E7766, a Macrocycle-Bridged Stimulator of Interferon Genes (STING) Agonist with Potent Pan-Genotypic Activity

A strategy for creating potent and pan-genotypic stimulator of interferon genes (STING) agonists is described. Locking a bioactive U-shaped conformation of cyclic dinucleotides by introducing a transannular macrocyclic bridge between the nucleic acid bases leads to a topologically novel macrocycle-bridged STING agonist (MBSA). In addition to substantially enhanced potency, the newly designed MBSAs, exemplified by clinical candidate E7766 , exhibit broad pan-genotypic activity in all major human STING variants. E7766 is shown to have potent antitumor activity with long lasting immune memory response in a mouse liver metastatic tumor model. Two complementary stereoselective synthetic routes to E7766 are also described.     

Sarcopenia: Molecular Pathways and Potential Targets for Intervention

Aging is associated with sarcopenia. The loss of strength results in decreased muscle mass and motor function. This process accelerates the progressive muscle deterioration observed in older adults, favoring the presence of debilitating pathologies. In addition, sarcopenia leads to a decrease in quality of life, significantly affecting self-sufficiency. Altogether, these results in an increase in economic resources from the National Health Systems devoted to mitigating this problem in the elderly, particularly in developed countries. Different etiological determinants are involved in the progression of the disease, including: neurological factors, endocrine alterations, as well as nutritional and lifestyle changes related to the adoption of more sedentary habits. Molecular and cellular mechanisms have not been clearly characterized, resulting in the absence of an effective treatment for sarcopenia. Nevertheless, physical activity seems to be the sole strategy to delay sarcopenia and its symptoms. The present review intends to bring together the data explaining how physical activity modulates at a molecular and cellular level all factors that predispose or favor the progression of this deteriorating pathology.     

Heifers with positive genetic merit for fertility traits reach puberty earlier and have a greater pregnancy rate than heifers with negative genetic merit for fertility traits

This study investigated the hypothesis that dairy heifers divergent in genetic merit for fertility traits differ in the age of puberty and reproductive performance. New Zealand's fertility breeding value (FertBV) is the proportion of a sire's daughters expected to calve in the first 42 d of the seasonal calving period. We used the New Zealand national dairy database to identify and select Holstein-Friesian dams with either positive (POS, +5 FertBV, n = 1,334) or negative FertBV (NEG, ?5% FertBV, n = 1,662) for insemination with semen from POS or NEG FertBV sires, respectively. The resulting POS and NEG heifers were predicted to have a difference in average FertBV of 10 percentage points. We enrolled 640 heifer calves (POS, n = 324; NEG, n = 316) at 9 d ± 5.4 d (± standard deviation; SD) for the POS calves and 8 d ± 4.4 d old for the NEG calves. Of these, 275 POS and 248 NEG heifers were DNA parent verified and retained for further study. The average FertBV was +5.0% (SD = 0.74) and ?5.1% (SD = 1.36) for POS and NEG groups, respectively. Heifers were reared at 2 successive facilities as follows: (1) calf rearing (enrollment to ～13 wk of age) and (2) grazier, after 13 wk until 22 mo of age. All heifers wore a collar with an activity sensor to monitor estrus events starting at 8 mo of age, and we collected weekly blood samples when individual heifers reached 190 kg of body weight (BW) to measure plasma progesterone concentrations. Puberty was characterized by plasma progesterone concentrations >1 ng/mL in at least 2 of 3 successive weeks. Date of puberty was defined when the first of these samples was >1 ng/mL. Heifers were seasonally bred for 98 d starting at ～14 mo of age. Transrectal ultrasound was used to confirm pregnancy and combined with activity data to estimate breeding and pregnancy dates. We measured BW every 2 wk, and body condition and stature at 6, 9, 12, and 15 mo of age. The significant FertBV by day interaction for BW was such that the NEG heifers had increasingly greater BW with age. This difference was mirrored with the significant FertBV by month interaction for average daily gain, with the NEG heifers having a greater average daily gain between 9 and 18 mo of age. There was no difference in heifer stature between the POS and NEG heifers. The POS heifers were younger and lighter at puberty, and were at a lesser mature BW, compared with the NEG heifers. As a result, 94 ± 1.6% of the POS and 82 ± 3.2% of the NEG heifers had reached puberty at the start of breeding. The POS heifers were 20% and 11% more likely to be pregnant after 21 d and 42 d of breeding than NEG heifers (relative risk = 1.20, 95% confidence interval of 1.03–1.34; relative risk = 1.11, 95% confidence interval of 1.01–1.16). Results from this experiment support an association between extremes in genetic merit for fertility base on cow traits and heifer reproduction. Our results indicate that heifer puberty and pregnancy rates are affected by genetic merit for fertility traits, and these may be useful phenotypes for genetic selection.     

The three Rs of river ecosystem resilience: Resources,recruitment, and refugia

Resilience in river ecosystems requires that organisms must persist in the face of highly dynamic hydrological and geomorphological variations. Disturbance events such as floods and droughts are postulated to shape life history traits that support resilience, but river management and conservation would benefit from greater understanding of the emergent effects in communities of river organisms. We unify current knowledge of taxonomic‐, phylogenetic‐, and trait‐based aspects of river communities that might aid the identification and quantification of resilience mechanisms. Temporal variations in river productivity, physical connectivity, and environmental heterogeneity resulting from floods and droughts are highlighted as key characteristics that promote resilience in these dynamic ecosystems. Three community‐wide mechanisms that underlie resilience are (a) partitioning (competition/facilitation) of dynamically varying resources, (b) dispersal, recolonization, and recruitment promoted by connectivity, and (c) functional redundancy in communities promoted by resource heterogeneity and refugia. Along with taxonomic and phylogenetic identity, biological traits related to feeding specialization, dispersal ability, and habitat specialization mediate organism responses to disturbance. Measures of these factors might also enable assessment of the relative contributions of different mechanisms to community resilience. Interactions between abiotic drivers and biotic aspects of resource use, dispersal, and persistence have clear implications for river conservation and management. To support these management needs, we propose a set of taxonomic, phylogenetic, and life‐history trait metrics that might be used to measure resilience mechanisms. By identifying such indicators, our proposed framework can enable targeted management strategies to adapt river ecosystems to global change.     

Proteome profiling of exosomes derived from plasma of heifers with divergent genetic merit for fertility

The current study evaluated exosomes isolated from plasma of heifers bred to have high or low fertility through developing extreme diversity in fertility breeding values, however, key animal traits (e.g., body weight, milk production, and percentage of North American genetics) remained similar between the 2 groups. The exosomes were isolated by a combined ultracentrifugation and size exclusion chromatography approach and characterized by their size distribution (nanoparticle tracking analysis), morphology (transmission electron microscopy), and presence of exosomal markers (immunoblotting). In addition, a targeted mass spectrometry approach was used to confirm the presence of 2 exosomal markers, tumor susceptibility gene 101 and flotillin 1. The number of exosomes from plasma of high fertility heifers was greater compared with low fertility heifers. Interestingly, the exosomal proteomic profile, evaluated using mass spectrometry, identified 89 and 116 proteins in the high and low fertility heifers respectively, of which 4 and 31 were unique, respectively. These include proteins associated with specific biological processes and molecular functions of fertility. Most notably, the tetratricopeptide repeat protein 41-related, glycodelin, and kelch-like protein 8 were identified in plasma exosomes unique to the low fertility heifers. These proteins are suggested to play a role in reproduction; however, the role of these proteins in dairy cow reproduction remains to be elucidated. Their identification underscores the potential for proteins within exosomes to provide information on the fertility status and physiological condition of the cow. This may potentially lead to the development of prognostic tools and interventions to improving dairy cow fertility.     

Modified Galacto- or Fuco-Clusters Exploiting the Siderophore Pathway to Inhibit the LecA- or LecB-Associated Virulence of Pseudomonas aeruginosa

Galacto- and fuco-clusters conjugated with one to three catechol or hydroxamate motifs were synthesised to target LecA and LecB lectins of Pseudomonas aeruginosa (PA) localised in the outer membrane and inside the bacterium. The resulting glycocluster–pseudosiderophore conjugates were evaluated as Trojan horses to cross the outer membrane of PA by iron transport. The data suggest that glycoclusters with catechol moieties are able to hijack the iron transport, whereas those with hydroxamates showed strong nonspecific interactions. Mono- and tricatechol galactoclusters ( G1C and G3C ) were evaluated as inhibitors of infection by PA in comparison with the free galactocluster ( G0 ). All of them exhibited an inhibitory effect between 46 to 75 % at 100 μM, with a higher potency than G0 . This result shows that LecA localised in the outer membrane of PA is involved in the infection mechanism.     

Chromia Scale Thermally Grown on Pure Chromium Under Controlled <Emphasis Type="Italic">p</Emphasis>(O<Subscript>2</Subscript>) Atmosphere: II—Spallation Investigation Using Photoelectrochemical Techniques at a Microscale

Pure chromium oxidized at 900 °C at low oxygen partial pressure (10^?12 atm) gives duplex Cr₂O₃ scale with an internal part made of equiaxed grains and exhibiting an n-type conduction, and an external part made of columnar grains and exhibiting a p-type conduction. Spalled regions occurring during cooling have been studied with photoelectrochemical techniques at a microscale. New information in the form of a specific image (structural quality image) could be obtained and revealed a level of structural defect density in the internal chromia subscale higher than that measured in the non-spalled region. The results complement the spallation scenario proposed in part I of this work.