Induced Power Scaling Alone Cannot Explain Griffenfly Gigantism.

Paleozoic skies were ruled by extinct odonatopteran insects called 'griffenflies', some with wingspans three times that of the largest extant dragonflies and ten times that of common extant dragonflies. Previous studies suggested that flight was possible for larger fliers because of higher atmospheric oxygen levels that would have increased air density. We use actuator disk theory to evaluate this hypothesis. Actuator disk theory gives similar estimates of induced power as has been estimated for micro-air vehicles based on insect flight. We calculate that for a given mass of griffenfly, and assuming isometry, a higher density atmosphere would only have reduced the induced power required to hover by 11%, which would have supported a flyer 3% larger in linear dimensions. Steady level forward flight would have further reduced induced power but could only account for a flier 5% larger in linear dimensions. Further accounting for the higher power available due to high oxygen air, and assuming isometry, we calculate that the largest flyer hovering would have been only 1.19 times longer than extant dragonflies. We also consider known allometry in dragonflies and estimated allometry in extinct griffenflies. But such allometry only increases flyer size to 1.22 times longer while hovering. We also consider profile and parasite power, but both would have been higher in denser air and thus would not have enhanced the flyability of larger griffenflies. The largest meganeurid griffenflies might have adjusted flight behaviors to reduce power required. Alternatively, the scaling of flight muscle power may have been sufficient to support the power demands of large griffenflies. In literature estimates, mass-specific power output scales as mass0.24 in extant dragonflies. We need only more conservatively assume that mass-specific muscle power scales with mass0, when combined with higher oxygen concentrations and induced power reductions in higher density air to explain griffenflies 3.4 times larger than extant odonates. Experimental measurement of flight muscle power scaling in odonates is necessary to test this hypothesis.

The structure of wing in the earliest Permopsocida.

Permopsocids are small acercarian insects with mouthparts specialized for sucking. They are closely related to Hemiptera and Thysanoptera. The earliest known representatives are from the Early Permian. Here evidence is presented that the Permopsocida occurred even earlier in Pennsylvanian (Moscovian) deposits in the Piesberg quarry near Osnabrück (Lower Saxony, Germany). This material is assigned to the Permian family Psocidiidae; Carbonopsocus mercuryi gen. et sp. nov., based on the wing venation diagnosed by the unique branching pattern of the main veins, the shape of the areola postica being longer than wide, the angular shape of the pterostigma, the ir crossvein directed proximally mid of pterostigma (apomorphy) and the vannus formed by the three veins of PCu, A1 and A2. The shape of the veins, with a Y-vein formed by the distal fusion of PCu with A1, could be a putative symplesiomorphy of the Psocodea with Permopsocida and Hemiptera. C. mercuryi gen. et sp. nov. is the first appearance date for Permopsocida and roots the Acercaria tree. In addition, another specimen of Dichentomum cf. arroyo (Psocidiidae) from Carrizo Arroyo is presented and figured, confirming the presence of the genus Dichentomum near the Carboniferous-Permian boundary and linking it to the Artinskian species from Elmo in Kansas, USA.

Reprogramming the pancreatic cancer stroma and immune landscape by a silicasome nanocarrier delivering nintedanib, a protein tyrosine kinase inhibitor.

The prevailing desmoplastic stroma and immunosuppressive microenvironment within pancreatic ductal adenocarcinoma (PDAC) pose substantial challenges to therapeutic intervention. Despite the potential of protein tyrosine kinase (PTK) inhibitors in mitigating the desmoplastic stromal response and enhancing the immune milieu, their efficacy is curtailed by suboptimal pharmacokinetics (PK) and insufficient tumor penetration. To surmount these hurdles, we have pioneered a novel strategy, employing lipid bilayer-coated mesoporous silica nanoparticles (termed "silicasomes") as a carrier for the delivery of Nintedanib. Nintedanib, a triple PTK inhibitor that targets vascular endothelial growth factor, platelet-derived growth factor and fibroblast growth factor receptors, was encapsulated in the pores of silicasomes via a remote loading mechanism for weak bases. This innovative approach not only enhanced pharmacokinetics and intratumor drug concentrations but also orchestrated a transformative shift in the desmoplastic and immune landscape in a robust orthotopic KRAS-mediated pancreatic carcinoma (KPC) model. Our results demonstrate attenuation of vascular density and collagen content through encapsulated Nintedanib treatment, concomitant with significant augmentation of the CD8+/FoxP3+ T-cell ratio. This remodeling was notably correlated with tumor regression in the KPC model. Strikingly, the synergy between encapsulated Nintedanib and anti-PD-1 immunotherapy further potentiated the antitumor effect. Both free and encapsulated Nintedanib induced a transcriptional upregulation of PD-L1 via the extracellular signal-regulated kinase (ERK) pathway. In summary, our pioneering approach involving the silicasome carrier not only improved antitumor angiogenesis but also profoundly reshaped the desmoplastic stromal and immune landscape within PDAC. These insights hold excellent promise for the development of innovative combinatorial strategies in PDAC therapy.

A crane fly of the genus Gynoplistia Macquart (Diptera, Limoniidae) from the early Miocene of New Zealand.

The first fossil limoniid fly from the Miocene Fossil-Lagerstätte of Foulden Maar in New Zealand is described on the basis of an isolated well-preserved wing. The specimen is tentatively attributed to a new species Gynoplistiafouldensensissp. nov. in the large extant genus Gynoplistia, which is well diversified in the country. It is the second fossil record of this genus, the first one being an isolated wing from the Cretaceous Weald Clay Formation in the United Kingdom.

The Interplay Between the Immune System, Tumor Suppressor Genes, and Immune Senescence in Mesothelioma Development and Response to Immunotherapy.

Despite efforts to ban asbestos mining and manufacturing, mesothelioma deaths in the United States have remained stable at approximately 2500 cases annually. This trend is not unique to the United States but is also a global phenomenon, associated with increased aging of populations worldwide. Although geoeconomic factors such as lack of regulations and continued asbestos manufacturing in resource-poor countries play a role, it is essential to consider biological factors such as immune senescence and increased genetic instability associated with aging. Recognizing that mesothelioma shares genetic instability and immune system effects with other age-related cancers is crucial because the impact of aging on mesothelioma is frequently assessed in the context of disease latency after asbestos exposure. Nevertheless, the long latency period, often cited as a reason for mesothelioma's elderly predominance, should not overshadow the shared mechanisms. This communication focuses on the role of immune surveillance in mesothelioma, particularly exploring the impact of immune escape resulting from altered TSG function during aging, contributing to the phylogenetic development of gene mutations and mesothelioma oncogenesis. The interplay between the immune system, TSGs, and aging not only shapes the immune landscape in mesothelioma but also contributes to the development of heterogeneous tumor microenvironments, significantly influencing responses to immunotherapy approaches and survival rates. By understanding the complex interplay between aging, TSG decline, and immune senescence, health care professionals can pave the way for more effective and personalized immunotherapies, ultimately offering hope for better outcomes in the fight against mesothelioma.

The earliest fossil mosquito.

Female mosquitoes are among the most notorious blood-feeding insects, sometimes causing severe allergic responses or vectoring a variety of microbial pathogens.1,2 Hematophagy in insects is likely a feeding shift from plant fluids, with the piercing-sucking mouthparts serving as suitable exaptation for piercing vertebrates' skin. The origins of these habits are mired in an often-poor fossil record for many hematophagous lineages,3,4 particularly those of sufficient age, as to give insights into the paleoecological context in which blood feeding first appeared or even to arrive at gross estimates as to when such shifts have occurred. This is certainly the case for mosquitoes, a clade estimated molecularly to date back to the Jurassic.5 The known Mesozoic Culicidae are Late Cretaceous, assigned to the modern Anophelinae or to the extinct Burmaculicinae, sister to other Culicidae, all with mouthparts of a modern type. Here, we report the discovery, in Lower Cretaceous amber from Lebanon, of two conspecific male mosquitoes unexpectedly with piercing mouthparts, armed with denticulate sharp mandibles and laciniae. These male fossils were likely hematophagous. They represent a lineage that diverged earlier than Burmaculicinae, extending the definitive occurrence of the family into the Early Cretaceous and serving to narrow the ghost-lineage gap for mosquitoes.

Use of Stromal Intervention and Exogenous Neoantigen Vaccination to Boost Pancreatic Cancer Chemo-Immunotherapy by Nanocarriers.

Despite the formidable treatment challenges of pancreatic ductal adenocarcinoma (PDAC), considerable progress has been made in improving drug delivery via pioneering nanocarriers. These innovations are geared towards overcoming the obstacles presented by dysplastic stroma and fostering anti-PDAC immune reactions. We are currently conducting research aimed at enhancing chemotherapy to stimulate anti-tumor immunity by inducing immunogenic cell death (ICD). This is accomplished using lipid bilayer-coated nanocarriers, which enable the attainment of synergistic results. Noteworthy examples include liposomes and lipid-coated mesoporous silica nanoparticles known as "silicasomes". These nanocarriers facilitate remote chemotherapy loading, as well as the seamless integration of immunomodulators into the lipid bilayer. In this communication, we elucidate innovative ways for further improving chemo-immunotherapy. The first is the development of a liposome platform engineered by the remote loading of irinotecan while incorporating a pro-resolving lipoxin in the lipid bilayer. This carrier interfered in stromal collagen deposition, as well as boosting the irinotecan-induced ICD response. The second approach was to synthesize polymer nanoparticles for the delivery of mutated KRAS peptides in conjunction with a TLR7/8 agonist. The dual delivery vaccine particle boosted the generation of antigen-specific cytotoxic T-cells that are recruited to lymphoid structures at the cancer site, with a view to strengthening the endogenous vaccination response achieved by chemo-immunotherapy.

Non-asbestiform elongate mineral particles and mesothelioma risk: Human and experimental evidence.

The presentations in this session of the Monticello II conference were aimed at summarizing what is known about asbestiform and non-asbestiform elongate mineral particles (EMPs) and mesothelioma risks based on evidence from experimental and epidemiology studies. Dr. Case discussed case reports of mesothelioma over the last several decades. Dr. Taioli indicated that the epidemiology evidence concerning non-asbestiform EMPs is weak or lacking, and that progress would be limited unless mesothelioma registries are established. One exception discussed is that of taconite miners, who are exposed to grunerite. Drs. Mandel and Odo noted that studies of taconite miners in Minnesota have revealed an excess rate of mesothelioma, but the role of non-asbestiform EMPs in this excess incidence of mesothelioma is unclear. Dr. Becich discussed the National Mesothelioma Virtual Bank (NMVB), a virtual mesothelioma patient registry that includes mesothelioma patients' lifetime work histories, exposure histories, biospecimens, proteogenomic information, and imaging data that can be used in epidemiology research on mesothelioma. Dr. Bernstein indicated that there is a strong consensus that long, highly durable respirable asbestiform EMPs have the potential to cause mesothelioma, but there is continued debate concerning the biodurability required, and the dimensions (both length and diameter), the shape, and the dose associated with mesothelioma risk. Finally, Dr. Nel discussed how experimental studies of High Aspect Ratio Engineered Nanomaterials have clarified dimensional and durability features that impact disease risk, the impact of inflammation and oxidative stress on the epigenetic regulation of tumor suppressor genes, and the generation of immune suppressive effects in the mesothelioma tumor microenvironment. The session ended with a discussion of future research needs.

Carbon nanotube pathogenicity conforms to a unified theory for mesothelioma causation by elongate materials and fibers.

The purpose of this review is to elucidate how dimensional and durability characteristics of high aspect ratio nanomaterials (HARN), including carbon nanotubes (CNT) and metal nanowires (MeNW), contribute to understanding the fiber pathogenicity paradigm (FPP), including by explaining the structure-activity relationships (SAR) of a diverse range of natural and synthetic elongate materials that may or may not contribute to mesothelioma development in the lung. While the FPP was originally developed to explain the critical importance of asbestos and synthetic vitreous fiber length, width, aspect ratio and biopersistence in mesothelioma development, there are a vast number of additional inhalable materials that need to be considered in terms of pathogenic features that may contribute to mesothelioma or lack thereof. Not only does the ability to exert more exact control over the length and biopersistence of HARNs confirm the tenets of the FPP, but could be studied by implementating more appropriate toxicological tools for SAR analysis. This includes experimentation with carefully assembled libraries of CNTs and MeNWs, helping to establish more precise dimensional features for interfering in lymphatic drainage from the parietal pleura, triggering of lysosomal damage, frustrated phagocytosis and generation of chronic inflammation. The evidence includes data that long and rigid, but not short and flexible multi-wall CNTs are capable of generating mesotheliomas in rodents based on an adverse outcome pathway requiring access to pleural cavity, obstruction of pleural stomata, chronic inflammation and transformation of mesothelial cells. In addition to durability and dimensional characteristics, bending stiffness of CNTs is a critical factor in determining the shape and rigidity of pathogenic MWCNTs. While no evidence has been obtained in humans that CNT exposure leads to a mesothelioma outcome, it is important to monitor exposure levels and health effect impacts in workers to prevent adverse health outcomes in humans.

Use of a Liver-Targeting Immune-Tolerogenic mRNA Lipid Nanoparticle Platform to Treat Peanut-Induced Anaphylaxis by Single- and Multiple-Epitope Nucleotide Sequence Delivery.

While oral desensitization is capable of alleviating peanut allergen anaphylaxis, long-term immune tolerance is the sought-after goal. We developed a liver-targeting lipid nanoparticle (LNP) platform to deliver mRNA-encoded peanut allergen epitopes to liver sinusoidal endothelial cells (LSECs), which function as robust tolerogenic antigen-presenting cells that induce FoxP3+ regulatory T-cells (Tregs). The mRNA strand was constructed by including nucleotide sequences encoding for nonallergenic MHC-II binding T-cell epitopes, identified in the dominant peanut allergen, Ara h2. These epitopes were inserted in the mRNA strand downstream of an MHC-II targeting sequence, further endowed in vitro with 5' and 3' capping sequences, a PolyA tail, and uridine substitution. Codon-optimized mRNA was used for microfluidics synthesis of LNPs with an ionizable cationic lipid, also decorated with a lipid-anchored mannose ligand for LSEC targeting. Biodistribution to the liver was confirmed by in vivo imaging, while ELISpot assays demonstrated an increase in IL-10-producing Tregs in the spleen. Prophylactic administration of tandem-repeat or a combination of encapsulated Ara h2 epitopes induced robust tolerogenic effects in C3H/HeJ mice, sensitized to and subsequently challenged with crude peanut allergen extract. In addition to alleviating physical manifestations of anaphylaxis, there was suppression of Th2-mediated cytokine production, IgE synthesis, and mast cell release, accompanied by increased IL-10 and TGF-ß production in the peritoneum. Similar efficacy was demonstrated during LNP administration postsensitization. While nondecorated particles had lesser but significant effects, PolyA/LNP-Man lacked protective effects. These results demonstrate an exciting application of mRNA/LNP for treatment of food allergen anaphylaxis, with the promise to be widely applicable to the allergy field.

Diversity, Form, and Postembryonic Development of Paleozoic Insects.

While Mesozoic, Paleogene, and Neogene insect faunas greatly resemble the modern one, the Paleozoic fauna provides unique insights into key innovations in insect evolution, such as the origin of wings and modifications of postembryonic development including holometaboly. Deep-divergence estimates suggest that the majority of contemporary insect orders originated in the Late Paleozoic, but these estimates reflect divergences between stem groups of each lineage rather than the later appearance of the crown groups. The fossil record shows the initial radiations of the extant hyperdiverse clades during the Early Permian, as well as the specialized fauna present before the End Permian mass extinction. This review summarizes the recent discoveries related to the documented diversity of Paleozoic hexapods, as well as current knowledge about what has actually been verified from fossil evidence as it relates to postembryonic development and the morphology of different body parts.

Multiple drivers and lineage-specific insect extinctions during the Permo-Triassic.

The Permo-Triassic interval encompasses three extinction events including the most dramatic biological crisis of the Phanerozoic, the latest Permian mass extinction. However, their drivers and outcomes are poorly quantified and understood for terrestrial invertebrates, which we assess here for insects. We find a pattern with three extinctions: the Roadian/Wordian (≈266.9 Ma; extinction of 64.5% insect genera), the Permian/Triassic (≈252 Ma; extinction of 82.6% insect genera), and the Ladinian/Carnian boundaries (≈237 Ma; extinction of 74.8% insect genera). We also unveil a heterogeneous effect of these extinction events across the major insect clades. Because extinction events have impacted Permo-Triassic ecosystems, we investigate the influence of abiotic and biotic factors on insect diversification dynamics and find that changes in floral assemblages are likely the strongest drivers of insects' responses throughout the Permo-Triassic. We also assess the effect of diversity dependence between three insect guilds; an effect ubiquitously found in current ecosystems. We find that herbivores held a central position in the Permo-Triassic interaction network. Our study reveals high levels of insect extinction that profoundly shaped the evolutionary history of the most diverse non-microbial lineage.

South African Lagerstätte reveals middle Permian Gondwanan lakeshore ecosystem in exquisite detail.

Continental ecosystems of the middle Permian Period (273-259 million years ago) are poorly understood. In South Africa, the vertebrate fossil record is well documented for this time interval, but the plants and insects are virtually unknown, and are rare globally. This scarcity of data has hampered studies of the evolution and diversification of life, and has precluded detailed reconstructions and analyses of ecosystems of this critical period in Earth's history. Here we introduce a new locality in the southern Karoo Basin that is producing exceptionally well-preserved and abundant fossils of novel freshwater and terrestrial insects, arachnids, and plants. Within a robust regional geochronological, geological and biostratigraphic context, this Konservat- and Konzentrat-Lagerstätte offers a unique opportunity for the study and reconstruction of a southern Gondwanan deltaic ecosystem that thrived 266-268 million years ago, and will serve as a high-resolution ecological baseline towards a better understanding of Permian extinction events.

Phylogenomic Analyses of the Tenthredinoidea Support the Familial Rank of Athaliidae (Insecta, Tenthredinoidea).

The systematic status of the genus Athalia and related genera is a perennial controversy in sawfly taxonomy. Several authors have hypothesized that the placement of Athalia within the Tenthredinidae is artificial, but no studies have focused on this topic. If the hypothesis that Athalia does not belong to Tenthredinidae can be supported, the taxonomic framework of Tenthredinoidea needs revision. We present a comprehensive phylogenomic study of Tenthredinoidae, focusing on the positions of Athalia and related genera by sampling 80 representatives mainly of the Tenthredinoidea, including Heptamelinae and Blasticotomidae. Our phylogenetic reconstructions based on nuclear genes and mitochondrial (mt) sequences support Athalia and related genera as a distinct clade sister to Tenthredinidae + (Cimbicidae + Diprionidae). A comparison of symphytan mitochondrial genomes reveals an innovative gene rearrangement pattern in Athaliidae, in which Dentathalia demonstrates a more ancestral pattern than Athalia and Hypsathalia. The lineage specificity of mt rRNA secondary structures also provides sufficient support to consider Athaliidae as a separate family. In summary, the phylogeny and genomic structural changes unanimously support the taxonomic treatment of Athaliidae as a family and the re-establishment of Dentathalia as a valid genus.

The First Representative of the Roachoid Family Spiloblattinidae (Insecta, Dictyoptera) from the Late Pennsylvanian of the Iberian Peninsula.

Sysciophlebia 'sp. form Villablino', the first Iberian representative of the Palaeozoic-Early Mesozoic family Spiloblattinidae, is described and illustrated. Its forewing colour pattern is strongly similar to those of the Gzhelian-early-middle Asselian species Sysciophlebia euglyptica, Sysciophlebia ilfeldensis, Sysciophlebia rubida, and 'Sysciophlebia sp. form KBQ', supporting the currently proposed Gzhelian age for its type locality. It supports the use of the representatives of the Spiloblattinidae for stratigraphic purposes. The diagnoses and limits of the families Subioblattidae, Phyloblattidae, Compsoblattidae, Spiloblattinidae, and of the spiloblattinid genera are discussed.

Nanocarrier Co-formulation for Delivery of a TLR7 Agonist plus an Immunogenic Cell Death Stimulus Triggers Effective Pancreatic Cancer Chemo-immunotherapy.

Although toll-like receptor (TLR) agonists hold great promise as immune modulators for reprogramming the suppressive immune landscape in pancreatic ductal adenocarcinoma (PDAC), their use is limited by poor pharmacokinetics (PK) and off-target systemic inflammatory effects. To overcome these challenges as well as to attain drug synergy, we developed a lipid bilayer (LB)-coated mesoporous silica nanoparticle (silicasome) platform for co-delivery of the TLR7/8 agonist 3M-052 with the immunogenic chemotherapeutic agent irinotecan. This was accomplished by incorporating the C18 lipid tail of 3M-052 in the coated LB, also useful for irinotecan remote loading in the porous interior. Not only did the co-formulated carrier improve PK, but it strengthened the irinotecan-induced immunogenic cell death response by 3M-052-mediated dendritic cell activation at the tumor site as well as participating lymph nodes. The accompanying increase in CD8+ T-cell infiltration along with a reduced number of regulatory T-cells was associated with tumor shrinkage and metastasis disappearance in subcutaneous and orthotopic KRAS-mediated pancreatic carcinoma tumor models. Moreover, this therapeutic outcome was accomplished without drug or nanocarrier toxicity. All considered, dual-delivery strategies that combine chemo-immunotherapy with co-formulated TLR agonists or other lipid-soluble immune modulators predict successful intervention in heterogeneous PDAC immune landscapes.

A New Sternorrhynchan Genus and Species from the Triassic Period of China That Is Likely Related to Protopsyllidioid (Insecta, Hemiptera).

Triassopsyllidiida pectinata gen. et sp. nov. is described from the latest Middle Triassic Tongchuan biota of China and tentatively attributed to the superfamily Protopsyllidioidea. Its forewing venation is unique among this superfamily in the anteriorly pectinate vein ScP + RA and the presence of a veinlet between R and M + CuA. Its exact position in this group remains uncertain, mainly because of the weak diagnostic value of the wing venation characters in these insects. The phylogenetic relationships of the Protopsyllidioidea are discussed.

Abdominal serial homologues of wings in Paleozoic insects.

The Late Paleozoic acquisition of wings in insects represents one of the key steps in arthropod evolution. While the origin of wings has been a contentious matter for nearly two centuries, recent evolutionary developmental studies suggest either the participation of both tergal and pleural tissues in the formation of wings1 or wings originated from exites of the most proximal leg podite incorporated into the insect body wall.2 The so-called "dual hypothesis" for wing origins finds support from studies of embryology, evo-devo, and genomics, although the degree of the presumed contribution from tergal and pleural tissues differ.3-6 Ohde et al.,7 confirmed a major role for tergal tissue in the formation of the cricket wing and suggested that "wings evolved from the pre-existing lateral terga of a wingless insect ancestor." Additional work has focused on identifying partial serially homologous structures of wings on the prothorax8,9 and abdominal segments.10 Thus, several studies have suggested that the prothoracic horns in scarab beetles,9 gin traps of tenebrionid and scarab beetle pupae,11,12 or abdominal tracheal gills of mayfly larvae1,13 evolved from serial homologues of wings. Here, we present critical information from abdominal lateral outgrowths (flaps) of Paleozoic palaeodictyopteran larvae, which show comparable structure to thoracic wings, consisting of cordate lateral outgrowths antero-basally hinged by muscle attachments. These flaps therefore most likely represent wing serial homologues. The presence of these paired outgrowths on abdominal segments I-IX in early diverging Pterygota likely corresponds to crustacean epipods14,15 and resembles a hypothesized ancestral body plan of a "protopterygote" model.