E7766, a Macrocycle-Bridged Stimulator of Interferon Genes (STING) Agonist with Potent Pan-Genotypic Activity

A strategy for creating potent and pan-genotypic stimulator of interferon genes (STING) agonists is described. Locking a bioactive U-shaped conformation of cyclic dinucleotides by introducing a transannular macrocyclic bridge between the nucleic acid bases leads to a topologically novel macrocycle-bridged STING agonist (MBSA). In addition to substantially enhanced potency, the newly designed MBSAs, exemplified by clinical candidate E7766 , exhibit broad pan-genotypic activity in all major human STING variants. E7766 is shown to have potent antitumor activity with long lasting immune memory response in a mouse liver metastatic tumor model. Two complementary stereoselective synthetic routes to E7766 are also described.     

The Innate Immune Glycoprotein Lactoferrin Represses the Helicobacter pylori cag Type IV Secretion System

Chronic infection with Helicobacter pylori increases risk of gastric diseases including gastric cancer. Despite development of a robust immune response, H. pylori persists in the gastric niche. Progression of gastric inflammation to serious disease outcomes is associated with infection with H. pylori strains which encode the cag Type IV Secretion System (cag T4SS). The cag T4SS is responsible for translocating the oncogenic protein CagA into host cells and inducing pro-inflammatory and carcinogenic signaling cascades. Our previous work demonstrated that nutrient iron modulates the activity of the T4SS and biogenesis of T4SS pili. In response to H. pylori infection, the host produces a variety of antimicrobial molecules, including the iron-binding glycoprotein, lactoferrin. Our work shows that apo-lactoferrin exerts antimicrobial activity against H. pylori under iron-limited conditions, while holo-lactoferrin enhances bacterial growth. Culturing H. pylori in the presence of holo-lactoferrin prior to co-culture with gastric epithelial cells, results in repression of the cag T4SS activity. Concomitantly, a decrease in biogenesis of cag T4SS pili at the host-pathogen interface was observed under these culture conditions by high-resolution electron microscopy analyses. Taken together, these results indicate that acquisition of alternate sources of nutrient iron plays a role in regulating the pro-inflammatory activity of a bacterial secretion system and present novel therapeutic targets for the treatment of H. pylori-related disease.     

江森自控亚太总部

正位于上海的江森自控亚太总部是创新设计、可持续性和智能科技的领先典范。晋思建筑事务所上海和芝加哥办公室与拥有领先建筑技术和解决方案的江森自控携手合作,创建了世界级的总部大楼和企业园区,最大限度地减少了对自然环境的影响,增强了建筑的美观度与功能性,力求达到最高水平的入住舒适度。由于其前瞻性设计、智能节能解决方案以及对可持续发展承诺,该总部赢得了国际金融公司-世界银行集团     

A cathode support structure for use in a magnetron oscillator experiment

A low temperature co-fired ceramic (LTCC) material system has been used to develop a protype field emission cathode structure for use in an experimental magnetron oscillator. The structure is designed for used with 30 gated field emission array (GFEA) die electrically connected through silver metal traces and electrical vias. To approximate a cylinder, the cathode structure (48 mm long and 13.7 mm in diameter) is comprised of 10 faceted plates which cover the GFEA dies. Slits in the facet plates allow electron injection. The GFEA die (3 mm × 8 mm) are placed in axial columns of 3 and spaced azimuthally around a cylindrical support structure in a staggered configuration resulting in 10 azimuthal locations. LTCC manufacturing techniques were developed in order to fabricate the newly designed cathode with seven layers wrapped to form the cylinder with electrical traces and vias. Two different cathode wrapping techniques and two different via filling techniques were studied and compared. Two different facet plate manufacturing techniques were studied. Finally, four different support stand configurations for firing the cylindrical structure were also compared with a square post stand having the best circularity and linearity measurements of the fired structure.     

Beyond economics—understanding the decision-making of German small private landlords in terms of energy efficiency investment

The German government aims to achieve virtually climate-neutral building stock by 2050 to tackle climate change. To realise this goal, comprehensive policy packages based on neoclassical economic theory are in place to foster energy efficiency investment. However, in the building sector, there is increasingly a gap between this aspiration and the reality. It is claimed that one of the main reasons for this is that the existing policy framework fails to address the specific characteristics and needs of different groups of building owners. This is a particular challenge in Germany, where 80% of all dwellings are owned privately and 37% are rented out by small private landlords (SPL). Despite the significant numbers of SPL, they often follow black box decision-making processes when considering energy renovations. In this study, the author uses an explanatory model to understand the decision-making processes of SPL, combining theoretical aspects from different research disciplines. This model was applied to a low-demand housing market in a neighbourhood in the Ruhr area. Eighteen semi-structured interviews (each lasting between 37 and 115 min) were conducted, demonstrating that in addition to economic factors, the values, beliefs, norms and routines of SPL—as well as their personal capabilities and contextual factors—play an important role in their decision-making. Based on the findings, recommendations are made for enhancing the effectiveness of existing energy efficiency policies and other supporting instruments (e.g. tenancy law and social legislation), tailored to the specific needs of SPL.     

Investigation of the grinding temperature and energy partition during cylindrical grinding

In this study, the distribution of temperature and energy under the process parameter conditions and thermal physical parameters are investigated using a physics-based model via the finite element modeling (FEM) simulation and experimental validation during cylindrical grinding. A cylindrical grinding model is modeled to simulate the chip removal behavior in the grinding process and to measure the workpiece and chip temperatures by refining the temperature field. Workpiece speed affects the energy partition into chip more obviously than other grinding parameters. Reasonable selection of grinding parameters greatly reduces the energy partition into the workpiece from 80% to 50–30% or even lower. This study offers a comprehensive understanding of heating mechanisms during grinding and thus is very beneficial for process optimization.     

Association of aerobic anoxygenic phototrophs and zebra mussels,Dreissena polymorpha,within the littoral zone of Lake Winnipeg

While nutrient loading has affected all levels of Lake Winnipeg’s ecology, its greatest influence has likely been on the microbial community. In addition to eutrophication, zebra mussels (Dreissena polymorpha) have recently invaded the ecosystem and threaten food web dynamics. Their filter-feeding predation and association with bacteria, specifically phototrophs, was investigated. A sampling trip to Lake Winnipeg in October 2017, focused on the isolation, enumeration, and identification of aerobic anoxygenic phototrophs in littoral water, sediment, and tissues of mussels. Gimli, Patricia, and Grand beaches, separated by >15 km across the South Basin, had similar bacterial counts when cultivated on rich organic, BG-11, purple non-sulphur, and K₂TeO₃-supplemented media. Culture-based enumeration on rich organic medium revealed 1.74% of heterotrophs from littoral waters were aerobic anoxygenic phototrophs, and represented 13.98% within sediments. In contrast, 0.48, 1.15, and 0.16% of cultured heterotrophs were aerobic anoxygenic phototrophs within zebra mussel gill, gut, and gonadal tissues, respectively. High-throughput sequencing of bacterial 16S V4 rDNA maintained similar trends in respective bivalve organs, where 0.22, 1.13, and 0.20% of total 16S genes belonged to these phototrophs. Several Sphingomonadaceae isolates were recovered from gut tissues, all with filamentous morphology large enough for predation. Bioaccumulation of metals was also studied in D. polymorpha. All tested associated aerobic anoxygenic phototrophs were capable of resisting the metalloid oxide tellurite. The consistent distribution of aerobic anoxygenic phototrophs within microbial communities across Lake Winnipeg, and their predominance in the gut tissues of zebra mussels suggested bacterial consumption by this invasive species.     

Evaluation of the effects of two alternative participatory ergonomics intervention strategies for construction companies

To improve the use of ergonomics tools by construction workers, the effect of two guidance strategies – a face-to-face strategy (F2F) and an e-guidance strategy (EG) – of a participatory ergonomics intervention was studied. Twelve construction companies were randomly assigned to the F2F group or the EG group. The primary outcome measure, the percentage of workers using ergonomics tools, and secondary outcome measures – work ability, physical functioning and limitations due to physical problems – were assessed using surveys at baseline and after 6 months. Additionally, a cost-benefit analysis was performed on company level. No differences in primary and secondary outcomes were found with the exception of the use of ergonomics tools to adjust working height (F2F +1%; EG +10%; p?=?.001). Newly-implemented tools were used by 23% (F2F) and 42% (EG) of the workers (p?=?.271). Costs were mainly determined by guidance costs (F2F group) or purchase costs (EG group).

Practitioner Summary: Participatory strategies aim to stimulate behavioural change of stakeholders to increase the use of ergonomics tools. Two guidance strategies – face-to-face or e-mail interventions – among construction companies were studied. Both guidance strategies led to an increase in the use of new ergonomics tools.     

How to ‘find’ an error minimized genetic code: neutral emergence as an alternative to direct Darwinian selection for evolutionary optimization

Error minimization (EM) of the standard genetic code (SGC) refers to the assignment of amino acids to codons in such a way that the deleterious impact of mutations is reduced. The SGC is nearly optimal for the property of EM, compared to randomly generated codes, and prompts the question of how the property arose. Brute force searching of alternative genetic codes is unlikely to have occurred, given the high number of alternative codes. Therefore, a heuristic search of ‘code space’, the space of alternative codes, would have been necessary. Uncovering the nature of this heuristic search is key to understanding the evolution of the genetic code, and consequently the origin of life. Scenarios that rely on direct selection for the property of EM require codon reassignments to sample code space, but these are problematic mechanistically. Alternatively, it has been shown that EM may have emerged in a neutral fashion as a byproduct of the process of genetic code expansion. In this scenario, similar amino acids are added to similar codons via the gene duplication of tRNAs and aminoacyl-tRNA synthetases. Mimicking this process via simulation indeed produces high levels of EM in the resulting genetic codes. These observations imply that optimization has occurred by an alternative to direct selection, commonly viewed as the only form of evolutionary optimization followed in nature. I propose that the neutral emergence of EM produced by code expansion is a genetic algorithm but unlike direct selection, the local selection criterion (amino acid and codon similarity) is distant from the global fitness function (EM), leading to the emergent optimization of EM. By presenting this counter example I clarify how evolutionary optimization in biological systems is not restricted to direct selection, and emphasize that additional processes may lead to the production of beneficial traits, via ‘non-Darwinian optimization’.

     

Synthesis and Preliminary Evaluation of 11C-Labeled VU0467485/AZ13713945 and Its Analogues for Imaging Muscarinic Acetylcholine Receptor Subtype 4

Muscarinic acetylcholine receptors (mAChRs) have five distinct subunits (M₁–M₅) and are involved in the action of the neurotransmitter acetylcholine in the central and peripheral nervous system. Attributed to the promising clinical efficacy of xanomeline, an M₁/M₄-preferring agonist, in patients of schizophrenia and Alzheimer's disease, M₁- or M₄-selective mAChR modulators have been developed that target the topographically distinct allosteric sites. Herein we report the synthesis and preliminary evaluation of ¹¹C-labeled positron emission tomography (PET) ligands based on a validated M₄R positive allosteric modulator VU0467485 (AZ13713945) to facilitate drug discovery. [¹¹C]VU0467485 and two other ligands were prepared in high radiochemical yields (>30 %, decay-corrected) with high radiochemical purity (>99 %) and high molar activity (>74 GBq μmol⁻¹). In vitro autoradiography studies indicated that these three ligands possess moderate-to-high in vitro specific binding to M₄R. Nevertheless, further physiochemical property optimization is necessary to overcome the challenges associated with limited brain permeability.