Discovery Centre

As a field, mobile media and communication (MMC) has centrally been concerned with how people use mobile communication technology and the implications for human sociality, psychology, and culture. This article encourages us to think more deeply, and differently, about concepts and practices of mobile media and mobile communication by examining the uses and consequences of MMC among whales . By looking at MMC in the animal world, we gain a new vantage point for thinking about the core elements of mobility, media, and communication, and how they can come together to shape everyday life and survival. By looking beyond the Anthropocene, this more-than-human perspective offers conceptual enrichment for scholarship in the field, while using MMC as a lens for considering how humans (“culture”) and animals (“nature”) are entangled in meaningful ways (natureculture).

Abstract Six-transmembrane Epithelial Antigen of the Prostate 1 (STEAP1) has emerged as a promising therapeutic target for prostate cancer. We have optimized the expression and purification conditions of human STEAP1 to maximize the production of its homotrimeric form, which is crucial for metal ion reduction and maintaining cellular redox balance. Proteins obtained from these optimized conditions were complexed with both heme and flavin-adenine dinucleotide (FAD), two cofactors that are fundamental to STEAP functionality, suggesting native folding and interactions of the protein. In addition, we compared the impact of stable and transient expression systems on the protein quality of STEAP1. We found that stable expression promoted heme incorporation, improved expression homogeneity, and ensured correct protein orientation on cell surfaces. Our findings present effective strategies for optimizing the recombinant production of STEAP1, with potential applicability to other STEAP family proteins to facilitate therapeutic discovery.

Genetically encoded (GE) libraries enable identification of high-affinity ligands for diverse molecular targets through iterative in vitro selection and DNA sequencing or next-generation sequencing (NGS). Despite their impact in therapeutic development, a systematic framework for evaluating reproducibility in GE-molecular discoveries remains limited. To aid such analysis, we introduce the concept of baseline response, which reproducibly partitions active and inactive members of in vitro selection. The baseline response is provided by spiking a random DNA-barcoded population. We calibrated the baseline concept using Bioconductor EdgeR differential enrichment (DE) analysis of NGS of phage-displayed selection on oligosaccharide chitin and hepatitis virus NS3a* protease as model targets. We further show that mixing discovery campaigns also offers an effective baseline: chitin-enriched peptides serve as a baseline for DE-analysis of NS3a* selection and NS3a*-enriched peptides serve as a baseline for chitin binders. We applied baseline-stratified DE-analysis to 66 parallel selections performed in 3–5 replicates across 22 extracellular targets, including HER1–3, EpCAM, CAIX, PD-L1, and eight integrin receptors. Automated DE-analysis across hundreds of NGS files produced hits validated in a secondary screen and yielded synthetic macrocyclic ligands with mid-nanomolar affinity confirmed in 2–3 biophysical assays. For PD-L1, we further demonstrated how baseline-calibrated NGS data provide decision-enabling information for optimization of peptide macrocycles to yield potent single-digit nanomolar ligands for the cell-surface receptor. We anticipate that baseline-based analyses of NGS data from in vitro selection procedures will offer a scalable framework for reproducible hit discovery and standardized analysis across diverse in vitro selection campaigns.

Clinical-ready neuromodulation devices for real-time monitoring and treatment of neurological disorders require a neural interface integrated circuit (IC) that supports therapeutic neurostimulation together with concurrent recording of neural activities from large brain regions. To address this need, this article presents an IC with 32 high dynamic range (HDR) electrocorticography (ECoG) recording channels and two programmable neurostimulators allowing bi-directional neural interfacing. The recording channel uses a 2nd-order continuous-time <inline-formula xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink"> <tex-math notation="LaTeX">$\Delta \Sigma $</tex-math> </inline-formula> modulator (CTDSM) architecture with 12-tap finite impulse response digital-to-analog converter (FIRDAC) feedback facilitated by a pre-emptive current-steering excess loop delay (ELD) compensation scheme. By employing a high-performance linearized low-noise/low-power transconductance amplifier (L<sup xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">3</sup>TA) in the input integration stage, the recording channel achieves 83-dB dynamic range (DR) with up to 222-mV<sub xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">pp</sub> linear input range, and thus can accommodate large electrode dc offsets (EDOs) and stimulation artifacts. Thanks to the FIRDAC that relaxes component matching requirements, each recording channel occupies only 0.028 mm<sup xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">2</sup> and consumes <inline-formula xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink"> <tex-math notation="LaTeX">$5.39~{\mu }$</tex-math> </inline-formula>W while being manufactured in standard 180-nm CMOS technology. The concurrent neural recording and stimulation capabilities of the chip have been validated in a mouse experiment in vivo, which shows that the recording channel can tolerate real stimulation artifacts and the recorded ECoG signals can be separated from the artifacts with high fidelity.

ObjectivesDysferlinopathy is an autosomal recessive muscular dystrophy caused by pathogenic variants of the DYSF gene. Currently, no clinical effective treatment is available. Given the myopathologic and animal model evidence on complement activation in dysferlinopathy, we explored the potential therapeutic effect of complement inhibition.MethodsWe reported a case of teenager-onset dysferlinopathy with progressive proximal weakness, markedly elevated serum creatine kinase levels, and assistance requirement for ambulation when admission. Muscle biopsy showed dysferlin deficiency and marked deposition of complement C5b-9 on nonnecrotic sarcolemma. Based on these findings and previous preclinical studies, the patient received eculizumab (900 mg weekly for 4 weeks) with informed consent.ResultsClinical improvement was observed following complement inhibition therapy. By week 5, all tested muscle groups reached Medical Research Council grade 5/5, and the North Star Assessment for Dysferlinopathy score increased from 28 to 39. The 6-minute walk test (6MWT) improved from 220 m to 363 m. The muscle MRI revealed reduced muscle edema after eculizumab treatment. These benefits were sustained at 13-month follow-up.DiscussionComplement inhibition showed promising clinical improvement in this single case of dysferlinopathy. Further studies with larger sample sizes are needed to investigate the efficacy and safety of complement inhibitors in dysferlinopathy.

The GPR176 protein is a cell membrane protein implicated in human diseases, especially cancers. Numerous studies have highlighted its overexpression, which is considered a major driver of tumorigenesis. Reducing its overexpression has been shown by many studies to be a viable pharmacological strategy for cancer therapy, prompting this study to search for drug molecules from existing FDA-approved drugs. We performed homology modeling of the GPR176 protein to obtain its 3D structure, conducted docking simulations of FDA-approved drugs retrieved from ReDO_DB to identify compounds with strong binding affinities, and carried out density functional theory quantum calculations and molecular dynamic simulations to assess stability and compactness. Additionally, pharmacokinetic profiling and drug-likeness analyses were performed to identify molecules capable of inhibiting and potentially deorphanizing GPR176. We identified Fostamatinib and Ticagrelor as both compounds exhibited binding affinities of -11.503 kcal/mol and − 11.882 kcal/mol, which indicates that both compounds effectively interact with the protein; they both had minimal deviations from their natural states as the RMSD values of 0.35 and 0.45 characterize their stability profile; energy gap of -0.1327 eV and − 0.1371 eV, which illuminates their reactivity to the protein and favorable pharmacokinetic profiles compared to the control, Vismodegib. This leads to the identification of Fostamatinib and Ticagrelor as potential inhibitors of the protein, and thus, we recommend further experimental studies to validate these findings.

Covering: January 2014-June 2025. Previous review: Natural Product Reports, 2014, 31, 1612Natural products (NPs) have long been foundational in medicine, from ancient herbal remedies to the discovery of transformative drugs like morphine and quinine. The mid-20th century marked a 'golden age' for antibiotic discovery from natural sources, which then expanded into other therapeutic areas. However, by the late 20th century, other technological advances had shifted NPs from being a central component of the discovery process to one of several options. This review explores the current role of NPs in pharmaceuticals by analysing NP-derived (NP-D) drugs approved since 2014 and clinical candidates in development as of the end of 2024. 58 NP-related drugs launched between January 2014 and June 2025 were identified, which included 45 NP and NP-D new chemical entities (NCEs) and 13 NP-antibody drug conjugates (NP-ADCs). Next, all 579 drugs-388 (67%) of which were NCEs and 191 (33%) were new biological entities (NBEs)-approved globally from 2014 to 2024 were analysed. In total, 56 (9.7%) of these 579 drugs were classified as NPs or NP-Ds using this review's NP definition: 44 NCEs (7.6% overall; 11.3% of NCEs) and 12 NP-ADCs (2.1% overall; 6.3% of NBEs). The number of new NP-D NCEs and NP-ADCs has fluctuated between 0 and 8 annually since 2014, with an average of five approvals per year. Next, 125 NP and NP-D compounds were identified that were undergoing clinical trials or in the registration phase at the end of December 2024. Thirty-three new pharmacophores not previously found in approved drugs are now in development; however, only one has been discovered in the past 15 years. This review highlights the enduring promise of NPs, despite their diminished role in drug discovery, and advocates for renewed emphasis on bioassay-guided isolation and mode of action studies to identify new drug leads.

Hematopoietic bone marrow progenitors are increasingly implicated as an origin of immunosuppression in cancer. We have previously shown that trained immunity induction using nanomedicine potentiates checkpoint blockade therapy. Here, we studied how this approach’s induction of trained immunity systemically overcomes the immunosuppressive tumor microenvironment. We found changes in the tumor microenvironment to mirror functional changes in the hematopoietic system in a melanoma mouse model. Single cell sequencing methods disclosed a shift in the tumor-associated macrophage population from immunosuppressive to antitumorigenic. Uniquely, a trained immunity and checkpoint blockade combination therapy mobilized natural killer cells which, in conjunction with the functional changes in the myeloid cell compartment, effectively activated T cells. Last, we established the effectiveness of our approach in mouse models of breast, lung, and pancreatic cancer. Collectively, our data show that the systemic induction of trained immunity rebalances the immune system for effective checkpoint blockade therapy.

Even without detailed instruction from the brain, spinal locomotor circuitry generates coordinated behavior characterized by left-right alternation, segment-to-segment propagation, and variable-speed control. While existing models have emphasized the contributions of cellular- and network-level properties, the core mechanisms underlying rhythmogenesis remain incompletely understood. Further, neither family of models has fully accounted for recent experimental results in zebrafish and other organisms pointing to the importance of cell-type-specific intersegmental connectivity patterns and recruitment of speed-selective subpopulations of interneurons. In-formed by these experimental findings and others, we developed a hierarchy of increasingly detailed models of the locomotor network. We find that coordinated locomotion emerges in an inhibition-dominated network in which connectivity is determined by intersegmental phase relationships among interneurons and variable-speed control is implemented by recruitment of speed-selective subpopulations. Further, while structured excitatory connections are not necessary for rhythmogenesis, they are useful for increasing peak locomotion frequency, albeit at the cost of smooth transitions at intermediate frequencies, suggesting a basic computational trade-off between speed and control. Together, this family of models shows that network-level interactions are sufficient to generate coordinated, variable-speed locomotion, providing new interpretations of intersegmental excitatory and inhibitory connectivity, as well as the basic, recruitment-based mechanism of speed control.