Shallow, organic matter-rich lakes located at lower elevations tended to have the highest concentrations of both gases, though CH4 content was more heterogeneous and only abundant in oxygen-depleted lakes, while CO2 was negatively correlated to oxygen content. Isotopic values of CO2 spanned a narrow range (−10‰ to −23‰) compared to CH4, which ranged over 50‰ (−19‰ to −71‰), indicating CH4 source pathways and sink strength varied widely between lakes. Miller-Tans and Keeling plots qualitatively suggested two groups of lakes were present; one with isotopically enriched source CH4 possibly more dominated by acetoclastic methanogenesis, and one with depleted signatures suggesting a dominance of the hydrogenotrophic production. Overall, regional lake differences in winter under ice GHG content appear to track landscape position, oxygen, and organic matter content and composition, causing patterns to vary widely even within a relatively small geographic area of interior Alaska.
Until recently, Ebola virus (EBOV) was a rarely encountered human pathogen that caused disease among small populations with extraordinarily high lethality. At the end of 2013, EBOV initiated an ...unprecedented disease outbreak in West Africa that is still ongoing and has already caused thousands of deaths. Recent studies revealed the genomic changes this particular EBOV variant undergoes over time during human-to-human transmission. Here we highlight the genomic changes that might negatively impact the efficacy of currently available EBOV sequence-based candidate therapeutics, such as small interfering RNAs (siRNAs), phosphorodiamidate morpholino oligomers (PMOs), and antibodies. Ten of the observed mutations modify the sequence of the binding sites of monoclonal antibody (MAb) 13F6, MAb 1H3, MAb 6D8, MAb 13C6, and siRNA EK-1, VP24, and VP35 targets and might influence the binding efficacy of the sequence-based therapeutics, suggesting that their efficacy should be reevaluated against the currently circulating strain.
We report the discovery of a transiting exoplanet, KELT-11b, orbiting the bright (V = 8.0) subgiant HD 93396. A global analysis of the system shows that the host star is an evolved subgiant star with ...K, , , , and . The planet is a low-mass gas giant in a P = 4.736529 0.00006 day orbit, with MP = 0.195 0.018 , , g cm−3, surface gravity , and equilibrium temperature K. KELT-11 is the brightest known transiting exoplanet host in the southern hemisphere by more than a magnitude and is the sixth brightest transit host to date. The planet is one of the most inflated planets known, with an exceptionally large atmospheric scale height (2763 km), and an associated size of the expected atmospheric transmission signal of 5.6%. These attributes make the KELT-11 system a valuable target for follow-up and atmospheric characterization, and it promises to become one of the benchmark systems for the study of inflated exoplanets.
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