Cilia are present across most eukaryotic phyla and have diverse sensory and motility roles in animal physiology, cell signalling and development. Their biogenesis and maintenance depend on vesicular ...and intraciliary (intraflagellar) trafficking pathways that share conserved structural and functional modules. The functional units of the interconnected pathways, which include proteins involved in membrane coating as well as small GTPases and their accessory factors, were first experimentally associated with canonical vesicular trafficking. These components are, however, ancient, having been co-opted by the ancestral eukaryote to establish the ciliary organelle, and their study can inform us about ciliary biology in higher organisms.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
In this paper we report the annulation reaction between 2-iodobenzaldehyde derivatives and various ynamides. This palladium-catalyzed reaction leads to rare polysubstituted amino-indenones in good ...yields with a regioselectivity up to complete. Remarkably, a regiodivergent selectivity has been identified between aryl and alkyl or silyl ynamides, with the first leading mainly to 2-amido-indenones and the second to 3-amido-indenones.
A novel approach towards highly functionalized fluoroalkyl pyrazoles was developed by using fluoroalkyl amino reagents in combination with a variety of fluorinated ketimines. Tuneable introduction of ...fluoroalkyl groups in the 3‐ and 5‐positions was possible by using vinamidinium intermediates or the corresponding enamino ketones after hydrolysis. These high‐value building blocks can give rise to a large number of analogues for bioactivity screening and discovering new heterocyclic bioactive ingredients in various life science fields.
FAR better: An efficient method to access highly functionalized fluoroalkyl pyrazoles with tuneable regioselectivity is reported. The method uses fluoroalkyl amino reagents (FARs) in combination with a variety of fluorinated ketimines (see scheme).
The synthesis of trifluoromethylthiolated ketenimines is herein described. They are easily synthesized from the corresponding α‐trifluoromethylthiolated oximes upon activation with triflic anhydride ...and a base. The presumed nitrilium ion resulting from the Beckmann rearrangement is deprotonated to lead to the key intermediate, whose stability brought by the fluorinated substituent was unforeseeable. The reaction of these new building blocks with a variety of nucleophiles affords a vast array of cyclic and acyclic products bearing the valuable SCF3 moiety.
The first synthesis of trifluoromethylthiolated ketenimines is herein disclosed. They are quickly and easily formed from α‐trifluoromethylthiolated oximes through a Beckmann rearrangement and deprotonation of the nitrilium intermediate. Their interest is exemplified by many reactions, such as the direct addition of several C‐, O‐, N‐, S‐ and P‐centered nucleophiles as well as their incorporation into valuable heterocycles through cascade reactions.
4D printing has a great potential for the manufacturing of soft robotics and medical devices. The alliance of digital light processing (DLP) 3D printing and novel shape-memory photopolymers allows ...for the fabrication of smart 4D-printed medical devices in high resolution and with tailorable functionalities. However, most of the reported 4D-printed materials are nondegradable, which limits their clinical applications. On the other hand, 4D printing of biodegradable shape-memory elastomers is highly challenging, especially when transition points close to physiological temperature and shape fixation under ambient conditions are required. Here, we report the 4D printing of biodegradable shape-memory elastomers with tailorable transition points covering physiological temperature, by using poly(D,L-lactide-co-trimethylene carbonate) methacrylates at various monomer feed ratios. After the programming step, the high-resolution DLP printed stents preserved their folded shape at room temperature, and showed efficient shape recovery at 37 °C. The materials were cytocompatible and readily degradable under physiological conditions. Furthermore, drug-loaded devices with tuneable release kinetics were realized by DLP-printing with resins containing polymers and levofloxacin or nintedanib. This study offers a new perspective for the development of next-generation 4D-printed medical devices.
Digital light 4D printing of biodegradable drug-eluting elastomeric devices with tailorable thermal response at the physiological temperature and tunable drug release. Display omitted
•Biodegradable shape-memory elastomers were DLP printed.•The materials displayed elasticity below and above their transition temperatures.•4D printed elastomeric stents showed efficient shape recovery at 37 °C.•4D printed drug-loaded devices showed tuneable release kinetics.
Arginine-rich antimicrobial peptides (AMPs) are emerging therapeutics of interest. However, their applicability is limited by their short circulation half-life, caused in part by their small size and ...digestion by blood proteases. This study reports a strategy to temporarily mask arginine residues within AMPs with methoxy poly(ethylene glycol). Based on the reagent used, release of AMPs occurred in hours to days in a completely traceless fashion.
In vitro
, conjugates were insensitive to serum proteases, and released native AMP with full
in vitro
bioactivity. This strategy is thus highly relevant and should be adaptable to the entire family of arginine-rich AMPs. It may potentially be used to improve AMP-therapies by providing a more steady concentration of AMP in the blood after a single injection, avoiding toxic effects at high AMP doses, and reducing the number of doses required over the treatment duration.
This study reports a strategy to temporarily mask arginine residues within antimicrobial peptides (AMPs) with methoxy poly(ethylene glycol) (mPEG). PEGylation protects AMPs from serum proteases, and can be released at a pharmaceutically-relevant rate. Fully active and unmodified (
i.e.
, native) AMPs are released with time.
A general and convenient protocol for the electrophilic borylation of aryl Grignard reagents prepared from arylbromides by direct insertion of magnesium in the presence of LiCl or by Mg/Br exchange ...with i PrMgCl·LiCl has been developed. Various aryl boronic acids were synthesized in a straightforward manner in excellent yields at 0 °C.
RNA therapeutics offer great potential to transform the biomedical landscape, encompassing the treatment of hereditary conditions and the development of better vaccines. However, the delivery of RNAs ...into the cell is hampered, among others, by poor endosomal escape. This major hurdle is often tackled using special lipids, polymers, or protein-based delivery vectors. In this review, we will focus on the most prominent peptide- and protein-based endosomal escape strategies with focus on RNA drugs. We discuss cell penetrating peptides, which are still incorporated into novel transfection systems today to promote endosomal escape. However, direct evidence for enhanced endosomal escape by the action of such peptides is missing and their transfection efficiency, even in permissive cell culture conditions, is rather low. Endosomal escape by the help of pore forming proteins or phospholipases, on the other hand, allowed to generate more efficient transfection systems. These are, however, often hampered by considerable toxicity and immunogenicity. We conclude that the perfect enhancer of endosomal escape has yet to be devised. To increase the chances of success, any new transfection system should be tested under relevant conditions and guided by assays that allow direct quantification of endosomal escape.
The key objective of vaccination is the induction of an effective pathogen-specific immune response that leads to protection against infection and/or disease caused by that pathogen, and that may ...ultimately result in its eradication from humanity. The concept that the immune response to pathogen antigens can be improved by the addition of certain compounds into the vaccine formulation was demonstrated about one hundred years ago when aluminium salts were introduced. New vaccine technology has led to vaccines containing highly purified antigens with improved tolerability and safety profiles, but the immune response they induce is suboptimal without the help of adjuvants. In parallel, the development of effective vaccines has been facing more and more important challenges linked to complicated pathogens (e.g. malaria, TB, HIV, etc.) and/or to subjects with conditions that jeopardize the induction or persistence of a protective immune response. A greater understanding of innate and adaptive immunity and their close interaction at the molecular level is yielding insights into the possibility of selectively stimulating immunological pathways to obtain the desired immune response. The better understanding of the mechanism of 'immunogenicity' and 'adjuvanticity' has prompted the research of new vaccine design based on new technologies, such as naked DNA or live vector vaccines and the new adjuvant approaches. Adjuvants can be used to enhance the magnitude and affect the type of the antigen-specific immune response, and the combination of antigens with more than one adjuvant, the so called adjuvant system approach, has been shown to allow the development of vaccines with the ability to generate effective immune responses adapted to both the pathogen and the target population. This review focuses on the adjuvants and adjuvant systems currently in use in vaccines, future applications, and the remaining challenges the field is facing.
The reachability problem in vector addition systems is a central question, not only for the static verification of these systems, but also for many inter-reducible decision problems occurring in ...various fields. The currently best known upper bound on this problem is not primitive-recursive, even when considering systems of fixed dimension. We provide significant refinements to the classical decomposition algorithm of Mayr, Kosaraju, and Lambert and to its termination proof, which yield an ACKERMANN upper bound in the general case, and primitive-recursive upper bounds in fixed dimension. While this does not match the currently best known TOWER lower bound for reachability, it is optimal for related problems.
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