Abstract The development of scalable and efficient manufacturing of high‐volume complex synthetic peptides and proteins, like tirzepatide (TZP, 1), faces major hurdles due to the limitations of traditional Solid Phase Peptide Synthesis (SPPS) and Liquid Phase Peptide Synthesis (LPPS). To enable the commercial synthesis of tirzepatide, we pioneered an innovative four‐fragment convergent hybrid SPPS/LPPS strategy combining their individual strengths. Integrating advanced techniques, like flow chemistry for fragment condensation and nanofiltration for intermediate purification, ensures high efficiency and scalability, setting a new standard for large‐scale production. Given the broader reliance on inefficient linear SPPS in the field, our work underscores the potential of hybrid synthesis strategies to transform peptide manufacturing. The convergent approach allows for the simultaneous synthesis of high purity peptide fragments, significantly reducing overall manufacturing time and increasing API throughput. Concurrently, we established a two‐fragment route leveraging Native Chemical Ligation (NCL) followed by tandem desulfurization. This method achieves the chemoselective coupling of unprotected peptide fragments in aqueous media, without epimerization. Crucially, we employed tangential flow filtration (TFF) to effectively purify intermediates between ligation and desulfurization, circumventing solvent‐intensive steps. This NCL/TFF combination offers a powerful, orthogonal, and greener path to TZP, representing a meaningful innovation in synthetic peptide process chemistry.

The development of scalable and efficient manufacturing of high-volume complex synthetic peptides and proteins, like tirzepatide (TZP, 1), faces major hurdles due to the limitations of traditional Solid Phase Peptide Synthesis (SPPS) and Liquid Phase Peptide Synthesis (LPPS). To enable the commercial synthesis of tirzepatide, we pioneered an innovative four-fragment convergent hybrid SPPS/LPPS strategy combining their individual strengths. Integrating advanced techniques, like flow chemistry for fragment condensation and nanofiltration for intermediate purification, ensures high efficiency and scalability, setting a new standard for large-scale production. Given the broader reliance on inefficient linear SPPS in the field, our work underscores the potential of hybrid synthesis strategies to transform peptide manufacturing. The convergent approach allows for the simultaneous synthesis of high purity peptide fragments, significantly reducing overall manufacturing time and increasing API throughput. Concurrently, we established a two-fragment route leveraging Native Chemical Ligation (NCL) followed by tandem desulfurization. This method achieves the chemoselective coupling of unprotected peptide fragments in aqueous media, without epimerization. Crucially, we employed tangential flow filtration (TFF) to effectively purify intermediates between ligation and desulfurization, circumventing solvent-intensive steps. This NCL/TFF combination offers a powerful, orthogonal, and greener path to TZP, representing a meaningful innovation in synthetic peptide process chemistry.

ZAP inhibits double-stranded RNA virus infection by degrading negative-strand RNA and blocking the elongation phase of viral protein synthesis.

Dysregulated protein synthesis has been implicated in multiple neurodevelopmental, neurodegenerative, and neuropsychiatric diseases. Protein synthesis or mRNA translation is critically regulated through phosphorylation of eukaryotic elongation factor 2 (eEF2) by its kinase eEF2K. Increased eEF2K activity leads to elevated phosphorylation and inhibition of eEF2 and inhibits the elongation phase of protein synthesis. Recent studies suggest a link between eEF2 hyper-phosphorylation and several neuronal diseases characterized by cognitive impairments. Phosphorylation of eEF2 by eEF2K has also been implicated as a molecular mechanism for the rapid antidepressant effect of ketamine. Whether there exists a causal relationship between overactive eEF2K/eEF2 signaling and impaired synaptic and cognitive function remains unknown. To fill this critical knowledge gap, we generated a transgenic mouse model (eEF2K-cKI) overexpressing eEF2K in excitatory neurons to investigate how eEF2K/eEF2 signaling can impact cognitive functions and neuropsychiatric behaviors. We assessed hippocampal-dependent learning and memory, as well as multiple neuropsychiatric domains associated with a depressive phenotype including despair, anhedonia, apathy, anxiety, and sociability. The eEF2K-cKI mice exhibit learning and memory impairments, and robust apathy-like phenotype without other despair/depression-like behaviors. We also found impaired long-term potentiation and altered dendritic spine and synaptic morphology in the hippocampus of the eEF2K-cKI mice. Proteomic analysis revealed changes in levels of proteins associated with neuropsychiatric and neurodegenerative disorders. Our findings present direct evidence supporting the pathophysiological role of aberrant eEF2K/eEF2 signaling in brain function and help provide insight into novel mechanisms and therapeutic avenues for neuronal diseases characterized by dementia and neuropsychiatric symptoms.

A novel in vivo toxicity profiling of solid lipid nanoparticles (SLNPs) in Vicia faba seedlings as a plant model.

The exposure of soft material templates to alternating volatile chemical precursors may produce inorganic deposition within a polymer template in a process referred to as sequential infiltration synthesis (SIS) or vapor phase infiltration (VPI). These processes, akin to atomic layer deposition (ALD), have most often been used to deposit metal oxides to produce robust hybrid thick films or fired to produce a porous oxide framework. We find that careful selection of precursors and process conditions for metal sulfide deposition may be leveraged to produce molecularly defined multi‐metal clusters with potential application to solar energy conversion and catalysis. More specifically, dimethyl cadmium and hydrogen sulfide precursors infiltrated into poly(4-vinylpyridine) thin films result in the 3D-nucleation of clusters consistent with a cubane-type Cd4S4 core. Similarly, the SIS of trimethylindium vapor and hydrogen sulfide gas into poly(methyl methacrylate) leads to the formation of clusters with uniform properties consistent with a magic size cluster - In6S6(CH3)6. A comparison between traditional (solution) and novel (vapor phase) syntheses of few-atom transition metal sulfide clusters will include prospects for molecular level control through leveraging the large library of ALD precursors and synthesis science. Figure 1

Higher education is undergoing a profound reconfiguration driven by accelerated digitalisation, emerging technologies, and the need to revisit its pedagogical frameworks to respond to dynamic social and productive contexts. This process involves not only technological adoption but also curricular transformation, changes in teaching models, and institutional relationships, positioning pedagogical innovation as a crucial strategy to enhance the quality and relevance of university education. Simultaneously, critical thinking is established as an indispensable competence within complex digital environments, where information abundance, artificial intelligence, and socio-economic challenges demand integrated analytical, evaluative, and metacognitive skills, alongside ethical and communicative dimensions. This study, through a systematic literature review guided by the PRISMA 2020 method, examines how pedagogical innovation strengthens critical thinking in digital higher education, following a rigorous protocol that organised the phases of search, selection, and synthesis of evidence. The findings indicate that the convergence of active methodologies, formative assessment, and technological integration creates opportunities to transform educational practices, yet its impact depends on alignment with solid pedagogical foundations and a deep understanding of the cognitive processes involved in fostering critical thinking, thereby establishing itself as a strategic pillar for educational improvement in the digital era.

This study uses high-resolution cryo-electron microscopy (cryo-EM) to reveal the precise binding site of the antibiotic GE81112 on the bacterial ribosome's 30S subunit. GE81112 targets the initiation phase of bacterial protein synthesis, specifically interacting within the mRNA channel, distant from the initiation factor and initiator tRNA-binding sites. This indicates that GE81112 acts allosterically, disrupting and preventing conformational rearrangements in IF3 and the proper positioning of the initiator tRNA, stalling the ribosome in an unlocked pre-initiation complex. The findings identify key ribosomal interactions, including conserved nucleotides in helices 23, 24, and 45, and protein S11, highlighting GE81112's unique binding mode among initiation inhibitors. This structural characterization enhances our understanding of antibiotic interference with translation initiation and provides insights to support rational design strategies for improved GE81112 derivatives.

Initiator and elongator tRNA recognition mechanism in Mycobacterium tuberculosis methionyl-tRNA synthetase

Unscheduled polyploidy synergizes with oncogenic mutations to enhance genome instability and tumorigenesis.

Abstract Since many decades ago, it is known that V oxides may be conductive, in addition to other interesting properties, as the ability to insert/extract cations and to form mixed valence oxides of different colors, which make them useful for the fabrication of devices in which electrons and cation transport are required, as well as batteries, supercapacitors, sensors, and electrochromic devices. This contribution documents, from a historical perspective, the advancements that have been made in the use of V‐oxide‐based materials in these devices with a detailed discussion on their synthesis methods, phases formed, and analysis of the applications to offer a coherent synthesis on the relationships between the structure and the behavior of the V‐based devices for energy applications.

The article addresses the insufficient attention paid by secondary school literature teaching to affective and social dimensions and examines the potential of play as a mediator for developing social-emotional skills in this process. Using a qualitative, exploratory, and documentary design, a systematic review of the literature (2010–2025) was conducted in databases such as Scopus, Web of Science, ERIC, Dialnet, and Redalyc, applying inclusion criteria on adolescence/secondary school, educational games, literary reading, and social-emotional skills. The analysis was organized into phases of screening, in-depth reading, and interpretive synthesis with thematic matrices. The findings converge in four dimensions: (i) play intensifies the emotional connection with texts by placing students in narrative roles and decisions; (ii) it promotes empathy, self-regulation, perspective-taking, and cooperation; (iii) there is low explicit integration between literary practices and playful methodologies; and (iv) there are persistent gaps in teacher training and resources to implement them. It is concluded that integrating playful structures into literary mediation is relevant and feasible, but requires intentional instructional design, teacher training, specific resources, and more empirical evidence, with attention to ethical and contextual considerations.

A novel polymorphic phase in NaGd(MoO4)2: Synthesis and temperature-induced phase transition

Enhanced sodium-ion energy storage with MoS₂@GO composites via hydrothermal synthesis and glucose-induced 1T phase transition

The critical role of the C-terminal lobe of calmodulin in activating eukaryotic elongation factor 2 kinase

Effects of the α-ketoglutaric acid on the performance, hair follicle development and antioxidant capacity of Rex rabbits

A rapidly expanding array of Artificial Intelligence (AI) tools, with continually evolving features and functionalities, offers unprecedented opportunities to streamline literature reviews, expediting the screening, extraction, and synthesis phases. We present preliminary findings of evaluating various AI tools' strengths and limitations.

EEF1D signaling contributes to Bovine alpha herpesvirus 1 productive infection, potentially through regulation of viral replication compartments.

The systematic collection, analysis, and interpretation of antimicrobial resistance (AMR) data are imperative to quantify the AMR burden, monitor and identify emerging AMR, and inform global, international, and national health strategies and guidelines. Despite ongoing global efforts to improve surveillance capacities across Nigeria and other African countries, laboratory information management systems (LIMS) that could improve data quality, and completeness remain underutilized. We used a participatory research approach, drawing on the unique experiences of various stakeholders, such as data analysts, laboratory scientists, infection prevention and control specialists, medical doctors, and representatives from the National Coordinating Center in Nigeria. Over two phases of evidence synthesis, involving in-depth interviews and a participatory co-design workshop, we sought to understand the experiences of key stakeholders in using the LIMS tool, WHONET, for AMR surveillance, and co-develop solutions and priorities to address the challenges they experience. We identified a complex interplay of systemic/political factors and structural/user-related factors that influence the use of WHONET as a LIMS. Key areas for intervention identified by stakeholders include addressing infrastructural deficits, enhancing stakeholder engagement, and improving the perceived usefulness of the system, as well as the need for management support. Stakeholders also identified 18 potential solutions to tackle key challenges, ten of which require low effort and have a high influence on LIMS use behaviors. Our study highlights the multifaceted challenges affecting the effective utilization of WHONET for AMR surveillance in Nigeria. The co-developed solutions provide a roadmap for targeted interventions to strengthen AMR surveillance capacity and inform evidence-based public health strategies.

Wound healing is a dynamic and intricate physiological process requiring adequate oxygenation to support cellular functions critical for tissue repair. Oxygen plays an essential role in all phases of wound healing, including inflammation, angiogenesis, collagen synthesis, and epithelialization. Inadequate oxygen supply, often observed in chronic wounds such as diabetic foot ulcers and pressure sores, can lead to delayed healing, infection, and poor clinical outcomes. As a result, therapeutic strategies aimed at improving oxygen availability in wound tissues have gained increasing attention. This narrative review explores the physiological role of oxygen in the wound healing process and examines the clinical utility of oxygen-based interventions. A focused literature search was conducted using online databases including PubMed, Scopus, and Google Scholar to identify relevant studies, reviews, and clinical guidelines on oxygen therapy in wound management. The review discusses key modalities of topical Oxygen delivery and innovative oxygen-delivery systems. While these techniques promise to promote healing in hypoxic and non-healing wounds, their use requires careful patient selection and clinical judgment. By summarizing current evidence and emerging trends, this review aims to provide clinicians and researchers with a comprehensive understanding of how oxygen therapy can be integrated into effective wound care strategies.