(Phenoxyimine)nickel-Catalyzed C(sp2)-C(sp3) Suzuki-Miyaura Cross-Coupling: Evidence for a Recovering Radical Chain Mechanism.

Phenoxyimine (FI)-nickel(II)(2-tolyl)(DMAP) compounds were synthesized and evaluated as precatalysts for the C(sp2)-C(sp3) Suzuki-Miyaura cross coupling of (hetero)arylboronic acids with alkyl bromides. With 5 mol % of the optimal (MeOMeFI)Ni(Aryl)(DMAP) precatalyst, the scope of the cross-coupling reaction was established and included a variety of (hetero)arylboronic acids and alkyl bromides (>50 examples, 33-97% yield). A ß-hydride elimination-reductive elimination sequence from reaction with potassium isopropoxide base, yielding a potassium (FI)nickel(0)ate, was identified as a catalyst activation pathway that is responsible for halogen atom abstraction from the alkyl bromide. A combination of NMR and EPR spectroscopies identified (FI)nickel(II)-aryl complexes as the resting state during catalysis with no evidence for long-lived organic radical or odd-electron nickel intermediates. These data establish that the radical chain is short-lived and undergoes facile termination and also support a "recovering radical chain" process whereby the (FI)nickel(II)-aryl compound continually (re)initiates the radical chain. Kinetic studies established that the rate of C(sp2)-C(sp3) product formation was proportional to the concentration of the (FI)nickel(II)-aryl resting state that captures the alkyl radical for chain propagation. The proposed mechanism involves two key and concurrently operating catalytic cycles; the first involving a nickel(I/II/III) radical propagation cycle consisting of radical capture at (FI)nickel(II)-aryl, C(sp2)-C(sp3) reductive elimination, bromine atom abstraction from C(sp3)-Br, and transmetalation; and the second involving an off-cycle catalyst recovery process by slow (FI)nickel(II)-aryl → (FI)nickel(0)ate conversion for nickel(I) regeneration.

Do comparative judgements affect the perceived relevance of mobile phone road safety campaigns?

OBJECTIVE: Given the prevalence of illegal mobile phone use while driving and reliance upon messaging campaigns in deterring the behavior, there is a need to explore to what extent comparative judgements may influence desired outcomes of such campaigns. This exploratory study investigated (a) the perceived relevance and influence of different mobile phone road safety campaigns within a sample of Queensland motorists who reported using their mobile phone while driving and (b) if these varied depending on whether participants believed that their crash risk whilst using a phone was higher (comparative pessimism), lower (comparative optimism) or similar to the same-age and sex driver. METHODS: A total of 350 licensed drivers residing within Queensland (Australia) were included in this study, of which 200 reported using their hand-held phone on some occasion. Participation involved completing a 20-25 min online anonymous survey, which included viewing three mobile phone road safety campaigns (injury-based, sanction-based and humor) and responding to questions about the perceived relevance and impact of each campaign. RESULTS: A total of 64 (32%) participants displayed comparative optimism, 50 displayed similar judgements (25%) and 86 (43%) exhibited comparative pessimism. First, it was found that the injury-based campaign was perceived to be significantly more relevant than the humor campaign. Second, whilst the relevance of each campaign did not vary as a function of group membership, the campaigns were significantly less relevant to those displaying comparative optimism relative to those with similar judgements and comparative pessimism. Finally, the injury-based campaign was perceived to be significantly more influential than the other campaigns. However, overall, participants displaying comparative optimism believed that they would be less influenced by the campaigns compared to those with comparative pessimism. CONCLUSIONS: Although preliminary, these findings suggest that low perceptions of risk may dilute or extinguish the desired behavioral outcomes of mobile phone road safety campaigns. Nonetheless, experimental research is needed to examine these effects directly.

Phenoxythiazoline (FTz)-Cobalt(II) Precatalysts Enable C(sp2 )-C(sp3 ) Bond-Formation for Key Intermediates in the Synthesis of Toll-like Receptor 7/8 Antagonists.

Evaluation of the relative rates of the cobalt-catalyzed C(sp2 )-C(sp3 ) Suzuki-Miyaura cross-coupling between the neopentylglycol ester of 4-fluorophenylboronic acid and N-Boc-4-bromopiperidine established that smaller N-alkyl substituents on the phenoxyimine (FI) supporting ligand accelerated the overall rate of the reaction. This trend inspired the design of optimal cobalt catalysts with phenoxyoxazoline (FOx) and phenoxythiazoline (FTz) ligands. An air-stable cobalt(II) precatalyst, (FTz)CoBr(py)3 was synthesized and applied to the cross-coupling of an indole-5-boronic ester nucleophile with a piperidine-4-bromide electrophile that is relevant to the synthesis of reported toll-like receptor (TLR) 7/8 antagonist molecules including afimetoran. Addition of excess KOMe⋅B(Oi Pr)3 improved catalyst lifetime due to attenuation of alkoxide basicity that otherwise resulted in demetallation of the FI chelate. A first-order dependence on the cobalt precatalyst and a saturation regime in nucleophile were observed, supporting turnover-limiting transmetalation and the origin of the observed trends in N-imine substitution.

Mechanistic Investigations of Phenoxyimine-Cobalt(II)-Catalyzed C(sp2)-C(sp3) Suzuki-Miyaura Cross-Coupling.

The mechanism of phenoxyimine (FI)-cobalt-catalyzed C(sp2)-C(sp3) Suzuki-Miyaura cross-coupling was studied using a combination of kinetic measurements and catalytic and stoichiometric experiments. A series of dimeric (FI)cobalt(II) bromide complexes, [(4-CF3PhFI)CoBr]2, [(4-OMePhFI)CoBr]2, and [(2,6-diiPrPhFI)CoBr]2, were isolated and characterized by 1H and 19F NMR spectroscopies, solution and solid-state magnetic susceptibility, electron paramagnetic resonance (EPR) spectroscopy, X-ray crystallography, and diffusion-ordered NMR spectroscopy (DOSY). One complex, [(4-CF3PhFI)CoBr]2, was explored as a single-component precatalyst for C(sp2)-C(sp3) Suzuki-Miyaura cross-coupling. Addition of potassium methoxide to [(4-CF3PhFI)CoBr]2 generated the corresponding (FI)cobalt(II) methoxide complex as determined by 1H and 19F NMR and EPR spectroscopies. These spectroscopic signatures were used to identify this compound as the resting state during catalytic C(sp2)-C(sp3) coupling. Variable time normalization analysis (VTNA) of in situ catalytic 19F NMR spectroscopic data was used to establish an experimental rate law that was first-order in a (FI)cobalt(II) precatalyst, zeroth-order in the alkyl halide, and first-order in an activated potassium methoxide-aryl boronate complex. These findings are consistent with turnover-limiting transmetalation that occurs prior to activation of the alkyl bromide electrophile. The involvement of boronate intermediates in transmetalation was corroborated by Hammett studies of electronically differentiated aryl boronic esters. Together, a cobalt(II)/cobalt(III) catalytic cycle was proposed that proceeds through a "boronate"-type mechanism.

The evolution of white-tailed jackrabbit camouflage in response to past and future seasonal climates.

The genetic basis of adaptive traits has rarely been used to predict future vulnerability of populations to climate change. We show that light versus dark seasonal pelage in white-tailed jackrabbits (Lepus townsendii) tracks snow cover and is primarily determined by genetic variation at endothelin receptor type B (EDNRB), corin serine peptidase (CORIN), and agouti signaling protein (ASIP). Winter color variation was associated with deeply divergent alleles at these genes, reflecting selection on both ancestral and introgressed variation. Forecasted reductions in snow cover are likely to induce widespread camouflage mismatch. However, simulated populations with variation for darker winter pelage are predicted to adapt rapidly, providing a trait-based genetic framework to facilitate evolutionary rescue. These discoveries demonstrate how the genetic basis of climate change adaptation can inform conservation.

Colour moult phenology and camouflage mismatch in polymorphic populations of Arctic foxes.

Species that seasonally moult from brown to white to match snowy backgrounds become conspicuous and experience increased predation risk as snow cover duration declines. Long-term adaptation to camouflage mismatch in a changing climate might occur through phenotypic plasticity in colour moult phenology and or evolutionary shifts in moult rate or timing. Also, adaptation may include evolutionary shifts towards winter brown phenotypes that forgo the winter white moult. Most studies of these processes have occurred in winter white populations, with little attention to polymorphic populations with sympatric winter brown and winter white morphs. Here, we used remote camera traps to record moult phenology and mismatch in two polymorphic populations of Arctic foxes in Sweden over 2 years. We found that the colder, more northern population moulted earlier in the autumn and later in the spring. Next, foxes moulted earlier in the autumn and later in the spring during colder and snowier years. Finally, white foxes experienced relatively low camouflage mismatch while blue foxes were mismatched against snowy backgrounds most of the autumn through the spring. Because the brown-on-white mismatch imposes no evident costs, we predict that as snow duration decreases, increasing blue morph frequencies might help facilitate species persistence.

Cobalt-Catalyzed C(sp2)-C(sp3) Suzuki-Miyaura Cross-Coupling Enabled by Well-Defined Precatalysts with L,X-Type Ligands.

Cobalt(II) halides in combination with phenoxy-imine (FI) ligands generated efficient precatalysts in situ for the C(sp2)-C(sp3) Suzuki-Miyaura cross coupling between alkyl bromides and neopentylglycol (hetero)arylboronic esters. The protocol enabled efficient C-C bond formation with a host of nucleophiles and electrophiles (36 examples, 34-95%) with precatalyst loadings of 5 mol%. Studies with alkyl halide electrophiles that function as radical clocks support the intermediacy of alkyl radicals during the course of the catalytic reaction. The improved performance of the FI-cobalt catalyst was correlated with decreased lifetimes of cage-escaped radicals as compared to diamine-type ligands. Studies of the phenoxy(imine)-cobalt coordination chemistry validate the L,X interaction leading to the discovery of an optimal, well defined, air-stable mono-FI cobalt(II) precatalyst structure.

Contrasting seasonal effects of climate change influence density in a cold-adapted species.

Many ecological processes are profoundly influenced by abiotic factors, such as temperature and snow. However, despite strong evidence linking shifts in these ecological processes to corresponding shifts in abiotic factors driven by climate change, the mechanisms connecting population size to season-specific climate drivers are little understood. Using a 21-year dataset and a Bayesian state space model, we identified biologically informed seasonal climate covariates that influenced densities of snowshoe hares (Lepus americanus), a cold-adapted boreal herbivore. We found that snow and temperature had strong but conflicting season-dependent effects. Reduced snow duration in spring and fall and warmer summers were associated with lowered hare density, whereas warmer winters were associated with increased density. When modeled simultaneously and under two climate change scenarios, the negative effects of reduced fall and spring snow duration and warmer summers overwhelm the positive effect of warmer winters, producing projected population declines. Ultimately, the contrasting population-level impacts of climate change across seasons emphasize the critical need to examine the entire annual climate cycle to understand potential long-term population consequences of climate change.

Decyanation-(hetero)arylation of malononitriles to access α-(hetero)arylnitriles.

Quaternary α-(hetero)arylnitriles are desirable biologically relevant products, however the existing methods for their synthesis can be unselective or require the use of undesirable reagents, such as cyanide salts. Herein we report a one-pot method for transnitrilation-mediated decyanation-metalation of disubstituted malononitriles, followed by treatment with (hetero)aryl electrophiles to access quaternary α-(hetero)arylnitrile products. A number of products were prepared using this method (34 examples, 27-99% yield). This method highlights the usefulness of malononitriles as precursors for alkylnitrile-containing compounds.

Feasibility and outcomes of a general practice and specialist alcohol and other drug collaborative care program in Sydney, Australia.

Alcohol and other drug (AoD) use is an important health and community issue and may be positively affected by collaborative care programs between specialist AoD services and general practice. This paper describes the feasibility, model of care and patient outcomes of a pilot general practice and specialist AoD (GP-AoD) collaborative care program, in Sydney, Australia, based on usual care data, the minimum data set, service utilisation information and the Australian Treatment Outcome Profile (ATOP), a patient-reported outcome measure. There were 367 referrals to the collaborative care program. GPs referred 210 patients, whereas the AoD service referred 157 patients. Most GP referrals (91.9%) were for AoD problems, whereas nearly half the AoD service referrals were for other issues. The primary drugs of concern in the GP group were either opioids or non-opioids (mostly alcohol). The AoD service-referred patients were primarily using opioids. An ATOP was completed for 152 patients. At the time of referral, those in the GP-referred non-opioid group were significantly less likely to be abstinent, used their primary drug of concern more days and were more likely to be employed (all P < 0.001). A second ATOP was completed for 93 patients. These data showed a significant improvement in the number of days the primary drug of concern was used (P = 0.026) and trends towards abstinence, improved quality of life and physical and psychological well-being for patients in the program. There are few studies of GP-AoD collaborative care programs and nothing in the Australian context. This study suggests that GP-AoD collaborative care programs in Australia are feasible and improve drug use.

Ni-Catalyzed Synthesis of Thiocarboxylic Acid Derivatives.

A Ni-catalyzed cross-coupling of readily accessible O-alkyl xanthate esters or thiocarbonyl imidazolides and organozinc reagents for the synthesis of thiocarboxylic acid derivatives has been developed. This method benefits from a fast reaction time, mild reaction conditions, and ease of starting material synthesis. The use of transition-metal catalysis to access a diverse range of thiocarbonyl-containing compounds provides a useful complementary approach when compared with previously established methodologies.

Immunocompromised children and young people are at no increased risk of severe COVID-19.

OBJECTIVES: We aimed to prospectively describe the incidence and clinical spectrum of SARS-CoV-2 infection in immunocompromised paediatric patients in the UK. METHODS: From March 2020 to 2021 weekly questionnaires were sent to immunocompromised paediatric patients or their parents. Information, including symptom presentation and SARS-CoV-2 PCR test results, was collected from 1527 participants from 46 hospitals. Cross-sectional serology was investigated in February and March 2021. RESULTS: Until the end of September 2020, no cases were reported. From September 28th 2020 to March 2021 a total of 38 PCR-detected SARS-CoV-2 infections were reported. Of these, four children were admitted to hospital but none had acute severe COVID-19. Increasing age in association with immunodeficiency increased reporting of SARS-CoV-2 infection. Worsening of fever, cough, and sore throat were associated with participants reporting SARS-CoV-2 infection. Serology data included 452 unvaccinated participants. In those reporting prior positive SARS-CoV-2 PCR, there were detectable antibodies in 9 of 18 (50%). In those with no prior report of infection, antibodies were detected in 32 of 434 (7•4%). CONCLUSIONS: This study shows SARS-CoV-2 infections have occurred in immunocompromised children and young people with no increased risk of severe disease. No children died.

Design of an Electron-Withdrawing Benzonitrile Ligand for Ni-Catalyzed Cross-Coupling Involving Tertiary Nucleophiles.

The design of new ligands for cross-coupling is essential for developing new catalytic reactions that access valuable products such as pharmaceuticals. In this report, we exploit the reactivity of nitrile-containing additives in Ni catalysis to design a benzonitrile-containing ligand for cross-coupling involving tertiary nucleophiles. Kinetic and Hammett studies are used to elucidate the role of the optimized ligand, which demonstrate that the benzonitrile moiety acts as an electron-acceptor to promote reductive elimination over ß-hydride elimination and stabilize low-valent Ni. With these conditions, a protocol for decyanation-metalation and Ni-catalyzed arylation is conducted, enabling access to quaternary α-arylnitriles from disubstituted malononitriles.

Museomics Dissects the Genetic Basis for Adaptive Seasonal Coloration in the Least Weasel.

Dissecting the link between genetic variation and adaptive phenotypes provides outstanding opportunities to understand fundamental evolutionary processes. Here, we use a museomics approach to investigate the genetic basis and evolution of winter coat coloration morphs in least weasels (Mustela nivalis), a repeated adaptation for camouflage in mammals with seasonal pelage color moults across regions with varying winter snow. Whole-genome sequence data were obtained from biological collections and mapped onto a newly assembled reference genome for the species. Sampling represented two replicate transition zones between nivalis and vulgaris coloration morphs in Europe, which typically develop white or brown winter coats, respectively. Population analyses showed that the morph distribution across transition zones is not a by-product of historical structure. Association scans linked a 200-kb genomic region to coloration morph, which was validated by genotyping museum specimens from intermorph experimental crosses. Genotyping the wild populations narrowed down the association to pigmentation gene MC1R and pinpointed a candidate amino acid change cosegregating with coloration morph. This polymorphism replaces an ancestral leucine residue by lysine at the start of the first extracellular loop of the protein in the vulgaris morph. A selective sweep signature overlapped the association region in vulgaris, suggesting that past adaptation favored winter-brown morphs and can anchor future adaptive responses to decreasing winter snow. Using biological collections as valuable resources to study natural adaptations, our study showed a new evolutionary route generating winter color variation in mammals and that seasonal camouflage can be modulated by changes at single key genes.

Selective Carbon-Carbon Bond Cleavage of Cyclopropanols.

The carbon-carbon (C-C) bond cleavage of cyclopropanols is a wide area of research with much current activity. This review highlights new developments in this area over the past two decades. A summary is made of the three main reactivity modes, namely, homoenolate chemistry, ß-keto radical chemistry, and acid-catalyzed ring-opening, as well as all other methods for the C-C bond cleavage and functionalization of cyclopropanols, including base-mediated ring-opening, metal-catalyzed C-C insertions and eliminations, oxidative fragmentation using hypervalent iodine reagents, reactions of donor-acceptor cyclopropanols, and pericylic reactions. Emphasis is placed on the synthetic utility of cyclopropanols and related derivatives, which have emerged as unique three-carbon synthons.

The Legacy of Recurrent Introgression during the Radiation of Hares.

Hybridization may often be an important source of adaptive variation, but the extent and long-term impacts of introgression have seldom been evaluated in the phylogenetic context of a radiation. Hares (Lepus) represent a widespread mammalian radiation of 32 extant species characterized by striking ecological adaptations and recurrent admixture. To understand the relevance of introgressive hybridization during the diversification of Lepus, we analyzed whole exome sequences (61.7 Mb) from 15 species of hares (1-4 individuals per species), spanning the global distribution of the genus, and two outgroups. We used a coalescent framework to infer species relationships and divergence times, despite extensive genealogical discordance. We found high levels of allele sharing among species and show that this reflects extensive incomplete lineage sorting and temporally layered hybridization. Our results revealed recurrent introgression at all stages along the Lepus radiation, including recent gene flow between extant species since the last glacial maximum but also pervasive ancient introgression occurring since near the origin of the hare lineages. We show that ancient hybridization between northern hemisphere species has resulted in shared variation of potential adaptive relevance to highly seasonal environments, including genes involved in circadian rhythm regulation, pigmentation, and thermoregulation. Our results illustrate how the genetic legacy of ancestral hybridization may persist across a radiation, leaving a long-lasting signature of shared genetic variation that may contribute to adaptation. [Adaptation; ancient introgression; hybridization; Lepus; phylogenomics.].

Lack of phenological shift leads to increased camouflage mismatch in mountain hares.

Understanding whether organisms will be able to adapt to human-induced stressors currently endangering their existence is an urgent priority. Globally, multiple species moult from a dark summer to white winter coat to maintain camouflage against snowy landscapes. Decreasing snow cover duration owing to climate change is increasing mismatch in seasonal camouflage. To directly test for adaptive responses to recent changes in snow cover, we repeated historical (1950s) field studies of moult phenology in mountain hares (Lepus timidus) in Scotland. We found little evidence that population moult phenology has shifted to align seasonal coat colour with shorter snow seasons, or that phenotypic plasticity prevented increases in camouflage mismatch. The lack of responses resulted in 35 additional days of mismatch between 1950 and 2016. We emphasize the potential role of weak directional selection pressure and low genetic variability in shaping the scope for adaptive responses to anthropogenic stressors.

Identifying Candidate Genetic Markers of CDV Cross-Species Pathogenicity in African Lions.

Canine distemper virus (CDV) is a multi-host pathogen with variable clinical outcomes of infection across and within species. We used whole-genome sequencing (WGS) to search for viral markers correlated with clinical distemper in African lions. To identify candidate markers, we first documented single-nucleotide polymorphisms (SNPs) differentiating CDV strains associated with different clinical outcomes in lions in East Africa. We then conducted evolutionary analyses on WGS from all global CDV lineages to identify loci subject to selection. SNPs that both differentiated East African strains and were under selection were mapped to a phylogenetic tree representing global CDV diversity to assess if candidate markers correlated with documented outbreaks of clinical distemper in lions (n = 3). Of 54 SNPs differentiating East African strains, ten were under positive or episodic diversifying selection and 20 occurred in the clinical strain despite strong purifying selection at those loci. Candidate markers were in functional domains of the RNP complex (n = 19), the matrix protein (n = 4), on CDV glycoproteins (n = 5), and on the V protein (n = 1). We found mutations at two loci in common between sequences from three CDV outbreaks of clinical distemper in African lions; one in the signaling lymphocytic activation molecule receptor (SLAM)-binding region of the hemagglutinin protein and another in the catalytic center of phosphodiester bond formation on the large polymerase protein. These results suggest convergent evolution at these sites may have a functional role in clinical distemper outbreaks in African lions and uncover potential novel barriers to pathogenicity in this species.

Boronic acid-mediated ring-opening and Ni-catalyzed arylation of 1-arylcyclopropyl tosylates.

Herein, we describe a protocol for the ring-opening arylation of 1-arylcyclopropyl tosylates, in which boronic acids promote ring-opening and a Ni catalyst facilitates arylation in high regioselectivity. A number of 2-arylated allyl derivatives are synthesized, which are relevant motifs found in biologically active molecules.

The Origin and Spread of Locally Adaptive Seasonal Camouflage in Snowshoe Hares.

AbstractAdaptation is central to population persistence in the face of environmental change, yet we seldom precisely understand the origin and spread of adaptive variation in natural populations. Snowshoe hares (Lepus americanus) along the Pacific Northwest coast have evolved brown winter camouflage through positive selection on recessive variation at the Agouti pigmentation gene introgressed from black-tailed jackrabbits (Lepus californicus). Here, we combine new and published whole-genome and exome sequences with targeted genotyping of Agouti to investigate the evolutionary history of local seasonal camouflage adaptation in the Pacific Northwest. We find evidence of significantly elevated inbreeding and mutational load in coastal winter-brown hares, consistent with a recent range expansion into temperate coastal environments that incurred indirect fitness costs. The genome-wide distribution of introgression tract lengths supports a pulse of hybridization near the end of the last glacial maximum, which may have facilitated range expansion via introgression of winter-brown camouflage variation. However, signatures of a selective sweep at Agouti indicate a much more recent spread of winter-brown camouflage. Through simulations, we show that the delay between the hybrid origin and subsequent selective sweep of the recessive winter-brown allele can be largely attributed to the limits of natural selection imposed by simple allelic dominance. We argue that while hybridization during periods of environmental change may provide a critical reservoir of adaptive variation at range edges, the probability and pace of local adaptation will strongly depend on population demography and the genetic architecture of introgressed variation.