Fragment-based lead discovery has emerged as a leading drug development strategy for novel therapeutic targets. Although fragment-based drug discovery benefits immensely from access to atomic-resolution information, structure-based virtual screening has rarely been used to drive fragment discovery and optimization. Here, molecular docking of 0.3 million fragments to a crystal structure of cancer t

Here we present a two-step diastereoselective methodology building on a multicomponent aza-Diels-Alder reaction. Using previously unexplored cyclic ketones, heterocyclic amines and cyclopentadiene derivatives, we obtained novel spiro-heterocyclic frameworks at the interphase between "drug-like" molecules and natural products.

Botulinum neurotoxins are known to have seven serotypes (BoNT/A-G). Here we report a new BoNT serotype, tentatively named BoNT/X, which has the lowest sequence identity with other BoNTs and is not recognized by antisera against known BoNTs. Similar to BoNT/B/D/F/G, BoNT/X cleaves vesicle-associated membrane proteins (VAMP) 1, 2 and 3, but at a novel site (Arg66-Ala67 in VAMP2). Remarkably, BoNT/X

Botulinum neurotoxin B is a Food and Drug Administration-approved therapeutic toxin. However, it has lower binding affinity toward the human version of its major receptor, synaptotagmin II (h-Syt II), compared to mouse Syt II, because of a residue difference. Increasing the binding affinity to h-Syt II may improve botulinum neurotoxin B's therapeutic efficacy and reduce adverse effects. Here we ut

The tetanus neurotoxin (TeNT) is a highly potent toxin produced by Clostridium tetani that inhibits neurotransmission of inhibitory interneurons, causing spastic paralysis in the tetanus disease. TeNT differs from the other clostridial neurotoxins by its unique ability to target the central nervous system by retrograde axonal transport. The crystal structure of the tetanus toxin reveals a "closed"

In this article, we review the evolution of radio access networks and introduce fifth generation (5G), based on the current plans and expectations, as reported in the 2017 Ericsson Mobility Reports. Standardization is an ongoing effort, and much industry research is devoted to finding a good match of requirements, including balancing system performance, flexibility, and implementation implications

The use of a wake-up receiver (WUR) is an attractive means to reduce power consumption. However, when the wake-up signal (WUS) is sent in-band, the use of a WUR may potentially reduce the spectrum efficiency of the system. In this paper, we propose to multiplex the WUS, based on ON-OFF keying, with the user data using FDMA or OFDMA to allow for spectrum efficient use of WURs. The proposed WUR arch

Arbetet omfattar uppföljningav ställda kriterier förlåg klimatpåverkan från betong vid upphandling av betongstommeför brf. Viva i Göteborg. Kriterierna följdes upp dels genom att LCA studien som genomförtsunder programskedet uppdaterades med data för den färdigupphandlade byggnadenoch dels genom att interljuva ett urval av aktörer för att få en inblick över hur branschen ser på de ställda kraven. This work includes monitoring of set criteria for low climate impact from concrete in procurement of concrete structures for brf. Viva in Gothenburg. The criteria were followed up by updating the LCA study performed during the program phase with new data for the completed building, plus a selection of the project stakeholders were also interviewed to gain an insight into how the industry received

IEEE 1687 enables flexible access to on-chip instruments via dynamically reconfigurable networks. Reconfiguration allows reducing instrument access time by keeping only those instruments on the scan-path which are required for each access. To perform reconfiguration and execute commands described in instrument access procedures, scan vectors are generated in a process called retargeting. These vec

Purpose – This paper will examine the unsafe work practices that are plaguing the construction industry. Statistics show that four out of five of all workplace accidents are attributed to unsafe behaviour. Research studies have sought to understand worker self-protection. For example, it is difficult to make predictions of conditions that influenced worker’s behaviour to act unsafely or safely in

Many white dwarf stars show signs of having accreted smaller bodies, implying that they may host planetary systems. A small number of these systems contain gaseous debris discs, visible through emission lines. We report a stable 123.4-minute periodic variation in the strength and shape of the Ca II emission line profiles originating from the debris disc around the white dwarf SDSS J122859.93+10403

Det relativt lugna området bakom barriärö är en fördelaktig plats för hamn trots att navigationen genom själva inloppet kan vara utmanande. Olika åtgärder såsom muddring eller kuststrukturer kan vara nöd-vändiga för att säkerställa det önskade vattendjupet för en säker navigering. Island som är en önation är beroende av tillförlitliga navigeringsvägar som förbinder hamnar med havet. Detta för att The relatively calm area behind barrier island are favored locations for harbors even though the navigation through the inlet itself can be challenging. Different measures like dredging or coastal structures might be necessary to ensure the desired water depth to maintain a safe navigation. Iceland as an island country depends strongly on reliable navigational routes connecting harbors to the ocea

The transition to a Circular Economy (CE) aims for more efficient use of resources and reconsideration of how products are designed and used, including promoting longer lifetimes through design and repair. However, several factors influence whether it is an option for the consumer to repair the product. These range from legal and market impediments to factors of cost, convenience, and consumer pre

Temperature is a key constraint on ecosystem respiration but is typically measured at only one or a few points across a study site. Given the exponential relationship between temperature and respiration, small differences in temperature across a heterogeneous ecosystem may result in large differences in respiration fluxes. These differences are not captured in current respiration models which use