Alkyne metathesis is increasingly explored as a reliable method to close macrocyclic rings, but there are no prior examples of an alkyne‐metathesis‐based homodimerization approach to natural ...products. In this approach to the cytotoxic C2‐symmetric marine‐derived bis(lactone) disorazole C1, a highly convergent, modular strategy is employed featuring cyclization through an ambitious one‐pot alkyne cross‐metathesis/ring‐closing metathesis self‐assembly process.
Heads or tails? The self‐assembly of disorazole C1, a cytotoxic bis(lactone) natural product, has been achieved through alkyne cross‐metathesis and ring‐closing alkyne metathesis. The coupling favored the production of the desired head‐to‐tail dimer over its head‐to‐head counterpart with a ratio of 5:1.
Objectives
To assess the feasibility of local anaesthetic transperineal (LATP) technique using a single‐freehand transperineal (TP) access device, and report initial prostate cancer (PCa) detection, ...infection rates, and tolerability.
Patients and methods
Observational study of a multicentre prospective cohort, including all consecutive cases. LATP was performed in three settings: (i) first biopsy in suspected PCa, (ii) confirmatory biopsies for active surveillance, and (iii) repeat biopsy in suspected PCa. All patients received pre‐procedure antibiotics according to local hospital guidelines. Local anaesthesia was achieved by perineal skin infiltration and periprostatic nerve block without sedation. Ginsburg protocol principles were followed for systematic biopsies including cognitive magnetic resonance imaging‐targeted biopsies when needed using the PrecisionPoint™ TP access device. Procedure‐related complications and oncological outcomes were prospectively and consecutively collected. A validated questionnaire was used in a subset of centres to collect data on patient‐reported outcome measures (PROMs).
Results
Some 1218 patients underwent LATP biopsies at 10 centres: 55%, 24%, and 21% for each of the three settings, respectively. Any grade PCa was diagnosed in 816 patients (67%), of which 634 (52% of total) had clinically significant disease. Two cases of sepsis were documented (0.16%) and urinary retention was observed in 19 patients (1.6%). PROMs were distributed to 419 patients, with a 56% response rate (n = 234). In these men, pain during the biopsy was described as either ‘not at all’ or ‘a little’ painful by 64% of patients. Haematuria was the most common reported symptom (77%). When exploring attitude to re‐biopsy, 48% said it would be ‘not a problem’ and in contrast 8.1% would consider it a ‘major problem’. Most of the patients (81%) described the biopsy as a ‘minor or moderate procedure tolerable under local anaesthesia’, while 5.6% perceived it as a ‘major procedure that requires general anaesthesia’.
Conclusion
Our data suggest that LATP biopsy using a TP access system mounted to the ultrasound probe achieves excellent PCa detection, with a very low sepsis rate, and is safe and well tolerated. We believe a randomised controlled trial comparing LATP with transrectal ultrasound‐guided biopsy (TRUS) to investigate the relative trade‐offs between each biopsy technique would be helpful.
Improving the sustainability of synthesis is a major goal in green chemistry, which has been greatly aided by the development of asymmetric transition metal catalysis. Recent advances in asymmetric ...catalysis show that the ability to control the coordination sphere of substrates can lead to improvements in enantioselectivity and activity, in a manner resembling the operation of enzymes. Peptides can be used to mimic enzyme structures and their secondary interactions and they are easily accessible through solid-phase peptide synthesis. Despite this, cyclic peptides remain underexplored as chiral ligands for catalysis due to synthetic complications upon macrocyclization. Here, we show that the solid-phase synthesis of peptides containing metal-binding amino acids, bipyridylalanine (
), phenyl pyridylalanine (
) and
dimethylhistidine (
) can be combined with peptide macrocylization using peptide cyclase 1 (PCY1) to yield cyclic peptides under mild conditions. High conversions of the linear peptides were observed (approx. 90%) and the Cu-bound cyclo(FSAS(
)SSKP) was shown to be a competent catalyst in the Friedel-Crafts/conjugate addition of indole. This study shows that PCY1 can tolerate peptides containing amino acids with classic inorganic and organometallic ligands as side chains, opening the door to the streamlined and efficient development of cyclic peptides as metal ligands.
Verifying a conjecture of Brewster, Foucaud, Hell and Naserasr, we show that signed (H,Π)-colouring is NP-complete for any signed graph (H,Π) whose s-core has at least 3 edges.
Given a graph G $G$, the k $k$‐mixing problem asks: Starting with a k $k$‐colouring of G $G$, can one obtain all k $k$‐colourings of G $G$ by changing the colour of only one vertex at a time, while ...at each step maintaining a k $k$‐colouring? More generally, for a graph H $H$, the H $H$‐mixing problem asks: Can one obtain all homomorphisms G
→
H $G\to H$, starting from one homomorphism f $f$, by changing the image of only one vertex at a time, while at each step maintaining a homomorphism G
→
H $G\to H$? This paper focuses on a generalization of k $k$‐colourings, namely, (p
,
q
) $(p,q)$‐circular colourings. We show that when 2
<
p
q
<
4 $2\lt \frac{p}{q}\lt 4$, a graph G $G$ is (p
,
q
) $(p,q)$‐mixing if and only if for any (p
,
q
) $(p,q)$‐colouring f $f$ of G $G$, and any cycle C $C$ of G $G$, the wind of the cycle under the colouring equals a particular value (which intuitively corresponds to having no wind). As a consequence we show that (p
,
q
) $(p,q)$‐mixing is closed under a restricted homomorphism called a fold. Using this, we deduce that (2
k
+
1
,
k
) $(2k+1,k)$‐mixing is co‐NP‐complete for all k
∈
N $k\in {\mathbb{N}}$, and by similar ideas we show that if the circular chromatic number of a connected graph G $G$ is 2
k
+
1
k $\frac{2k+1}{k}$, then G $G$ folds to C2
k
+
1 ${C}_{2k+1}$. We use the characterization to settle a conjecture of Brewster and Noel, specifically that the circular mixing number of bipartite graphs is 2. Lastly, we give a polynomial time algorithm for (p
,
q
) $(p,q)$‐mixing in planar graphs when 3
≤
p
q
<
4 $3\le \frac{p}{q}\lt 4$.
For a fixed graph H, the reconfiguration problem for H‐colorings (ie, homomorphisms to H) asks: given a graph G and two H‐colorings φ and ψ of G, does there exist a sequence f0,…,fm of H‐colorings ...such that f0=φ, fm=ψ, and fi(u)fi+1(v)∈E(H) for every 0≤i<m and uv∈E(G)? If the graph G is loop‐free, then this is the equivalent to asking whether it possible to transform φ into ψ by changing the color of one vertex at a time such that all intermediate mappings are H‐colorings. In the affirmative, we say that φ reconfigures to ψ. Currently, the complexity of deciding whether an H‐coloring φ reconfigures to an H‐coloring ψ is only known when H is a clique, a circular clique, a C4‐free graph, or in a few other cases which are easily derived from these. We show that this problem is PSPACE‐complete when H is an odd wheel. An important notion in the study of reconfiguration problems for H‐colorings is that of a frozen H‐coloring; that is, an H‐coloring φ such that φ does not reconfigure to any H‐coloring ψ such that ψ≠φ. We obtain an explicit dichotomy theorem for the problem of deciding whether a given graph G admits a frozen H‐coloring. The hardness proof involves a reduction from a constraint satisfaction problem which is shown to be nondeterministic polynomial time NP‐complete by establishing the nonexistence of a certain type of polymorphism.
The fundamental biology and application of bacterial exopolysaccharides is gaining increasing attention. However, current synthetic biology efforts to produce the major component of
slime, colanic ...acid, and functional derivatives thereof have been limited. Herein, we report the overproduction of colanic acid (up to 1.32 g/L) from d-glucose in an engineered strain of
JM109. Furthermore, we report that chemically synthesized l-fucose analogues containing an azide motif can be metabolically incorporated into the slime layer via a heterologous fucose salvage pathway from
and used in a click reaction to attach an organic cargo to the cell surface. This molecular-engineered biopolymer has potential as a new tool for use in chemical, biological, and materials research.
Rapid, site-selective modification of cysteine residues with chloromethyl-triazole derivatives generates pseudo-acyl sLys motifs, mimicking important post-translational modifications. Near-native ...biotinylation of peptide and protein substrates is shown to be site-selective and modified histone H4 retains functional activity.
We study homomorphism problems of signed graphs from a computational point of view. A signed graph (G,Σ) is a graph G where each edge is given a sign, positive or negative; Σ⊆E(G) denotes the set of ...negative edges. Thus, (G,Σ) is a 2-edge-coloured graph with the property that the edge-colours, {+,−}, form a group under multiplication. Central to the study of signed graphs is the operation of switching at a vertex, that results in changing the sign of each incident edge. We study two types of homomorphisms of a signed graph (G,Σ) to a signed graph (H,Π): ec-homomorphisms and s-homomorphisms. Each is a standard graph homomorphism of G to H with some additional constraint. In the former, edge-signs are preserved. In the latter, edge-signs are preserved after the switching operation has been applied to a subset of vertices of G.
We prove a dichotomy theorem for s-homomorphism problems for a large class of (fixed) target signed graphs (H,Π). Specifically, as long as (H,Π) does not contain a negative (respectively a positive) loop, the problem is polynomial-time solvable if the core of (H,Π) has at most two edges, and is NP-complete otherwise. (Note that this covers all simple signed graphs.) The same dichotomy holds if (H,Π) has no negative digons, and we conjecture that it holds always. In our proofs, we reduce s-homomorphism problems to certain ec-homomorphism problems, for which we are able to show a dichotomy. In contrast, we prove that a dichotomy theorem for ec-homomorphism problems (even when restricted to bipartite target signed graphs) would settle the dichotomy conjecture of Feder and Vardi.
Microorganisms can be programmed to perform chemical synthesis via metabolic engineering. However, despite an increasing interest in the use of de novo metabolic pathways and designer whole‐cells for ...small molecule synthesis, the inherent synthetic capabilities of native microorganisms remain underexplored. Herein, we report the use of unmodified E. coli BL21(DE3) cells for the reduction of keto‐acrylic compounds and apply this whole‐cell biotransformation to the synthesis of aminolevulinic acid from a lignin‐derived feedstock. The reduction reaction is rapid, chemo‐, and enantioselective, occurs under mild conditions (37 °C, aqueous media), and requires no toxic transition metals or external reductants. This study demonstrates the remarkable promiscuity of central metabolism in bacterial cells and how these processes can be leveraged for synthetic chemistry without the need for genetic manipulation.
Alken‐reduzierende Bazillen: Der Mikroorganismus Escherichia coli BL21(DE3) reduziert verschiedene Keton‐substituierte Acrylate ohne genetische Modifizierung. Die Biokompatibilität der Reaktion wurde in zellulärer Umgebung untersucht und zur Entwicklung einer metallfreien Synthese von Aminolävulinsäure aus einem von Lignin abgeleiteten Substrat verwendet.
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