Repurposing p97 inhibitors for chemical modulation of the bacterial ClpB–DnaK bichaperone system

The ClpB–DnaK bichaperone system reactivates aggregated cellular proteins and is essential for survival of bacteria, fungi, protozoa, and plants under stress. AAA+ ATPase ClpB is a promising target for the development of antimicrobials because a loss of its activity is detrimental for survival of many pathogens and no apparent ClpB orthologs are found in metazoans. We investigated ClpB activity in the presence of several compounds that were previously described as inhibitor leads for the human AAA+ ATPase p97, an antitumor target. We discovered that N2,N4-dibenzylquinazoline-2,4-diamine (DBeQ), the least potent among the tested p97 inhibitors, binds to ClpB with a Kd∼60 μM and inhibits the casein-activated, but not the basal, ATPase activity of ClpB with an IC50∼5 μM. The remaining p97 ligands, which displayed a higher affinity toward p97, did not affect the ClpB ATPase. DBeQ also interacted with DnaK with a Kd∼100 μM and did not affect the DnaK ATPase but inhibited the DnaK chaperone activity in vitro. DBeQ inhibited the reactivation of aggregated proteins by the ClpB–DnaK bichaperone system in vitro with an IC50∼5 μM and suppressed the growth of cultured Escherichia coli. The DBeQ-induced loss of E. coli proliferation was exacerbated by heat shock but was nearly eliminated in a ClpB-deficient E. coli strain, which demonstrates a significant selectivity of DBeQ toward ClpB in cells. Our results provide chemical validation of ClpB as a target for developing novel antimicrobials. We identified DBeQ as a promising lead compound for structural optimization aimed at selective targeting of ClpB and/or DnaK

A Criminological Analysis on Burglary Related Environmental Factors in Sri Lanka

With the birth and growth of criminology related sub discipline, ‘environmental criminology’ or in other words, crime designated ecological perspective has gained a wide acceptance among the criminology academia. As a consequent, the immediate surrounding of an individual has been identified as a criminogenic factor. Criminology has been specifically focusing on the characteristics of offenders as well as offences and has been somewhat disregarding the criminogenic spatial factors of crime. Focusing and identifying the designated burglary related ecological factors have been the prime intention of this criminological research study. Thus, a purposive sample of 57 crime scenes under burglary has been observed during a period of two years (2017-2019) within the Western Province of Sri Lanka. Data were retrieved by using qualitative methodology. The research revealed three types of environmental factors linked with the burglary crime scenes namely, natural, built, and social. The built and social eco factors have been main criminogenic features in urban and semi-urban spaces. Specifically, weather, land usage and location could be identified as burglary related environmental factors. Apart from natural environmental factors, architectural and landscape features were recognized as associated-built environmental factors with housebreak. As this is a pioneering research study connected to the environmental aspect of crimes, the study has filled the existing research gap from the Sri Lankan perspective. Measures in controlling and preventing crime can be achieved through the management of environmental elements and using environmental designing with the advanced technology.DOI: http://doi.org/10.31357/fhss/vjhss.v06i01.0

The potential synergistic behaviour of inter- and intra-genus probiotic combinations in the pattern and rate of short chain fatty acids formation during fibre fermentation

This study compared the rate of short chain fatty acid (SCFA) production by different probiotic combinations of Lactobacillus and Bifidobacterium to determine any synergistic effects. Six different fibre fractions were fermented with nine combinations of Lactobacillus rhamnosus (LR), Lactobacillus acidophilus (LA), Bifidobacterium longum (BL) and Bifidobacterium breve (BB) for 0, 6, 24 and 48 h. SCFAs were quantified by gas chromatography. Inter-genus combinations of bacteria produced more SCFA, especially BB + BL + LR, compared to intra-genus that yielded the lowest SCFA production. Acetate was the most abundant, while propionate and butyrate were the most utilised. The SCFA formation was as acetate \u3e propionate \u3e butyrate and the total dietary fibre produced most of the SCFA. Most combinations utilised 60–80% of the fibre; BB + BL + LR digested the fibre completely. The quantity, pattern and the time of release of SCFA depends on the genus, but the combination of pre and probiotics is of great importance for the outcome

ES11MA110N OF GLOBAL WARMING DAMAGE COST DUE TO THE FOREST RRES IN THE IMBULPE DIVISIONAL SECRETARIAT DIVISION, 2003 IN SRI LANKA

The objective of the study was to estimate the global warming damage costs caused byman made catastrophic forest fires in the Imbulpe divisional secretariat division (23140ha), Balangoda electorate in the Ratnapura district in Sri Lanka in 2003. The climaticforest fires occur every year during the period June to mid October in this area, creatingnumerous environmental and socio-economic problems such as declining of water table,extinction of endemic flora and fauna species, loss of bio diversity and pollution of air,water, and land and occasionally rendering people homeless. Even though the gravity ofthose forest fires in this region every year was devastating, the majority of the researchersdid not take this aspect into their consideration.Hence to combat this menace the Sabaragamuwa University Centre for Environment andSustainable Development (SUCEDS) had launched a number of projects since 2000 andthe current study is one such project. To accomplish this task primary data (forest fireaffected land areas and types of forests) were collected by means of household surveysand land surveying techniques. In addition to that maps and previous reports pertainingto the area were used to obtain secondary data (land use types, population of that area,endemic plant species). Determination of the extent of burnt land of diverse types and theconsideration of catastrophic forest fires caused in the Imbulpe area were identified using1:50000 map. The estimation of the global warming damage cost of the burnt area wascarried out by carbon Sequestration value of the burnt forest in the Imbulpe area by theTurner's (1994) value of $20. This value has been suggested as the financial damagecaused by every ton of carbon released from burning tropical rain forests, whichcontributes the global warming. The estimated global warming damage costs based onlost carbon sequestration function was Rs. 126.5 millionFurther this research disclosed that the main reasons for such fires were fires set out forunknown reasons, fires to prepare fresh grazing land for cattle feeding, hunters also setfire to forests for poaching of wild animals, fires caused by butt-ends of cigarettes andfires set to clear virgin forests for agricultural purposes.

Structural insights into the catalysis and regulation of E3 ubiquitin ligases

Covalent attachment (conjugation) of one or more ubiquitin molecules to protein substrates governs numerous eukaryotic cellular processes, including apoptosis, cell division and immune responses. Ubiquitylation was originally associated with protein degradation, but it is now clear that ubiquitylation also mediates processes such as protein–protein interactions and cell signalling depending on the type of ubiquitin conjugation. Ubiquitin ligases (E3s) catalyse the final step of ubiquitin conjugation by transferring ubiquitin from ubiquitin-conjugating enzymes (E2s) to substrates. In humans, more than 600 E3s contribute to determining the fates of thousands of substrates; hence, E3s need to be tightly regulated to ensure accurate substrate ubiquitylation. Recent findings illustrate how E3s function on a structural level and how they coordinate with E2s and substrates to meticulously conjugate ubiquitin. Insights regarding the mechanisms of E3 regulation, including structural aspects of their autoinhibition and activation are also emerging

Multidrug efflux pumps:structure, function and regulation

Infections arising from multidrug-resistant pathogenic bacteria are spreading rapidly throughout the world and threaten to become untreatable. The origins of resistance are numerous and complex, but one underlying factor is the capacity of bacteria to rapidly export drugs through the intrinsic activity of efflux pumps. In this Review, we describe recent advances that have increased our understanding of the structures and molecular mechanisms of multidrug efflux pumps in bacteria. Clinical and laboratory data indicate that efflux pumps function not only in the drug extrusion process but also in virulence and the adaptive responses that contribute to antimicrobial resistance during infection. The emerging picture of the structure, function and regulation of efflux pumps suggests opportunities for countering their activities