The ever-growing number of fluorinated compounds in medicinal and agrochemical applications has led to a remarkable positive emulation in research. The last few years have been the witness of several ...advances in the search of more effective and user-friendlier methods for the introduction of fluorine as substituent or of fluorinated groups on various structures. In particular, the synthesis of trifluoromethyl ethers and thioethers is receiving increasing attention due to the peculiar properties of the OCF3 and SCF3 groups. This review will cover the different methods for the preparation of trifluoromethyl ethers and thioethers, and will emphasize on the most recent developments, including the use of catalytic methods or of methodologies for trifluoromethylation or trifluoromethanesulfanylation.
Axial chirality is a key feature of many important organic molecules, such as biologically active compounds, stereogenic ligands and optically pure materials. Significant efforts in the field of the ...atropisomeric synthesis of biaryls have hence been undertaken over the past decade. Several major improvements of the already known methods to build up such chiral backbones (
e.g.
oxidative couplings and stereoselective Suzuki-Miyaura arylations) have been achieved and, in parallel, novel concepts have emerged enabling unprecedented synthetic routes toward molecules of this kind. These outstanding steps further unlocked the door to the preparation of previously difficult-to-access precursors of privileged ligands like BINOL, BINAM, QUINAP and many other molecules of interest.
Over the past decade the field of the synthesis of axially chiral compounds has been rapidly expanding. Not only key advances have been achieved concerning the already established strategies but also new synthetic routes have been devised. This review showcases the recent developments in this domain.
Research in applied ecology provides scientific evidence to guide conservation policy and management. Applied ecology is becoming increasingly quantitative and model selection via information ...criteria has become a common statistical modeling approach. Unfortunately, parameters that contain little to no useful information are commonly presented and interpreted as important in applied ecology. I review the concept of an uninformative parameter in model selection using information criteria and perform a literature review to measure the prevalence of uninformative parameters in model selection studies applying Akaike's Information Criterion (AIC) in 2014 in four of the top journals in applied ecology (Biological Conservation, Conservation Biology, Ecological Applications, Journal of Applied Ecology). Twenty-one percent of studies I reviewed applied AIC metrics. Many (31.5%) of the studies applying AIC metrics in the four applied ecology journals I reviewed had or were very likely to have uninformative parameters in a model set. In addition, more than 40% of studies reviewed had insufficient information to assess the presence or absence of uninformative parameters in a model set. Given the prevalence of studies likely to have uninformative parameters or with insufficient information to assess parameter status (71.5%), I surmise that much of the policy recommendations based on applied ecology research may not be supported by the data analysis. I provide four warning signals and a decision tree to assist authors, reviewers, and editors to screen for uninformative parameters in studies applying model selection with information criteria. In the end, careful thinking at every step of the scientific process and greater reporting standards are required to detect uninformative parameters in studies adopting an information criteria approach.
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Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
“… Drug‐delivery research is experiencing a major expansion, however the upsurge in published reports does not correlate with therapeutic advances. Reporting complex systems seems to have prevailed ...over the desire to treat a disease effectively with a robust and safe formulation. Another important issue is the lack of reproducibility of published findings …” Read more in the Editorial by Jean‐Christophe Leroux.
We present a way to lift up the Tower complexity lower bound of the reachability problem for Petri nets to match the Ackermannian upper bound closing a long standing open problem. We also prove that ...the reachability problem in dimension 17 is not elementary.
Reactive oxygen species (ROS) are endogenously produced oxidants with various functions ranging from host defense to signaling. These transient species can cause severe damage to the body when their ...production is dysregulated or when environmental factors elevate their concentrations. To study their effects and prevent oxidative harm, tools capable of monitoring ROS in cells and tissue in a sensitive and selective fashion are required. In this Review, a summary of existing ratiometric probes is provided, together with a critical discussion of selected examples.
Bright ideas: Reactive oxygen species (ROS) are endogenously produced oxidants with various functions ranging from host defense to signaling. To study their effects and prevent oxidative harm, tools capable of monitoring ROS in cells and tissue in a sensitive and selective fashion are required. In this Review, a summary of existing ratiometric probes is provided, together with a critical discussion of selected examples.
Since the first report of 3D printed biodegradable structures by stereolithography, vat photopolymerization has shown great potential in the fabrication of medical implants and devices. Despite its ...superior printing quality and manufacturing speed, the development of biodegradable devices by this technique remains challenging. This results from the conflicting viscosity requirements for the printing resins, i.e., low viscosity is required for high‐resolution 3D printing, whereas high viscosity is often needed to provide high mechanical strength. Recently emerging photopolymerization‐based 3D printing techniques, including heat‐assisted digital light processing (DLP) and volumetric printing, have brought new hope to the field. With its tolerance to high viscosity resins, heat‐assisted DLP enables the fabrication of complex, personalizes architectures from biodegradable photopolymers that are not printable by conventional printing techniques. On the other hand, volumetric printing, which abandons the layer‐by‐layer printing principle and thus circumvents the dependence on low viscosity resins, could be highly beneficial for the 3D printing of biodegradable devices. This perspective evaluates the key challenges associated with biodegradable photopolymers used in the 3D printing of medical implants and devices. One focuses on their chemical structures and physical properties and discusses future directions offered by these emerging techniques.
The key challenges associated with biodegradable photopolymers for 3D printed medical implants and devices are analyzed, and the new opportunities brought by recently emerged techniques in particular heat‐assisted vat photopolymerization and volumetric 3D printing are explored. An outlook on the possible future research directions involving material design and technical progress is also provided.
Additive manufacturing (AM) is a fast‐growing manufacturing approach that comes with the promise of delivering personalized medicine to treat individual patients. However, large‐scale commercial ...applications in the pharmaceutical industry have been limited. Here, some of the challenges are discussed along with some pharmaceutical products where AM has the potential to make a tangible impact and pave the way for more rapid adoption are highlighted.
3D printing is a fast‐growing manufacturing approach with the potential to disrupt the pharmaceutical industry by enabling personalized production. However, its application in this field thus far has been limited. As 3D printing is poised to make greater impact, the challenges for it to overcome to reach mainstream adoption are examined.
Three‐dimensional (3D) printing via vat photopolymerization is transforming the manufacturing paradigms of biomedical devices, offering tremendous advantages for the production of customized advanced ...drug delivery systems. However, the existing commercial inks often lack the ability to simultaneously provide elasticity, strength, and biodegradability. Herein, photopolymerizable inks based on poly(β‐aminoester) diacrylates and N‐vinyl pyrrolidone are used to address these limitations. These biodegradable polymers enable the digital light processing 3D printing of elastomers with adjustable elongation at break (103–762%), stress at failure (0.2–8.3 MPa), and hydrolysis rates ranging from 25 min to 80 days. The authors are able to synthesize a soft polymer that possess properties akin to natural latex, which can enhance its elastic modulus when subjected to high strains. It can withstand 762% stretch with a maximum strength of 8.3 MPa. In addition, this polymer demonstrates cytocompatibility and unique biodegradation properties under simulated gastrointestinal conditions (within hours at pH 6.8). By utilizing this elastomer, a prototype of an expandable oral drug delivery device that has the ability to degrade within the average transit time in the jejunum is manufactured. This study paves the way to leverage vat photopolymerization 3D printing in the creation of complex prototypes of biomedical devices where strength, elasticity and biodegradability are essential.
Different inks for vat photopolymerization based on poly(β‐amino)esters that require strength, elasticity, biodegradation and cytocompatibility are synthesized and characterized. A new formulation is developed that resembles natural latex and can degrade within several hours at pH 6.8. Finally, an expandable oral delivery device prototype is printed that can potentially enhance oral absorption of macromolecular drugs in the small intestine.
•Rabies glycoprotein-G mRNA in lipid nanoparticles (mRNA-LNP) was highly immunogenic.•Two low (1 or 2 μg) doses of mRNA-LNP induced immunity acceptable by WHO standard.•Low doses were well tolerated, ...but 5 μg dose had unacceptable reactogenicity.
In a first-in-human study immune responses to rabies virus glycoprotein (RABV-G)-mRNA vaccine were dependent on the route of administration, necessitating specialized devices. Following successful preclinical studies with mRNA encapsulated in lipid nanoparticles (LNP), we tested an mRNA-LNP formulation (CV7202).
In this phase 1, multi-center, controlled study in Belgium and Germany we enrolled 55 healthy 18–40-year-olds to receive intramuscular injections of 5 μg (n = 10), 1 μg (n = 16), or 2 μg (n = 16) CV7202 on Day 1; subsets (n = 8) of 1 μg and 2 μg groups received second doses on Day 29. Controls (n = 10) received rabies vaccine, Rabipur, on Days 1, 8 and 29. Safety and reactogenicity were assessed up to 28 days post-vaccination using diary cards; immunogenicity was measured as RABV-G-specific neutralizing titers (VNT) by RFFIT and IgG by ELISA.
As initially tested doses of 5 μg CV7202 elicited unacceptably high reactogenicity we subsequently tested 1 and 2 μg doses which were better tolerated. No vaccine-related serious adverse events or withdrawals occurred. Low, dose-dependent VNT responses were detectable from Day 15 and by Day 29%, 31% and 22% of 1, 2 and 5 μg groups, respectively, had VNTs ≥ 0·5 IU/mL, considered an adequate response by the WHO. After two 1 or 2 μg doses all recipients had titers ≥ 0.5 IU/mL by Day 43. Day 57 GMTs were not significantly lower than those with Rabipur, which elicited adequate responses in all vaccinees after two doses. CV7202-elicited VNT were significantly correlated with RABV-G-specific IgG antibodies (r2 = 0.8319, p < 0.0001).
Two 1 μg or 2 μg doses of CV7202 were well tolerated and elicited rabies neutralizing antibody responses that met WHO criteria in all recipients, but 5 μg had unacceptable reactogenicity for a prophylactic vaccine.
ClinicalTrials.gov Identifier: NCT03713086.
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