Skin graft rejection and delayed-type hypersensitivity responses to H-Y in an I-A b mutant

Based on graft rejection in C57BL/6 and B10.A(4R), but not in B10.A mice, skin graft rejection and delayed-type hypersensitivity (DTH) responses to the male HY antigen were considered to be under the control of the IBb gene in the mouse H-2 complex. These two phenomena were re-examined in the B6.C-H-2 ^bm12 mutant strain [mutation in the A gene in IA leading to an alteration in Ia ^b serologically detected specificities and the inability to generate cytotoxic T (Tc) cells to H-Y]. In this study the bm12 mutant was shown to produce weak DTH responses to H-Y. By contrast, bm12 female mice were unable to reject male skin grafts unless they had received prior footpad priming of male spleen cells, when graft rejection occurred, albeit slowly. In C57BL/6 mice the response to the HY antigen therefore appears to be solely under the control of the IA ^b gene. In other strains, response/nonresponse is presumably dictated by the ability of IA/IE interactions to produce T-helper responses.     

Heterocyclic ketones as inhibitors of histone deacetylase

Several heterocyclic ketones were investigated as potential inhibitors of histone deacetylase. Nanomolar inhibitors such as 22 and 25 were obtained, the anti-proliferative activity of which were shown to be mediated by HDAC inhibition.     

Seasonal weather effects on hydrology drive the metabolism of non-forest lowland streams

Weather variations change stream hydrological conditions, affecting the stream function. A seasonal study in three well-conserved first-order Pampean streams was carried out to test the hypothesis that rainfalls are the main drivers of whole-stream metabolism, through their effects on hydrology. We estimated the stream metabolism and metabolic contribution of six relevant communities (angiosperms, macroalgae, seston, epiphyton, epipelon, and hyporheos) during late spring, summer, and winter and examined the relation between gross primary production (GPP) and photosynthetic active radiation (PAR). Our results showed that the decrease in available streambed light due to the dissolved organic carbon after rainfalls was the main factor related to the decrease in the ecosystem and community metabolisms. For instance, GPP oscillated from ~10 gO₂ m^?2 d^?1 in early spring (low flows) to ~3 gO₂ m^?2 d^?1 in summer (high flows). Ecosystem respiration (ER) was less sensitive than GPP to rainfalls due to the increase of hyporheic respiration. Rainfalls also caused a significant loss of downstream macroalgal biomass. At a day scale, the high PAR of late spring and summer saturated GPP during the afternoon, and the low temperature of winter mornings constrained GPP. Hence, the knowledge of weather changes is key to understanding the main hydrological drivers of stream function.     

Investigating the effects of point mutations on the affinity between the cyanobacterial lectin microvirin and high mannose-type glycans present on the HIV envelope glycoprotein

Human immunodeficiency virus (HIV) infections continue to exert an enormous impact on global human health. This led experts to emphasize the importance of new measures for preventing HIV infections, including the development of vaccines and novel drugs. In this context, a promising approach involves the use of lectins that can bind the surface envelope glycoprotein gp120 of HIV with high affinity, preventing viral entry. The cyanobacterial lectin microvirin (MVN) has been proposed as a candidate for development as a topical microbicide because of its ability to bind to high mannose-type glycans, potently inhibiting HIV-1 entry. Thus, the aim of this computational study was to investigate the effects of four point mutations (D53Q, D53E, D53K, and D53W) on the structure and affinity of MVN with di-mannose (MAN). Molecular dynamics simulations followed by binding free energy calculations using MM-GBSA were employed. The calculated binding free energy of ligand-receptor complexation of MVN with MAN was ?26.02 kcal mol^-1. We identified in the wild-type protein that residues I45, T59, and Q81 have a major contribution to the binding free energy of di-mannose. Among the investigated mutants, the most promising one was the D53W mutation, with a theoretical binding free energy value of ?29.16 kcal mol^-1. We suggest that this increased stability is due to the introduction of extra rigidity on the hinge region connecting two key structural elements of the MVN binding site.     

Susceptibility of Cypriot Tuta absoluta populations to four targeted insecticides and control failure likelihood

Tuta absoluta, known as the South American tomato pinworm, is one of the most disastrous pests of tomato cultivations, presently menacing tomato cultivations worldwide. In 2006, T. absoluta invaded Spain from South America. Since then, it was rapidly spread to most European, African and Asian countries. Such alien invasive species can minimize crop production, whereas the increasing use of insecticides raises various environmental concerns as well as on control costs, control failure and the toxicity to non‐target organisms. The S. American tomato pinworm is mostly controlled by chemical insecticides, and failure to control it is not a rare phenomenon. Resistance to numerous insecticides has been reported and is mainly due to the fact that farmers do not follow a sustainable resistance management scheme. Several examples have been reported from several countries where the tomato pinworm is present. In order to develop a successful insecticide resistance management (IRM) strategy for any major pest, one needs to identify the baseline toxicity to insecticides and then monitor susceptibility levels . In Cyprus, the current status of susceptibility levels to the main insecticides that are used to control T. absoluta has never been studied before. Herein, nine Cypriot populations of the pest were subjected to laboratory bioassays between 2016 and 2018 using the main insecticides applied against it. We found that the insecticides chlorantraniliprole and indoxacarb could not control the Cypriot T. absoluta populations anymore, with a resistance ratio (RR) >28 and 3–23, respectively. Furthermore, mortality achieved by those two insecticides was 20.6%–72% for chlorantraniliprole and 27.5%–78% for indoxacarb. However, the insecticides emamectin benzoate and spinosad are very effective, since mortality to both of them ranged between 99.5% and 100%.     

Phlebotomine sandflies (Diptera-Psychodidae) of the isle of Cyprus. II--Isolation and typing of Leishmania (Leishmania infantum Nicolle, 1908 (zymodeme MON 1) from Phlebotomus (Larroussius) tobbi Adler and Theodor, 1930

During two surveys conducted in Cyprus (August 1998 and September 1999), 2,910 phlebotomine sandflies females were caught by CDC miniature light traps then dissected under binocular and examined on microscope. Eleven species were identified: Phlebotomus papatasi, P. sergenti, P. jacusieli, P. alexandri, P. tobbi, P. galilaeus, P. mascittii, P. economidesi, Sergentomyia fallax, S. minuta et S. azizi. The Larroussius species (P. galilaeus and P. tobbi) are the most abundant (more than 60% of our captures). Promastigotes were isolated from one specimen identified as P. tobbi. A Leishmania stock was successfully cultured and identified by isoenzyme characterisation as belonging to L. infantum zymodeme MON 1. The same zymodeme was isolated and identified from four dogs too. Because of the absence of usual vectors of L. infantum in the eastern part of the Mediterranean basin (P. neglectus and P. syriacus), and according to its distribution in Cyprus, P. tobbi constitute certainly a good local vector. It seems to be not very anthropophilic, that could explain the very few human cases.     

Roux-en-Y Gastric Bypass Alters Brain Activity in Regions that Underlie Reward and Taste Perception

Background

Roux-en-Y gastric bypass (RYGB) surgery is a very effective bariatric procedure to achieve significant and sustained weight loss, yet little is known about the procedure’s impact on the brain. This study examined the effects of RYGB on the brain’s response to the anticipation of highly palatable versus regular food.

Methods

High fat diet-induced obese rats underwent RYGB or sham operation and were then tested for conditioned place preference (CPP) for the bacon-paired chamber, relative to the chow-paired chamber. After CPP, animals were placed in either chamber without the food stimulus, and brain-glucose metabolism (BGluM) was measured using positron emission tomography (μPET).

Results

Bacon CPP was only observed in RYGB rats that had stable weight loss following surgery. BGluM assessment revealed that RYGB selectively activated regions of the right and midline cerebellum (Lob 8) involved in subjective processes related to reward or expectation. Also, bacon anticipation led to significant activation in the medial parabrachial nuclei (important in gustatory processing) and dorsomedial tegmental area (key to reward, motivation, cognition and addiction) in RYGB rats; and activation in the retrosplenial cortex (default mode network), and the primary visual cortex in control rats.

Conclusions

RYGB alters brain activity in areas involved in reward expectation and sensory (taste) processing when anticipating a palatable fatty food. Thus, RYGB may lead to changes in brain activity in regions that process reward and taste-related behaviors. Specific cerebellar regions with altered metabolism following RYGB may help identify novel therapeutic targets for treatment of obesity.     

Melatonin: a possible link between the presence of artificial light at night and reductions in biological fitness

The mechanisms underpinning the ecological impacts of the presence of artificial night lighting remain elusive. One suspected underlying cause is that the presence of light at night (LAN) supresses nocturnal production of melatonin, a key driver of biological rhythm and a potent antioxidant with a proposed role in immune function. Here, we briefly review the evidence for melatonin as the link between LAN and changes in behaviour and physiology. We then present preliminary data supporting the potential for melatonin to act as a recovery agent mitigating the negative effects of LAN in an invertebrate. Adult crickets (Teleogryllus commodus), exposed to constant illumination, were provided with dietary melatonin (concentrations: 0, 10 or 100 µg ml⁻¹) in their drinking water. We then compared survival, lifetime fecundity and, over a 4-week period, immune function (haemocyte concentration, lysozyme-like and phenoloxidase (PO) activity). Melatonin supplementation was able only partially to mitigate the detrimental effects of LAN: it did not improve survival or fecundity or PO activity, but it had a largely dose-dependent positive effect on haemocyte concentration and lysozyme-like activity. We discuss the implications of these relationships, as well as the usefulness of invertebrates as model species for future studies that explore the effects of LAN.     

Discovery of potent and selective thienopyrimidine inhibitors of Aurora kinases

In an effort to discover Aurora kinase inhibitors, an HTS hit revealed an amide containing pyrrolopyrimidine compound. Replacement of the pyrrolopyrimidine residue with a thienopyrimidine moiety led to a series of potent and selective Aurora inhibitors.     

Mutations in the gene KCNV2 encoding a voltage-gated potassium channel subunit cause "cone dystrophy with supernormal rod electroretinogram" in humans

"Cone dystrophy with supernormal rod electroretinogram (ERG)" is an autosomal recessive disorder that causes lifelong visual loss combined with a supernormal ERG response to a bright flash of light. We have linked the disorder to a 0.98-cM (1.5-Mb) region on chromosome 9p24, flanked by rs1112534 and rs1074449, using homozygosity mapping in one large consanguineous pedigree. Analysis of one gene within this region, KCNV2, showed a homozygous nonsense mutation. Mutations were also found in 17 alleles of 10 other unrelated families with the same disorder. In situ hybridization demonstrated KCNV2 expression in human rod and cone photoreceptors. The precise function of KCNV2 in human photoreceptors remains to be determined, although this work suggests that mutations might perturb or abrogate I(KX), the potassium current within vertebrate photoreceptor inner segments, which has been shown to set their resting potential and voltage response.