Engineering alginate hydrogel films with poly(3-hydroxybutyrate-co-3-valerate) and graphene nanoplatelets: Enhancement of antiviral activity, cell adhesion and electroactive properties.

A new biodegradable semi-interpenetrated polymer network (semi-IPN) of two US Food and Drug Administration approved materials, poly(3-hydroxybutyrate-co-3-valerate) (PHBV) and calcium alginate (CA) was engineered to provide an alternative strategy to enhance the poor adhesion properties of CA. The synthesis procedure allows the additional incorporation of 10 % w/w of graphene nanoplatelets (GNPs), which have no cytotoxic effect on human keratinocytes. This quantity of multilayer graphene provides superior antiviral activity to the novel semi-IPN against a surrogate virus of SARS-CoV-2. Adding GNPs hardly affects the water absorption or electrical conductivity of the pure components of CA and PHBV. However, the semi-IPN's electrical conductivity increases dramatically after adding GNP due to molecular rearrangements of the intertwined polymer chains that continuously distribute the GNP nanosheets, This new hydrophilic composite biomaterial film shows great promise for skin biomedical applications, especially those that require antiviral and/or biodegradable electroconductive materials.

Impaired ketogenesis ties metabolism to T cell dysfunction in COVID-19.

Anorexia and fasting are host adaptations to acute infection, and induce a metabolic switch towards ketogenesis and the production of ketone bodies, including ß-hydroxybutyrate (BHB)1-6. However, whether ketogenesis metabolically influences the immune response in pulmonary infections remains unclear. Here we show that the production of BHB is impaired in individuals with SARS-CoV-2-induced acute respiratory distress syndrome (ARDS) but not in those with  influenza-induced ARDS. We found that BHB promotes both the survival of and the production of interferon-γ by CD4+ T cells. Applying a metabolic-tracing analysis, we established that BHB provides an alternative carbon source to fuel oxidative phosphorylation (OXPHOS) and the production of bioenergetic amino acids and glutathione, which is important for maintaining the redox balance. T cells from patients with SARS-CoV-2-induced ARDS were exhausted and skewed towards glycolysis, but could be metabolically reprogrammed by BHB to perform OXPHOS, thereby increasing their functionality. Finally, we show in mice that a ketogenic diet and the delivery of BHB as a ketone ester drink restores CD4+ T cell metabolism and function in severe respiratory infections, ultimately reducing the mortality of mice infected with SARS-CoV-2. Altogether, our data reveal that BHB is an alternative source of carbon that promotes T cell responses in pulmonary viral infections, and highlight impaired ketogenesis as a potential confounding factor in severe COVID-19.

Different methods of eubiotic feed additive provision affect the health, performance, fermentation, and metabolic status of dairy calves during the preweaning period.

BACKGROUND: This study aimed to evaluate whether different methods of providing eubiotic feed additives to neonatal calves, during the preweaning period, can improve the calves' health, performance, ruminal fermentation, and metabolic status. Forty-four (3-day-old) Holstein-Friesian dairy calves (22 female and 22 male) were divided into four treatment groups for the duration of the 8-week trial. The eubiotic feed additive consisted of a combination of probiotic Lactobacillus spp. (multiple-strains at a dose of 250 mg/calf/day) and phytobiotics containing rosmarinic acid, as the main bioactive compound (at a dose of 50 mg/calf/day). The groups were named: CON (control, without eubiotic in either the milk replacer or the starter feed), MR (eubiotic in the milk replacer), SF (eubiotic in the starter feed), MRS (eubiotic in both the milk replacer and the starter feed). The individual intake of starter feed and the fecal scores were measured daily, and body weight and biometric measurements were taken weekly until calves were 56 days of age. Blood samples were collected on day 3 and then every 14 days to determine concentrations of insulin-like-growth-factor-I, ß-hydroxybutyrate, non-esterified fatty acids, and blood urea nitrogen. Ruminal fluid was collected on days 28 and 56 for short-chain fatty acids, NH3-N, and pH measurements. RESULTS: The body weight of the calves of the MR treatment group was higher compared to all other groups on days 28 and 56. Including the eubiotic feed additive in the milk replacer increased average daily gain, starter intake, and total dry matter intake from day 29 to day 56 and the overall experimental period compared to the CON group. The calves with MR treatment had lower fecal scores from days 3 to 28, a number of parasite oocysts/cysts per gram of feces on day 28, and the occurrences of fecal consistency scores of 3 (mild diarrhea) and 4 (severe diarrhea) were 3.2 and 3.0 times lower, respectively, compared with the CON group. The MR group had higher ruminal concentrations of short-chain-fatty-acids, propionate, and butyrate on day 56 than the CON group. Adding eubiotics into milk replacer resulted in the highest concentrations of blood insulin-like-growth-factor-I and ß-hydroxybutyrate from days 29 to 56 and the overall experimental period. CONCLUSION: The addition of eubiotic feed additives into the milk replacer can improve health, performance, ruminal fermentation, and biochemical blood indices in dairy calves during the preweaning period.

COVID-19: Proposing a Ketone-Based Metabolic Therapy as a Treatment to Blunt the Cytokine Storm.

Human SARS-CoV-2 infection is characterized by a high mortality rate due to some patients developing a large innate immune response associated with a cytokine storm and acute respiratory distress syndrome (ARDS). This is characterized at the molecular level by decreased energy metabolism, altered redox state, oxidative damage, and cell death. Therapies that increase levels of (R)-beta-hydroxybutyrate (R-BHB), such as the ketogenic diet or consuming exogenous ketones, should restore altered energy metabolism and redox state. R-BHB activates anti-inflammatory GPR109A signaling and inhibits the NLRP3 inflammasome and histone deacetylases, while a ketogenic diet has been shown to protect mice from influenza virus infection through a protective γδ T cell response and by increasing electron transport chain gene expression to restore energy metabolism. During a virus-induced cytokine storm, metabolic flexibility is compromised due to increased levels of reactive oxygen species (ROS) and reactive nitrogen species (RNS) that damage, downregulate, or inactivate many enzymes of central metabolism including the pyruvate dehydrogenase complex (PDC). This leads to an energy and redox crisis that decreases B and T cell proliferation and results in increased cytokine production and cell death. It is hypothesized that a moderately high-fat diet together with exogenous ketone supplementation at the first signs of respiratory distress will increase mitochondrial metabolism by bypassing the block at PDC. R-BHB-mediated restoration of nucleotide coenzyme ratios and redox state should decrease ROS and RNS to blunt the innate immune response and the associated cytokine storm, allowing the proliferation of cells responsible for adaptive immunity. Limitations of the proposed therapy include the following: it is unknown if human immune and lung cell functions are enhanced by ketosis, the risk of ketoacidosis must be assessed prior to initiating treatment, and permissive dietary fat and carbohydrate levels for exogenous ketones to boost immune function are not yet established. The third limitation could be addressed by studies with influenza-infected mice. A clinical study is warranted where COVID-19 patients consume a permissive diet combined with ketone ester to raise blood ketone levels to 1 to 2 mM with measured outcomes of symptom severity, length of infection, and case fatality rate.