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The article discusses point-of-care (POC) biochemical sensors have found broad applications in areas ranging from clinical diagnosis to environmental monitoring. However, POC sensors often suffer from poor sensitivity. Here, we synthesized a metal-organic framework, where the ligand is the aggregation-induced emission luminogen (AIEgen ), which we call metal-AIEgen frameworks (MAFs), for use in the ultrasensitive POC biochemical sensors.

A transgelin-2 agonist relaxes airway smooth muscle cells and provides therapeutic advantages for asthma. Tickling transgelin-2 for asthma relief: Asthmatics can be refractive to β2-agonists, creating a need for new pathways to be targeted in this disease. Yin et al. discovered that the protein metallothionein-2 was able to reduce airway resistance in rodent asthma models. This improvement was mediated through transgelin-2, and they further studied a transgelin-2 agonist as a new asthma therapeutic. The agonist improved airway function in multiple preclinical asthma models and relaxed human airway smooth muscle cells. These data indicate that activating transgelin-2 for asthma treatment may be more effective than targeting β2-adrenoceptors. There is a clinical need for new bronchodilator drugs in asthma, because more than half of asthmatic patients do not receive adequate control with current available treatments. We report that inhibition of metallothionein-2 protein expression in lung tissues causes the increase of pulmonary resistance. Conversely, metallothionein-2 protein is more effective than β2-agonists in reducing pulmonary resistance in rodent asthma models, alleviating tension in tracheal spirals, and relaxing airway smooth muscle cells (ASMCs). Metallothionein-2 relaxes ASMCs via transgelin-2 (TG2) and induces dephosphorylation of myosin phosphatase target subunit 1 (MYPT1). We identify TSG12 as a nontoxic, specific TG2-agonist that relaxes ASMCs and reduces asthmatic pulmonary resistance. In vivo, TSG12 reduces pulmonary resistance in both ovalbumin- and house dust mite–induced asthma in mice. TSG12 induces RhoA phosphorylation, thereby inactivating the RhoA-ROCK-MYPT1-MLC pathway and causing ASMCs relaxation. TSG12 is more effective than β2-agonists in relaxing human ASMCs and pulmonary resistance with potential clinical advantages. These results suggest that TSG12 could be a promising therapeutic approach for treating asthma. [ABSTRACT FROM AUTHOR]

The essential bacterial protein FtsZ is a guanosine triphosphatase that self-assembles into a structure at the division site termed the "Z ring". During cytokinesis, the Z ring exerts a constrictive force on the membrane by using the chemical energy of guanosine triphosphate hydrolysis. However, the structural basis of this constriction remains unresolved. Here, we present the crystal structure of a guanosine diphosphate-bound Mycobacterium tuberculosis FtsZ protofilament, which exhibits a curved conformational state. The structure reveals a longitudinal interface that is important for function. The protofilament curvature highlights a hydrolysis-dependent conformational switch at the T3 loop that leads to longitudinal bending between subunits, which could generate sufficient force to drive cytokinesis. [ABSTRACT FROM AUTHOR]

Women with mutations in the breast cancer susceptibility gene BRCA1 are predisposed to breast and ovarian cancers. Why the BRCA1 protein suppresses tumor development specifically in ovarian hormone-sensitive tissues remains unclear. We demonstrate that mammary glands of nulliparous Brca1/p53-deficient mice accumulate lateral branches and undergo extensive alveologenesis, a phenotype that occurs only during pregnancy in wild-type mice. Progesterone receptors, but not estrogen receptors, are overexpressed in the mutant mammary epithelial cells because of a defect in their degradation by the proteasome pathway. Treatment of Brca1/p53-deficient mice with the progesterone antagonist mifepristone (RU 486) prevented mammary tumorigenesis. These findings reveal a tissue-specific function for the BRCA1 protein and raise the possibility that antiprogesterone treatment may be useful for breast cancer prevention in individuals with BRCA1 mutations. [ABSTRACT FROM AUTHOR]

Phase modulation has scarcely been mentioned in diffusive physical systems because the diffusion process does not carry the momentum like waves. Recently, non-Hermitian physics provides a unique perspective for understanding diffusion and shows prospects in thermal phase regulation, exemplified by the discovery of anti-parity-time (APT) symmetry in diffusive systems. However, precise control of thermal phase remains elusive hitherto and can hardly be realized, due to the phase oscillations. Here we construct the PT-symmetric diffusive systems to achieve the complete suppression of thermal phase oscillation. The real coupling of diffusive fields is readily established through a strong convective background, and the decay-rate detuning is enabled by thermal metamaterial design. We observe the phase transition of PT symmetry breaking with the symmetry-determined amplitude and phase regulation of coupled temperature fields. Our work shows the existence of PT symmetry in dissipative energy exchanges and provides unique approaches for harnessing the mass transfer of particles, wave dynamics in strongly scattering systems, and thermal conduction. [ABSTRACT FROM AUTHOR]

The article focuses on large-scale whole-genome resequencing unravels the domestication history of Cannabis sativa. Topics include the Cannabis sativa has long been an important source of fiber extracted from hemp and both medicinal and recreational drugs based on cannabinoid compounds, and the domestication history using whole-genome resequencing of 110 accessions from worldwide origins.

Transcriptional dysregulation is a recurring pathogenic hallmark and an emerging therapeutic vulnerability in ovarian cancer. Here, we demonstrated that ovarian cancer exhibited a unique dependency on the regulatory machinery of transcriptional termination, particularly, cleavage and polyadenylation specificity factor (CPSF) complex. Genetic abrogation of multiple CPSF subunits substantially hampered neoplastic cell viability, and we presented evidence that their indispensable roles converged on the endonuclease CPSF3. Mechanistically, CPSF perturbation resulted in lengthened 30-untranslated regions, diminished intronic polyadenylation and widespread transcriptional readthrough, and consequently suppressed oncogenic pathways. Furthermore, we reported the development of specific CPSF3 inhibitors building upon the benzoxaborole scaffold, which exerted potent antitumor activity. Notably, CPSF3 blockade effectively exacerbated genomic instability by down-regulating DNA damage repair genes and thus acted in synergy with poly(adenosine 5'-diphosphate-ribose) polymerase inhibition. These findings establish CPSF3-dependent transcriptional termination as an exploitable driving mechanism of ovarian cancer and provide a promising class of boron-containing compounds for targeting transcription-addicted human malignancies. [ABSTRACT FROM AUTHOR]

Patients with advanced cancers who either do not experience initial response to or progress while on immune checkpoint inhibitors (ICIs) receive salvage radiotherapy to reduce tumor burden and tumor-related symptoms. Occasionally, some patients experience substantial global tumor regression with a rebound of cytotoxic CD8+ T cells. We have termed the rebound of cytotoxic CD8+ T cells in response to salvage therapy as T cell resilience and examined the underlying mechanisms of resilience. Resilient T cells are enriched for CX3CR1+ CD8+ T cells with low mitochondrial membrane potential, accumulate less reactive oxygen species (ROS), and express more malic enzyme 1 (ME1). ME1 overexpression enhanced the cytotoxicity and expansion of effector CD8+ T cells partially via the type I interferon pathway. ME1 also increased mitochondrial respiration while maintaining the redox state balance. ME1 increased the cytotoxicity of peripheral lymphocytes from patients with advanced cancers. Thus, preserved resilient T cells in patients rebound after salvage therapy and ME1 enhances their resiliency. [ABSTRACT FROM AUTHOR]

The article focuses on the development of wafer-patterned, permeable, and stretchable liquid metal microelectrodes for implantable bioelectronics. The topics include the challenges of low permeability and high modulus in thin-film substrates, the development of wafer-scale patterning of supersoft and permeable microelectrodes, and the demonstration of chronic biocompatibility and high-resolution mapping in neural interfaces.

The article presents a science and engineering research study on the conformability of flexible sheets on spherical surfaces, which is important for the development of three-dimensional surface-conformable electronics. Topics include the challenges of achieving conformability on nondevelopable surfaces, various empirical designs that have been explored to improve conformability; and conformability of cut circular sheets on spherical surfaces for using radial slits to improve conformability.

The article presents a study on the machine learning (ML) implementation for the discovery of innovative polymers for gas separation membranes. It discusses the mechanism and performance of ML models for gas permeability prediction along with chemical insights from the interpretation of ML models. It also analyzes the discovery of high-performance polymers and validates it using Molecular dynamics (MD) simulations.

The article presents a study on the effects of abscisic acid (ABA) on root growth and hydrotropism of Arabidopsis WT Col-0 in normal medium and water stress medium. It discusses the characterization of ABA, the effect of apoplastic acidication on Arabidopsis, the difference betwen Col-0 WT and a series of mutants impaired in protein phosphatases type 2C in terms of root growth and hydrotropism.

The article presents a study which aimed to improve the noise-equivalent differential temperature (NEDT) or finer thermal sensitivity of thermography, which is used to detect surface temperature and subsurface thermal activity of an object based on Stefan-Boltzmann law. In the study, it was found that the emissivity of thermal imaging sensitizer (TIS) abruptly increases at a preprogrammed temperature.

Mutations in the optineurin (OPTN) gene have been implicated in both familial and sporadic amyotrophic lateral sclerosis (ALS). However, the role of this protein in the central nervous system (CNS) and how it may contribute to ALS pathology are unclear. Here, we found that optineurin actively suppressed receptor-interacting kinase 1 (RIPK1)–dependent signaling by regulating its turnover. Loss of OPTN led to progressive dysmyelination and axonal degeneration through engagement of necroptotic machinery in the CNS, including RIPK1, RIPK3, and mixed lineage kinase domain–like protein (MLKL). Furthermore, RIPK1- and RIPK3-mediated axonal pathology was commonly observed in SOD1G93A transgenic mice and pathological samples from human ALS patients. Thus, RIPK1 and RIPK3 play a critical role in mediating progressive axonal degeneration. Furthermore, inhibiting RIPK1 kinase may provide an axonal protective strategy for the treatment of ALS and other human degenerative diseases characterized by axonal degeneration. [ABSTRACT FROM AUTHOR]

Werner syndrome (WS) is a premature aging disorder caused by WRN protein deficiency. Here, we report on the generation of a human WS model in human embryonic stem cells (ESCs). Differentiation of WRN-null ESCs to mesenchymal stem cells (MSCs) recapitulates features of premature cellular aging, a global loss of H3K9me3, and changes in heterochromatin architecture. We show that WRN associates with heterochromatin proteins SUV39H1 and HP1a and nuclear lamina--heterochromatin anchoring protein LAP2b. Targeted knock-in of catalytically inactive SUV39H1 in wild-type MSCs recapitulates accelerated cellular senescence, resembling WRN-deficient MSCs. Moreover, decrease in WRN and heterochromatin marks are detected in MSCs from older individuals. Our observations uncover a role for WRN in maintaining heterochromatin stability and highlight heterochromatin disorganization as a potential determinant of human aging. [ABSTRACT FROM AUTHOR]