The third-generation tyrosine kinase inhibitor osimertinib is approved to treat patients with T790M-positive non-small cell lung cancer (NSCLC) who have developed resistance to earlier-generation drugs. Acquired C797S mutation has been reported to mediate osimertinib resistance in some patients. However, the remaining resistance mechanisms are largely unknown. We performed mutation profiling using targeted next-generation sequencing (NGS) for 416 cancer-relevant genes on 93 osimertinib-resistant lung cancer patients' samples, mainly cell-free DNAs (cfDNAs), and matched pretreatment samples of 12 patients. experiments were conducted to functionally study the secondary mutations identified. G796/C797, L792, and L718/G719 mutations were identified in 24.7%, 10.8%, and 9.7% of the cases, respectively, with certain mutations coexisting in one patient with different prevalence. L792 and L718 mutants markedly increased the half inhibitory concentration (IC) of osimertinib , among which the L718Q mutation conferred the greatest resistance to osimertinib, as well as gefitinib resistance when not coexisting with T790M. Further analysis of the 12 matched pretreatment samples confirmed that these mutations were acquired during osimertinib treatment. Alterations in parallel or downstream oncogenes such as , and were also discovered, potentially contributing to the osimertinib-resistance in patients without secondary mutations. We present comprehensive mutation profiles of a large cohort of osimertinib-resistance lung cancer patients using mainly cfDNA. Besides C797 mutations, novel secondary mutations of L718 and L792 residues confer osimertinib resistance, both and , and are of great clinical and pharmaceutical relevance..

Cancer is a disease of complex genetic alterations, and comprehensive genetic diagnosis is beneficial to match each patient to appropriate therapy. However, acquisition of representative tumor samples is invasive and sometimes impossible. Circulating tumor DNA (ctDNA) is a promising tool to use as a non-invasive biomarker for cancer mutation profiling. Here we implemented targeted next generation sequencing (NGS) with a customized gene panel of 382 cancer-relevant genes on 605 ctDNA samples in multiple cancer types. Overall, tumor-specific mutations were identified in 87% of ctDNA samples, with mutation spectra highly concordant with their matched tumor tissues. 71% of patients had at least one clinically-actionable mutation, 76% of which have suggested drugs approved or in clinical trials. In particular, our study reveals a unique mutation spectrum in Chinese lung cancer patients which could be used to guide treatment decisions and monitor drug-resistant mutations. Taken together, our study demonstrated the feasibility of clinically-useful targeted NGS-based ctDNA mutation profiling to guide treatment decisions in cancer.

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Understanding how novel complex traits originate involves investigating the time of origin of the trait, as well as the origin of its underlying gene regulatory network in a broad comparative phylogenetic framework. The eyespot of nymphalid butterflies has served as an example of a novel complex trait, as multiple genes are expressed during eyespot development. Yet the origins of eyespots remain unknown. Using a dataset of more than 400 images of butterflies with a known phylogeny and gene expression data for five eyespot-associated genes from over twenty species, we tested origin hypotheses for both eyespots and eyespot-associated genes. We show that eyespots evolved once within the family Nymphalidae, approximately 90 million years ago, concurrent with expression of at least three genes associated with early eyespot development. We also show multiple losses of expression of most genes from this early three-gene cluster, without corresponding losses of eyespots. We propose that complex traits, such as eyespots, may have originated via co-option of a large pre-existing complex gene regulatory network that was subsequently streamlined of genes not required to fulfill its novel developmental function.

MXenes are an emerging class of highly conductive two-dimensional (2D) materials with electrochemical storage features. Oriented macroscopic Ti3C2T x fibers can be fabricated from a colloidal 2D nematic phase dispersion. The layered conductive Ti3C2T x fibers are ideal candidates for constructing high-speed ionic transport channels to enhance the electrochemical capacitive charge storage performance. In this work, we assemble Ti3C2T x fibers with a high degree of flake orientation by a wet spinning process with controlled spinning speeds and morphology of the spinneret. In addition to the effects of cross-linking of magnesium ions between Ti3C2T x flakes, the electronic conductivity and mechanical strength of the as-prepared fibers have been improved to 7200 S cm–1 and 118 MPa, respectively. The oriented Ti3C2T x fibers present a volumetric capacitive charge storage capability of up to 1360 F cm–3 even in a Mg-ion based neutral electrolyte, with contributions from both nanofluidic ion transport and Mg-ion intercalation pseudocapacitance. The oriented 2D Ti3C2T x driven nanofluidic channels with great electronic conductivity and mechanical strength endows the MXene fibers with attributes for serving as conductive ionic cables and active materials for fiber-type capacitive electrochemical energy storage, biosensors, and potentially biocompatible fibrillar tissues.

Functionalizing carbon cathode surfaces with oxygen functional groups is an effective way to simultaneously tailor the fundamental properties and customize the electrochemical properties of aqueous Zn‐ion hybrid capacitors. In this work, the oxygen functional groups of chemically reduced graphene oxide (rGO) are systematically regulated via a series of reductants and varied experimental conductions. Carboxyl and carbonyl have been proven to significantly enhance the aqueous electrolyte wettability, Zn‐ion chemical adsorption, and pseudocapacitive redox activity by experimental study and computational analysis. The rGO cathode produced through hydrogen peroxide assisted hydrothermal reduction exhibits a specific capacitance of 277 F g−1 in 1 m ZnSO4 after optimization of surface oxygen functional groups. In addition, a quasi‐solid‐state flexible Zn‐ion hybrid capacitor (ZHC) with a polyacrylamide gel electrolyte and a high loading mass of 5.1 mg cm−2 are assembled. The as‐prepared quasi‐solid state ZHC can offer a superior areal capacitance of 1257 mF cm−2 and distinguished areal energy density of 342 µW h cm−2. The significant enhancement of redox activity and Zn‐ion storage capability by regulating the oxygen functional groups can shed light on the promotion of electrochemical charge storage properties even beyond protic electrolyte systems.

Bodies are often made of repeated units, or serial homologs, that develop using the same core gene regulatory network. Local inputs and modifications to this network allow serial homologs to evolve different morphologies, but currently we do not understand which modifications allow these repeated traits to evolve different levels of phenotypic plasticity. Here we describe variation in phenotypic plasticity across serial homologous eyespots of the butterfly Bicyclus anynana, hypothesized to be under selection for similar or different functions in the wet and dry seasonal forms. Specifically, we document the presence of eyespot size and scale brightness plasticity in hindwing eyespots hypothesized to vary in function across seasons, and reduced size plasticity and absence of brightness plasticity in forewing eyespots hypothesized to have the same function across seasons. By exploring the molecular and physiological causes of this variation in plasticity across fore and hindwing serial homologs we discover that: 1) temperature experienced during the wandering stages of larval development alters titers of an ecdysteroid hormone, 20-hydroxyecdysone (20E), in the hemolymph of wet and dry seasonal forms at that stage; 2) the 20E receptor (EcR) is differentially expressed in the forewing and hindwing eyespot centers of both seasonal forms during this critical developmental stage; and 3) manipulations of EcR signaling disproportionately affected hindwing eyespots relative to forewing eyespots. We propose that differential EcR expression across forewing and hindwing eyespots at a critical stage of development explains the variation in levels of phenotypic plasticity across these serial homologues. This finding provides a novel signaling pathway, 20E, and a novel molecular candidate, EcR, for the regulation of levels of phenotypic plasticity across body parts or serial homologs.

Wearable and portable self-powered units have stimulated considerable attention in both the scientific and technological realms. However, their innovative development is still limited by inefficient bulky connections between functional modules, incompatible energy storage systems with poor cycling stability, and real safety concerns. Herein, we demonstrate a flexible solar-charging integrated unit based on the design of printed magnesium ion aqueous asymmetric supercapacitors. This power unit exhibits excellent mechanical robustness, high photo-charging cycling stability (98.7% capacitance retention after 100 cycles), excellent overall energy conversion and storage efficiency (ηoverall = 17.57%), and outstanding input current tolerance. In addition, the Mg ion quasi-solid-state asymmetric supercapacitors show high energy density up to 13.1 mWh cm−3 via pseudocapacitive ion storage as investigated by an operando X-ray diffraction technique. The findings pave a practical route toward the design of future self-powered systems affording favorable safety, long life, and high energy.