Early evolution of Anamorphidae (Coleoptera: Coccinelloidea): the oldest known anamorphid beetles from Upper Cretaceous amber of northern Myanmar and the first report of potential glandular pores in the family.

In order to place newly discovered fossil taxa (Palaeosymbius gen. nov. with P. groehni and P. mesozoicus spp. nov.) from the mid-Cretaceous amber from northern Myanmar, we investigated the relations of extant and extinct lineages of the coccinellid group of Coccinelloidea with emphasis on the family Anamorphidae. We assembled a taxonomic sampling of 34 taxa, including 15 genera and 19 species of Anamorphidae, the most comprehensive sampling of Anamorphidae at the generic level in a phylogenetic analysis. A morphological dataset of 47 characters was built as well as a molecular alignment of 7140 bp including fragments of eight genes (12S, 16S, 18S, 28S, COI, COII, H3 and CAD). Five anamorphid and one endomychid species were sequenced for the first time and added to the dataset. We performed parsimony-based analysis of the morphological dataset and Bayesian inference analysis of the combined matrix (morphological plus molecular data). Our results confirm that Palaeosymbius belongs to Anamorphidae and represents the oldest known member of this family so far. Among Anamorphidae, Symbiotes (with extant and known Eocene species) was recovered as the most probable closest relative of Palaeosymbius. Our morphological studies additionally revealed the presence of probable glandular openings in the anterolateral corners of the pronotal margins in Asymbius sp. and Anamorphus sp., representing the first report of secretory openings in the family Anamorphidae. Similar openings are found in other cucujiform beetles such as Cryptophagidae and Boganiidae with possible defensive purposes.

An enigmatic Cretaceous beetle with possible affinity to Erotylidae (Coleoptera: Cucujiformia).

The morphology of beetles of the recently defined superfamilies Erotyloidea, Nitiduloidea and Cucujoidea is varied. Determining the systematic positions of Mesozoic fossils within these groups can often be challenging. Here we describe and illustrate a puzzling cucujiform beetle, Isocryptophilus exilipunctus Li & Cai gen. & sp. nov., based on an individual from mid-Cretaceous Burmese amber. While we cannot definitively pinpoint the exact phylogenetic position of Isocryptophilus, its possible affinity to Erotylidae is discussed in light of our phylogenetic analyses. A broader-sampled morphological matrix, coupled with a robust molecular phylogeny of these groups, will be promising for clarifying the systematic placement of the fossil.

Phylogenomics of weevils revisited: data curation and modelling compositional heterogeneity.

Weevils represent one of the most prolific radiations of beetles and the most diverse group of herbivores on land. The phylogeny of weevils (Curculionoidea) has received extensive attention, and a largely satisfactory framework for their interfamilial relationships has been established. However, a recent phylogenomic study of Curculionoidea based on anchored hybrid enrichment (AHE) data yielded an abnormal placement for the family Belidae (strongly supported as sister to Nemonychidae + Anthribidae). Here we reanalyse the genome-scale AHE data for Curculionoidea using various models of molecular evolution and data filtering methods to mitigate anticipated systematic errors and reduce compositional heterogeneity. When analysed with the infinite mixture model CAT-GTR or using appropriately filtered datasets, Belidae are always recovered as sister to the clade (Attelabidae, (Caridae, (Brentidae, Curculionidae))), which is congruent with studies based on morphology and other sources of molecular data. Although the relationships of the 'higher Curculionidae' remain challenging to resolve, we provide a consistent and robust backbone phylogeny of weevils. Our extensive analyses emphasize the significance of data curation and modelling across-site compositional heterogeneity in phylogenomic studies.

Kekveus brevisulcatus sp. nov., a new featherwing beetle from mid-Cretaceous amber of northern Myanmar (Coleoptera: Ptiliidae).

Ptiliidae (featherwing beetles) is a group of minute staphylinoid beetles with a scarce fossil record. Here a second member of the Mesozoic genus Kekveus Yamamoto et al. is reported from mid-Cretaceous Burmese amber, with detailed morphology obtained through confocal microscopy. Kekveus brevisulcatus Li, Yamamoto, Newton & Cai sp. nov. shares with K. jason Yamamoto et al. the unpaired medial pronotal fovea and narrowly separated transverse metacoxae, but can be separated from the latter based on its less elongate body, shorter pronotal foveae, and much weaker transverse depression on the head. Our phylogenetic analyses support the discheramocephalin affinity of Kekveus, although its relationship with other members of Discheramocephalini cannot be confidently resolved.

NeuronMotif: Deciphering cis-regulatory codes by layer-wise demixing of deep neural networks.

Discovering DNA regulatory sequence motifs and their relative positions is vital to understanding the mechanisms of gene expression regulation. Although deep convolutional neural networks (CNNs) have achieved great success in predicting cis-regulatory elements, the discovery of motifs and their combinatorial patterns from these CNN models has remained difficult. We show that the main difficulty is due to the problem of multifaceted neurons which respond to multiple types of sequence patterns. Since existing interpretation methods were mainly designed to visualize the class of sequences that can activate the neuron, the resulting visualization will correspond to a mixture of patterns. Such a mixture is usually difficult to interpret without resolving the mixed patterns. We propose the NeuronMotif algorithm to interpret such neurons. Given any convolutional neuron (CN) in the network, NeuronMotif first generates a large sample of sequences capable of activating the CN, which typically consists of a mixture of patterns. Then, the sequences are "demixed" in a layer-wise manner by backward clustering of the feature maps of the involved convolutional layers. NeuronMotif can output the sequence motifs, and the syntax rules governing their combinations are depicted by position weight matrices organized in tree structures. Compared to existing methods, the motifs found by NeuronMotif have more matches to known motifs in the JASPAR database. The higher-order patterns uncovered for deep CNs are supported by the literature and ATAC-seq footprinting. Overall, NeuronMotif enables the deciphering of cis-regulatory codes from deep CNs and enhances the utility of CNN in genome interpretation.

Optimizing Genomic Control in Hit Network-Target Set Model Associations with Lung Adenocarcinoma.

Background: Hit network-target sets (HNSs), compiled sets of different network nodes of the same type, are available and play a significant role in cancer development but are notoriously more difficult to select than a single target. This is due to a combination of challenges attributed to the differential of node interactions, node heterogeneity, and the limitations of node-hit information. Methods: In this study, we constructed a lung adenocarcinoma regulatory network using TCGA data and obtained different HNSs of driver nodes (DNs), core modules (CMs) and core nodes (CNs) through three kinds of methods. Then, the optimized HNS (OHNS) was obtained by integrating CMs, CNs and DNs, and the performance of different HNSs was evaluated according to network structure importance, control capability, and clinical value. Results: We found that the OHNS has two main advantages, the central location of the network and the ability to control the network, and it plays an important role in the disease network through its multifaceted capabilities. Three unique pathways were discovered in the OHNS, which is consistent with previous experiments. Additionally, 13 genes were predicted to play roles in risk prognosis, disease drivers, and cell perturbation effects of lung adenocarcinoma, of which 12 may be candidates for new drugs and biomarkers of lung adenocarcinoma. Conclusion: This study can help us understand and control a network more effectively to determine the development trend of a disease, design effective multitarget drugs, and guide the therapeutic community to optimize appropriate strategies according to different research aims in cancer treatment.

A new species of Burmalestes Tomaszewska & lipiski from mid-Cretaceous Kachin amber (Coleoptera: Endomychidae).

The second species of the extinct genus Burmalestes Tomaszewska & lipiski, B. jingruoyaae Li & Cai sp. nov., is reported from mid-Cretaceous Kachin amber of northern Myanmar. The new species shares characters with both Burmalestes (antennomere 5 elongate and procoxae subcontiguous) and Cretaparamecus Tomaszewska et al. (protibiae toothed and pronotum without basolateral sulci), providing valuable information on the morphological variability of this group.

Fracture Process Analysis and Acoustic Emission Response of Cemented Tailings Backfill with Different Sizes under Uniaxial Compression.

To investigate the effect of dimensional changes on the mechanical properties of cemented tailings backfill (CTB), uniaxial compression tests are performed on square CTBs of four different sizes. Combining digital image correlation (DIC) and acoustic emission (AE) methods, the fracture process and AE behavior characteristics of backfills with different sizes are analyzed. The results show that as the backfill size increases, its uniaxial compressive strength decreases, and its strength stabilizes gradually when it measures 100 mm. Under uniaxial compression loading, surface cracks on the smaller specimens evolve rapidly and aggressively, with no significant shedding area, whereas the larger specimens show plastic failure. The cracks expand and penetrate gradually, forming a large shedding area. As the specimen size increases, the backwards trend of the peak value of the ringing count relative to the peak value of the stress becomes increasingly evident. Combining the change law between the r value and the average frequency centroid, the sudden drop point of r value and the lowest value of average frequency centroid can be regarded as the precursor of macroscopic damage.

Polyoxometalate-based nanocomposites for antitumor and antibacterial applications.

Polyoxometalates (POMs), as emerging inorganic metal oxides, have been shown to have significant biological activity and great medicinal value. Nowadays, biologically active POM-based organic-inorganic hybrid materials have become the next generation of antibacterial and anticancer drugs because of their customizable molecular structures related to their highly enhanced antitumor activity and reduced toxicity to healthy cells. In this review, the current developed strategies with POM-based materials for the purpose of antibacterial and anticancer activities from different action principles inducing cell death and hyperpolarization, cell plasma membrane destruction, interference with bacterial respiratory chain and inhibiting bacterial growth are overviewed. Moreover, specific interactions between POM-based materials and biomolecules are highlighted for a better understanding of their antibacterial and anticancer mechanisms. POMs have great promise as next-generation antibacterial and anticancer drugs, and this review will provide a valuable systematic reference for the further development of POM-based nanomaterials.

Revisiting the Raractocetus Fossils from Mesozoic and Cenozoic Amber Deposits (Coleoptera: Lymexylidae).

The fossils once assigned to Raractocetus Kurosawa from the Mesozoic and Cenozoic amber deposits differ from extant Raractocetus in the longer elytra, the more strongly projecting metacoxae, and the hind wing with vein 2A forked. Thus, these fossils should be removed from Raractocetus. Cretoquadratus engeli Chen from Kachin amber appears to be conspecific with R. fossilis Yamamoto. As a result, R. fossilis and R. extinctus Yamamoto from Kachin amber, R. balticus Yamamoto from Baltic amber, and R. sverlilo Nazarenko, Perkovsky & Yamamoto from Rovno amber are transferred to Cretoquadratus Chen, as C. fossilis (Yamamoto) comb. nov., C. extinctus (Yamamoto) comb. nov., C. balticus (Yamamoto) comb. nov., and C. sverlilo (Nazarenko, Perkovsky & Yamamoto) comb. nov., and C. engeli syn. nov. is suggested to be a junior synonym of C. fossilis.

First Artematopodidae from mid-Cretaceous amber of northern Myanmar (Coleoptera: Elateroidea).

Artematopodid fossils from the mid-Cretaceous Burmese amber are reported for the first time, represented by three species in two genera. Bipogonia Li, Kundrata Cai gen. nov. with two species, B. trivialis Li, Kundrata Cai sp. nov. and B. fortis Li, Kundrata Cai sp. nov., is mainly characterized by the distinctly serrate antennae, mandibles with both apical and subapical teeth, and prosternum without paired longitudinal ridges. Carinibipogonia xiai Li, Kundrata Cai gen. et sp. nov. shares with Bipogonia the distinctly serrate antennae and mandibles with both apical and subapical teeth but differs mainly in the prosternum with short paired longitudinal ridges. Based on their morphology, the two new genera might be related to the extant Allopogonia; however, this needs to be tested in the future with a phylogenetic framework.

New species of Vetuprostomis from mid-Cretaceous amber of northern Myanmar (Coleoptera: Tenebrionoidea: Prostomidae).

Two new species of the prostomid genus Vetuprostomis Engel Grimaldi (Coleoptera: Tenebrionoidea: Prostomidae), V. angularis Li Cai sp. nov. and V. gaoi Li Cai sp. nov., are described from the mid-Cretaceous Burmese amber. Vetuprostomis is suggested to be more closely related to extant Dryocora Pascoe distributed in Australia and New Zealand, rather than the widespread genus Prostomis Latreille. A key to prostomid genera, as well as species in genus Vetuprostomis, is provided.

A new marsh beetle from mid-Cretaceous amber of northern Myanmar (Coleoptera: Scirtidae).

As one of the earliest-diverging lineage of the megadiverse beetle suborder Polyphaga, marsh beetles (Scirtidae) are crucial for reconstructing the ancestor of all polyphagan beetles and the ecomorphological underpinnings of their remarkable evolutionary success. The phylogeny of marsh beetles has nonetheless remained challenging to infer, not least because of their fragmentary Mesozoic fossil record. Here we describe a new scirtid beetle genus and species, Varcalium lawrencei gen. et sp. nov., preserving internal tissue, from Albian-Cenomanian Kachin amber (ca 99 Ma), representing the second member of this family known from the deposit. Based on a formal morphological phylogenetic analysis, Varcalium is recovered within the crown-group of Scirtinae, forming a clade with other genera that possess subocular carinae. The finding suggests that the crown-group of Scirtinae has already diversified by the mid-Cretaceous.

Evaluating methylation of human ribosomal DNA at each CpG site reveals its utility for cancer detection using cell-free DNA.

Ribosomal deoxyribonucleic acid (DNA) (rDNA) repeats are tandemly located on five acrocentric chromosomes with up to hundreds of copies in the human genome. DNA methylation, the most well-studied epigenetic mechanism, has been characterized for most genomic regions across various biological contexts. However, rDNA methylation patterns remain largely unexplored due to the repetitive structure. In this study, we designed a specific mapping strategy to investigate rDNA methylation patterns at each CpG site across various physiological and pathological processes. We found that CpG sites on rDNA could be categorized into two types. One is within or adjacent to transcribed regions; the other is distal to transcribed regions. The former shows highly variable methylation levels across samples, while the latter shows stable high methylation levels in normal tissues but severe hypomethylation in tumors. We further showed that rDNA methylation profiles in plasma cell-free DNA could be used as a biomarker for cancer detection. It shows good performances on public datasets, including colorectal cancer [area under the curve (AUC) = 0.85], lung cancer (AUC = 0.84), hepatocellular carcinoma (AUC = 0.91) and in-house generated hepatocellular carcinoma dataset (AUC = 0.96) even at low genome coverage (<1×). Taken together, these findings broaden our understanding of rDNA regulation and suggest the potential utility of rDNA methylation features as disease biomarkers.

Decoding multilevel relationships with the human tissue-cell-molecule network.

Understanding the biological functions of molecules in specific human tissues or cell types is crucial for gaining insights into human physiology and disease. To address this issue, it is essential to systematically uncover associations among multilevel elements consisting of disease phenotypes, tissues, cell types and molecules, which could pose a challenge because of their heterogeneity and incompleteness. To address this challenge, we describe a new methodological framework, called Graph Local InfoMax (GLIM), based on a human multilevel network (HMLN) that we established by introducing multiple tissues and cell types on top of molecular networks. GLIM can systematically mine the potential relationships between multilevel elements by embedding the features of the HMLN through contrastive learning. Our simulation results demonstrated that GLIM consistently outperforms other state-of-the-art algorithms in disease gene prediction. Moreover, GLIM was also successfully used to infer cell markers and rewire intercellular and molecular interactions in the context of specific tissues or diseases. As a typical case, the tissue-cell-molecule network underlying gastritis and gastric cancer was first uncovered by GLIM, providing systematic insights into the mechanism underlying the occurrence and development of gastric cancer. Overall, our constructed methodological framework has the potential to systematically uncover complex disease mechanisms and mine high-quality relationships among phenotypical, tissue, cellular and molecular elements.

Nothotytthonyx, a new genus of Malthininae (Coleoptera, Cantharidae) from mid-Cretaceous amber of northern Myanmar.

A new fossil genus and species of Cantharidae, Nothotytthonyxserratus Li, Biffi, Kundrata & Cai gen. et sp. nov., is reported from mid-Cretaceous Burmese amber. The new species is tentatively attributed to the extant subfamily Malthininae based on a combination of characters, including the symmetrical apical maxillary palpomeres, shortened elytra, pronotum with arched margins and well-defined borders, tibiae with apical spurs, and tarsal claws simple, although its well-developed gonostyli are atypical in Malthininae. The discovery of Nothotytthonyx also suggests a possible Gondwanan origin for Malthininae.

Treatment of chronic diabetic macular oedema with intravitreal fluocinolone acetonide implant; real-life analysis of outcomes during overall treatment period.

PURPOSE: To assess the clinical efficacy of the fluocinolone acetonide (FA) intravitreal implant (Iluvien, Alimera Sciences) over a 12-month period in a population resistant to treatment with first-line anti-VEGF agents. METHODS: This study is a retrospective cohort study assessing functional and anatomical outcomes in 13 eyes of 12 patients treated for diabetic macular oedema (DMO) with a single fluocinolone implant (FA) (Iluvien) under real-world conditions. The follow-up period includes the time of first intravitreal treatment (incl anti-VEGF or short-lasting steroids) given until 12 months post FA implant insertion. Primary outcomes were best corrected visual acuity (BCVA), measured using the modified Early Treatment Diabetic Retinopathy Study (ETDRS) grading scale, and central foveal thickness (CFT), measured using Topcon 3DOCT-2000 (Topcon Inc) SD-OCT imaging. Mean BCVA and CFT were measured before anti-VEGF treatment, after anti-VEGF treatment, at the time of Iluvien implant insertion, and 6 and 12 months after Iluvien implant insertion. The t-paired sample test was used to ascertain statistical significance of changes in comparison of two samples while the ANOVA analysis was used in comparison of three or more samples. RESULTS: The baseline BCVA (SD) of the cohort prior to initiation of anti-VEGF treatment was 47.45 (12.27) ETDRS letters whilst the mean CFT (SD) was 579 (203) microns. Following completion of anti-VEGF therapy, the mean improvement in vision was 8.9 ETDRS letters (p = 0.1) whilst the mean reduction in CFT was 197 microns (p = 0.028). Mean BCVA (SD) at the time of insertion of the FA implant was 55.15 (11.16) ETDRS letters and mean (SD) CFT at time of insertion of the FA was 454.62 µm (109.51). Following the 12-month treatment period with the FA implant, BCVA (SD) was 62.15 (10.25) ETDRS letters (p = 0.0331) and the mean (SD) CFT was 404.36 µm (142.92), a change of -50.26 µm from baseline (p = 0.0369). CONCLUSIONS: This study has shown that statistically significant improvements in BCVA and CFT can be achieved over a 12-month period with the Iluvien implant. The implant has been shown to be a safe option in the treatment of DMO and may have a role to play in achieving good functional and anatomical outcomes in DMO while also reducing the frequency of follow-up appointments required to maintain stable vision in the working-age population.

Modular Screening Reveals Driver Induced Additive Mechanisms of Baicalin and Jasminoidin on Cerebral Ischemia Therapy.

Combination therapy with increased efficacy and reduced toxicity plays a crucial role in treating complex diseases, such as stroke, but it remains an insurmountable barrier to elucidate the mechanisms of synergistic effects. Here, we present a Driver-induced Modular Screening (DiMS) strategy integrated synergistic module and driver gene identification to elucidate the additive mechanisms of Baicalin (BA) and Jasminoidin (JA) on cerebral ischemia (CI) therapy. Based on anti-ischemia genomic networks BA, JA, and their combination (BJ), we obtained 4, 3, and 9 On-modules of BA, JA, and BJ by modular similarity analysis. Compared with the monotherapy groups, four additive modules (Add-module, BJ_Mod-4, 7, 9, and 13), 15 driver genes of BJ were identified by modular similarity and network control methods, and seven driver proteins (PAQR8, RhoA, EMC10, GGA2, VIPR1, FAM120A, and SEMA3F) were validated by animal experiments. The functional analysis found neuroprotective roles of the Add-modules and driver genes, such as the Neurotrophin signaling pathway and FoxO signaling pathway, which may reflect the additive mechanisms of BJ. Moreover, such a DiMS paradigm provides a new angle to explore the synergistic mechanisms of combination therapy and screen multi-targeted drugs for complex diseases.