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Abstract We introduce a versatile metal-organic framework (MOF) for encapsulation and immobilization of various guests using highly ordered internal water network. The unique water-mediated entrapment mechanism is applied for structural elucidation of 14 bioactive compounds, including 3 natural product intermediates whose 3D structures are clarified. The single-crystal X-ray diffraction analysis reveals that incorporated guests are surrounded by hydrogen-bonded water networks inside the pores, which uniquely adapt to each molecule, providing clearly defined crystallographic sites. The calculations of host-solvent-guest structures show that the guests are primarily interacting with the MOF through weak dispersion forces. In contrast, the coordination and hydrogen bonds contribute less to the total stabilization energy, however, they provide highly directional point interactions, which help align the guests inside the pore.

Abstract Off-target interactions between antisense oligonucleotides (ASOs) with state-of-the-art modifications and biological components still pose clinical safety liabilities. To mitigate a broad spectrum of off-target interactions and enhance the safety profile of ASO drugs, we here devise a nanoarchitecture named BRace On a THERapeutic aSo (BROTHERS or BRO), which is composed of a standard gapmer ASO paired with a partially complementary peptide nucleic acid (PNA) strand. We show that these non-canonical ASO/PNA hybrids have reduced non-specific protein-binding capacity. The optimization of the structural and thermodynamic characteristics of this duplex system enables the operation of an in vivo toehold-mediated strand displacement (TMSD) reaction, effectively reducing hybridization with RNA off-targets. The optimized BROs dramatically mitigate hepatotoxicity while maintaining the on-target knockdown activity of their parent ASOs in vivo. This technique not only introduces a BRO class of drugs that could have a transformative impact on the extrahepatic delivery of ASOs, but can also help uncover the toxicity mechanism of ASOs.

Abstract The stellar optoelectronic properties of metal halide perovskites provide enormous promise for next-generation optical devices with excellent conversion efficiencies and lower manufacturing costs. However, there is a long-standing ambiguity as to whether the perovskite surface/interface (e.g. structure, charge transfer or source of off-target recombination) or bulk properties are the more determining factor in device performance. Here we fabricate an array of CsPbI3 crystal and hybrid glass composites by sintering and globally visualise the property-performance landscape. Our findings reveal that the interface is the primary determinant of the crystal phases, optoelectronic quality, and stability of CsPbI3. In particular, the presence of a diffusion “alloying” layer is discovered to be critical for passivating surface traps, and beneficially altering the energy landscape of crystal phases. However, high-temperature sintering results in the promotion of a non-stoichiometric perovskite and excess traps at the interface, despite the short-range structure of halide is retained within the alloying layer. By shedding light on functional hetero-interfaces, our research offers the key factors for engineering high-performance perovskite devices.

Abstract We investigate laccase-mediated detoxification of aflatoxins, fungal carcinogenic food contaminants. Our experimental comparison between two aflatoxins with similar structures (AFB1 and AFG2) shows significant differences in laccase-mediated detoxification. A multi-scale modeling approach (Docking, Molecular Dynamics, and Density Functional Theory) identifies the highly substrate-specific changes required to improve laccase detoxifying performance. We employ a large-scale density functional theory-based approach, involving more than 7000 atoms, to identify the amino acid residues that determine the affinity of laccase for aflatoxins. From this study we conclude: (1) AFB1 is more challenging to degrade, to the point of complete degradation stalling; (2) AFG2 is easier to degrade by laccase due to its lack of side products and favorable binding dynamics; and (3) ample opportunities to optimize laccase for aflatoxin degradation exist, especially via mutations leading to π–π stacking. This study identifies a way to optimize laccase for aflatoxin bioremediation and, more generally, contributes to the research efforts aimed at rational enzyme optimization.

Organic crystals assembled by a well-established family of electron donors, tetrathiafulvalene (TTF)-based molecules, hold great potential for electronics, smart materials, and superconductors. Combining with Marcus' theory and first-principles calculations, we have adopted a fragment charge difference (FCD) method to investigate the charge transfer properties of the TTF-based crystals. Our FCD predictions are highly consistent with those obtained from a well-accepted site energy correction method. We have demonstrated the significant influence of both structure and chemistry on the charge transfer properties using polymorphs, i.e., α-phase tetrathiafulvalene (1) versus β-phase tetrathiafulvalene (2), and crystals with homologous molecular packings, i.e., 1 versus dithiophene-TTF (3). We have also introduced multiple factors to provide further insights into the variation in charge transfer properties of the TTF-based crystals, including energy gap (∆E), centroid distance (ri), orbital distribution correction factor (Hs), and reorganization energy (λ). By taking advantage of our analysis, we have rationalized high mobility in hexamethylene-TTF (4) and low mobility in bis(ethylenedithio)-TTF (5). Our multiple-factor evaluation could support an approach to designing electrically conducting TTF-based materials and provide a method to estimate charge transfer properties effectively.

Purpose: This research aims to understand employers' views and preferences on the assessment of holistic competencies (HCs) in graduates, a topic with existing gaps in literature. With the disparities between higher education practices and employer expectations concerning HC assessment, the study focuses on what employers wish to see in graduates' resumes. As resumes play a pivotal role in recruitment, influencing who gets shortlisted, this research seeks to discern how graduates can optimally make a good first impression. In essence, the study endeavours to enhance knowledge on employers' inferences about a candidate's HCs and employability skills based on resume content. Design/methodology/approach: A comprehensive 12-item survey was devised to collect employers' perceptions and expectations of holistic competencies (HCs) assessment. The survey was informed by a synthesis of discussions with employers, teachers and a critical review paper. It aimed to understand employers' HC assessment expectations and bridge the teachers' understanding gap of students' HC achievements. Questions included demographic data, and specifics about employers' perceptions of graduates' resumes. The survey was hosted on Qualtrics and disseminated via the authors' networks, social media and university departments in Hong Kong, with responses gathered from April to June 2021. Findings: This study reveals that employers value holistic competencies (HCs), especially those developed through work placements and extracurricular activities, as indicators of job readiness in graduates. It is imperative for students to highlight these competencies in their resumes, potentially also demonstrating them through digital portfolios. The research underscores the need for higher education institutions to systematically document and report students' HC attainments. They can support students by informing them about employer expectations, offering writing workshops and resume samples. Integrating experience-based opportunities into the curriculum can also enhance HC development, preparing students for job market competitiveness and readiness. Research limitations/implications: The research limitations include the lack of a widely accepted, standardized method to document and evidence students' holistic competencies (HCs). The implications, however, stress the necessity for students to effectively communicate their HCs to employers, requiring awareness of expectations and adaptability to evolving technologies. Educators and higher education institutions must provide resources and opportunities to students to develop, demonstrate and document these HCs. In the absence of a standardised method for HC reporting, alternative solutions like e-portfolios and platforms like YOCLE can help students gather feedback and present evidence of competencies to prospective employers. Practical implications: The study's practical implications revolve around enhancing job readiness in graduates. Universities need to bolster their support, helping students understand employer expectations, offering writing workshops, resume templates and resources. Incorporation of platforms like YOCLE can help gather and retain evaluations, while promoting internships and extracurricular activities enhances HC development. Graduates must include work experiences, HC achievements and extracurricular activities in their resumes, even exploring digital portfolios for broader evidence presentation. They should also prepare for digital interactions like Zoom calls or video resumes, adapting to the technological advancements propelled by recent global disruptions. Originality/value: This research provides original insights into employer preferences regarding job candidates' holistic competencies (HCs) in resumes, an area not deeply explored in past literature. Focusing on how resumes can best demonstrate HC attainments, it offers practical guidance for higher education institutions preparing students for the job market. Although the study's scope is limited by geographical and industry-specific sampling, it provides a foundational understanding of employers' recruitment expectations influenced by resumes. Its value lies in its potential to spur further research into varying contexts and industries, leading to broader implications for graduate employability and resume building practices worldwide.

We compare the results from the oxidation of two unusual "enediamide" motifs (3,4-dihydropyrazin-2(1H)-ones), where a double bond is flanked by two amides. In one case the oxidation led to a ring-opened product arising from the cleavage of the double bond, and in the other a rare cis-dioxygenated compound was obtained. Both products have been characterized by X-ray crystallography. The outcomes of the key reactions are rationalized based on calculated free energies of intermediates.

Since 2014, highly pathogenic avian influenza viruses (HPAIVs) with H5 hemagglutinin (HA) genes grouped in the genetic clade 2.3.4.4 have spread globally causing severe outbreaks in Africa, Europe, Asia, and [...]

Sporadic inclusion body myositis (sIBM) is a distinct subcategory of Idiopathic Inflammatory Myopathies (IIM), characterized by unique pathological features such as muscle inflammation, rimmed vacuoles, and protein aggregation within the myofibers. Although hyperactivation of the immune system is widely believed as the primary cause of IIM, it is debated whether non-immune tissue dysfunction might contribute to the disease’s onset as patients with sIBM are refractory to conventional immunosuppressant treatment. Moreover, the findings that mitochondrial dysfunction can elicit non-apoptotic programmed cell death and the subsequent immune response further support this hypothesis. Notably, abnormal mitochondrial structure and activities are more prominent in the muscle of sIBM than in other types of IIM, suggesting the presence of defective mitochondria might represent an overlooked contributor to the disease onset. The large-scale mitochondrial DNA deletion, aberrant protein aggregation, and slowed organelle turnover have provided mechanistic insights into the genesis of impaired mitochondria in sIBM. This article reviews the disease hallmarks of sIBM, the plausible contributors of mitochondrial damage in the sIBM muscle, and the immunological responses associated with mitochondrial perturbations. Additionally, the potential application of mitochondrial-targeted chemicals as a new treatment strategy to sIBM is explored and discussed. [ABSTRACT FROM AUTHOR]

Background/Aims: Fibronectin type III domain-containing protein 5 (FNDC5), also known as irisin, is a myokine secreted from muscle in response to exercise. However, the molecular mechanisms that regulate FNDC5 expression and the functional significance of irisn in skeletal muscle remain unknown. In this study, we explored the potential pathways that induce FNDC5 expression and delineated the metabolic effects of irisin on skeletal muscle. Methods: C2C12 myotubes were treated with drugs at various concentrations and durations. The expression and activation of genes were measured by real-time polymerase chain reaction (qRT-PCR) and Western blotting. Oxidative phosphorylation was quantified by measuring the oxygen consumption rate (OCR). Results: We found that the exercise-mimicking treatment (cAMP, forskolin and isoproterenol) increased Fndc5 expression in C2C12 myotubes. CREB over-expressed C2C12 myotubes displayed higher Fndc5 expression. CREB over-expression also promoted peroxisome proliferator-activated receptor gamma coactivator 1α (PGC-1α) expression. PGC-1α-induced Fndc5 expression was blocked when the dominant negative form of CREB (S133A) was present. PGC-1α mutation (S570A) also decreased Fndc5 expression. Immunoprecipitation showed that overexpressed PGC-1α complexed with CREB in HEK293 cells. C2C12 myotubes treated with forskolin also increased endogenous CREB and PGC-1α binding. Functionally, irisin treatment increased mitochondrial respiration, enhanced ATP production, promoted fatty acid oxidation but decreased glycolysis in myotubes. Conclusion: Our observation indicates that cAMP-mediated PGC-1α/CREB interaction triggers Fndc5 expression, which acts as an autocrine/paracrine to shape the metabolic phenotype of myotubes.

In the present study, we have examined the utility of counterpoise (CP) corrections, the zerocost geometric counterpoise (gCP) correction, and the double-ζ vDZP basis set, in representative examples of computational chemistry investigations. The tests include reaction energies and barriers in mechanisms of catalysis, and binding of substrates with enzyme active sites. Drawbacks of the CP approach include: it is more costly than calculations with the same basis set without applying CP corrections, multiple computations may be required where a single species is used in multiple instances, and it is only applicable to intermolecular interactions. In comparison, using gCP or vDZP is less costly. Their overall accuracy is comparable to CP, although the three approaches show variable performances for different systems. Thus, the use of a large basis set remains more consistent in obtaining results that are closer to the basis-set limit. Where the computational cost poses a challenge, the use of gCP or vDZP would be more advantageous than CP in terms of cost and simplicity. [ABSTRACT FROM AUTHOR]