Exercise training reverses cardiac aging phenotypes associated with heart failure with preserved ejection fraction in male mice

Heart failure with preserved ejection fraction (HFpEF) is the most common type of HF in older adults. Although no pharmacological therapy has yet improved survival in HFpEF, exercise training (ExT) has emerged as the most effective intervention to improving functional outcomes in this age‐related disease. The molecular mechanisms by which ExT induces its beneficial effects in HFpEF, however, remain largely unknown. Given the strong association between aging and HFpEF, we hypothesized that ExT might reverse cardiac aging phenotypes that contribute to HFpEF pathophysiology and additionally provide a platform for novel mechanistic and therapeutic discovery. Here, we show that aged (24–30 months) C57BL/6 male mice recapitulate many of the hallmark features of HFpEF, including preserved left ventricular ejection fraction, subclinical systolic dysfunction, diastolic dysfunction, impaired cardiac reserves, exercise intolerance, and pathologic cardiac hypertrophy. Similar to older humans, ExT in old mice improved exercise capacity, diastolic function, and contractile reserves, while reducing pulmonary congestion. Interestingly, RNAseq of explanted hearts showed that ExT did not significantly modulate biological pathways targeted by conventional HF medications. However, it reversed multiple age‐related pathways, including the global downregulation of cell cycle pathways seen in aged hearts, which was associated with increased capillary density, but no effects on cardiac mass or fibrosis. Taken together, these data demonstrate that the aged C57BL/6 male mouse is a valuable model for studying the role of aging biology in HFpEF pathophysiology, and provide a molecular framework for how ExT potentially reverses cardiac aging phenotypes in HFpEF.     

A Multiscale Framework for Deconstructing the Ecosystem Physical Template of High-Altitude Lakes

An ecosystem is generally sustained by a set of integrated physical elements forming a functional landscape unit—ecotope, which supplies nutrients, microclimate, and exchanges matter and energy with the wider environment. To better predict environmental change effects on ecosystems, particularly in critically sensitive regions such as high altitudes, it is imperative to recognise how their natural landscape heterogeneity works at different scales to shape habitats and sustain biotic communities prior to major changes. We conducted a comprehensive survey of catchment physical, geological and ecological properties of 380 high-altitude lakes and ponds in the axial Pyrenees at a variety of scales, to formulate and test an integrated model encompassing major flows and interactions that drive lake ecosystems. Three composite drivers encompassed most of the variability in lake catchment characteristics. In order of total percentage of variance explained, they were (i) hydrology/hydrodynamics—responsible for type and discharge of inlets/outlets, and for waterbody size; (ii) bedrock geomorphology, summarising geology, slope and fractal order—all dictating vegetation cover of catchment slope and lake shore, and the presence of aquatic vegetation; and (iii) topography, that is, catchment formation type—driving lakes connectivity, and the presence of summer snow deposits. Although driver (i) appeared to be local, (ii) and (iii) showed gradient changes along altitude and latitude. These three drivers differentiated several lake ecotopes based on their landscape similarities. The three-driver model was successfully tested on a riparian vegetation composition dataset, further illustrating the validity and fundamental nature of the concept. The findings inform on the relative contribution of scale-dependent catchment physical elements to lake ecotope and ecosystem formation in high-altitude lakes, which should be considered in any assessment of potentially major deleterious effects due to environmental/climate change.     

Expansion of Bacteriophages Is Linked to Aggravated Intestinal Inflammation and Colitis

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Structural insights into pharmacophore-assisted in silico identification of protein–protein interaction inhibitors for inhibition of human toll-like receptor 4 – myeloid differentiation factor-2 (hTLR4−MD-2) complex

Toll-like receptor 4 (TLR4) is a member of Toll-Like Receptors (TLRs) family that serves as a receptor for bacterial lipopolysaccharide (LPS). TLR4 alone cannot recognize LPS without aid of co-receptor myeloid differentiation factor-2 (MD-2). Binding of LPS with TLR4 forms a LPS?TLR4?MD-2 complex and directs downstream signaling for activation of immune response, inflammation and NF-κB activation. Activation of TLR4 signaling is associated with various pathophysiological consequences. Therefore, targeting protein–protein interaction (PPI) in TLR4?MD-2 complex formation could be an attractive therapeutic approach for targeting inflammatory disorders. The aim of present study was directed to identify small molecule PPI inhibitors (SMPPIIs) using pharmacophore mapping-based approach of computational drug discovery. Here, we had retrieved the information about the hot spot residues and their pharmacophoric features at both primary (TLR4?MD-2) and dimerization (MD-2?TLR4*) protein–protein interaction interfaces in TLR4?MD-2 homo-dimer complex using in silico methods. Promising candidates were identified after virtual screening, which may restrict TLR4?MD-2 protein–protein interaction. In silico off-target profiling over the virtually screened compounds revealed other possible molecular targets. Two of the virtually screened compounds (C11 and C15) were predicted to have an inhibitory concentration in μM range after HYDE assessment. Molecular dynamics simulation study performed for these two compounds in complex with target protein confirms the stability of the complex. After virtual high throughput screening we found selective hTLR4?MD-2 inhibitors, which may have therapeutic potential to target chronic inflammatory diseases.     

Baylis-Hillman reaction: convenient ascending syntheses and biological evaluation of acyclic deoxy monosaccharides as potential antimycobacterial agents

A series of acyclic deoxy carbohydrate derivatives from easily available carbohydrate enals 1, 2, 3 or 5 were prepared involving the Baylis-Hillman reaction. These newly formed carbohydrate based Baylis-Hillman adducts and their amino derivatives were evaluated for their antimycobacterial activity against Mycobacterium tuberculosis H(37)R(v). Among the compounds evaluated for their antimycobacterial activity, compound (10) showed the desired activity in the range of 3.125 microg/mL.     

Degradative potential of Stenotrophomonas strain HPC383 having genes homologous to dmp operon

A strain, Stenotrophomonas HPC383 is isolated from effluent treatment plant treating wastewater from pesticide industry; degrades various aromatic compounds (cresols, phenol, catechol, 4methyl-catechol and hydroquinone) and crude oil, as determined through HPLC and GC analysis. Culture HPC383 could degrade (%) various compounds (1 mM) from a mixture: phenol - 99, p-cresol - 100, 4-methylcatechol - 96 and hydroquinone - 43 within 48 h of incubation, whereas it took 7 days to degrade 94% of 0.5% crude oil. Gene locus dmpN, to identify phenol degrading capacity was determined by PCR followed by southern analysis. The sequenced DNA fragment exhibited 99% sequence similarity to phenol hydroxylase gene from Arthrobacter sp. W1 (FJ610336). Amino acid sequence analysis of phenol hydroxylase reveals it to belong to high-Ks (affinity constant) group. Application of HPC383 in bioremediation of aquatic and terrestrial sites contaminated with petrochemical has been suggested.     

Synthesis, molecular modeling and bio-evaluation of cycloalkyl fused 2-aminopyrimidines as antitubercular and antidiabetic agents

An economical and efficient one step synthesis of a series of 8-(arylidene)-4-(aryl)-5,6,7,8-tetrahydro-quinazolin-2-ylamines and 9-(arylidene)-4-(aryl)-6,7,8,9-tetrahydro-5H-cycloheptapyrimidin-2-ylamines by the reaction of bis-benzylidene cycloalkanones and guanidine hydrochloride in presence of NaH has been developed. All the synthesized compounds were evaluated against Mycobacterium tuberculosis H₃₇Rv strain and the α-glucosidase and glycogen phosphorylase enzymes. Few of the compounds have shown interesting in vitro activity with MIC up to 3.12 μg/mL against M. tuberculosis and very good inhibition of α-glucosidase and glycogen phosphorylase enzymes. The most potent non toxic compound 40 exhibited about 58% ex vivo activity at MIC of 3.12 μg/mL. The present study opens a new gate to synthesize antitubercular agents for diabetic TB patients. In silico docking studies indicate that mycobacterial dihydrofolate reductase is the possible target of these compounds.     

Evaluation of efficacy of stabilizers on the thermostability of live attenuated thermo-adapted <Emphasis Type="Italic">Peste des petits ruminants</Emphasis> vaccines

In this study, thermo-adapted (Ta) PPR vaccines were assessed for their stability at 25, 37, 40, 42 and 45°C in lyophilized form using two extrinsic stabilizers {lactalbumin hydrolysate-sucrose (LS) and stabilizer E} and in reconstituted form with the diluents (1 mol/L MgSO₄ or 0.85% NaCl). The lyophilized vaccines showed an expiry period of 24–26 days at 25°C, 7–8 days at 37°C and 3–4 days at 40°C. LS stabilizer was superior at 42°C with a shelf-life of 44 h, whereas in stabilizer E, a 40 h shelf-life with a comparable half-life was observed. At 45°C, the half-life in stabilizer E was better than LS and lasted for 1 day. Furthermore, the reconstituted vaccine maintained the titre for 48 h both at 4°C and 25°C and for 24–30 h at 37°C. As both the stabilizers performed equally well with regard to shelf-life and half-life, the present study suggests LS as stabilizer as a choice for lyophilization with 0.85% NaCl diluent, because it has better performance at higher temperature. These Ta vaccines can be used as alternatives to existing vaccines for the control of the disease in tropical countries as they are effective in avoiding vaccination failure due to the breakdown in cold-chain maintenance, as this vaccine is considerably more stable at ambient temperatures.