Synthesis and evaluation of analogues of the tuberculosis drug bedaquiline containing heterocyclic B-ring units

Analogues of bedaquiline where the phenyl B-unit was replaced with monocyclic heterocycles of widely differing lipophilicity (thiophenes, furans, pyridines) were synthesised and evaluated. While there was an expected broad positive correlation between lipophilicity and anti-TB activity, the 4-pyridyl derivatives appeared to have an additional contribution to antibacterial potency. The majority of the compounds were (desirably) more polar and had higher rates of clearance than bedaquiline, and showed acceptable oral bioavailability, but there was only limited (and unpredictable) improvement in their hERG liability.     

Resilient Cosmologies: Water Deities and Divine Agency in Post-Mao China

ABSTRACT

This article explores ritual practices among the Premi people in Southwest China at the beginning of the new millennium. Living in the periphery of Tibetan, Han Chinese and other Tibeto-Burman ethnic groups, Premi villagers have continued to keep an understanding of how the world works that is markedly different from their neighbours. The all-encompassing economic development of China is posing new challenges to the intangible entities in Premi cosmology. In its management of forests, waterways or birth control, the Chinese state is increasingly interfering with Premi ways of dealing with their surroundings. The chapter proposes to focus on the way one category of intangible entities of Premi cosmology, the lwéjabu or water deities, are seen as acting towards these challenges, rather than on the underlying ontological changes. An event where a member of a neighbouring ethnic group becomes an unwitting participant in a Premi medium séance makes the case for approaching extra-human forms of agency by beginning with the ‘work’ or ‘effect’ of the divine entities.     

The “epimerring” highlights the potential of carbohydrate epimerases for rare sugar production

Rare sugars can find applications in various industrial sectors and, therefore, hold significant economic value. Due to their low natural abundance, efficient production processes are needed to enable their commercial exploitation. About a decade ago, the available biosynthetic routes were summarized in the so-called “Izumoring”, which mainly comprised reactions catalysed by keto-aldol isomerases and oxidoreductases. Although just a single epimerase specificity (acting on the 3-position of ketoses) was included, these enzymes hold the potential to truly revolutionize the field as they offer shortcuts in conversion processes. For example, C2-epimerases could replace double isomerization reactions, whereas C4/5-epimerases could form a new bridge between d- and l-sugars as alternative to the current two-step oxidoreduction reaction. Here, we present the “Epimerring” to highlight the potential of new epimerases that can still be discovered and/or engineered, which may open doors to new and improved synthesis routes for rare sugars. Several efforts and options in the search of such biocatalysts are shortly summarized.     

Functional community structure of African monodominant Gilbertiodendron dewevrei forest influenced by local environmental filtering

Monodominant patches of forest dominated by Gilbertiodendron dewevrei are commonly found in central African tropical forests, alongside forests with high species diversity. Although these forests are generally found sparsely distributed along rivers, their occurrence is not thought to be (clearly) driven by edaphic conditions but rather by trait combinations of G. dewevrei that aid in achieving monodominance. Functional community structure between these monodominant and mixed forests has, however, not yet been compared. Additionally, little is known about nondominant species in the monodominant forest community. These two topics are addressed in this study. We investigate the functional community structure of 10 one‐hectare plots of monodominant and mixed forests in a central region of the Congo basin, in DR Congo. Thirteen leaf and wood traits are measured, covering 95% (basal area weighted) of all species present in the plots, including leaf nutrient contents, leaf isotopic compositions, specific leaf area, wood density, and vessel anatomy. The trait‐based assessment of G. dewevrei shows an ensemble of traits related to water use and transport that could be favorable for its location near forest rivers. Moreover, indications have been found for N and P limitations in the monodominant forest, possibly related to ectomycorrhizal associations formed with G. dewevrei. Reduced leaf N and P contents are found at the community level for the monodominant forest and for different nondominant groups, as compared to those in the mixed forest. In summary, this work shows that environmental filtering does prevail in the monodominant G. dewevrei forest, leading to lower functional diversity in this forest type, with the dominant species showing beneficial traits related to its common riverine locations and with reduced soil N and P availability found in this environment, both coregulating the tree community assembly.     

Zika virus persistence in the male macaque reproductive tract

Zika virus (ZIKV) is unique among mosquito-borne flaviviruses in that it is also vertically and sexually transmitted by humans. The male reproductive tract is thought to be a ZIKV reservoir; however, the reported magnitude and duration of viral persistence in male genital tissues vary widely in humans and non-human primate models. ZIKV tissue and cellular tropism and potential effects on male fertility also remain unclear. The objective of this study was to resolve these questions by analyzing archived genital tissues from 51 ZIKV-inoculated male macaques and correlating data on plasma viral kinetics, tissue tropism, and ZIKV-induced pathological changes in the reproductive tract. We hypothesized that ZIKV would persist in the male macaque genital tract for longer than there was detectable viremia, where it would localize to germ and epithelial cells and associate with lesions. We detected ZIKV RNA and infectious virus in testis, epididymis, seminal vesicle, and prostate gland. In contrast to prepubertal males, sexually mature macaques were significantly more likely to harbor persistent ZIKV RNA or infectious virus somewhere in the genital tract, with detection as late as 60 days post-inoculation. ZIKV RNA localized primarily to testicular stem cells/sperm precursors and epithelial cells, including Sertoli cells, epididymal duct epithelium, and glandular epithelia of the seminal vesicle and prostate gland. ZIKV infection was associated with microscopic evidence of inflammation in the epididymis and prostate gland of sexually mature males, pathologies that were absent in uninfected controls, which could have significant effects on male fertility. The findings from this study increase our understanding of persistent ZIKV infection which can inform risk of sexual transmission during assisted reproductive therapies as well as potential impacts on male fertility.     

The Roles of Structural Order and Intermolecular Interactions in Determining Ionization Energies and Charge‐Transfer State Energies in Organic Semiconductors

The energy landscape in organic semiconducting materials greatly influences charge and exciton behavior, which are both critical to the operation of organic electronic devices. These energy landscapes can change dramatically depending on the phases of material present, including pure phases of one molecule or polymer and mixed phases exhibiting different degrees of order and composition. In this work, ultraviolet photoelectron spectroscopy measurements of ionization energies (IEs) and external quantum efficiency measurements of charge‐transfer (CT) state energies (E_CT) are applied to molecular photovoltaic material systems to characterize energy landscapes. The results show that IEs and E_CT values are highly dependent on structural order and phase composition. In the sexithiophene:C₆₀ system both the IEs of sexithiophene and C₆₀ shift by over 0.4 eV while E_CT shifts by 0.5 eV depending on molecular composition. By contrast, in the rubrene:C₆₀ system the IE of rubrene and C₆₀ vary by ≤ 0.11 eV and E_CT varies by ≤ 0.04 eV as the material composition varies. These results suggest that energy landscapes can exist whereby the binding energies of the CT states are overcome by energy offsets between charges in CT states in mixed regions and free charges in pure phases.     

The ekeko mutant demonstrates a role for tetraspanin-like protein in plant development

A new mutant with disturbed cell differentiation and severely altered plant morphology was obtained by visual screening of a T-DNA mutagenized population of Arabidopsis thaliana. The T-DNA in this mutant was inserted in an unknown gene (ORF At5g46700) located on chromosome V. This gene and additional 12 genes in the Arabidopsis genome show structural homologies to a class of abundantly expressed mammalian proteins with four transmembrane domains (TM4) called tetraspanins. In animals tetraspanins are involved in different cell functions like cell development, adhesion, motility, and differentiation, probably by organizing other proteins into a network of multimolecular membrane microdomains, called the tetraspanin web. So far no function for tetraspanins in plants has been described. Here, we show that a mutation in the TM4-like gene EKEKO results in severe developmental defects that could be the result of incorrect regulation of cell differentiation.