Profiling SARS-CoV-2 HLA-I peptidome reveals T cell epitopes from out-of-frame ORFs

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Confocal-based cell-specific finite element modeling extended to study variable cell shapes and intracellular structures: The example of the adipocyte

This communication extends the recently reported cell-specific finite element (FE) method in Slomka and Gefen (2010) in which geometrically realistic FE cell models are created from confocal microscopy scans for large deformation analyses. The cell-specific FE method is extended here in the following aspects: (i) we demonstrate that cell-specific FE is versatile enough to deal with cells of substantially different geometrical shapes. The examples of an “elongated” pre-adipocyte and a “round” mature adipocyte are used to demonstrate this feature. (ii) We demonstrate that cell-specific FE can be used to analyze the mechanical behavior of cells that incorporate complex intracellular structures and are subjected to large deformations—again through the example of an adipocyte which contains a multitude of lipid droplets, each having a different size and shape. By demonstrating feasibility of inclusion of such inhomogeneities in the cytoplasm, the present work paves the way for modeling cellular organelles such as Golgi bodies, lysosomes and mitochondria in mechanically loaded cells using cell-specific FE.     

Addition of Rapamycin to Anti-CD3 Antibody Improves Long-Term Glycaemia Control in Diabetic NOD Mice

Aims/Hypothesis

Non-Fc-binding Anti CD3 antibody has proven successful in reverting diabetes in the non-obese diabetes mouse model of type 1 diabetes and limited efficacy has been observed in human clinical trials. We hypothesized that addition of rapamycin, an mTOR inhibitor capable of inducing operational tolerance in allogeneic bone marrow transplantation, would result in improved diabetes reversal rates and overall glycemia.

Methods

Seventy hyperglycemic non-obese diabetic mice were randomized to either a single injection of anti CD3 alone or a single injection of anti CD3 followed by 14 days of intra-peritoneal rapamycin. Mice were monitored for hyperglycemia and metabolic control.

Results

Mice treated with the combination of anti CD3 and rapamycin had similar rates of diabetes reversal compared to anti CD3 alone (25/35 vs. 22/35). Mice treated with anti CD3 plus rapamycin had a significant improvement in glycemia control as exhibited by lower blood glucose levels in response to an intra-peritoneal glucose challenge; average peak blood glucose levels 30 min post intra-peritoneal injection of 2 gr/kg glucose were 6.9 mmol/L in the anti CD3 plus rapamycin group vs. 10 mmo/L in the anti CD3 alone (P<0.05).

Conclusions/Interpretation

The addition of rapamycin to anti CD3 results in significant improvement in glycaemia control in diabetic NOD mice.     

Mating interference of glassy‐winged sharpshooters,Homalodisca vitripennis

Animal communication is a complex behavior that is influenced by abiotic and biotic factors of the environment. Glassy‐winged sharpshooters (GWSS), Homalodisca vitripennis (Germar) (Hemiptera: Cicadellidae), primarily use vibrational signaling for courtship communication. Because GWSS is a major pest, transmitting the plant pathogenic bacterium Xylella fastidiosa Wells et al., interruption of communication is a possible avenue for control. Playback of white noise, pre‐recorded female signals, and artificial female noise (continuously overlapping female signals) significantly reduced mating of GWSS when compared to silent control mating trials. Furthermore, to begin to determine the mechanism underlying playback control, female signaling activity was recorded in the presence of stimuli. In response to playback of female signals, females signaled (duet‐like) more often than females tested in the absence of playback. After the first playback, almost two‐thirds of females signaled a response within 3 s. Additionally, one‐third of the females signaled within 1 s after cessation of white noise, and significantly more in the time periods following noise termination. Results highlight how GWSS responds to differing competitive disturbances in the environment and lays important ground work that possibly could be used to develop pesticide‐free control methods.     

Comparable Long-Term Efficacy of Lopinavir/Ritonavir and Similar Drug-Resistance Profiles in Different HIV-1 Subtypes

Background

Analysis of potentially different impact of Lopinavir/Ritonavir (LPV/r) on non-B subtypes is confounded by dissimilarities in the conditions existing in different countries. We retrospectively compared its impact on populations infected with subtypes B and C in Israel, where patients infected with different subtypes receive the same treatment.

Methods

Clinical and demographic data were reported by physicians. Resistance was tested after treatment failure. Statistical analyses were conducted using SPSS.

Results

607 LPV/r treated patients (365 male) were included. 139 had HIV subtype B, 391 C, and 77 other subtypes. At study end 429 (71%) were receiving LPV/r. No significant differences in PI treatment history and in median viral-load (VL) at treatment initiation and termination existed between subtypes. MSM discontinued LPV/r more often than others even when the virologic outcome was good (p = 0.001). VL was below detection level in 81% of patients for whom LPV/r was first PI and in 67% when it was second (P = 0.001). Median VL decrease from baseline was 1.9±0.1 logs and was not significantly associated with subtype. Median CD4 increase was: 162 and 92cells/µl, respectively, for patients receiving LPV/r as first and second PI (P = 0.001), and 175 and 98, respectively, for subtypes B and C (P<0.001). Only 52 (22%) of 237 patients genotyped while under LPV/r were fully resistant to the drug; 12(5%) were partially resistant. In48%, population sequencing did not reveal resistance to any drug notwithstanding the virologic failure. No difference was found in the rates of resistance development between B and C (p = 0.16).

Conclusions

Treatment with LPV/r appeared efficient and tolerable in both subtypes, B and C, but CD4 recovery was significantly better in virologically suppressed subtype-B patients. In both subtypes, LPV/r was more beneficial when given as first PI. Mostly, reasons other than resistance development caused discontinuation of treatment.     

Listening to the environment: hearing differences from an epigenetic effect in solitarious and gregarious locusts

Locusts display a striking form of phenotypic plasticity, developing into either a lone-living solitarious phase or a swarming gregarious phase depending on population density. The two phases differ extensively in appearance, behaviour and physiology. We found that solitarious and gregarious locusts have clear differences in their hearing, both in their tympanal and neuronal responses. We identified significant differences in the shape of the tympana that may be responsible for the variations in hearing between locust phases. We measured the nanometre mechanical responses of the ear''s tympanal membrane to sound, finding that solitarious animals exhibit greater displacement. Finally, neural experiments signified that solitarious locusts have a relatively stronger response to high frequencies. The enhanced response to high-frequency sounds in the nocturnally flying solitarious locusts suggests greater investment in detecting the ultrasonic echolocation calls of bats, to which they are more vulnerable than diurnally active gregarious locusts. This study highlights the importance of epigenetic effects set forth during development and begins to identify how animals are equipped to match their immediate environmental needs.     

Characterization of PfiT/PfiA toxin–antitoxin system of Pseudomonas aeruginosa that affects cell elongation and prophage induction

Toxin–antitoxin (TA) systems are small genetic modules usually consisting of two elements—a toxin and an antitoxin. The abundance of TA systems among various bacterial strains may indicate an important evolutionary role. Pseudomonas aeruginosa, which can be found in a variety of niches in nature, is an opportunistic pathogen for various hosts. While P. aeruginosa strains are very versatile and diverse, only a few TA systems were characterized in this species. Here, we describe a newly characterized TA system in P. aeruginosa that is encoded within the filamentous Pf4 prophage. This system, named PfiT/PfiA, is a homologue of the ParE/YefM TA system. It is a type II TA system, in which the antitoxin is a protein that binds the toxic protein and eliminates the toxic effect. PfiT/PfiA carries several typical type II characteristics. Specifically, it constitutes two small genes expressed in a single operon, PfiT inhibits growth and PfiA eliminates this effect, PfiA binds PfiT, and PfiT expression results in elongated cells. Finally, we assigned a novel function to this TA system, where an imbalance between PfiT and PfiA, favouring the toxin, resulted in cell elongation and an increase in virion production.     

Phenology and polyploidy in annual Brachypodium species (Poaceae) along the aridity gradient in Israel

Local adaptation of plants along environmental gradients provides strong evidence for clinal evolution mediated by natural selection. Plants have developed diverse strategies to mitigate stress, for example, drought escape is a phenological strategy to avoid drought stress, while polyploidy was proposed as a genomic adaptation to stress. Polyploidy as an adaptation to aridity (an environmental parameter integrating temperature and precipitation) was previously documented in annual Brachypodium spp. (Poaceae) in the Western Mediterranean. Here, we examined whether polyploidy or phenology are associated with aridity in annual Brachypodium spp. along the aridity gradient in the Eastern Mediterranean. Using flow cytometry, we determined ploidy levels of plants from natural populations along the Israeli gradient, spanning ∼424 km from mesic Mediterranean to extreme desert climates. In a common garden we recorded time of seedling emergence, flowering and senescence. We tested whether the proportion of allotetraploids in the populations and phenological traits were associated with aridity. Contrary to a previous study in the Western Mediterranean, we found no effect of aridity on the proportion of allotetraploids and diploids within populations. Interestingly, phenology was associated with aridity: time of emergence was later, while flowering and senescence were earlier in desert plants. Our results indicate that in the Eastern Mediterranean, adaptation of Brachypodium to aridity is mediated mainly by phenology, rather than ploidy level. Therefore, we suggest that genome duplication is not the main driver of adaptation to environmental stress; rather, phenological change as a drought escape mechanism may be the major adaptation.