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Unc-51-like kinase 4 (ULK4) is a pseudokinase that has been linked to the development of several diseases. Even though sequence motifs required for ATP binding in kinases are lacking, ULK4 still tightly binds ATP and the presence of the co-factor is required for structural stability of ULK4. Here, we present a high-resolution structure of a ULK4-ATPγS complex revealing a highly unusual ATP binding mode in which the lack of the canonical VAIK motif lysine is compensated by K39, located N-terminal to αC. Evolutionary analysis suggests that degradation of active site motifs in metazoan ULK4 has co-occurred with an ULK4-specific activation loop, which stabilizes the C helix. In addition, cellular interaction studies using BioID and biochemical validation data revealed high confidence interactors of the pseudokinase and armadillo repeat domains. Many of the identified ULK4 interaction partners were centrosomal and tubulin-associated proteins and several active kinases suggesting interesting regulatory roles for ULK4.
Unc-51-like kinase 4 (ULK4) is a pseudokinase that has been linked to the development of several diseases. Even though sequence motifs required for ATP binding in kinases are lacking, ULK4 still tightly binds ATP and the presence of the cofactor is required for structural stability of ULK4. Here we present a high-resolution structure of a ULK4-ATPγS complex revealing a highly unusual ATP binding mode in which the lack of the canonical VAIK motif lysine is compensated by K39, located N-terminal to αC. Evolutionary analysis suggests that degradation of active site motifs in metazoan ULK4 has co-occurred with an ULK4 specific activation loop, which stabilizes the C-helix. In addition, cellular interaction studies using BioID and biochemical validation data revealed high confidence interactors of the pseudokinase and armadillo repeat domains. Many of the identified ULK4 interaction partners were centrosomal and tubulin associated proteins and several active kinases suggesting new roles for ULK4.
Highlights: Structure of the ULK4 ATP complex reveals a unique ATP binding mode.
Disease associated mutations modulate ATP binding and ULK4 stability
Degradation of active site motifs co-occurred in evolution with an ULK4 specific activation loop
BioID suggests a role of ULK4 regulating centrosomal and cytoskeletal functions,
Certain electron-rich 1,4-diborabenzene derivatives efficiently activate single, double, and triple bonds and thereby increasingly compete with transition metals in homogeneous catalysis. This review compares the activation of three model substrates (H2, H2C=CH2, CO2) by (i) 9,10-dihydro-9,10-diboraanthracene dianions, (ii) their neutral carbene-stabilized congeners, (iii) 1,3,2,5-diazadiborinines, and (iv) 1,4,2,5-diazadiborinines. Distinct structure-properties relationships become apparent, the most influential factors being (i) the steric demands of the B-bonded substituents, (ii) the charges on the B-doped (hetero)arenes, (iii) charge polarization as a result of additional N-doping, and (iv) the energies and nodal structures of the frontier orbitals. The observed reactions are explained by a transition metal-like activation mechanism. If the two boron atoms are chemically inequivalent, contributions of a B(+I)/B(+III) mixed-valence state determine the observed regioselectivities when polar substrates are added. The lessons learned from the conversions of the model substrates are subsequently used to rationalize the behavior of the B2 heterocycles also toward more sophisticated substrate molecules. Finally, catalytic cycles based on H2- and H−-transfers, hydroboration reactions, and CO2 reductions will be covered.
Formulation scientists have developed a toolkit of strategies that can improve the solubility and subsequent bioavailability of poorly soluble candidates. Amorphous formulations are especially appealing due to the significant improvement in solubility the amorphous form can provide, but must be stabilized for effective performance (Timpe, 2007).
2. The Importance of Drug Polymer Interactions in Precipitation Inhibition
Polymeric “precipitation inhibitors” have seen widespread usage in the literature (Warren, 2010). The precipitation inhibition effect of polymers on precipitations is related to interference with nucleation and crystal growth (Xu, 2013). Many techniques have been reported in the literature to predict these interactions, however, they are not suitable to screening due to API and time resources required, which are not amenable to early stage pharmaceutical development.
3. Mesoporous Silica: An Emerging Formulation Technology
Mesoporous silicon dioxide has emerged in recent years as a new option for stabilizing the amorphous form. Upon impregnation of the silica with a concentrated drug solution, the drug can be molecularly adsorbed and locally and sterically confined, preventing recrystallization (Ditzinger, 2018). Upon administration of mesoporous silica formulations to the body the amorphous formulation generates supersaturation which must be stabilized using precipitation inhibitors (Guzman, 2007).
4. Co-incorporation: A New Method to Combine Precipitation Inhibitors with Mesoporous Silica
There has been no systematic study of how best to incorporate precipitation inhibitors into mesoporous silica formulations. The current standard practice involves combining inhibitors in a physical mixture with the drug-loaded silica, either by pestle and mortar or overhead stirring. Due to the lack of a defined protocol, there is uncertainty about how reliably the precipitation inhibitor is combined with the drug-loaded silica on a batch to batch basis. In this work, a novel co-incorporated formulation of glibenclamide and the precipitation inhibitor, HPMCAS, onto mesoporous silica was described. By co-incorporating the precipitation inhibitor, the formulation significantly outperformed the commonly applied simple physical blend due to the formation of drug-polymer interactions in the solid state.
5. In Silico Pharmaceutics: A New Method to Select Precipitation Inhibitors for Mesoporous Silica
An approach that can incorporate understanding of the drug-polymer interactions with a quick and efficient screening process would be very useful. The COnductor like Screening MOdel for Real Solvents (COSMO-RS) is a quantum mechanical theory, which can be used to derive thermodynamic properties of interest. (Klamt, 1993, 1995, 2003). We proposed excess mixing enthalpies of drug and polymer could be calculated using the COSMO-RS theory. This new approach was applied to screen precipitation inhibitors for three model compounds, all of which showed a strong positive correlation between the rank assigned based on the calculated free enthalpy of mixing and the overall formulation performance.
6. Conclusion
This body of work aimed to improve the processes underpinning the design and development of mesoporous silica with precipitation inhibitors. Firstly, this involved two extensive literature reviews in the area of solubility enhancement formulation technologies and precipitation inhibition. Secondly, a mechanistic rational and experimental approach was developed to improve the formulation of precipitation inhibitors with mesoporous silica, the “co-incorporation” approach significantly improved process efficiency and formulation performance. Finally, combining insights from the aforementioned review, and learnings from the mechanistic analysis of the “co-incorporation” approach, an in silico screening protocol was developed to calculate the enthalpy of interaction between drug and polymer, to identify the most optimal precipitation inhibitor for a given formulation.
Mesoporous silica has emerged as an enabling formulation for poorly soluble active pharmaceutical ingredients (APIs). Unlike other formulations, mesoporous silica typically does not inhibit precipitation of supersaturated API therefore, a suitable precipitation inhibitor (PI) should be added to increase absorption from the gastrointestinal (GI) tract. However, there is limited research about optimal processes for combining PIs with silica formulations. Typically, the PI is added by simply blending the API-loaded silica mechanically with the selected PI. This has the drawback of an additional blending step and may also not be optimal with regard to release of drug and PI. By contrast, loading PI simultaneously with the API onto mesoporous silica, i.e. co-incorporation, is attractive from both a performance and practical perspective. The aim of this study was to demonstrate the utility of a co-incorporation approach for combining PIs with silica formulations, and to develop a mechanistic rationale for improvement of the performance of silica formulations using the co-incorporation approach. The results indicate that co-incorporating HPMCAS with glibenclamide onto silica significantly improved the extent and duration of drug supersaturation in single-medium and transfer dissolution experiments. Extensive spectroscopic characterization of the formulation revealed that the improved performance was related to the formation of drug-polymer interactions already in the solid state; the immobilization of API-loaded silica on HPMCAS plates, which prevents premature release and precipitation of API; and drug-polymer proximity on disintegration of the formulation, allowing for rapid onset of precipitation inhibition. The data suggests that co-incorporating the PI with the API is appealing for silica formulations from both a practical and formulation performance perspective.
The transcription factor ∆Np63 is a master regulator of epithelial cell identity and essential for the survival of squamous cell carcinoma (SCC) of lung, head and neck, oesophagus, cervix and skin. Here, we report that the deubiquitylase USP28 stabilizes ∆Np63 and maintains elevated ∆NP63 levels in SCC by counteracting its proteasome‐mediated degradation. Impaired USP28 activity, either genetically or pharmacologically, abrogates the transcriptional identity and suppresses growth and survival of human SCC cells. CRISPR/Cas9‐engineered in vivo mouse models establish that endogenous USP28 is strictly required for both induction and maintenance of lung SCC. Our data strongly suggest that targeting ∆Np63 abundance via inhibition of USP28 is a promising strategy for the treatment of SCC tumours.
The policy studies literature is divided on how information processing takes place in policy processes. Punctuated equilibrium theory claims that policymakers tend to process information disproportionately, giving more weight to some incoming signals than to others. By contrast, thermostatic models of policymaking argue that policymakers respond in a more proportionate way. In this paper, we analyse information processing in the adoption of Total Allowable Catches (TACs) under the European Union’s (EU) Common Fisheries Policy. Based on a novel measure for the proportionality of information processing, it shows that over time TACs have become more closely aligned with incoming signals about fish stocks. This development can be explained through a combination of changing discourses around fisheries conservation and institutional adjustments in EU fisheries policy. This analysis has implications for the debate between punctuated equilibrium and thermostatic models of policymaking and our understanding of the effectiveness of EU fisheries policies.
Knowledge on the postmortem interval (PMI) of wild boar (Sus scrofa) carcasses is crucial in the event of an outbreak of African swine fever in a wild boar population. Therefore, a thorough understanding of the decomposition process of this species in different microhabitats is necessary. We describe the decomposition process of carcasses exposed in cages. Trial 1 compared a wild boar and a domestic pig (Sus scrofa domesticus) under similar conditions; Trial 2 was performed with three wild boar piglets in the sunlight, shade, or in a wallow, and Trial 3 with two adult wild boar in the sun or shade. The wild boar decomposed more slowly than the domestic pig, which shows that standards derived from forensic studies on domestic pigs are not directly applicable to wild boar. The carcasses exposed to the sun decomposed faster than those in the shade did, and the decomposition of the carcass in the wallow took longest. To assess the state of decomposition, we adapted an existing total body scoring system originally developed for humans. Based on our studies, we propose a checklist tailored to wild boar carcasses found in the field that includes the most important information for a reliable PMI estimation.
La Escuela de Frankfurt ha jugado un papel determinante en la recepción posterior del Empirismo Lógico. Sin embargo, la revisión histórica del Empirismo Lógico ha revelado que esta visión partía de ciertas simplificaciones que no hacían justicia a la diversidad y complejidad de posturas que el movimiento incluía. En El ataque más reciente a la Metafísica Horkheimer sostiene que el positivismo es necesariamente irreflexivo y ahistórico en su explicación de las ciencias, y que su carencia de una teoría social que las contextualice lo vuelve incapaz de criticar el rol de la ciencia y de la razón instrumental en su aceptación del orden establecido, comprometiéndolo con una visión conservadora de la política. Se problematizará la atribución hecha al Empirismo Lógico de sostener una concepción de “razón instrumental” generalizada, y se sostendrá que, desde la visión de Neurath, el carácter auto-reflexivo de la ciencia admite una consideración crítica de los fines y propósitos del conocimiento.
Background: Ever decreasing costs along with advances in sequencing and library preparation technologies enable even small research groups to generate chromosome-level assemblies today. Here we report the generation of an improved chromosome-level assembly for the Siamese fighting fish (Betta splendens) that was carried out during a practical university Master’s course. The Siamese fighting fish is a popular aquarium fish and an emerging model species for research on aggressive behaviour. We updated the current genome assembly by generating a new long-read nanopore-based assembly with subsequent scaffolding to chromosome-level using previously published HiC data.
Findings: The use of nanopore-based long-read data sequenced on a MinION platform (Oxford Nanopore Technologies) allowed us to generate a baseline assembly of only 1,276 contigs with a contig N50 of 2.1 Mbp, and a total length of 441 Mbp. Scaffolding using previously published HiC data resulted in 109 scaffolds with a scaffold N50 of 20.7 Mbp. More than 99% of the assembly is comprised in 21 scaffolds. The assembly showed the presence of 95.8% complete BUSCO genes from the Actinopterygii dataset indicating a high quality of the assembly.
Conclusion: We present an improved full chromosome-level assembly of the Siamese fighting fish generated during a university Master’s course. The use of ~35× long-read nanopore data drastically improved the baseline assembly in terms of continuity. We show that relatively in-expensive high-throughput sequencing technologies such as the long-read MinION sequencing platform can be used in educational settings allowing the students to gain practical skills in modern genomics and generate high quality results that benefit downstream research projects.