Tristetraprolin inhibits Ras-dependent tumor vascularization by inducing vascular endothelial growth factor mRNA degradation

Vascular endothelial growth factor (VEGF) is one of the most important regulators of physiological and pathological angiogenesis. Constitutive activation of the extracellular signal-regulated kinase (ERK) pathway and overexpression of VEGF are common denominators of tumors from different origins. We have established a new link between these two fundamental observations converging on VEGF mRNA stability. In this complex phenomenon, tristetraprolin (TTP), an adenylate and uridylate-rich element-associated protein that binds to VEGF mRNA 3′-untranslated region, plays a key role by inducing VEGF mRNA degradation, thus maintaining basal VEGF mRNA amounts in normal cells. ERKs activation results in the accumulation of TTP mRNA. However, ERKs reduce the VEGF mRNA-destabilizing effect of TTP, leading to an increase in VEGF expression that favors the angiogenic switch. Moreover, TTP decreases RasVal12-dependent VEGF expression and development of vascularized tumors in nude mice. As a consequence, TTP might represent a novel antiangiogenic and antitumor agent acting through its destabilizing activity on VEGF mRNA. Determination of TTP and ERKs status would provide useful information for the evaluation of the angiogenic potential in human tumors.     

The public and private benefit of an impure public good determines the sensitivity of bacteria to population collapse in a snowdrift game

When cooperation is critical for survival, cheating can lead to population collapse. One mechanism of cooperation that permits the coexistence of cooperators and cheaters is an impure public good, whose public benefits are shared, but with a private benefit retained by the cooperator. It has yet to be determined how the contributions of the public and private benefit affect population survival. Using simulations and experiments with β-lactamase-expressing bacteria, we found that for a given amount of public and private benefit, the population was most sensitive to collapse when initiated from an intermediate fraction of cooperators due to the near-concurrent collapse of the cooperator and cheater populations. We found that increasing the ratio of public to private benefit increased sensitivity to collapse. A low ratio allowed cooperators to survive on their private benefit after the public benefit could not rescue the cheaters. A high ratio allowed the cheaters to survive to high concentrations of ampicillin due to the high public benefit. However, small increases in ampicillin caused a rapid decline in the entire population as the private benefit was insufficient to allow self-rescue of the cooperators. Our findings have implications in the persistence of populations that rely on cooperation for survival.     

A SARS-CoV-2 variant elicits an antibody response with a shifted immunodominance hierarchy

Many SARS-CoV-2 variants have mutations at key sites targeted by antibodies. However, it is unknown if antibodies elicited by infection with these variants target the same or different regions of the viral spike as antibodies elicited by earlier viral isolates. Here we compare the specificities of polyclonal antibodies produced by humans infected with early 2020 isolates versus the B.1.351 variant of concern (also known as Beta or 20H/501Y.V2), which contains mutations in multiple key spike epitopes. The serum neutralizing activity of antibodies elicited by infection with both early 2020 viruses and B.1.351 is heavily focused on the spike receptor-binding domain (RBD). However, within the RBD, B.1.351-elicited antibodies are more focused on the “class 3” epitope spanning sites 443 to 452, and neutralization by these antibodies is notably less affected by mutations at residue 484. Our results show that SARS-CoV-2 variants can elicit polyclonal antibodies with different immunodominance hierarchies.     

Comparative toxicity of different chemical and biological insecticides against the scale insect Dactylopius opuntiae and their side effects on the predator Cryptolaemus montrouzieri

The contact toxicity of various chemical and biological pesticides for the first and second instar nymphs and adults of the Opuntia cochineal scale insect Dactylopius opuntiae and the predator ladybird Cryptolaemus montrouzieri was determined under Morocco semi field conditions. d-limonene (60?g/l) at 100 and 150?cc/hl, mineral oil (780?g/l) at 2400?cc/hl and malathion (500?g/l) at 300?cc/hl caused the highest mortality (99–100%) among first instar nymphs of D. opuntiae 24?h after treatment. d-limonene (60?g/l) at 150?cc/hl caused greatest mortality (99%) in second instar nymphs. The highest mortality (99%) among adult female D. opuntiae was observed 120?h after treatment with d-limonene (60?g/l) at 150?cc/hl and mineral oil (780?g/l) at 2400?cc/hl. For the predator C. montrouzieri the highest mortality (92–97%) among adults 24?h after treatment was caused by malathion (500?g/l) at 100, 200 and 300?cc/hl and alpha-cypermethrin (100?g/l) at 75, 150 and 225?cc/hl. The most harmful pesticides to C. montrouzieri larvae 24?h after treatment were malathion and alpha-cypermethrin with mortality rates of 89–95%. Mortality in larvae ranged from 87 to 100% 120?h after treatment with chlorpyriphos-methyl (480?g/l) at 75, 150 and 225?cc/hl and spinosad (480?g/l) at 100, 200 and 300?cc/hl. d-limonene (60?g/l) at 50?cc/hl and mineral oil (780?g/l) at 1000?cc/hl had the least impact on C. montrouzieri adults and larvae, causing mortality of 11 and 15%, respectively, 120?h after treatment. d-limonene (60?g/l) and mineral oil (780?g/l) may therefore be viable alternatives to others high-risk chemical pesticides. These two biological insecticides are effective in controlling the Opuntia cochineal scale insect but have little adverse impact on the predator C. montrouzieri.     

Antibody responses against SARS-CoV-2 variants induced by four different SARS-CoV-2 vaccines in health care workers in the Netherlands: A prospective cohort study

BackgroundEmerging and future SARS-CoV-2 variants may jeopardize the effectiveness of vaccination campaigns. Therefore, it is important to know how the different vaccines perform against diverse SARS-CoV-2 variants.Methods and findingsIn a prospective cohort of 165 SARS-CoV-2 naive health care workers in the Netherlands, vaccinated with either one of four vaccines (BNT162b2, mRNA-1273, AZD1222 or Ad26.COV2.S), we performed a head-to-head comparison of the ability of sera to recognize and neutralize SARS-CoV-2 variants of concern (VOCs; Alpha, Beta, Gamma, Delta and Omicron). Repeated serum sampling was performed 5 times during a year (from January 2021 till January 2022), including before and after booster vaccination with BNT162b2. Four weeks after completing the initial vaccination series, SARS-CoV-2 wild-type neutralizing antibody titers were highest in recipients of mRNA-1273, followed by recipients of BNT162b2 (geometric mean titers (GMT) of 358 [95% CI 231–556] and 214 [95% CI 153–299], respectively; p<0.05), and substantially lower in those vaccinated with the adenovirus vector-based vaccines AZD1222 and Ad26.COV2.S (GMT of 18 [95% CI 11–30] and 14 [95% CI 8–25] IU/ml, respectively; p<0.001). VOCs neutralization was reduced in all vaccine groups, with the greatest reduction in neutralization GMT observed against the Omicron variant (fold change 0.03 [95% CI 0.02–0.04], p<0.001). The booster BNT162b2 vaccination increased neutralizing antibody titers for all groups with substantial improvement against the VOCs including the Omicron variant. We used linear regression and linear mixed model analysis. All results were adjusted for possible confounding of age and sex. Study limitations include the lack of cellular immunity data.ConclusionsOverall, this study shows that the mRNA vaccines appear superior to adenovirus vector-based vaccines in inducing neutralizing antibodies against VOCs four weeks after initial vaccination and after booster vaccination, which implies the use of mRNA vaccines for both initial and booster vaccination.

Marit J. van Gils and colleagues investigate antibody responses against diverse emerging SARS-CoV-2 variants induced by four different SARS-CoV-2 vaccines in health care workers in the Netherlands.     

Pharmacological glycerol-3-phosphate acyltransferase inhibition decreases food intake and adiposity and increases insulin sensitivity in diet-induced obesity

Storage of excess calories as triglycerides is central to obesity and its associated disorders. Glycerol-3-phosphate acyltransferases (GPATs) catalyze the initial step in acylglyceride syntheses, including triglyceride synthesis. We utilized a novel small-molecule GPAT inhibitor, FSG67, to investigate metabolic consequences of systemic pharmacological GPAT inhibition in lean and diet-induced obese (DIO) mice. FSG67 administered intraperitoneally decreased body weight and energy intake, without producing conditioned taste aversion. Daily FSG67 (5 mg/kg, 15.3 μmol/kg) produced gradual 12% weight loss in DIO mice beyond that due to transient 9- to 10-day hypophagia (6% weight loss in pair-fed controls). Continued FSG67 maintained the weight loss despite return to baseline energy intake. Weight was lost specifically from fat mass. Indirect calorimetry showed partial protection by FSG67 against decreased rates of oxygen consumption seen with hypophagia. Despite low respiratory exchange ratio due to a high-fat diet, FSG67-treated mice showed further decreased respiratory exchange ratio, beyond pair-fed controls, indicating enhanced fat oxidation. Chronic FSG67 increased glucose tolerance and insulin sensitivity in DIO mice. Chronic FSG67 decreased gene expression for lipogenic enzymes in white adipose tissue and liver and decreased lipid accumulation in white adipose, brown adipose, and liver tissues without signs of damage. RT-PCR showed decreased gene expression for orexigenic hypothalamic neuropeptides AgRP or NPY after acute and chronic systemic FSG67. FSG67 given intracerebroventricularly (100 and 320 nmol icv) produced 24-h weight loss and feeding suppression, indicating contributions from direct central nervous system sites of action. Together, these data point to GPAT as a new potential therapeutic target for the management of obesity and its comorbidities.     

NrdH-redoxin of Mycobacterium tuberculosis and Corynebacterium glutamicum Dimerizes at High Protein Concentration and Exclusively Receives Electrons from Thioredoxin Reductase

NrdH-redoxins are small reductases with a high amino acid sequence similarity with glutaredoxins and mycoredoxins but with a thioredoxin-like activity. They function as the electron donor for class Ib ribonucleotide reductases, which convert ribonucleotides into deoxyribonucleotides. We solved the x-ray structure of oxidized NrdH-redoxin from Corynebacterium glutamicum (Cg) at 1.5 Å resolution. Based on this monomeric structure, we built a homology model of NrdH-redoxin from Mycobacterium tuberculosis (Mt). Both NrdH-redoxins have a typical thioredoxin fold with the active site CXXC motif located at the N terminus of the first α-helix. With size exclusion chromatography and small angle x-ray scattering, we show that Mt_NrdH-redoxin is a monomer in solution that has the tendency to form a non-swapped dimer at high protein concentration. Further, Cg_NrdH-redoxin and Mt_NrdH-redoxin catalytically reduce a disulfide with a specificity constant 1.9 × 10⁶ and 5.6 × 10⁶ m⁻¹ min⁻¹, respectively. They use a thiol-disulfide exchange mechanism with an N-terminal cysteine pK_a lower than 6.5 for nucleophilic attack, whereas the pK_a of the C-terminal cysteine is ∼10. They exclusively receive electrons from thioredoxin reductase (TrxR) and not from mycothiol, the low molecular weight thiol of actinomycetes. This specificity is shown in the structural model of the complex between NrdH-redoxin and TrxR, where the two surface-exposed phenylalanines of TrxR perfectly fit into the conserved hydrophobic pocket of the NrdH-redoxin. Moreover, nrdh gene deletion and disruption experiments seem to indicate that NrdH-redoxin is essential in C. glutamicum.     

A new Palaeocene Megalopidae (Teleostei,Elopomorpha) from the phosphate basins of Morocco

Abstract

A new Megalopidae (Teleostei, Elopomorpha, Elopiformes), Protarpon boualii sp. nov., is described on the basis of two neurocrania gathered from the Lower Palaeocene (Danian) beds of the Oulad Abdoun basin, in Morocco. Its inclusion in the family Megalopidae and the genus Protarpon is supported by the L-shaped pterotics, the flat skull roof, the well developed epiotic processes and the roofed dilatator fossae. It differs from Protarpon priscus and P. oblongus from the Ypresian of the London Clay Formation (England) mainly by the proportions of the subtemporal and the post-temporal fossa openings, the proportions of skull roof bones and its larger size. Protarpon boualii sp. nov. represents the first fossil occurrence of a megalopid in North Africa. Its close phylogenetic relationships with forms from the London Clay Formation highlight the strong biogeographical affinities between the faunas of these two localities during the Palaeocene-Eocene period.

http://www.zoobank.org/urn:lsid:zoobank.org:pub:D5FEE8B3-B220-461F-B635-31DD7F2CF921