The Amphibian Genomics Consortium: advancing genomic and genetic resources for amphibian research and conservation.

Amphibians represent a diverse group of tetrapods, marked by deep divergence times between their three systematic orders and families. Studying amphibian biology through the genomics lens increases our understanding of the features of this animal class and that of other terrestrial vertebrates. The need for amphibian genomics resources is more urgent than ever due to the increasing threats to this group. Amphibians are one of the most imperiled taxonomic groups, with approximately 41% of species threatened with extinction due to habitat loss, changes in land use patterns, disease, climate change, and their synergistic effects. Amphibian genomics resources have provided a better understanding of ontogenetic diversity, tissue regeneration, diverse life history and reproductive modes, antipredator strategies, and resilience and adaptive responses. They also serve as critical models for understanding widespread genomic characteristics, including evolutionary genome expansions and contractions given they have the largest range in genome sizes of any animal taxon and multiple mechanisms of genetic sex determination. Despite these features, genome sequencing of amphibians has significantly lagged behind that of other vertebrates, primarily due to the challenges of assembling their large, repeat-rich genomes and the relative lack of societal support. The advent of long-read sequencing technologies, along with computational techniques that enhance scaffolding capabilities and streamline computational workload is now enabling the ability to overcome some of these challenges. To promote and accelerate the production and use of amphibian genomics research through international coordination and collaboration, we launched the Amphibian Genomics Consortium (AGC) in early 2023. This burgeoning community already has more than 282 members from 41 countries (6 in Africa, 131 in the Americas, 27 in Asia, 29 in Australasia, and 89 in Europe). The AGC aims to leverage the diverse capabilities of its members to advance genomic resources for amphibians and bridge the implementation gap between biologists, bioinformaticians, and conservation practitioners. Here we evaluate the state of the field of amphibian genomics, highlight previous studies, present challenges to overcome, and outline how the AGC can enable amphibian genomics research to "leap" to the next level.

Synthesis of 4-Alkyl-2-chloro Imidazoles Using Intermolecular Radical Additions.

Here, we report an intermolecular radical addition-based reaction sequence that permits preparation of functionalized imidazoles via a 5-step/3-pot procedure. In contrast to traditional, transition-metal mediated protocols, which generally provide access to 2-substituted imidazoles, the strategy described here allows incorporation of a structurally diverse range of complex alkyl side chains at the 4-position. This work demonstrates that intermolecular free-radical addition reactions are a powerful alternative to traditional methods used to synthesize medicinally important heterocyclic frameworks.

Total Syntheses of the Structures Assigned to Denigrins A, B, C, F, and G, 3,4-Diaryl-Pyrrole and -Pyrrolidinone Alkaloids, and the Conversion of Congener B into the Co-metabolite Spirodactylone.

The title marine natural products have been prepared by total synthesis and in the case of congeners 3, 6, and 7 for the first time. Each of these was obtained by manipulation of readily prepared denigrin B (2). The structure, 3, assigned to denigrin C is shown to be incorrect. Reaction of compound 2 with DDQ has led, in high yield, to the related natural product spirodactylone (16), while treating the corresponding permethyl ether 15 with PIFA/BF3·Et2O provides compound 20, embodying an isomeric framework.

Short Formal Syntheses of Lycorine and Congeners Using a 5-Endo-Trig/6-Endo-Trig Radical Cyclization Sequence.

Here, we report a practical route to medicinally interesting lycorine congeners alongside formal syntheses of various lycorine-type natural products, including lycorine itself. The efficiency of our strategy derives from a back-to-back 5-endo-trig/6-endo-trig radical cyclization sequence, which we systematically studied both experimentally and computationally. The results of our work will facilitate future development of urgently needed antiviral therapeutics based on lycorine.

Revisiting Diagnosis and Treatment of Hypertrophic Cardiomyopathy: Current Practice and Novel Perspectives.

Sarcomeric hypertrophic cardiomyopathy (HCM) is a prevalent genetic disorder characterised by left ventricular hypertrophy, myocardial disarray, and an increased risk of heart failure and sudden cardiac death. Despite advances in understanding its pathophysiology, treatment options for HCM remain limited. This narrative review aims to provide a comprehensive overview of current clinical practice and explore emerging therapeutic strategies for sarcomeric HCM, with a focus on cardiac myosin inhibitors. We first discuss the conventional management of HCM, including lifestyle modifications, pharmacological therapies, and invasive interventions, emphasizing their limitations and challenges. Next, we highlight recent advances in molecular genetics and their potential applications in refining HCM diagnosis, risk stratification, and treatment. We delve into emerging therapies, such as gene editing, RNA-based therapies, targeted small molecules, and cardiac myosin modulators like mavacamten and aficamten, which hold promise in modulating the underlying molecular mechanisms of HCM. Mavacamten and aficamten, selective modulators of cardiac myosin, have demonstrated encouraging results in clinical trials by reducing left ventricular outflow tract obstruction and improving symptoms in patients with obstructive HCM. We discuss their mechanisms of action, clinical trial outcomes, and potential implications for the future of HCM management. Furthermore, we examine the role of precision medicine in HCM management, exploring how individualised treatment strategies, including exercise prescription as part of the management plan, may optimise patient outcomes. Finally, we underscore the importance of multidisciplinary care and patient-centred approaches to address the complex needs of HCM patients. This review also aims to encourage further research and collaboration in the field of HCM, promoting the development of novel and more effective therapeutic strategies, such as cardiac myosin modulators, to hopefully improve the quality of life and outcome of patients with sarcomeric HCM.

The first linkage map for Australo-Papuan Treefrogs (family: Pelodryadidae) reveals the sex-determination system of the Green-eyed Treefrog (Litoria serrata).

Amphibians represent a useful taxon to study the evolution of sex determination because of their highly variable sex-determination systems. However, the sex-determination system for many amphibian families remains unknown, in part because of a lack of genomic resources. Here, using an F1 family of Green-eyed Treefrogs (Litoria serrata), we produce the first genetic linkage map for any Australo-Papuan Treefrogs (family: Pelodryadidae). The resulting linkage map contains 8662 SNPs across 13 linkage groups. Using an independent set of sexed adults, we identify a small region in linkage group 6 matching an XY sex-determination system. These results suggest Litoria serrata possesses a male heterogametic system, with a candidate sex-determination locus on linkage group 6. Furthermore, this linkage map represents the first genomic resource for Australo-Papuan Treefrogs, an ecologically diverse family of over 220 species.

The useful biological properties of sucrose esters: Opportunities for the development of new functional foods.

Sucrose esters have been deployed as surfactants in many food products since the 1950s. In addition to their useful physical characteristics, sucrose esters also have interesting biological properties that enhance their utility. This review critically examines the broad suite of biological activities that has been attributed to both synthetically-derived and naturally-occurring sucrose esters. These include insecticidal, molluscicidal, plant growth-regulating, anti-microbial, anti-tumor, anti-oxidant, anti-depressive, neuro-protective, anti-inflammatory and anti-plasmodial effects. In addition to providing a summary of the structure-activity profiles of sucrose esters, the various known mechanisms-of action of these compounds are also discussed. Furthermore, since sucrose esters are well-known surfactants, the potential to advantageously apply their industrially desirable physical characteristics in combination with their biological properties is considered. Recent advances in synthetic chemistry that have facilitated the deployment of biologically active sucrose esters as food additives are also described.

Formal Total Syntheses of (+)- and (-)-Aspidophytine from a Common, Homochiral Precursor.

A formal total synthesis of (-)-aspidophytine (2), a key substructure associated with the heterodimeric indole alkaloid haplophytine (1) and itself a natural product, has been established by employing the homochiral and enzymatically derived cis-1,2-dihydrocatechol 8 as a starting material. Specifically, compound 8 has been converted into the pentacyclic product 26, an advanced intermediate associated with a previously reported synthesis of aspidophytine (2). Simple modifications to the reaction sequence have also allowed for the identification of a synthetic pathway leading from dihydrocatechol 8 to (+)-aspidophytine (ent-2).

Solasodine suppress MCF7 breast cancer stem-like cells via targeting Hedgehog/Gli1.

BACKGROUND: Recently, a novel therapy to treat cancer has been to target cancer stem-like cells (CSCs). The aim of this study was to investigate the effect of solasodine, a steroidal alkaloid isolated from Solanum incanum L., on MCF7 CSCs and to understand the compound's underlying mechanism of action. METHOD: A tumorsphere formation assay was used to evaluate the effects of solasodine on the proliferation and self-renewal ability of MCF7 CSCs. The level of expression of proteins associated with cancer stemness markers and Hh signaling mediators was determined. The interaction between solasodine and Gli1 was calculated by molecular docking and further demonstrated by cellular thermal shift assay. RESULTS: Solasodine significantly decreased the proliferation of MCF7 tumorspheres and showed a stronger cytotoxicity on breast cancer cells with higher levels of Gli1 expression. The results showed that the levels of CD44 and ALDH1 expression were suppressed. Furthermore, expression of CD24 was enhanced by solasodine, via a mechanism that involved dampening Gli1 expression and blocking the nuclear translocation of this protein in MCF7 tumorspheres. Computational studies predicted that solasodine showed a high affinity with the Gli1 zinc finger domain that resulted from hydrogen-bonds to the THR243 and ASP216 amino acids residues. In addition, solasodine specifically bound with Gli1 and enhanced Gli1 protein stability in MCF7 cells. CONCLUSION: Here, our findings indicated that solasodine can directly suppresses Hh/Gli1 signaling, and is a novel anticancer candidate that targets CSCs.

Total Syntheses of the Structures Assigned to the Marine Natural Products Orthoscuticellines A-E.

The readily prepared and vinylated ß-carboline 11 has been converted over one or two steps into compounds 1-5, the structures assigned to the recently reported marine natural products orthoscuticellines A-E. The spectral data recorded on the synthetically derived compounds are fully consistent with the assigned structures and, on making allowances for variations in the pH of the medium in which the spectra of the natural products were recorded, it is concluded that the structures assigned to orthoscuticellines A-E are most likely correct. Certainly, the calculated 13C NMR spectra of the α-, γ-, and δ-carboline isomers of compounds 1-5 suggest that orthoscuticellines A-E do incorporate the assigned ß-carboline core.

Expeditious Access to Morphinans by Chemical Synthesis.

Morphinans are essential medicines derived entirely from poppy supply chains rendered increasingly volatile by climate change. Here, we report a seven-step, asymmetric chemical synthesis of (-)-codeine from simple materials that requires a total combined reaction time of fewer than 24 hours. The efficiency of our approach arises from a double-Heck cyclization reaction that generates two rings and two contiguous stereogenic carbon centres in the one pot. A subsequent photo-redox hydroamination protocol provides a novel, atom-economical means for assembling the piperidine D-ring of codeine. Simple modifications to the closing stages of our sequence offer effective access to pharmacologically valuable derivatives of N-demethyl codeine. Our work highlights the capacity for contemporary, stand-alone chemical synthesis regimes to diversify access to essential opiate medicines.

The Inhibition of RNA Viruses by Amaryllidaceae Alkaloids: Opportunities for the Development of Broad-Spectrum Anti-Coronavirus Drugs.

The global COVID-19 pandemic has claimed the lives of millions and disrupted nearly every aspect of human society. Currently, vaccines remain the only widely available medical means to address the cause of the pandemic, the SARS-CoV-2 virus. Unfortunately, current scientific consensus deems the emergence of vaccine-resistant SARS-CoV-2 variants highly likely. In this context, the design and development of broad-spectrum, small-molecule based antiviral drugs has been described as a potentially effective, alternative medical strategy to address circulating and re-emerging CoVs. Small molecules are well-suited to target the least-rapidly evolving structures within CoVs such as highly conserved RNA replication enzymes, and this renders them less vulnerable to evolved drug resistance. Examination of the vast literature describing the inhibition of RNA viruses by Amaryllidaceae alkaloids suggests that future, broad-spectrum anti-CoV drugs may be derived from this family of natural products.

The Chemical Synthesis of the Crinine and Haemanthamine Alkaloids: Biologically Active and Enantiomerically-Related Systems that Serve as Vehicles for Showcasing New Methodologies for Molecular Assembly.

The title alkaloids, often referred to collectively as crinines, are a prominent group of structurally distinct natural products with additional members being reported on a regular basis. As such, and because of their often notable biological properties, they have attracted attention as synthetic targets since the mid-1950s. Such efforts continue unabated and more recent studies on these alkaloids have focused on using them as vehicles for showcasing the utility of new synthetic methods. This review provides a comprehensive survey of the nearly seventy-year history of these synthetic endeavors.

Quantitative Proteomics Reveals Cellular Off-Targets of a DDR1 Inhibitor.

Target identification of small molecules is a great challenge but an essential step in drug discovery. Here, a quantitative proteomics approach has been used to characterize the cellular targets of DR, a DDR1 inhibitor. By taking advantage of competitive affinity-based protein profiling coupled with bioimaging, Cathepsin D (CTSD) was found to be the principle off-target of DR in human cancer cells. Further findings suggest the potential of DR as a novel CTSD inhibitor for breast cancer treatment. In addition, a trans-cyclooctene (TCO) containing probe was developed to track the binding between DR and its target proteins in living systems and could be a useful tool for DDR1 detection.

EGFR mutation and HPV infection in sinonasal inverted papilloma and squamous cell carcinoma.

BACKGROUND: To evaluate the involvement of EGFR signalling and HPV infection in a cohort of inverted sinonasal papilloma (ISP) and sinonasal squamous cell carcinoma (SNSCC) and their value for prognosis and clinical treatment. METHODS: We analysed 55 ISP, 14 SNSCC associated with ISP (SNSCC-isp) and and 60 SNSCC not associated with ISP (SNSCC-novo) for EGFR gene mutation and copy number gain, protein expression of EGFR and phosporylated EGFR (pEGFR), and HPV-infection and KRAS mutation. Findings were correlated to clinico-pathological and follow-up data. RESULTS: We found EGFR exon 20 mutations in 38% (7/18) ISP, in 50% (6/12) SNSCC-isp and in 5% (1/19) SNSCC-novo. EGFR was expressed in 92% of ISP, while pEGFR was observed in 54% (21/39). SNSCC-isp and SNSCC-novo demonstrated comparable expression of EGFR (57% and 33%) and of pEGFR (44% and 38%). We observed an inverse relation between EGFR exon 20 mutation and pEGFR expression. Four of 39 (10%) ISP carried HPV-16. Oncogenic HPV was detected in 3/12 (25%) SNSSC-isp and in 1/8 (13%) SNSCC-novo. KRAS mutations were not detected in any of the samples. HPV infection was inversely correlated with pEGFR expression but not with EGFR mutation. ISP with EGFR activation by mutation or by phosphorylation had longer ISP-free survival, however, neither EGFR exon 20 mutation, pEGFR expression nor HPV infection demonstrated prognostic value in SNSCC. CONCLUSIONS: EGFR exon 20 mutation is frequent in ISP and SNSCC-isp, while activation of EGFR through phosphorylation also plays an important role. Our data indicate that a large proportion of SNSCC patients could benefit from therapy with modern EGFR inhibitors.

A new species of Phyllurus leaf-tailed gecko (Lacertilia: Carphodactylidae) from The Pinnacles, north-east Australia.

Recent surveys of rocky rainforest in the Townsville region have found additional populations of Phyllurus geckos. One of these populations was discovered at The Pinnacles, an isolated area of habitat in between the distributions of P. gulbaru and P. amnicola. Genetic and morphological data shows that this population is most similar to P. gulbaru Hoskin, Couper Schneider, 2003 but divergent in a number of traits. Here we describe this population as a new species, P. pinnaclensis sp. nov., based on genetic divergence and differences in a number of morphometric and scalation traits from other populations of Phyllurus. Phyllurus pinnaclensis sp. nov. appears to be restricted to a few small areas of deeply layered rock with associated dry rainforest. This habitat is fire-sensitive and increased frequency and intensity of fires (due to late season burns and high fuel loads of invasive grasses) threatens to reduce and fragment these dry rainforest patches. Other threats include potential future invasion of the habitat by introduced Asian House Geckos (Hemidactylus frenatus Duméril Bibron, 1836) and illegal collecting. Given the very small and fragmented distribution and potential reduction in habitat area due to fire, P. pinnaclensis sp. nov. warrants a Critically Endangered listing. Resolving the distributional change of dry rainforest in the Townsville region in recent decades, particularly in regards to fire, is key to resolving the status of this and other locally threatened taxa that depend on this habitat.

Development of biocompatible and fully bioabsorbable PLA/Mg films for tissue regeneration applications.

During recent years, Mg reinforced polylactic acid (PLA) composites have emerged as potential biocompatible and bioabsorbable materials for biomedical applications. It has been shown that Mg particles added to a matrix based on a biodegradable polymer can address the lack of bioactivity and the low mechanical properties of the polymers and, furthermore, it can counteract the detrimental effects associated to the high degradation rate of Mg, as alkalinization and elevated H2 release. Additionally, the polymer can protect the Mg particles, by tailoring their degradation rate. Former processing of these composites performed by extrusion, compression and injection molding employed Mg contents up to 10 wt%. Higher amounts of Mg resulted in heterogeneous materials and thermally degraded matrices, with the corresponding higher degradation rate. In the present work, Mg reinforced PLA films with Mg content as high as 50 wt% were obtained without compromising the thermal stability of the polymer. Firstly, a successful dispersion of Mg microparticles was achieved by a breakthrough in processing introducing a colloidal step where organic additives were added to modify the Mg particle surface and promote a chemically stable suspension. The resulting colloidal suspension was then used as feedstock to obtain composite films by tape casting. The films show advantageous in vitro behaviour in terms of degradation, hydrogen release and oxygen permeability. In addition, the viability with fibroblast cells (MEF) opens a window of opportunity for these composite films as bioabsorbable material for tissue engineering and wound dressing applications. STATEMENT OF SIGNIFICANCE: Magnesium materials have extraordinary biodegradable properties and bioactive behavior due to release of Mg2+ ions, which offer a promising opportunity for their applicability as biomaterials for tissue regeneration. However, Mg is one of the most reactive metals with a high degradation rate. In contact with water produces H2, associated with a risk of failure of the implant. One alternative to minimize this drawback is the use of Mg particles surrounded by a biodegradable biocompatible polymer such as polylactic acid (PLA) to obtain PLA/Mg composites. In this work we processed Mg reinforced PLA in the shape of films that would be suitable for tissue regeneration. In vitro behavior of PLA/Mg films demonstrated that Mg2+ ions increase the fibroblast cells growth.

Investigation of reverse ionic diffusion in forward-osmosis-aided dewatering of microalgae: A molecular dynamics study.

This study aimed to investigate the transport mechanisms of ions during forward-osmosis-driven (FO-driven) dewatering of microalgae using molecular dynamics (MD) simulations. The dynamical and structural properties of ions in FO systems of varying NaCl or MgCl2 draw solution (DS) concentrations were calculated and correlated. Results indicate that FO systems with higher DS concentration caused ions to have lower hydration numbers and higher coordination numbers leading to lower diffusion coefficients. The higher hydration number of Mg2+ ions resulted in significantly lower ionic permeability as compared to Na+ ions at all concentrations (p = 0.002). The simulations also revealed that higher DS concentrations led to higher accumulation of ions in the membrane. This study provides insights on the proper selection of DS for FO systems.

Valorization of poly(lactic acid) wastes via mechanical recycling: Improvement of the properties of the recycled polymer.

Poly(lactic acid) (PLA) is a biobased polymer that represents one of the most interesting alternatives to fossil-fuel based polymers in food packaging applications. Most of the PLA used in food packaging is used only once and then discarded, even though the PLA types used in packaging have good properties and stability. Therefore, it seems reasonable to consider the possibility of recycling the used polymer through a mechanical recycling process. The main aims of this work are to study the effect of the mechanical recycling on the properties of PLA and the usefulness of different upgrading methods to obtain recycled PLA with improved properties. A commercial type of PLA was subjected to accelerated thermal, photochemical and hydrolytic aging and then reprocessed. During reprocessing, aged PLA was blended with virgin PLA and a commercial chain extender was added. Results point out that recycling causes the degradation of PLA, and negatively affects the thermal stability and mechanical properties. However, addition of virgin PLA, and the chain extender, led to an increase of up to 9% in the intrinsic viscosity and 8% in the Vickers hardness of the recycled material. These results suggest that mechanically recycled PLA with improved performance can be obtained, a fact which might improve the recyclability of PLA and thus the environmental impact of this material.