Aminoalkylation of Alkenes Enabled by Triple Radical Sorting.

The direct synthesis of C(sp)-rich architectures is a driving force for innovation in synthetic organic chemistry. Such scaffolds impart beneficial properties onto drug molecules that correlate with greater clinical success. Consequently, there is a strong impetus to develop new methods by which to access sp-rich molecules from commercial feedstocks, such as alkenes.

Clinical and patient-reported outcomes in women offered oncoplastic breast-conserving surgery as an alternative to mastectomy: ANTHEM multicentre prospective cohort study.

Background: Oncoplastic breast-conserving surgery may be a better option than mastectomy, but high-quality comparative evidence is lacking. The aim of the ANTHEM study (ISRCTN18238549) was to explore clinical and patient-reported outcomes in a multicentre cohort of women offered oncoplastic breast-conserving surgery as an alternative to mastectomy with or without immediate breast reconstruction.

Methods: Women with invasive/pre-invasive breast cancer who were offered oncoplastic breast-conserving surgery with volume replacement or displacement techniques to avoid mastectomy were recruited prospectively.

Parallel Proteomic and Transcriptomic Microenvironment Mapping (μMap) of Nuclear Condensates in Living Cells.

Cellular activity is spatially organized across different organelles. While several structures are well-characterized, many organelles have unknown roles. Profiling biomolecular composition is key to understanding function but is difficult to achieve in the context of small, dynamic structures.

Iron-Catalyzed Cross-Electrophile Coupling for the Formation of All-Carbon Quaternary Centers.

Quaternary carbon centers are desirable targets for drug discovery and complex molecule synthesis, yet the synthesis of these motifs within traditional cross-coupling paradigms remains a significant challenge due to competing β-hydride elimination pathways. In contrast, the bimolecular homolytic substitution (S2) mechanism offers a unique and attractive alternative pathway. Metal porphyrin complexes have emerged as privileged catalysts owing to their ability to selectively form primary metal-alkyl complexes, thereby eliminating the challenges associated with tertiary alkyl complexation with a metal center.

μMap-Interface: Temporal Photoproximity Labeling Identifies F11R as a Functional Member of the Transient Phagocytic Surfaceome.

Phagocytosis is usually carried out by professional phagocytic cells in the context of pathogen response or wound healing. The transient surface proteins that regulate phagocytosis pose a challenging proteomics target; knowledge thereof could lead to new therapeutic insights. Herein, we describe a novel photocatalytic proximity labeling method: "μMap-Interface", allowing for spatiotemporal mapping of phagocytosis.

Exploring maternal and developmental toxicity of perfluoroalkyl ether acids PFO4DA and PFO5DoA using hepatic transcriptomics and serum metabolomics.

Production of per- and polyfluoroalkyl substances (PFAS) has shifted from long-chain perfluoroalkyl acids to short-chain compounds and those with ether bonds in the carbon chain. Next-generation perfluoroalkylether PFAS include HFPO-DA ("GenX chemicals"), Nafion Byproducts, and the PFOx homologous series that includes perfluoro-3,5,7,9-butaoxadecanoic acid (PFO4DA) and perfluoro-3,5,7,9,11-pentaoxadodecanoic acid (PFO5DoA). PFO4DA and PFO5DoA have been detected in serum and/or tissues from humans and wildlife proximal to contamination point sources.

µMap proximity labeling in living cells reveals stress granule disassembly mechanisms.

Phase-separated condensates are membrane-less intracellular structures comprising dynamic protein interactions that organize essential biological processes. Understanding the composition and dynamics of these organelles advances our knowledge of cellular behaviors and disease pathologies related to granule dysregulation. In this study, we apply microenvironment mapping with a HaloTag-based platform (HaloMap) to characterize intracellular stress granule dynamics in living cells.

Understanding decision-making for and against oncoplastic breast-conserving surgery as an alternative to a mastectomy in early breast cancer: UK ANTHEM qualitative study.

Background: Oncoplastic breast-conserving surgery may allow women with early breast cancer to avoid a mastectomy, but many women undergo more extensive surgery, even when breast-conserving options are offered. The aim of the ANTHEM qualitative study was to explore factors influencing women's surgical decision-making for and against oncoplastic breast-conserving surgery.

Methods: Semi-structured interviews were conducted with a purposive sample of women who had received either oncoplastic breast-conserving surgery or a mastectomy with or without immediate breast reconstruction to explore their rationale for procedure choice.

Unlocking carbene reactivity by metallaphotoredox α-elimination.

The ability to tame high-energy intermediates is important for synthetic chemistry, enabling the construction of complex molecules and propelling advances in the field of synthesis. Along these lines, carbenes and carbenoid intermediates are particularly attractive, but often unknown, high-energy intermediates. Classical methods to access metal carbene intermediates exploit two-electron chemistry to form the carbon-metal bond.

Triple Radical Sorting: Aryl-Alkylation of Alkenes.

The cross-coupling of aryl bromides with alkenes can provide access to diverse combinatorial chemical space. Two-component couplings between these partners are well-known, but three-component aryl-functionalizations of unactivated alkenes remain underdeveloped. In particular, the aryl-alkylation of unactivated alkenes would allow for rapid construction of molecular complexity and the expedient exploration of a pharmaceutically relevant and C(sp)-rich structural landscape.

Free-Radical Deoxygenative Amination of Alcohols via Copper Metallaphotoredox Catalysis.

Alcohols are among the most abundant chemical feedstocks, yet they remain vastly underutilized as coupling partners in transition metal catalysis. Herein, we describe a copper metallaphotoredox manifold for the open shell deoxygenative coupling of alcohols with -nucleophiles to forge C()-N bonds, a linkage of high value in pharmaceutical agents that is challenging to access via conventional cross-coupling techniques. -heterocyclic carbene (NHC)-mediated conversion of alcohols into the corresponding alkyl radicals followed by copper-catalyzed C-N coupling renders this platform successful for a broad range of structurally unbiased alcohols and 18 classes of -nucleophiles.

A systematic scoping review of the neurological effects of COVID-19.

Background: The global coronavirus 2019 (COVID-19) pandemic began in early 2020, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). In mid-2020 the CIAO (Modelling the Pathogenesis of COVID-19 Using the Adverse Outcome Pathway Framework) project was established, bringing together over 75 interdisciplinary scientists worldwide to collaboratively investigate the underlying biological mechanisms of COVID-19 and consolidate the data using the Adverse Outcome Pathway (AOP) Framework. Neurological symptoms such as anosmia and encephalitis have been frequently reported to be associated with infection with SARS-CoV-2.

Current advances in photocatalytic proximity labeling.

Understanding the intricate network of biomolecular interactions that govern cellular processes is a fundamental pursuit in biology. Over the past decade, photocatalytic proximity labeling has emerged as one of the most powerful and versatile techniques for studying these interactions as well as uncovering subcellular trafficking patterns, drug mechanisms of action, and basic cellular physiology. In this article, we review the basic principles, methodologies, and applications of photocatalytic proximity labeling as well as examine its modern development into currently available platforms.

Engaging Alkenes in Metallaphotoredox: A Triple Catalytic, Radical Sorting Approach to Olefin-Alcohol Cross-Coupling.

Metallaphotoredox cross-coupling is a well-established strategy for generating clinically privileged aliphatic scaffolds via single-electron reactivity. Correspondingly, expanding metallaphotoredox to encompass new C()-coupling partners could provide entry to a novel, medicinally relevant chemical space. In particular, alkenes are abundant, bench-stable, and capable of versatile C()-radical reactivity via metal-hydride hydrogen atom transfer (MHAT), although metallaphotoredox methodologies invoking this strategy remain underdeveloped.

Alcohol-alcohol cross-coupling enabled by S2 radical sorting.

Alcohols represent a functional group class with unparalleled abundance and structural diversity. In an era of chemical synthesis that prioritizes reducing time to target and maximizing exploration of chemical space, harnessing these building blocks for carbon-carbon bond-forming reactions is a key goal in organic chemistry. In particular, leveraging a single activation mode to form a new C(sp)-C(sp) bond from two alcohol subunits would enable access to an extraordinary level of structural diversity.

Couple-close construction of polycyclic rings from diradicals.

Heteroarenes are ubiquitous motifs in bioactive molecules, conferring favourable physical properties when compared to their arene counterparts. In particular, semisaturated heteroarenes possess attractive solubility properties and a higher fraction of sp carbons, which can improve binding affinity and specificity. However, these desirable structures remain rare owing to limitations in current synthetic methods.

Development of a General Organophosphorus Radical Trap: Deoxyphosphonylation of Alcohols.

Here we report the design of a general, redox-switchable organophosphorus alkyl radical trap that enables the synthesis of a broad range of C()-P(V) modalities. This "plug-and-play" approach relies upon activation of alcohols and O═P(R)H motifs, two broadly available and inexpensive sources of molecular complexity. The mild, photocatalytic deoxygenative strategy described herein allows for the direct conversion of sugars, nucleosides, and complex pharmaceutical architectures to their organophosphorus analogs.

Consumer characteristics and preferences for mobulid gill plates in China.

Mobulid species are endangered globally, and the market trade for gill plates is believed to be a major threat. Successful conservation and the sustainable use of mobulids therefore require an objective understanding of consumer characteristics and preferences for gill plates. Previous studies focused on qualitative descriptions, and reliable quantitative analyses are currently lacking.

Direct Bioisostere Replacement Enabled by Metallaphotoredox Deoxydifluoromethylation.

The replacement of a functional group with its corresponding bioisostere is a widely employed tactic during drug discovery campaigns that allows medicinal chemists to improve the ADME properties of candidates while maintaining potency. However, the incorporation of bioisosteres typically requires lengthy de novo resynthesis of potential candidates, which represents a bottleneck in their broader evaluation. An alternative would be to directly convert a functional group into its corresponding bioisostere at a late stage.

Alkene dialkylation by triple radical sorting.

The development of bimolecular homolytic substitution (S2) catalysis has expanded cross-coupling chemistries by enabling the selective combination of any primary radical with any secondary or tertiary radical through a radical sorting mechanism. Biomimetic S2 catalysis can be used to merge common feedstock chemicals-such as alcohols, acids and halides-in various permutations for the construction of a single C(sp)-C(sp) bond. The ability to sort these two distinct radicals across commercially available alkenes in a three-component manner would enable the simultaneous construction of two C(sp)-C(sp) bonds, greatly accelerating access to complex molecules and drug-like chemical space.

The last resort requirement under REACH: From principle to practice.

REACH (Registration, Evaluation, Authorisation and Restriction of Chemicals) is a European Union regulation that aims to protect human health and the environment from the risks posed by chemicals. Article 25 clearly states that: "[i]n order to avoid animal testing, testing on vertebrate animals for the purposes of this Regulation shall be undertaken only as a last resort." In practice, however, the standard information requirements under REACH are still primarily filled using animal studies.

Dose Response, Dosimetric, and Metabolic Evaluations of Replacement PFAS Perfluoro-(2,5,8-trimethyl-3,6,9-trioxadodecanoic) Acid (HFPO-TeA).

Few studies are available on the environmental and toxicological effects of perfluoroalkyl ether carboxylic acids (PFECAs), such as GenX, which are replacing legacy PFAS in manufacturing processes. To collect initial data on the toxicity and toxicokinetics of a longer-chain PFECA, male and female Sprague Dawley rats were exposed to perfluoro-(2,5,8-trimethyl-3,6,9-trioxadodecanoic) acid (HFPO-TeA) by oral gavage for five days over multiple dose levels (0.3-335.

HIV reservoirs are dominated by genetically younger and clonally enriched proviruses.

Characterizing the human immunodeficiency virus (HIV) reservoir that endures despite antiretroviral therapy (ART) is critical to cure efforts. We observed that the oldest proviruses persisting during ART were exclusively defective, while intact proviruses (and rebound HIV) dated to nearer ART initiation. This helps explain why studies that sampled sub-genomic proviruses on-ART (which are largely defective) routinely found sequences dating to early infection, whereas those that sampled replication-competent HIV found almost none.

Exploiting the Marcus inverted region for first-row transition metal-based photoredox catalysis.

Second- and third-row transition metal complexes are widely employed in photocatalysis, whereas earth-abundant first-row transition metals have found only limited use because of the prohibitively fast decay of their excited states. We report an unforeseen reactivity mode for productive photocatalysis that uses cobalt polypyridyl complexes as photocatalysts by exploiting Marcus inverted region behavior that couples increases in excited-state energies with increased excited-state lifetimes. These cobalt (III) complexes can engage in bimolecular reactivity by virtue of their strong redox potentials and sufficiently long excited-state lifetimes, catalyzing oxidative C(sp)-N coupling of aryl amides with challenging sterically hindered aryl boronic acids.