Integrated proteomic profiling identifies amino acids selectively cytotoxic to pancreatic cancer cells.

Pancreatic adenocarcinoma (PDAC) is one of the most deadly cancers, characterized by extremely limited therapeutic options and a poor prognosis, as it is often diagnosed during late disease stages. Innovative and selective treatments are urgently needed, since current therapies have limited efficacy and significant side effects. Through proteomics analysis of extracellular vesicles, we discovered an imbalanced distribution of amino acids secreted by PDAC tumor cells. Our findings revealed that PDAC cells preferentially excrete proteins with certain preferential amino acids, including isoleucine and histidine, via extracellular vesicles. These amino acids are associated with disease progression and can be targeted to elicit selective toxicity to PDAC tumor cells. Both in vitro and in vivo experiments demonstrated that supplementation with these specific amino acids effectively eradicated PDAC cells. Mechanistically, we also identified XRN1 as a potential target for these amino acids. The high selectivity of this treatment method allows for specific targeting of tumor metabolism with very low toxicity to normal tissues. Furthermore, we found this treatment approach is easy-to-administer and with sustained tumor-killing effects. Together, our findings reveal that exocytosed amino acids may serve as therapeutic targets for designing treatments of intractable PDAC and potentially offer alternative treatments for other types of cancers.

Multiconfiguration afocal freeform telescopes.

An approach to designing multiconfiguration afocal telescopes is developed and demonstrated. Freeform surfaces are used to maximize the achievable diffraction-limited zoom ratio while staying in a compact volume for a two-position multiconfiguration afocal optical system. The limitations of these systems with three-mirror beam paths are discussed and subsequently overcome by introducing an additional degree of freedom. In a four-mirror beam path system, the goal of a 5x zoom ratio is achieved with a compensated exit pupil and diffraction-limited performance. A significant benefit in optical performance when using freeform surfaces is shown compared to more conventional surface types.

Workflow for modeling of generalized mid-spatial frequency errors in optical systems.

We propose a workflow for modeling generalized mid-spatial frequency (MSF) errors in optical imaging systems. This workflow enables the classification of MSF distributions, filtering of bandlimited signatures, propagation of MSF errors to the exit pupil, and performance predictions that differentiate performance impacts due to the MSF distributions. We demonstrate the workflow by modeling the performance impacts of MSF errors for both transmissive and reflective imaging systems with near-diffraction-limited performance.

The natural and human-mediated expansion of a human-commensal lizard into the fringes of Southeast Asia.

BACKGROUND: Human-commensal species often display deep ancestral genetic structure within their native range and founder-effects and/or evidence of multiple introductions and admixture in newly established areas. We investigated the phylogeography of Eutropis multifasciata, an abundant human-commensal scincid lizard that occurs across Southeast Asia, to determine the extent of its native range and to assess the sources and signatures of human introduction outside of the native range. We sequenced over 350 samples of E. multifasciata for the mitochondrial ND2 gene and reanalyzed a previous RADseq population genetic dataset in a phylogenetic framework. RESULTS: Nuclear and mitochondrial trees are concordant and show that E. multifasciata has retained high levels of genetic structure across Southeast Asia despite being frequently moved by humans. Lineage boundaries in the native range roughly correspond to several major biogeographic barriers, including Wallace's Line and the Isthmus of Kra. Islands at the outer fringe of the range show evidence of founder-effects and multiple introductions. CONCLUSIONS: Most of enormous range of E. multifasciata across Southeast Asia is native and it only displays signs of human-introduction or recent expansion along the eastern and northern fringe of its range. There were at least three events of human-introductions to Taiwan and offshore islands, and several oceanic islands in eastern Indonesia show a similar pattern. In Myanmar and Hainan, there is a founder-effect consistent with post-warming expansion after the last glacial maxima or human introduction.

Sigma vector calculations in nodal aberration theory and experimental validation using a Cassegrain telescope.

Nodal Aberration Theory (NAT) was developed to explain the field dependency of aberration field centers in the image plane of nominally rotationally symmetric optical systems that have lost their symmetry through misalignments. A new insight into the theory led to calculating the sigma vectors, which locate the aberration field centers, using the angle between a real-ray trace of the optical axis ray (OAR) and the normal of the local surface where "local" refers to the object and image optical spaces of that surface. Here, we detail the sigma vector calculations for general optical systems and provide an experimental investigation of a misaligned system with a high-precision customized Cassegrain telescope. In the simulations, a Newtonian telescope, a Cassegrain telescope, and a three-mirror anastigmat telescope were misaligned intentionally in ray-tracing software. The sigma vectors were calculated analytically for the third-order aberrations of astigmatism and coma. Experimentally, the same perturbations were implemented for the Cassegrain telescope system, and the aberrations were quantified through interferometric measurements on a grid of field points in the image plane that verified the analytical derivation and simulations.

Specimen collection is essential for modern science.

Natural history museums are vital repositories of specimens, samples and data that inform about the natural world; this Formal Comment revisits a Perspective that advocated for the adoption of compassionate collection practices, querying whether it will ever be possible to completely do away with whole animal specimen collection.

Phylogeny of dwarf geckos of the genus Lygodactylus (Gekkonidae) in the Western Indian Ocean.

Diurnal dwarf geckos of the genus Lygodactylus are distributed in tropical and subtropical regions and live in highly diverse habitats. The genus currently comprises 79 species and several candidates for new species or subspecies. Most of these taxa occur in Sub-Saharan Africa and Madagascar, with only two described species in South America. Although the main center of diversity of Lygodactylus currently is Africa, the genus probably has a Malagasy origin, followed by two or three independent transoceanic dispersal events between Madagascar and Africa and one trans-Atlantic dispersal from Africa to South America. A few species colonised islands in the Western Indian Ocean belonging to the Zanzibar Archipelago and to the Îles Éparses. Here we examined L. grotei pakenhami from Pemba Island, L. insularis from Juan de Nova, and L. verticillatus from Europa Island to clarify their taxonomic status and their origin. Concerning L. grotei pakenhami and L. insularis, preceding studies pointed to a relation to species of the African L. capensis group. In contrast, L. verticillatus on Europa Island is considered to be conspecific with Malagasy populations. Therefore, we conducted a phylogenetic study of the African L. capensis group and the Malagasy L. verticillatus group, and examined color pattern, selected morphological characters and two mitochondrial markers (ND2 for African and 16S rRNA for Malagasy Lygodactylus). Lygodactylus grotei pakenhami from Pemba and L. grotei from mainland Africa cannot be distinguished by their scalation, but their reciprocal monophyly suggested by mitochondrial DNA, conspicuously different coloration (both in adults and hatchlings) and their high genetic distances (16.3% in ND2) support the hypothesis that these taxa represent two distinct species. Consequently, we elevate L. grotei pakenhami to species level, as Lygodactylus pakenhami Loveridge, 1941. Lygodactylus pakenhami is endemic to Pemba Island which was possibly separated from the African mainland during the late Miocene or Early Pliocene (6 million years ago). The simplest explanation for the existence of L. pakenhami on Pemba is vicariance. A recent, human-mediated transportation is excluded, as the molecular data clearly indicate a longer period of isolation. Lygodactylus insularis has been supposed to be related to the taxa 'capensis' or 'grotei'. However, it is impossible to discern the relationship of L. insularis, L. capensis and L. grotei by means of scalation or coloration alone. Our molecular phylogenetic analyses reveal that L. insularis is embedded within the L. capensis group, clearly indicating its African origin. The single gene (ND2) as well as the multigene analyses fully support a closer common origin of L. insularis and L. capensis than of L. insularis and L. grotei. However, the position of L. insularis within the clade formed by L. insularis, L. nyaneka, L. capensis sensu stricto and six L. aff. capensis groups is not clearly resolved. Lygodactylus insularis is endemic on Juan de Nova Island, an old low elevation atoll. That all L. insularis mitochondrial sequences are very similar to each other and together form a monophyletic lineage is in agreement with the hypothesis of a single dispersal event to the island. For the L. verticillatus population from Europa Island our mitochondrial data suggest close relationships to conspecific samples from the coastal regions of south-western Madagascar. As we found no relevant morphological or genetic differences between the insular and the Malagasy populations of L. verticillatus, and no remarkable genetic variation within the monophyletic lineage on Europa, we suggest a single, very recent dispersal event, perhaps human-mediated. Although the genus Lygodactylus colonised Africa, islands in the Gulf of Guinea, South America and some islands in the Western Indian Ocean, it seems-compared to other lizard genera-to be only moderately successful in transoceanic long-distance dispersal.

Tropidonotus nicobarensis Sclater, 1891 is a junior synonym of Thamnophis saurita (Linnaeus, 1766) (Squamata: Serpentes: Natricinae).

Tropidonotus nicobarensis Sclater, 1891 is an enigmatic snake currently referred to the natricine genus Hebius Thompson, 1913. No specimens have been recorded since the original discovery of the name-bearing type in the late 19th century, which was allegedly collected on Kamorta Island in India's Nicobar Archipelago. Recently, a second observation of this species was reported from Havelock Island (Swarajdweep) in the nearby Andaman Archipelago. However, the snake in question is clearly conspecific with another natricine, Thamnophis saurita (Linnaeus, 1766), native to eastern North America. This discovery prompted us to examine the type specimen of Tropidonotus nicobarensis, which revealed that it too is conspecific with Thamnophis saurita. The provenance of the Tropidonotus nicobarensis type specimen and the Havelock Island snake are discussed, with the latter likely representing an introduced animal.

Exit pupil quality analysis and optimization in freeform afocal telescope systems.

Afocal telescopes are often used as foreoptics to existing imaging systems to allow for application flexibility. To properly combine an afocal telescope with an existing imaging system, the exit pupil of the afocal telescope and the entrance pupil of the imaging system must be coincident. Additionally, the exit pupil of the afocal telescope must be well-formed; that is, it must be the correct size and shape to mitigate pupil-matching challenges. This work introduces processes for designing freeform afocal telescopes with an emphasis on understanding how to analyze and control the exit pupil quality of such systems. The included 3-mirror design examples demonstrate the advantages of using freeform surfaces in afocal systems and quantify the tradeoffs required to improve the exit pupil quality.

Reappraising the evolutionary history of the largest known gecko, the presumably extinct Hoplodactylus delcourti, via high-throughput sequencing of archival DNA.

Hoplodactylus delcourti is a presumably extinct species of diplodactylid gecko known only from a single specimen of unknown provenance. It is by far the largest known gekkotan, approximately 50% longer than the next largest-known species. It has been considered a member of the New Zealand endemic genus Hoplodactylus based on external morphological features including shared toe pad structure. We obtained DNA from a bone sample of the only known specimen to generate high-throughput sequence data suitable for phylogenetic analysis of its evolutionary history. Complementary sequence data were obtained from a broad sample of diplodactylid geckos. Our results indicate that the species is not most closely related to extant Hoplodactylus or any other New Zealand gecko. Instead, it is a member of a clade whose living species are endemic to New Caledonia. Phylogenetic comparative analyses indicate that the New Caledonian diplodactylid clade has evolved significantly more disparate body sizes than either the Australian or New Zealand clades. Toe pad structure has changed repeatedly across diplodactylids, including multiple times in the New Caledonia clade, partially explaining the convergence in form between H. delcourti and New Zealand Hoplodactylus. Based on the phylogenetic results, we place H. delcourti in a new genus.

Global Protected Areas as refuges for amphibians and reptiles under climate change.

Protected Areas (PAs) are the cornerstone of biodiversity conservation. Here, we collated distributional data for >14,000 (~70% of) species of amphibians and reptiles (herpetofauna) to perform a global assessment of the conservation effectiveness of PAs using species distribution models. Our analyses reveal that >91% of herpetofauna species are currently distributed in PAs, and that this proportion will remain unaltered under future climate change. Indeed, loss of species' distributional ranges will be lower inside PAs than outside them. Therefore, the proportion of effectively protected species is predicted to increase. However, over 7.8% of species currently occur outside PAs, and large spatial conservation gaps remain, mainly across tropical and subtropical moist broadleaf forests, and across non-high-income countries. We also predict that more than 300 amphibian and 500 reptile species may go extinct under climate change over the course of the ongoing century. Our study highlights the importance of PAs in providing herpetofauna with refuge from climate change, and suggests ways to optimize PAs to better conserve biodiversity worldwide.

Ultraconserved elements-based phylogenomic systematics of the snake superfamily Elapoidea, with the description of a new Afro-Asian family.

The highly diverse snake superfamily Elapoidea is considered to be a classic example of ancient, rapid radiation. Such radiations are challenging to fully resolve phylogenetically, with the highly diverse Elapoidea a case in point. Previous attempts at inferring a phylogeny of elapoids produced highly incongruent estimates of their evolutionary relationships, often with very low statistical support. We sought to resolve this situation by sequencing over 4,500 ultraconserved element loci from multiple representatives of every elapoid family/subfamily level taxon and inferring their phylogenetic relationships with multiple methods. Concatenation and multispecies coalescent based species trees yielded largely congruent and well-supported topologies. Hypotheses of a hard polytomy were not retained for any deep branches. Our phylogenies recovered Cyclocoridae and Elapidae as diverging early within Elapoidea. The Afro-Malagasy radiation of elapoid snakes, classified as multiple subfamilies of an inclusive Lamprophiidae by some earlier authors, was found to be monophyletic in all analyses. The genus Micrelaps was consistently recovered as sister to Lamprophiidae. We establish a new family, Micrelapidae fam. nov., for Micrelaps and assign Brachyophis to this family based on cranial osteological synapomorphy. We estimate that Elapoidea originated in the early Eocene and rapidly diversified into all the major lineages during this epoch. Ecological opportunities presented by the post-Cretaceous-Paleogene mass extinction event may have promoted the explosive radiation of elapoid snakes.

A portable elliptical dichroism spectrometer targeting secondary structural features of tumorous protein for pancreatic cancer detection.

Stereochemical analysis is essential for understanding the complex function of biomolecules. Various direct and indirect approaches can be used to explore the allosteric configuration. However, the size, cost, and delicate nature of these systems limit their biomedical usage. Here, we constructed elliptical dichroism (ED) spectrometer for biomedical applications, whose performance is validated by experiment and theoretical simulation (Jones/Mueller calculus and time-dependent density-functional theory). Instead of complicated control of circular polarization, ED spectrometer adopted the absorbance of left- and right-oriented elliptically polarized light. With a simplified design, we demonstrated the potential of ED spectrometry as an alternative for secondary structural analysis of biomolecules, their conformation and chirality. It not only provides a portable, low-cost alternative to the sophisticated instruments currently used for structural analysis of biomolecules but also provides superior translational features: low sample consumption(200 µl), easy operation, and multiple working modes, for noninvasive cancer detection.

Resurrection of the African gecko genus Ancylodactylus Mller, 1907 (Squamata: Gekkonidae) and description of six new species from Kenya.

The genus Cnemaspis as presently construed is polyphyletic, with African, South Asian and Southeast Asian clades each representing independent lineages. The name Ancylodactylus Mller, 1907 is available for the African clade of forest geckos and features previously identified as putatively diagnostic of this group (loss or reduction of the second phalanx of digit IV of manus and pes, as well as a markedly dilated basal portions of the digits) are here regarded as characters supporting the monophyly of Ancylodactylus. Six new species of Ancylodactylus are described: A. kenyaensis sp. nov., A. kituiensis sp. nov., A. mathewsensis sp. nov., A. laikipiensis sp. nov., A. spawlsi sp. nov., and A. chyuluensis sp. nov. on the basis of unique combinations of body size, trunk and tail tubercles, median subcaudal scales, precloacal pores, enlarged subdigital plates, ventral color, and throat color and patterning. Ancylodactylus kenyaensis is among the largest members of the genus, reaching 65 mm SVL, whereas A. spawlsi and A. chyuluensis, with maximum SVLs of 30 mm or less, are the smallest of all members of the genus. All these geckos are chiefly scansorial, occurring on tree trunks, fallen logs and/or in rock outcrops. Ancylodactylus kituiensis and A. mathewsensis occur in isolated dryland hilltop forests surrounded by large tracts of arid lands and are locally abundant in suitable rock outcrops or caves, where they occur in small colonies. Ancylodactylus kenyaensis is a montane forest species found on tree trunks with cracks and crevices, whereas A. spawlsi is a montane forest species found in crevices and beneath loose bark of tree trunks as well as in rock crevices and slabs. Ancylodactylus laikipiensis is likewise both rupicolous and arboreal and A. chyuluensis has been taken only from a pitfall trap in a dry forest patch. All the new species are endemic to relatively small, circumscribed areas within Kenya and all occur within protected areas. At present we consider their IUCN conservation status to be Data Deficient. Herpetological surveys are recommended in other unexplored or under-explored forest areas, particularly hilltop montane forests in isolated dryland rocky hills as these may harbor other undescribed Ancylodactylus species or previously undocumented populations of known species.

Ontogeny of the paraphalanges and derived phalanges of Hemidactylus turcicus (Squamata: Gekkonidae).

Gekkotan lizards of the genus Hemidactylus exhibit derived digital morphologies. These include heavily reduced antepenultimate phalanges of digits III and IV of the manus and digits III-V of the pes, as well as enigmatic cartilaginous structures called paraphalanges. Despite this well-known morphological derivation, no studies have investigated the development of these structures. We aimed to determine if heterochrony underlies the derived antepenultimate phalanges of Hemidactylus. Furthermore, we aimed to determine if convergently evolved paraphalanges exhibit similar or divergent developmental patterns. Herein we describe embryonic skeletal development in the hands and feet of four gekkonid species, exhibiting a range of digital morphologies. We determined that the derived antepenultimate phalanges of Hemidactylus are the products of paedomorphosis. Furthermore, we found divergent developmental patterns between convergently evolved paraphalanges.

A new gecko from the earliest Eocene of Dormaal, Belgium: a thermophilic element of the 'greenhouse world'.

We here describe a new gekkotan lizard from the earliest Eocene (MP 7) of the Dormaal locality in Belgium, from the time of the warmest global climates of the past 66 million years (Myr). This new taxon, with an age of 56 Myr, together with indeterminate gekkotan material reported from Silveirinha (Portugal, MP 7) represent the oldest Cenozoic gekkotans known from Europe. Today gekkotan lizards are distributed worldwide in mainly warm temperate to tropical areas and the new gecko from Dormaal represents a thermophilic faunal element. Given the Palaeocene-Eocene thermal maximum at that time, the distribution of this group in such northern latitudes (above 50° North - the latitude of southern England) is not surprising. Although this new gekkotan is represented only by a frontal (further, dentaries and a mandibular fragment are described here as Gekkota indet. 1 and 2-at least two gekkotan species occurred in Dormaal), it provides a new record for squamate diversity from the earliest Eocene 'greenhouse world'. Together with the Baltic amber gekkotan Yantarogekko balticus, they document the northern distribution of gekkotans in Europe during the Eocene. The increase in temperature during the early Eocene led to a rise in sea level, and many areas of Eurasia were submerged. Thus, the importance of this period is magnified by understanding future global climate change.

Three New Species of Cnemaspis (Sauria: Gekkonidae) from Sarawak, East Malaysia, Borneo.

Three new species of Cnemaspis are described from karst regions of Sarawak, Malaysia, on the island of Borneo. These are Cnemaspis matahari sp. nov. and C. sirehensis sp. nov. from limestone hills located in the Serian Division of western Sarawak, and C. lagang sp. nov. from Gunung Mulu, Miri Division, in northern Sarawak. All can be distinguished from congeners using mitochondrial DNA as well as an enlarged metatarsal scales on the first toe. Individually, each species can be diagnosed by differences in subcaudal scale morphology: Cnemaspis lagang sp. nov. lacks enlarged subcaudals; Cnemaspis matahari sp. nov. has keeled subcaudals bearing an enlarged median row of smooth scales; and Cnemaspis sirehensis sp. nov. has an enlarged median row of weakly keeled scales. The discovery of these species suggests that additional unrecognized species may exist within the genus on Borneo, especially in association with karst formations. High endemism and species diversity notwithstanding, these karst formations are under severe pressure from limestone extraction and deforestation.

All in all its just another branch in the tree: A new species of Acanthocercus Fitzinger, 1843 (Squamata: Agamidae), from Angola.

Recent integrative taxonomic studies of the agamid genus Acanthocercus Fitzinger, 1843 have shown that Angola harbors three different taxa, all within the Acanthocercus atricollis (Smith, 1849) species complexA. cyanocephalus (Falk, 1925) in the northeastern parts of the country, A. margaritae Wagner et al. 2021 in the southern regions, and an unnamed species in the central and northwestern parts of Angola. Using the previously published molecular data as evidence of phylogenetic support and newly collected morphological, meristic and coloration data, we here describe this unnamed lineage as a new species. The new species is morphologically very similar to A. cyanocephalus, but it can easily be differentiated from the latter by the coloration pattern of displaying males, with a blue coloration restricted to the head region, and by its inferior scale counts compared to other species of the A. atricollis complex group. As reported in other studies in this group, male breeding coloration is an effective trait for diagnosing these morphologically conserved species. This description raises the number of Acanthocercus species recognized to 15 and is another contribution revealing the rich but still incompletely described herpetological diversity of Angola.

Auriculocondylar syndrome 2 results from the dominant-negative action of PLCB4 variants.

Auriculocondylar syndrome 2 (ARCND2) is a rare autosomal dominant craniofacial malformation syndrome linked to multiple genetic variants in the coding sequence of phospholipase C ß4 (PLCB4). PLCB4 is a direct signaling effector of the endothelin receptor type A (EDNRA)-Gq/11 pathway, which establishes the identity of neural crest cells (NCCs) that form lower jaw and middle ear structures. However, the functional consequences of PLCB4 variants on EDNRA signaling is not known. Here, we show, using multiple signaling reporter assays, that known PLCB4 variants resulting from missense mutations exert a dominant-negative interference over EDNRA signaling. In addition, using CRISPR/Cas9, we find that F0 mouse embryos modeling one PLCB4 variant have facial defects recapitulating those observed in hypomorphic Ednra mouse models, including a bone that we identify as an atavistic change in the posterior palate/oral cavity. Remarkably, we have identified a similar osseous phenotype in a child with ARCND2. Our results identify the disease mechanism of ARCND2, demonstrate that the PLCB4 variants cause craniofacial differences and illustrate how minor changes in signaling within NCCs may have driven evolutionary changes in jaw structure and function. This article has an associated First Person interview with the first author of the paper.