Aluminium‐Catalyzed C(sp)−H Borylation of Alkynes

Historically used in stoichiometric hydroalumination chemistry, recent advances have transformed aluminium hydrides into versatile catalysts for the hydroboration of unsaturated multiple bonds. This catalytic ability is founded on the defining reactivity of aluminium hydrides with alkynes and alkenes: 1,2‐hydroalumination of the unsaturated π‐system. This manuscript reports the aluminium hydride catalyzed dehydroborylation of terminal alkynes. A tethered intramolecular amine ligand controls reactivity at the aluminium hydride centre, switching off hydroalumination and instead enabling selective reactions at the alkyne C−H σ‐bond. Chemoselective C−H borylation was observed across a series of aryl‐ and alkyl‐substituted alkynes (21 examples). On the basis of kinetic and density functional theory studies, a mechanism in which C−H borylation proceeds by σ‐bond metathesis between pinacolborane (HBpin) and alkynyl aluminium intermediates is proposed

RIPK1 is a critical modulator of both tonic and TLR-responsive inflammatory and cell death pathways in human macrophage differentiation

In this study, we took advantage of human-induced pluripotent stem cells (hiPSC) and CRISPR/Cas9 technology to investigate the potential roles of RIPK1 in regulating hematopoiesis and macrophage differentiation, proinflammatory activation, and cell death pathways. Knock-out of RIPK1 in hiPSCs demonstrated that this protein is not required for erythro-myeloid differentiation. Using a well-established macrophage differentiation protocol, knock-out of RIPK1 did not block the differentiation of iPSC-derived macrophages, which displayed a similar phenotype to WT hiPSC-derived macrophages. However, knock-out of RIPK1 leads to a TNFα-dependent apoptotic death of differentiated hiPSC-derived macrophages (iPS-MΦ) and progressive loss of iPS-MΦ production irrespective of external pro-inflammatory stimuli. Live video analysis demonstrated that TLR3/4 activation of RIPK1 KO hiPSC-derived macrophages triggered TRIF and RIPK3-dependent necroptosis irrespective of caspase-8 activation. In contrast, TLR3/4 activation of WT macrophages-induced necroptosis only when caspases were inhibited, confirming the modulating effect of RIPK1 on RIPK3-mediated necroptosis through the FADD, Caspase-8 pathway. Activation of these inflammatory pathways required RIPK3 kinase activity while RIPK1 was dispensable. However, loss of RIPK1 sensitizes macrophages to activate RIPK3 in response to inflammatory stimuli, thereby exacerbating a potentially pathological inflammatory response. Taken together, these results reveal that RIPK1 has an important role in regulating the potent inflammatory pathways in authentic human macrophages that are poised to respond to external stimuli. Consequently, RIPK1 activity might be a valid target in the development of novel therapies for chronic inflammatory diseases.España, MINECO/FEDER SAF2015-64171

Appropriate Inhibition of Orexigenic Hypothalamic Arcuate Nucleus Neurons Independently of Leptin Receptor/STAT3 Signaling

Leptin directly suppresses the activity of orexigenic neurons in the hypothalamic arcuate nucleus (ARC). We examined c-Fos-like immunoreactivity (CFLIR) as a marker of ARC neuronal activity in db/db mice devoid of the signaling form of the leptin receptor (LRb) and s/s mice that express LRbS1138 [which is defective for STAT3 (signal transducer and activator of transcription) signaling]. Both db/db and s/s animals are hyperphagic and obese. This analysis revealed that CFLIR in agouti related peptide-expressing orexigenic ARC neurons is basally elevated in db/db but not s/s mice. Consistent with these observations, electrophysiologic evaluation of a small number of neurons in s/s animals suggested that leptin appropriately suppresses the frequency of IPSCs on ARC proopiomelanocortin (POMC) neurons that are mediated by the release of GABA from orexigenic ARC neurons. CFLIR in POMC neurons of s/s mice was also increased compared with db/db animals. Thus, these data suggest that, although LRb→STAT3 signaling is crucial for the regulation of feeding, it is not required for the acute or chronic regulation of orexigenic ARC neurons, and the activation of STAT3-mediated transcription by leptin is not required for the appropriate development of leptin responsiveness in these neurons

Diffractive point sets with entropy

After a brief historical survey, the paper introduces the notion of entropic model sets (cut and project sets), and, more generally, the notion of diffractive point sets with entropy. Such sets may be thought of as generalizations of lattice gases. We show that taking the site occupation of a model set stochastically results, with probabilistic certainty, in well-defined diffractive properties augmented by a constant diffuse background. We discuss both the case of independent, but identically distributed (i.i.d.) random variables and that of independent, but different (i.e., site dependent) random variables. Several examples are shown.Comment: 25 pages; dedicated to Hans-Ude Nissen on the occasion of his 65th birthday; final version, some minor addition

COVID-19 mitigation measures in primary schools and association with infection and school staff wellbeing: An observational survey linked with routine data in Wales, UK

IntroductionSchool-based COVID-19 mitigation strategies have greatly impacted the primary school day (children aged 3–11) including: wearing face coverings, two metre distancing, no mixing of children, and no breakfast clubs or extra-curricular activities. This study examines these mitigation measures and association with COVID-19 infection, respiratory infection, and school staff wellbeing between October to December 2020 in Wales, UK.MethodsA school staff survey captured self-reported COVID-19 mitigation measures in the school, participant anxiety and depression, and open-text responses regarding experiences of teaching and implementing measures. These survey responses were linked to national-scale COVID-19 test results data to examine association of measures in the school and the likelihood of a positive (staff or pupil) COVID-19 case in the school (clustered by school, adjusted for school size and free school meals using logistic regression). Linkage was conducted through the SAIL (Secure Anonymised Information Linkage) Databank.ResultsResponses were obtained from 353 participants from 59 primary schools within 15 of 22 local authorities. Having more direct non-household contacts was associated with a higher likelihood of COVID-19 positive case in the school (1–5 contacts compared to none, OR 2.89 (1.01, 8.31)) and a trend to more self-reported cold symptoms. Staff face covering was not associated with a lower odds of school COVID-19 cases (mask vs. no covering OR 2.82 (1.11, 7.14)) and was associated with higher self-reported cold symptoms. School staff reported the impacts of wearing face coverings on teaching, including having to stand closer to pupils and raise their voices to be heard. 67.1% were not able to implement two metre social distancing from pupils. We did not find evidence that maintaining a two metre distance was associated with lower rates of COVID-19 in the school.ConclusionsImplementing, adhering to and evaluating COVID-19 mitigation guidelines is challenging in primary school settings. Our findings suggest that reducing non-household direct contacts lowers infection rates. There was no evidence that face coverings, two metre social distancing or stopping children mixing was associated with lower odds of COVID-19 or cold infection rates in the school. Primary school staff found teaching challenging during COVID-19 restrictions, especially for younger learners and those with additional learning needs

Close-packed dimers on the line: diffraction versus dynamical spectrum

The translation action of \RR^{d} on a translation bounded measure $\omega$ leads to an interesting class of dynamical systems, with a rather rich spectral theory. In general, the diffraction spectrum of $\omega$, which is the carrier of the diffraction measure, live on a subset of the dynamical spectrum. It is known that, under some mild assumptions, a pure point diffraction spectrum implies a pure point dynamical spectrum (the opposite implication always being true). For other systems, the diffraction spectrum can be a proper subset of the dynamical spectrum, as was pointed out for the Thue-Morse sequence (with singular continuous diffraction) in \cite{EM}. Here, we construct a random system of close-packed dimers on the line that have some underlying long-range periodic order as well, and display the same type of phenomenon for a system with absolutely continuous spectrum. An interpretation in terms of `atomic' versus `molecular' spectrum suggests a way to come to a more general correspondence between these two types of spectra.Comment: 14 pages, with some additions and improvement

EVLA Observations Constrain the Environment and Progenitor System of Type Ia Supernova 2011fe

We report unique EVLA observations of SN 2011fe representing the most sensitive radio study of a Type Ia supernova to date. Our data place direct constraints on the density of the surrounding medium at radii ~10^15-10^16 cm, implying an upper limit on the mass loss rate from the progenitor system of Mdot <~ 6 x 10^-10 Msol/yr (assuming a wind speed of 100 km/s), or expansion into a uniform medium with density n_CSM <~ 6 cm^-3. Drawing from the observed properties of non-conservative mass transfer among accreting white dwarfs, we use these limits on the density of the immediate environs to exclude a phase space of possible progenitors systems for SN 2011fe. We rule out a symbiotic progenitor system and also a system characterized by high accretion rate onto the white dwarf that is expected to give rise to optically-thick accretion winds. Assuming that a small fraction, 1%, of the mass accreted is lost from the progenitor system, we also eliminate much of the potential progenitor parameter space for white dwarfs hosting recurrent novae or undergoing stable nuclear burning. Therefore, we rule out the most popular single degenerate progenitor models for SN 2011fe, leaving a limited phase space inhabited by some double degenerate systems and exotic progenitor scenarios.Comment: Accepted to Ap

Activation of Central Melanocortin Pathways by Fenfluramlne

D-fenfluramine (d-FEN) was once widely prescribed and was among the most effective weight loss drugs, but was withdrawn from clinical use because of reports of cardiac complications in a subset of patients. Discerning the neurobiology underlying the anorexic action of d-FEN may facilitate the development of new drugs to prevent and treat obesity. Through a combination of functional neuroanatomy, feeding, and electrophysiology studies in rodents, we show that d-FEN-induced anorexia requires activation of central nervous system melanocortin pathways. These results provide a mechanistic explanation of d-FEN\u27s anorexic actions and indicate that drugs targeting these downstream melanocortin pathways may prove to be effective and more selective antiobesity treatments

Definition of ambulatory blood pressure targets for diagnosis and treatment of hypertension in relation to clinic blood pressure: prospective cohort study

Background Twenty-four hour ambulatory blood pressure thresholds have been defined for the diagnosis of mild hypertension but not for its treatment or for other blood pressure thresholds used in the diagnosis of moderate to severe hypertension. We aimed to derive age and sex related ambulatory blood pressure equivalents to clinic blood pressure thresholds for diagnosis and treatment of hypertension