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We present a novel small molecule antiviral chemotype that was identified by an unconventional cell-free protein synthesis and assembly-based phenotypic screen for modulation of viral capsid assembly. Activity of PAV-431, a representative compound from the series, has been validated against infectious viruses in multiple cell culture models for all six families of viruses causing most respiratory diseases in humans. In animals, this chemotype has been demonstrated efficacious for porcine epidemic diarrhoea virus (a coronavirus) and respiratory syncytial virus (a paramyxovirus). PAV-431 is shown to bind to the protein 14-3-3, a known allosteric modulator. However, it only appears to target the small subset of 14-3-3 which is present in a dynamic multi-protein complex whose components include proteins implicated in viral life cycles and in innate immunity. The composition of this target multi-protein complex appears to be modified upon viral infection and largely restored by PAV-431 treatment. An advanced analog, PAV-104, is shown to be selective for the virally modified target, thereby avoiding host toxicity. Our findings suggest a new paradigm for understanding, and drugging, the host-virus interface, which leads to a new clinical therapeutic strategy for treatment of respiratory viral disease.

The ongoing evolution of SARS-CoV-2 to evade vaccines and therapeutics underlines the need for innovative therapies with high genetic barriers to resistance. Therefore, there is pronounced interest in identifying new pharmacological targets in the SARS-CoV-2 viral life cycle. The small molecule PAV-104, identified through a cell-free protein synthesis and assembly screen, was recently shown to target host protein assembly machinery in a manner specific to viral assembly. In this study, we investigate the capacity of PAV-104 to inhibit SARS-CoV-2 replication in human airway epithelial cells (AECs). We show that PAV-104 inhibits >99% of infection with diverse SARS-CoV-2 variants in immortalized AECs, and in primary human AECs cultured at the air-liquid interface (ALI) to represent the lung microenvironment in vivo. Our data demonstrate that PAV-104 inhibits SARS-CoV-2 production without affecting viral entry, mRNA transcription, or protein synthesis. PAV-104 interacts with SARS-CoV-2 nucleocapsid (N) and interferes with its oligomerization, blocking particle assembly. Transcriptomic analysis reveals that PAV-104 reverses SARS-CoV-2 induction of the type-I interferon response and the maturation of nucleoprotein signaling pathway known to support coronavirus replication. Our findings suggest that PAV-104 is a promising therapeutic candidate for COVID-19 with a mechanism of action that is distinct from existing clinical management approaches.

The market for degrees preparing for careers in European politics has developed over the last 20 years. Starting from the French case, this paper proposes to understand how students move towards these orientations. Based on mixed-methods sociological study, the article shows that students in European politics masters programmes are not so much from the international upper bourgeoisie as from the rising middle and upper social classes, for whom international capital is a distinctive resource. Then, it shows that pursuing a European career allows them to reconcile two seemingly contradictory rationales: on the one hand the incentive to specialise urgently to enter the job market and on the other hand the eagerness to prolong their Erasmus experience. The driving force behind these careers is accordingly as in the possibility of starting more an international career than a European one.

Two structurally unrelated small molecule chemotypes, represented by compounds PAV-617 and PAV-951, with antiviral activity in cell culture against Mpox virus (formerly known as monkeypox virus) and human immunodeficiency virus (HIV) respectively, were studied for anti-cancer efficacy. Each exhibited apparent pan-cancer cytotoxicity with reasonable pharmacokinetics. Non-toxicity is demonstrated in a non-cancer cell line and in mice at doses achieving drug exposure at active concentrations. Anti-tumour properties of both chemotypes were validated in mouse xenografts against A549 human lung cancer and, for one of the chemotypes, against HT-29 colorectal cancer. The targets of these compounds are unconventional: each binds to a different transient, energy-dependent multi-protein complex. Treatment with these compounds alters the target multi-protein complexes in a manner that appears to remove a block, crucial for cancer survival and progression, on a homeostatic linkage between uncontrolled proliferation and apoptosis. These compounds provide starting points for development of novel, next-generation, non-toxic, pan-cancer therapeutics.

We propose digital-analog quantum kernels for enhancing the detection of complex features in the classification of images. We consider multipartite-entangled analog blocks, stemming from native Ising interactions in neutral-atom quantum processors, and individual operations as digital steps to implement the protocol. To further improve the detection of complex features, we apply multiple quantum kernels by varying the qubit connectivity according to the hardware constraints. An architecture that combines nontrainable quantum kernels and standard convolutional neural networks is used to classify realistic medical images, from breast cancer and pneumonia diseases, with a significantly reduced number of parameters. Despite this fact, the model exhibits better performance than its classical counterparts and achieves comparable metrics according to public benchmarks. These findings highlight the potential of digital-analog quantum convolutions in extracting complex and meaningful features from images, positioning them as a candidate model for addressing challenging classification problems.

The cornea acts as the eye foremost protective layer and is essential for its focusing power. Corneal blindness may arise from physical trauma or conditions like dystrophies, keratitis, keratoconus, or ulceration. While conventional treatments involve medical therapies and donor allografts—sometimes supplemented with keratoprostheses—these options are not suitable for all corneal defects. Consequently, the development of bioartificial corneal tissue has emerged as a critical research area, aiming to address the global shortage of human cornea donors. Bioengineered corneas hold considerable promise as substitutes, with the potential to replace either specific layers or the entire thickness of damaged corneas. This review first delves into the structural anatomy of the human cornea, identifying key attributes necessary for successful corneal tissue bioengineering. It then examines various corneal pathologies, current treatments, and their limitations. Finally, the review outlines the primary approaches in corneal tissue engineering, exploring cell-free, cell-based, and scaffold-based options as three emerging strategies to address corneal failure.

DOI: https://doi.org/10.26333/sts.xxxvii2.03 Kazimierz Twardowski elaborated an original conception of intentionality in his habilitation thesis, On the Content and Object of Presentations, in 1894. He gives a crucial place to the notion of content, as the basis of any presentation. This allows him to offer a solution to the problem of objectless presentations. But I will focus here on a property he attributes to content, that is, its ability to convey meaning. Outside the proper scope of philosophy of language, he provides a conception of meaning that does not focus on reference but rather on designation. His theory does not account for the Fregean distinction between sense and reference, so I will propose a comparison between the two philosophers’ conceptions of meaning.

State-of-the-art systems for spatial and immersive audio are typically very costly, being reliant on specialist audio hardware capable of performing computationally intensive signal processing and delivering output to many tens, if not hundreds, of loudspeakers. Centralised systems of this sort suffer from limited accessibility due to their inflexibility and expense. Building on the research of the past few decades in the transmission of audio data over computer networks, and the emergence in recent years of increasingly capable, low-cost microcontroller-based development platforms with support for both networking and audio functionality, we present a prototype decentralised, modular alternative. Having previously explored the feasibility of running a microcontroller device as a networked audio client, here we describe the development of a client-server system with improved scalability via multicast data transmission. The system operates on ubiquitous, commonplace computing and networking equipment, with a view to it being a simple, versatile, and highly-accessible platform, capable of granting users the freedom to explore audio spatialisation approaches at vastly reduced expense. Though faced by significant technical challenges, particularly with regard to maintaining synchronicity between distributed audio processors, the system produces perceptually plausible results. Findings are commensurate with a capability, with further development and research, to disrupt and democratise the fields of spatial and immersive audio.

A recent measure was developed to assess the Quality of Life (QoL) of young people with advanced cancer and is available for parents and professionals (Advance QoL). The present study aimed to elaborate self-reported versions for children and adolescents with advanced cancer. We adopted a four-phase research plan: (1) to elaborate the Advance QoL questionnaire for youth (8–12 and 13–18 years old) with a team of young research partners; (2) to evaluate the understandability of these versions in a sample of 12 young patients from the target population using cognitive interviews; (3) to assess social validity in the same group using a questionnaire and the content validity index (CVI); and (4) to refine the questionnaires according to these results. Four major themes were identified: (1) issues affecting the understanding of the tool; (2) issues that did not affect the understanding of the tool; (3) modifications to improve the tool; and (4) positive features of the tool. Advance QoL was well received, and feedback was positive. Adjustments were made according to young people’s comments and two self-reported versions are now available. It is essential to measure the key domains of QoL in advanced cancer. Advance QoL self-report versions will help target the specific needs of young people with this condition and their families.

This paper explores the interplay of Henri Lefebvre’s conceived, perceived, and lived spaces in the Real Convento de Santa Mónica, a nunnery located at the heart of the Portuguese Asian empire, in Goa, India. The sense of harmony produced by the conceived and perceived spaces, frameworks that produced a particular habitus among the nuns, which in turn facilitated congenial lived spaces that aligned with the nuns’ aspirations, was significantly disrupted by an external authority, the Archbishop of Goa Ignácio de Santa Teresa, in the early eighteenth century. The archbishop’s desire to curb the power of the Orders and elevate the local Goan ecclesiastical institutions had an unintended effect: it introduced a state of disharmony into the lived space of the nuns, and thus the dialectic between habitus and space led many nuns to experience the convent not as a place of calm and refuge, but rather as a prison. This article is part of the special theme section on Women, Children, and Enslaved People in the Portuguese Empire in Asia, 16th-18th Centuries, guest-edited by Rozely Vigas and Rômulo Ehalt.