Synthetic GPCRs for programmable sensing and control of cell behaviour.

Synthetic receptors that mediate antigen-dependent cell responses are transforming therapeutics, drug discovery and basic research. However, established technologies such as chimeric antigen receptors can only detect immobilized antigens, have limited output scope and lack built-in drug control. Here we engineer synthetic G-protein-coupled receptors (GPCRs) that are capable of driving a wide range of native or non-native cellular processes in response to a user-defined antigen.

Visual comfort models based on coloured text and neutral background combinations.

Reading on mobile phones can cause visual discomfort, negatively affecting visual health. Most studies have focused on neutral text-background combinations, with limited validation for coloured text-background combinations. This study investigates the impact of coloured text on neutral backgrounds and the colour difference between text and background on visual comfort during digital reading.

Methane emissions at pressure-regulating stations in China: A comparative analysis of various quantitative methods.

As a key component of the distribution system, metering and pressure-regulating (M&R) stations provide an opportunity for effective mitigation of methane emissions. Given that these stations are readily accessible, above-ground facilities, routine methane emission monitoring can identify issues and with repair or upgrades this can lead to reduced methane emissions. This practice has become an important measure for addressing climate change.

Cephalopod-inspired jetting devices for gastrointestinal drug delivery.

Needle-based injections currently enable the administration of a wide range of biomacromolecule therapies across the body, including the gastrointestinal tract, through recent developments in ingestible robotic devices. However, needles generally require training, sharps management and disposal, and pose challenges for autonomous ingestible systems. Here, inspired by the jetting systems of cephalopods, we have developed and evaluated microjet delivery systems that can deliver jets in axial and radial directions into tissue, making them suitable for tubular and globular segments of the gastrointestinal tract.

Enhancing transcription-replication conflict targets ecDNA-positive cancers.

Extrachromosomal DNA (ecDNA) presents a major challenge for cancer patients. ecDNA renders tumours treatment resistant by facilitating massive oncogene transcription and rapid genome evolution, contributing to poor patient survival. At present, there are no ecDNA-specific treatments.

Inhibition of GPX4 enhances CDK4/6 inhibitor and endocrine therapy activity in breast cancer.

CDK4/6 inhibition in combination with endocrine therapy is the standard of care for estrogen receptor (ER+) breast cancer, and although cytostasis is frequently observed, new treatment strategies that enhance efficacy are required. Here, we perform two independent genome-wide CRISPR screens to identify genetic determinants of CDK4/6 and endocrine therapy sensitivity. Genes involved in oxidative stress and ferroptosis modulate sensitivity, with GPX4 as the top sensitiser in both screens.

Interleukin-6, C-Reactive Protein, and Recurrence After Stroke: A Time-Course Analysis of Individual-Participant Data.

Background: Inflammation promotes atherogenesis. Randomized controlled trials of anti-inflammatory therapies for prevention after stroke have not yet demonstrated clear benefit. IL-6 (interleukin-6) and hsCRP (high-sensitivity C-reactive protein) are independently associated with major adverse cardiovascular events poststroke and may guide patient selection in future randomized controlled trials.

Changing Landscape of Randomized Clinical Trials in Stroke: Explaining Contemporary Trial Designs and Methods.

Evidence generated from randomized clinical trials (RCTs) plays an indispensable role in advancing clinical stroke care. Although the number of stroke-related RCTs published every year has grown exponentially over the past 25 years, the execution and completion of RCTs, particularly those conducted in a hyperacute setting, have grown more complicated and challenging over the years. In addition to the practical challenges associated with conducting a clinical trial, like obtaining human subjects approval, identifying clinical sites, training trial personnel, and enrolling the target number of patients within the available funding and timeline, the complexity of contemporary RCT designs and analyses has become much more exacting.

The role of noncoding RNAs in bacterial immunity.

The evolutionary arms race between bacteria and phages has driven the development of diverse anti-phage defense mechanisms. Recent studies have identified noncoding RNAs (ncRNAs) as key players in bacteria-phage conflicts, including CRISPR-Cas, toxin-antitoxin (TA), and reverse transcriptase (RT)-based defenses; however, our understanding of their roles in immunity is still emerging. In this review, we explore the multifaceted roles of ncRNAs in bacterial immunity, offering insights into their contributions to defense and anti-defense mechanisms, their influence on immune regulatory networks, and potential biotechnological applications.

IOP Reduction in Nonhuman Primates by Microneedle Injection of Drug-Free Hydrogel to Expand the Suprachoroidal Space.

Purpose: Expansion of the suprachoroidal space (SCS) by a hydrogel injection has been shown to reduce intraocular pressure (IOP) in rabbits as a potential treatment for ocular hypertension in glaucoma. Here, we evaluate the safety and efficacy of this approach in hypertensive and normotensive eyes in nonhuman primates.

Methods: A microneedle was used to inject a hyaluronic acid-based hydrogel or saline solution (control) into the SCS of cynomolgus monkey eyes that were either normotensive (n = 7 experimental; n = 2 control eyes) or had induced ocular hypertension (n = 6 experimental; n = 3 control eyes).

The epithelial barrier theory and its associated diseases.

The prevalence of many chronic noncommunicable diseases has been steadily rising over the past six decades. During this time, over 350,000 new chemical substances have been introduced to the lives of humans. In recent years, the epithelial barrier theory came to light explaining the growing prevalence and exacerbations of these diseases worldwide.

Behavioral state and stimulus strength regulate the role of somatostatin interneurons in stabilizing network activity.

Inhibition stabilization enables cortical circuits to encode sensory signals across diverse contexts. Somatostatin-expressing (SST) interneurons are well-suited for this role through their strong recurrent connectivity with excitatory pyramidal cells. We developed a cortical circuit model predicting that SST cells become increasingly important for stabilization as sensory input strengthens.

Significant enhancement in the magnetic properties of CrTe nanosheets by atom substitution doping.

Ferromagnetic CrTe nanocrystals, with their high spin-orbit coupling and low symmetry, have attracted considerable attention as rare-earth-free magnetic nanomaterials due to their potential to achieve high magnetic anisotropy. However, their relatively low values of remanence () and saturation () magnetisation limit their energy product, making them unsuitable for practical applications. Herein, we report a straightforward one-pot heat-injection technique for the synthesis of high-remanence hexagonal CrTe nanosheets by heterogeneous doping with atoms of M (M = V, Mn and Se).

TGF-β and RAS jointly unmask primed enhancers to drive metastasis.

Epithelial-to-mesenchymal transitions (EMTs) and extracellular matrix (ECM) remodeling are distinct yet important processes during carcinoma invasion and metastasis. Transforming growth factor β (TGF-β) and RAS, signaling through SMAD and RAS-responsive element-binding protein 1 (RREB1), jointly trigger expression of EMT and fibrogenic factors as two discrete arms of a common transcriptional response in carcinoma cells. Here, we demonstrate that both arms come together to form a program for lung adenocarcinoma metastasis and identify chromatin determinants tying the expression of the constituent genes to TGF-β and RAS inputs.

Identification of Rocaglate Acyl Sulfamides as Selective Inhibitors of Glioblastoma Stem Cells.

Glioblastoma (GBM) is the most aggressive and frequently occurring type of malignant brain tumor in adults. The initiation, progression, and recurrence of malignant tumors are known to be driven by a small subpopulation of cells known as tumor-initiating cells or cancer stem cells (CSCs). GBM CSCs play a pivotal role in orchestrating drug resistance and tumor relapse.

Long-wavelength triggered iridium(III) complex nanoparticles for photodynamic therapy against hypoxic cancer.

A long-wavelength triggered cationic iridium(III) complex, Ir5, and its corresponding nanoparticles with the ability to generate type I and type II reactive oxygen species have been synthesised. The complex targets mitochondria and achieves an excellent photodynamic therapy effect in hypoxic cancer cells.

Integrative Multiomics in the Lung Reveals a Protective Role of Asporin in Pulmonary Arterial Hypertension.

Background: Integrative multiomics can elucidate pulmonary arterial hypertension (PAH) pathobiology, but procuring human PAH lung samples is rare.

Methods: We leveraged transcriptomic profiling and deep phenotyping of the largest multicenter PAH lung biobank to date (96 disease and 52 control) by integration with clinicopathologic data, genome-wide association studies, Bayesian regulatory networks, single-cell transcriptomics, and pharmacotranscriptomics.

Results: We identified 2 potentially protective gene network modules associated with vascular cells, and we validated , coding for asporin, as a key hub gene that is upregulated as a compensatory response to counteract PAH.

Uncovering patterns of inhaler technique and reliever use: the value of objective, personalized data from a digital inhaler.

Electronic inhalers provide information about patterns of routine inhaler use. During a 12-week study, 360 asthma patients using albuterol Digihaler generated 53,083 inhaler events that were retrospectively analyzed. A total of 41,528 (78%) of the recorded inhalation events were suitable for flow analysis (having a PIF ≥ 18 L/min and <120 L/min).