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AIM: To investigate the utilization of MRI using a MRI liver protocol with extracellular contrast-enhanced series for hepatocellular carcinoma (HCC) surveillance in high-risk patients. METHODS: Consecutive high-risk patients of a western European cohort who underwent repeated liver MRI for HCC screening were included. Lesions were registered according to the Liver Reporting & Data System (LIRADS) 2018. HCC was staged as very early stage HCC (BCLC stage 0) and more advanced stages of HCC (BCLC stage A-D). Differences in time interval between MRI's for BCLC stage 0 and stage A-D were calculated with the Mann-Whitney U test. The HCC cumulative incidence at one-, three- and five years was calculated with the Kaplan Meier estimator. RESULTS: From 2010 to 2019 a total of 240 patients were included (71% male; median age: 57 years; IQR: 50-64 years) with 1350 MRI's. Most patients (83 %) had cirrhosis with hepatitis C as the most common underlying cause. Patients underwent on average four MRI's (IQR: 3-7). Forty-two patients (17.5%) developed HCC (52 HCC lesions: 43 LIRADS-5, eight LIRADS-4, and one LIRADS-TIV). Eighteen patients (43%) had BCLC stage 0 HCC with a significant shorter screening time interval (10 months; IQR: 6-21) compared to patients with BCLC stage A-D (21 months; IQR: 10-32) (p = 0.03). Thirty seven percent of patients with a LIRADS-3 lesion (n=43) showed HCC development within twelve months (median: 7.4 months). One, three- and five-year HCC cumulative incidence in cirrhotic patients was 1%, 10% and 17%, respectively. CONCLUSION: High-risk patients who underwent surveillance with contrast-enhanced MRI developed HCC in 17.5 % during a follow up period of over 4 years median. Very early stage HCC was seen in compensated cirrhosis after a median time interval of 10 months. Later stages of HCC were related to prolonged screening time interval (median 21 months).

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Pf is a filamentous bacteriophage integrated in the chromosome of most clinical isolates of Pseudomonas aeruginosa. Under stress conditions, mutations occurring in the Pf genome result in the emergence of superinfective variants of Pf (SI-Pf) that are capable of circumventing phage immunity; therefore, SI-Pf can even infect Pf-lysogenized P. aeruginosa. Here, we identified specific mutations located between the repressor and the excisionase genes of Pf4 phage in the P. aeruginosa PAO1 strain that resulted in the emergence of SI-Pf. Based on these findings, we genetically engineered an SI-Pf (eSI-Pf) and tested it as a phage therapy tool for the treatment of life-threatening burn wound infections caused by PAO1. In validation experiments, eSI-Pf was able to infect PAO1 grown in a lawn as well as biofilms formed in vitro on polystyrene. eSI-Pf also infected PAO1 present in burned skin wounds on mice but was not capable of maintaining a sustained reduction in bacterial burden beyond 24 h. Despite not lowering bacterial burden in burned skin tissue, eSI-Pf treatment completely abolished the capability of P. aeruginosa to disseminate from the burn site to internal organs. Over the course of 10 days, this resulted in bacterial clearance and survival of all treated mice. We subsequently determined that eSI-Pf induced a small-colony variant of P. aeruginosa that was unable to disseminate systemically. This attenuated phenotype was due to profound changes in virulence determinant production and altered physiology. Our results suggest that eSI-Pf has potential as a phage therapy against highly recalcitrant antimicrobial-resistant P. aeruginosa infections of burn wounds. IMPORTANCE Pseudomonas aeruginosa is a major cause of burn-related infections. It is also the most likely bacterial infection to advance to sepsis and result in burn-linked death. Frequently, P. aeruginosa strains isolated from burn patients display a multidrug-resistant phenotype necessitating the development of new therapeutic strategies and prophylactic treatments. In this context, phage therapy using lytic phages has demonstrated exciting potential in the control P. aeruginosa infection. However, lytic phages can present a set of drawbacks during phage therapy, including the induction of bacterial resistance and limited bacteria-phage interactions in vivo. Here, we propose an alternative approach to interfere with P. aeruginosa pathogenesis in a burn infection model, i.e., by using an engineered superinfective filamentous phage. Our study demonstrates that treatment with the engineered Pf phage can prevent sepsis and death in a burn mouse model.

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Broad-spectrum ß-lactam antibiotic resistance in Staphylococcus aureus is a global healthcare burden1,2. In clinical strains, resistance is largely controlled by BlaR13, a receptor that senses ß-lactams through the acylation of its sensor domain, inducing transmembrane signalling and activation of the cytoplasmic-facing metalloprotease domain4. The metalloprotease domain has a role in BlaI derepression, inducing blaZ (ß-lactamase PC1) and mecA (ß-lactam-resistant cell-wall transpeptidase PBP2a) expression3-7. Here, overcoming hurdles in isolation, we show that BlaR1 cleaves BlaI directly, as necessary for inactivation, with no requirement for additional components as suggested previously8. Cryo-electron microscopy structures of BlaR1-the wild type and an autocleavage-deficient F284A mutant, with or without ß-lactam-reveal a domain-swapped dimer that we suggest is critical to the stabilization of the signalling loops within. BlaR1 undergoes spontaneous autocleavage in cis between Ser283 and Phe284 and we describe the catalytic mechanism and specificity underlying the self and BlaI cleavage. The structures suggest that allosteric signalling emanates from ß-lactam-induced exclusion of the prominent extracellular loop bound competitively in the sensor-domain active site, driving subsequent dynamic motions, including a shift in the sensor towards the membrane and accompanying changes in the zinc metalloprotease domain. We propose that this enhances the expulsion of autocleaved products from the active site, shifting the equilibrium to a state that is permissive of efficient BlaI cleavage. Collectively, this study provides a structure of a two-component signalling receptor that mediates action-in this case, antibiotic resistance-through the direct cleavage of a repressor.

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Defatted sesame flour (DSF), a coproduct of the sesame oil extraction process, is often discarded despite having high polyphenol content. The aim of this study was to improve the antioxidant properties of cookies with increasing amounts of DSF (5, 10, and 20%) and study its impact on processing and gastrointestinal digestion. Besides, we evaluated the effect of this incorporation on the technological and sensory properties of cookies. The formulation with 10% (SFC10) showed technological quality similar to control, and was the most accepted by consumers. After baking, 13 out of 25 polyphenols from DSF were observed, and only 19% of the initial SFC10 polyphenols would be potentially absorbed after digestion. Besides, the addition of DSF benefits the microbiota composition after colonic fermentation. In conclusion, supplementation with 10% of DSF in cookies improves sensorial acceptance and antioxidant properties, without affecting the technological ones.

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Chia, flax, and sesame seeds are considered superseeds due to their beneficial nutritional properties, and they are frequently included as functional ingredients in foods. Authenticity markers of these seeds, including bakery products containing them, have been identified by both liquid and gas chromatography coupled to mass spectrometry (LC-MS/MS and GC-MS/MS, respectively) targeted metabolomics. However, there are no reports describing the use of nuclear magnetic resonance (NMR) spectroscopy based metabolomics to identify authenticity markers in either the raw seeds or foods containing them. We herein report the application of an untargeted NMR-based metabolomics workflow to the identification of authenticity markers for the three seeds. Seven markers, belonging to the families of polyphenols and cyanogenic glycosides, allowed good differentiation of the raw materials. Validation in cookies containing different seed percentages showed that two markers resisted the processing stage, making them feasible authenticity markers for the food trade.

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Chia, flax, and sesame seeds are well known for their nutritional quality and are commonly included in bakery products. So far, the development of methods to verify their presence and authenticity in foods is a requisite and a raised need. In this work we applied untargeted metabolomics to propose authenticity markers. Seeds were analyzed by HPLC-MS/MS and 9938 features in negative mode and 9044 in positive mode were obtained by Mzmine. After isotopes grouping, alignment, gap-filling, filtering adducts, and normalization, PCA was applied to explore the dataset and recognize pre-existent classification patterns. OPLS-DA analysis and S-Plots were used as supervised methods. Twenty-five molecules (12 in negative mode and 13 in positive mode) were selected as discriminant for the three seeds, polyphenols and lignans were identified among them. To the best of our knowledge, this is the first approach using non-target HPLC-MS/MS for the authentication of chia, flax and sesame seeds.

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We performed stochastic simulations of hypothetical oil spills from a single-point buoy mooring and subsea pipeline for the Port of Taranto given that this port is an essential strategic hub in the European logistic chain. Our methodology integrates (1) the MEDSLIK-II oil spill model coupled to a high-resolution hydrodynamic model run on an unstructured grid in operational forecasting mode; (2) a hypothetical oil spill scenario based on a historical pipeline rupture at the Port of Genoa, 2016; and (3) randomly sampling the environmental conditions over 2018-2020. The main oil drift was found to be directed southwesterly towards the outlet to the open sea. When oil is transported by highly variable currents, waves and turbulent mixing, it is exposed to multiple strandings and washing-offs from concrete constructions in the port. Consequently, oil tends to be dispersed almost isotropically over the Mar Grande, indicating low to moderate pollution indices.

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Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), the pathogen that causes the disease COVID-19, produces replicase polyproteins 1a and 1ab that contain, respectively, 11 or 16 nonstructural proteins (nsp). Nsp5 is the main protease (Mpro) responsible for cleavage at eleven positions along these polyproteins, including at its own N- and C-terminal boundaries, representing essential processing events for subsequent viral assembly and maturation. We have determined X-ray crystallographic structures of this cysteine protease in its wild-type free active site state at 1.8 Å resolution, in its acyl-enzyme intermediate state with the native C-terminal autocleavage sequence at 1.95 Å resolution and in its product bound state at 2.0 Å resolution by employing an active site mutation (C145A). We characterize the stereochemical features of the acyl-enzyme intermediate including critical hydrogen bonding distances underlying catalysis in the Cys/His dyad and oxyanion hole. We also identify a highly ordered water molecule in a position compatible for a role as the deacylating nucleophile in the catalytic mechanism and characterize the binding groove conformational changes and dimerization interface that occur upon formation of the acyl-enzyme. Collectively, these crystallographic snapshots provide valuable mechanistic and structural insights for future antiviral therapeutic development including revised molecular docking strategies based on Mpro inhibition.

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Objetivos: Describir resultados de los últimos 11 años en el tratamiento de neuralgia del trigémino con termocoagulación por radiofrecuencia, analizar variables relacionadas a complicaciones y resultados. Material y Métodos: Estudio retrospectivo, descriptivo, longitudinal, comparativo y analítico. Se analizaron los resultados de los últimos 11 años de nuestro servicio evaluando las temperaturas de las lesiones armando dos grupos, de 65°C-70°C y 71°C-75°C para analizar su relación con resultados y complicaciones. Resultados: Se trataron 59 pacientes en los cuales se realizaron 74 procedimientos, la edad media fue 59.22 años (±13,45). Se observó recidiva en 23 procedimientos con una tasa global de 31%. El tiempo medio de recidiva fue de 28,19 meses (±26,21). El tiempo medio de seguimiento fue de 33,10 meses (±33,49). El tiempo medio de evolución del dolor, previo al primer procedimiento, fue de 5,35 años (±4,37). Analizando los grupos se observó que no existía relación significativamente estadística (p = 0,74) entre el grupo de pacientes de 65ºC-70ºC y el grupo de 71ºC-75ºC y recidiva. No se observó relación estadísticamente significativa entre el grupo de 65ºC-70ºC y el grupo de 71ºC-75ºC y tiempo de recidiva (p=0,12). Se observó más pacientes con hipoestesia inmediata en el grupo de pacientes de 65ºC-70ºC, sin significación estadística (p=0,47). Conclusión: La termocoagulación por radiofrecuencia de ganglio de Gasser es un procedimiento accesible, mínimamente invasivo que demostró buenos resultados y buen manejo del dolor con bajo índice de complicaciones.

Objectives: Describe results of the last 11 years in the treatment of trigeminal neuralgia with radiofrequency thermocoagulation, analyze variables related to complications and results. Methods: Retrospective, descriptive, longitudinal, comparative and analytical study. The results of the last 11 years of our service were analyzed by assessing the temperatures of the lesions by assembling two groups, 65° C-70° C and 71 ° C-75° C to analyze their relationship with results and complications. Results: 59 patients were treated in which 74 procedures were performed; the mean age was 59.22 years (± 13.45). Recurrence was observed in 23 procedures with an overall rate of 31%. The average recurrence time was 28.19 months (± 26.21). The average follow-up time was 33.10 months (± 33.49). The average time of pain evolution, prior to the first procedure, was 5.35 years (± 4.37). Analyzing the groups, it was observed that there was no significant statistical relationship (p = 0.74) between the group of patients from 65ºC-70ºC and the group from 71ºC-75ºC and recurrence. No statistically significant relationship was observed between the 65ºC-70ºC group and the 71ºC-75ºC group and recurrence time (p = 0.12). More patients with immediate hypoaesthesia were observed in the group of patients from 65ºC-70ºC, without statistical significance (p = 0.47). Conclusion: Gasser's ganglion radiofrequency thermocoagulation is an accessible, minimally invasive procedure that demonstrated good results and good pain management with a low complication rate

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In response to the oil spill caused by the collision between the Ro-Ro ship Ulysse and CSL Virginia on 7th October 2018, the Lagrangian oil spill model MEDSLIK-II was utilized to predict spill transport and fate. Oil drift was forced by the high-resolution sea circulation provided by CMEMS and the ECMWF wind. Successive model runs were restarted 5 times with the distinct overflight- and satellite-derived observations provided by REMPEC and the Copernicus Sentinel-1 mission. The results were verified based on the ability to predict the first oil-beaching event that happened near Saint-Tropez (France) in the early afternoon of 16th October. Despite the general consistency among the runs, only the last initialization was able to forecast the oil beaching. Stochastic MEDSLIK-II simulations forced by the historical meteo-oceanographic datasets 2014-2018 revealed that the coastlines between Cap Lardier and the Gulf of Saint-Tropez were among the most impacted areas.

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BACKGROUND: The cell membrane-derived initiators of coagulation, tissue factor (TF) and anionic phospholipid (aPL), are constitutive on the herpes simplex virus type 1 (HSV1) surface, bypassing physiological regulation. TF and aPL accelerate proteolytic activation of factor (F) X to FXa by FVIIa to induce clot formation and cell signaling. Thus, infection in vivo is enhanced by virus surface TF. HSV1-encoded glycoprotein C (gC) is implicated in this tenase activity by providing viral FX binding sites and increasing FVIIa function in solution. OBJECTIVE: To examine the biochemical influences of gC on FVIIa-dependent FX activation. METHODS: Immunogold electron microscopy (IEM), kinetic chromogenic assays and microscale thermophoresis were used to dissect tenase biochemistry. Recombinant TF and gC were solubilized (s) by substituting the transmembrane domain with poly-histidine, which could be orientated on synthetic unilamellar vesicles containing Ni-chelating lipid (Ni-aPL). These constructs were compared to purified HSV1 TF±/gC ± variants. RESULTS: IEM confirmed that gC, TF, and aPL are simultaneously expressed on a single HSV1 particle where the contribution of gC to tenase activity required the availability of viral TF. Unlike viral tenase activity, the cofactor effects of sTF and sgC on FVIIa was additive when bound to Ni-aPL. FVIIa was found to bind to sgC and this was enhanced by FX. Orientation of sgC on a lipid membrane was critical for FVIIa-dependent FX activation. CONCLUSIONS: The assembly of gC with FVIIa/FX parallels that of TF and may involve other constituents on the HSV1 envelope with implications in virus infection and pathology.

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Food fraud is perpetrated with increasing frequency along the food chain, triggering the need for new and modern tools to detect food authenticity. Chia, flax and sesame seeds are well known for the good nutritional characteristics of their oils, but there is a lack of knowledge regarding the authenticity of these seeds and food products containing them as well. In the present work, we propose a method based on targeted metabolomics to identify the polyphenols present in seeds, which can be used as markers of authenticity. We tentatively identified 44 polyphenols in the different seeds by HPLC-DAD-ESI-qTOF (MS/MS). Chemometrics allowed the selection of 12 compounds, which are nominated as novel markers for seed authentication. Some of these compounds were also found in a lab-scale preparation of cookies supplemented with the studied seeds. The proposed chemical markers resisted the baking process, representing good candidates to be used in the authentication of raw material and bakery products containing these seeds.

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Gram-positive bacteria, including major clinical pathogens such as Staphylococcus aureus, are becoming increasingly drug-resistant. Their cell walls are composed of a thick layer of peptidoglycan (PG) modified by the attachment of wall teichoic acid (WTA), an anionic glycopolymer that is linked to pathogenicity and regulation of cell division and PG synthesis. The transfer of WTA from lipid carriers to PG, catalyzed by the LytR-CpsA-Psr (LCP) enzyme family, offers a unique extracellular target for the development of new anti-infective agents. Inhibitors of LCP enzymes have the potential to manage a wide range of bacterial infections because the target enzymes are implicated in the assembly of many other bacterial cell wall polymers, including capsular polysaccharide of streptococcal species and arabinogalactan of mycobacterial species. In this study, we present the first crystal structure of S. aureus LcpA with bound substrate at 1.9 Å resolution and those of Bacillus subtilis LCP enzymes, TagT, TagU, and TagV, in the apo form at 1.6-2.8 Å resolution. The structures of these WTA transferases provide new insight into the binding of lipid-linked WTA and enable assignment of the catalytic roles of conserved active-site residues. Furthermore, we identified potential subsites for binding the saccharide core of PG using computational docking experiments, and multiangle light-scattering experiments disclosed novel oligomeric states of the LCP enzymes. The crystal structures and modeled substrate-bound complexes of the LCP enzymes reported here provide insights into key features linked to substrate binding and catalysis and may aid the structure-guided design of specific LCP inhibitors.

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The Caenorhabditis elegans Gene Knockout Consortium is tasked with obtaining null mutations in each of the more than 20,000 open reading frames (ORFs) of this organism. To date, approximately 15,000 ORFs have associated putative null alleles. As there has been substantial success in using CRISPR/Cas9 in C. elegans, this appears to be the most promising technique to complete the task. To enhance the efficiency of using CRISPR/Cas9 to generate gene deletions in C. elegans we provide a web-based interface to access our database of guide RNAs (http://genome.sfu.ca/crispr). When coupled with previously developed selection vectors, optimization for homology arm length, and the use of purified Cas9 protein, we demonstrate a robust and effective protocol for generating deletions for this large-scale project. Debate and speculation in the larger scientific community concerning off-target effects due to non-specific Cas9 cutting has prompted us to investigate through whole genome sequencing the occurrence of single nucleotide variants and indels accompanying targeted deletions. We did not detect any off-site variants above the natural spontaneous mutation rate and therefore conclude that this modified protocol does not generate off-target events to any significant degree in C. elegans We did, however, observe a number of non-specific alterations at the target site itself following the Cas9-induced double-strand break and offer a protocol for best practice quality control for such events.

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BACKGROUND: Splenic vein thrombosis is a complication of pancreatic carcinoma, pancreatitis or pancreatic pseudocyst. It may lead to segmental portal hypertension and bleeding from gastric varices. CLINICAL CASE: A 31 year-old man was diagnosed with pancreatitis of two weeks of evolution and was referred to our hospital in 2013. He had a history of alcohol consumption. Physical examination showed no stigmata of liver cirrhosis. Laboratory analyses revealed hemoglobin 9.5 g/dL, and leukocytes and platelets were normal. Liver function tests were normal as well. Abdominal CT showed a pseudocyst, which was drained by percutaneous puncture. By pseudocyst recurrence, drainage and necrosectomy by retroperitoneal laparascopy were performed. The patient presented hyperglycemia during his treatment in hospital. He was discharged, but he returned to emergency room because of gastrointestinal bleeding without hemodynamic instability. Gastroscopy showed bleeding gastric varices. The colonoscopy showed normal results. Liver biopsy was also normal. Abdominal CT angiography revealed blockage of the splenic vein. Patient underwent splenectomy and was discharged. CONCLUSION: This case is rare due to the high frequency of portal hypertension and cirrhosis. The isolated gastric varices with normal liver function are a sign of splenic thrombosis. The definitive treatment is splenectomy.

Introducción: la obstrucción aislada de la vena esplénica es una complicación de carcinoma pancreático, pancreatitis o pseudoquiste del páncreas. La trombosis de la vena esplénica puede conducir a hipertensión portal segmentaria y sangrado de várices gástricas. Caso clínico: un hombre de 31 años de edad fue referido a nuestro hospital en 2013 con el diagnóstico de pancreatitis de dos semanas de evolución. Tenía el antecedente de consumo de alcohol. El examen físico no mostró estigmas de cirrosis hepática. El laboratorio reveló hemoglobina de 9.5 g/dL con leucocitos y plaquetas normales. Las pruebas de función hepática fueron normales. La TAC abdominal mostró un pseudoquiste, el cual fue drenado por punción percutánea. Por recurrencia del pseudoquiste, se efectuó drenaje y necrosectomía por laparoscopia retroperitoneal. El paciente presentó hiperglucemia durante su estancia. Después de haber egresado, acudió a urgencias por sangrado gastrointestinal superior sin inestabilidad hemodinámica. La gastroscopia mostró várices gástricas sangrantes. La colonoscopia mostró resultados normales. La biopsia de hígado también resultó normal. La angio-TAC abdominal mostró obstrucción de la vena esplénica. Se sometió a esplenectomía y fue egresado. Conclusión: este caso es raro en nuestro medio debido a la alta frecuencia de hipertensión portal por cirrosis. Las várices gástricas aisladas con función hepática normal son un signo de trombosis de la vena esplénica. El tratamiento definitivo es la esplenectomía.

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Anticoagulant therapy-associated bleeding and pathological thrombosis pose serious risks to hospitalized patients. Both complications could be mitigated by developing new therapeutics that safely neutralize anticoagulant activity and inhibit activators of the intrinsic blood clotting pathway, such as polyphosphate (polyP) and extracellular nucleic acids. The latter strategy could reduce the use of anticoagulants, potentially decreasing bleeding events. However, previously described cationic inhibitors of polyP and extracellular nucleic acids exhibit both nonspecific binding and adverse effects on blood clotting that limit their use. Indeed, the polycation used to counteract heparin-associated bleeding in surgical settings, protamine, exhibits adverse effects. To address these clinical shortcomings, we developed a synthetic polycation, Universal Heparin Reversal Agent (UHRA), which is nontoxic and can neutralize the anticoagulant activity of heparins and the prothrombotic activity of polyP. Sharply contrasting protamine, we show that UHRA does not interact with fibrinogen, affect fibrin polymerization during clot formation, or abrogate plasma clotting. Using scanning electron microscopy, confocal microscopy, and clot lysis assays, we confirm that UHRA does not incorporate into clots, and that clots are stable with normal fibrin morphology. Conversely, protamine binds to the fibrin clot, which could explain how protamine instigates clot lysis and increases bleeding after surgery. Finally, studies in mice reveal that UHRA reverses heparin anticoagulant activity without the lung injury seen with protamine. The data presented here illustrate that UHRA could be safely used as an antidote during adverse therapeutic modulation of hemostasis.

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Forward genetic screens represent powerful, unbiased approaches to uncover novel components in any biological process. Such screens suffer from a major bottleneck, however, namely the cloning of corresponding genes causing the phenotypic variation. Reverse genetic screens have been employed as a way to circumvent this issue, but can often be limited in scope. Here we demonstrate an innovative approach to gene discovery. Using C. elegans as a model system, we used a whole-genome sequenced multi-mutation library, from the Million Mutation Project, together with the Sequence Kernel Association Test (SKAT), to rapidly screen for and identify genes associated with a phenotype of interest, namely defects in dye-filling of ciliated sensory neurons. Such anomalies in dye-filling are often associated with the disruption of cilia, organelles which in humans are implicated in sensory physiology (including vision, smell and hearing), development and disease. Beyond identifying several well characterised dye-filling genes, our approach uncovered three genes not previously linked to ciliated sensory neuron development or function. From these putative novel dye-filling genes, we confirmed the involvement of BGNT-1.1 in ciliated sensory neuron function and morphogenesis. BGNT-1.1 functions at the trans-Golgi network of sheath cells (glia) to influence dye-filling and cilium length, in a cell non-autonomous manner. Notably, BGNT-1.1 is the orthologue of human B3GNT1/B4GAT1, a glycosyltransferase associated with Walker-Warburg syndrome (WWS). WWS is a multigenic disorder characterised by muscular dystrophy as well as brain and eye anomalies. Together, our work unveils an effective and innovative approach to gene discovery, and provides the first evidence that B3GNT1-associated Walker-Warburg syndrome may be considered a ciliopathy.

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Two new IDO inhibitory meroterpenoids, xestolactone A (1) and xestosaprol O (2), have been isolated from the sponge Xestospongia vansoesti. Xestolactone A (1) has an unprecedented degraded meroterpenoid carbon skeleton. A short synthesis of the xestosaprol O (2) analogues 3 and 4 features the application of a rarely used photochemical coupling reaction. Synthetic analogue 3 is ∼40 times more potent than the inspirational natural product 2.

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