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The Grignard reaction has a storied place in the development of organic chemistry. Recognized by the Nobel Prize more than a century ago, this coupling of organomagnesium halides with carbonyl compounds remains a widely used route to carbon-carbon bonds. Nguyen et al. review an emerging alternative protocol that replaces the sensitive magnesium reagent with a catalytically activated olefin and a reductant such as hydrogen or an alcohol. In addition to safety and efficiency considerations, this class of reactions benefits from the high abundance and low cost of the olefins. Science , this issue p. 300 Metal-catalyzed reductive coupling of olefin-derived nucleophiles: Reinventing carbonyl addition α-Olefins are the most abundant petrochemical feedstock beyond alkanes, yet their use in commodity chemical manufacture is largely focused on polymerization and hydroformylation. The development of byproduct-free catalytic C–C bond–forming reactions that convert olefins to value-added products remains an important objective. Here, we review catalytic intermolecular reductive couplings of unactivated and activated olefin-derived nucleophiles with carbonyl partners. These processes represent an alternative to the longstanding use of stoichiometric organometallic reagents in carbonyl addition.

A method for 3D differentiation of human pluripotent stem cells yields brain cortical spheroids with functional neurons and astrocytes. The spheroids can be sliced for imaging and electrophysiological studies. The human cerebral cortex develops through an elaborate succession of cellular events that, when disrupted, can lead to neuropsychiatric disease. The ability to reprogram somatic cells into pluripotent cells that can be differentiated in vitro provides a unique opportunity to study normal and abnormal corticogenesis. Here, we present a simple and reproducible 3D culture approach for generating a laminated cerebral cortex–like structure, named human cortical spheroids (hCSs), from pluripotent stem cells. hCSs contain neurons from both deep and superficial cortical layers and map transcriptionally to in vivo fetal development. These neurons are electrophysiologically mature, display spontaneous activity, are surrounded by nonreactive astrocytes and form functional synapses. Experiments in acute hCS slices demonstrate that cortical neurons participate in network activity and produce complex synaptic events. These 3D cultures should allow a detailed interrogation of human cortical development, function and disease, and may prove a versatile platform for generating other neuronal and glial subtypes in vitro .

Exposure to cold drives IL-4-mediated alternative macrophage activation and catecholamine secretion in brown and white adipose tissues to stimulate thermogenesis. Macrophages turn on the heat In the prevailing model of thermogenesis in warm-blooded animals, when the hypothalamus senses cold temperatures it triggers noradrenaline release to coordinate the cellular program of adaptive thermogenesis in white and brown adipose tissues. By contrast, this paper shows that when mice are exposed to cold, it is the interleukin-4-mediated activation of adipose tissue macrophages that releases noradrenaline and other catecholamines. Thus the cells of the haematopoietic system, such as alternatively activated macrophages, may constitute a second circuit for controlling non-shivering thermogenesis acting in parallel with the sympathetic nerves. All homeotherms use thermogenesis to maintain their core body temperature, ensuring that cellular functions and physiological processes can continue in cold environments 1 , 2 , 3 . In the prevailing model of thermogenesis, when the hypothalamus senses cold temperatures it triggers sympathetic discharge, resulting in the release of noradrenaline in brown adipose tissue and white adipose tissue 4 , 5 . Acting via the β 3 -adrenergic receptors, noradrenaline induces lipolysis in white adipocytes 6 , whereas it stimulates the expression of thermogenic genes, such as PPAR-γ coactivator 1a ( Ppargc1a ), uncoupling protein 1 ( Ucp1 ) and acyl-CoA synthetase long-chain family member 1 ( Acsl1 ), in brown adipocytes 7 , 8 , 9 . However, the precise nature of all the cell types involved in this efferent loop is not well established. Here we report in mice an unexpected requirement for the interleukin-4 (IL-4)-stimulated program of alternative macrophage activation in adaptive thermogenesis. Exposure to cold temperature rapidly promoted alternative activation of adipose tissue macrophages, which secrete catecholamines to induce thermogenic gene expression in brown adipose tissue and lipolysis in white adipose tissue. Absence of alternatively activated macrophages impaired metabolic adaptations to cold, whereas administration of IL-4 increased thermogenic gene expression, fatty acid mobilization and energy expenditure, all in a macrophage-dependent manner. Thus, we have discovered a role for alternatively activated macrophages in the orchestration of an important mammalian stress response, the response to cold.

The role of IL-6 in obesity-associated inflammation remains controversial. Bruening and colleagues identify signaling by IL-6 as an important determinant for the alternative activation of macrophages during inflammation. Obesity and resistance to insulin are closely associated with the development of low-grade inflammation. Interleukin 6 (IL-6) is linked to obesity-associated inflammation; however, its role in this context remains controversial. Here we found that mice with an inactivated gene encoding the IL-6Rα chain of the receptor for IL-6 in myeloid cells ( Il6ra Δmyel mice) developed exaggerated deterioration of glucose homeostasis during diet-induced obesity, due to enhanced resistance to insulin. Tissues targeted by insulin showed increased inflammation and a shift in macrophage polarization. IL-6 induced expression of the receptor for IL-4 and augmented the response to IL-4 in macrophages in a cell-autonomous manner. Il6ra Δmyel mice were resistant to IL-4-mediated alternative polarization of macrophages and exhibited enhanced susceptibility to lipopolysaccharide (LPS)-induced endotoxemia. Our results identify signaling via IL-6 as an important determinant of the alternative activation of macrophages and assign an unexpected homeostatic role to IL-6 in limiting inflammation.

The liver is a central organ for the synthesis and storage of nutrients, production of serum proteins and hormones, and breakdown of toxins and metabolites. Because the liver is susceptible to toxin-or pathogen-mediated injury, it maintains a remarkable capacity to regenerate by compensatory growth. Specifically, in response to injury, quiescent hepatocytes enter the cell cycle and undergo DNA replication to promote liver regrowth. Despite the elucidation of a number of regenerative factors, the mechanisms by which liver injury triggers hepatocyte proliferation are incompletely understood. We demonstrate here that eosinophils stimulate liver regeneration after partial hepatectomy and toxin-mediated injury. Liver injury results in rapid recruitment of eosinophils, which secrete IL-4 to promote the proliferation of quiescent hepatocytes. Surprisingly, signaling via the IL-4Rα in macrophages, which have been implicated in tissue repair, is dispensable for hepatocyte proliferation and liver regrowth after injury. Instead, IL-4 exerts its proliferative actions via IL-4 Rot in hepatocytes. Our findings thus provide a unique mechanism by which eosinophil-derived IL-4 stimulates hepatocyte proliferation in regenerating liver.

Antibodies result from the competition of B cell lineages evolving under selection for improved antigen recognition, a process known as affinity maturation. High-affinity antibodies to pathogens such as HIV, influenza, and SARS-CoV-2 are frequently reported to arise from B cells whose receptors, the precursors to antibodies, are encoded by particular immunoglobulin alleles. This raises the possibility that the presence of particular germline alleles in the B cell repertoire is a major determinant of the quality of the antibody response. Alternatively, initial differences in germline alleles’ propensities to form high-affinity receptors might be overcome by chance events during affinity maturation. We first investigate these scenarios in simulations: when germline-encoded fitness differences are large relative to the rate and effect size variation of somatic mutations, the same germline alleles persistently dominate the response of different individuals. In contrast, if germline-encoded advantages can be easily overcome by subsequent mutations, allele usage becomes increasingly divergent over time, a pattern we then observe in mice experimentally infected with influenza virus. We investigated whether affinity maturation might nonetheless strongly select for particular amino acid motifs across diverse genetic backgrounds, but we found no evidence of convergence to similar CDR3 sequences or amino acid substitutions. These results suggest that although germline-encoded specificities can lead to similar immune responses between individuals, diverse evolutionary routes to high affinity limit the genetic predictability of responses to infection and vaccination.

The association between inflammation with depression and suicide has prompted many investigations of the potential contributors to inflammatory pathology in these psychiatric illnesses. However, a distillation of diverse clinical findings into an integrated framework of the possible involvement of major physiological processes in the elicitation of pathological inflammation in depression and suicide has not yet been explored. Therefore, this review aims to provide a concise synthesis of notable clinical correlates of inflammatory pathology in subjects with various depressive and suicidal clinical subtypes into a mechanistic framework, which includes aberrant immune activation, deregulated neuroendocrine signaling, and impaired host-microbe interaction. These issues are of significant research interest as their possible interplays might be involved in the development of distinct subtypes of depression and suicide. We conclude the review with discussion of a pathway-focused therapeutic approach to address inflammatory pathology in these psychiatric illnesses within the realm of personalized care for affected patients.

This study presented a simple and eco-friendly method to load copper nanoparticles on the surface of bacterial cellulose from nata de coco produced via the fermentation of coconut water by Acetobacter xylinum . The Cu modification of BC surface was based on the reduction of copper (II) acetate by hydrazine under ambient conditions in a dispersion system of Nata de coco in water, which was followed by freeze-drying, affording lightweight Cu-containing cellulose aerogels. The structural features of the obtained aerogels were investigated by scanning electron microscopy with energy dispersive X-ray analysis (SEM/EDX), thermogravimetric analysis (TGA), powder X-ray diffraction (PXRD), and nitrogen physisorption, indicating the high cellulose crystallinity, three-dimensional matrix and homogenous dispersion of Cu species on the cellulose bundles. The Cu-modified aerogel exhibited a significantly improved adsorption capacity of cyclohexane (66.4 g/g) as compared to that of pure cellulose (45 g/g). The excellent performances of 65.1–109.6 g/g were also observed for other water-insoluble liquids including n -hexane, toluene, tetrahydrofuran, ethyl acetate, chlorobenzene, 1,2-dichlorobenzene, dichloromethane, and chloroform depending their density.

Background Cerebellar ataxia refers to the disturbance in movement resulting from cerebellar dysfunction. It manifests as inaccurate movements with delayed onset and overshoot, especially when movements are repetitive or rhythmic. Identification of ataxia is integral to the diagnosis and assessment of severity, and is important in monitoring progression and improvement. Ataxia is identified and assessed by clinicians observing subjects perform standardised movement tasks that emphasise ataxic movements. Our aim in this paper was to use data recorded from motion sensors worn while subjects performed these tasks, in order to make an objective assessment of ataxia that accurately modelled the clinical assessment. Methods Inertial measurement units and a Kinect© system were used to record motion data while control and ataxic subjects performed four instrumented version of upper extremities tests, i.e. finger chase test (FCT), finger tapping test (FTT), finger to nose test (FNT) and dysdiadochokinesia test (DDKT). Kinematic features were extracted from this data and correlated with clinical ratings of severity of ataxia using the Scale for the Assessment and Rating of Ataxia (SARA). These features were refined using Feed Backward feature Elimination (the best performing method of four). Using several different learning models, including Linear Discrimination, Quadratic Discrimination Analysis, Support Vector Machine and K-Nearest Neighbour these extracted features were used to accurately discriminate between ataxics and control subjects. Leave-One-Out cross validation estimated the generalised performance of the diagnostic model as well as the severity predicting regression model. Results The selected model accurately ( 96.4 % ) predicted the clinical scores for ataxia and correlated well with clinical scores of the severity of ataxia ( r h o = 0.8 , p < 0.001 ). The severity estimation was also considered in a 4-level scale to provide a rating that is familiar to the current clinically-used rating of upper limb impairments. The combination of FCT and FTT performed as well as all four test combined in predicting the presence and severity of ataxia. Conclusion Individual bedside tests can be emulated using features derived from sensors worn while bedside tests of cerebellar ataxia were being performed. Each test emphasises different aspects of stability, timing, accuracy and rhythmicity of movements. Using the current models it is possible to model the clinician in identifying ataxia and assessing severity but also to identify those test which provide the optimum set of data. Trial registration Human Research and Ethics Committee, Royal Victorian Eye and Ear Hospital, East Melbourne, Australia (HREC Reference Number: 11/994H/16).

Alcohols are common alkylating agents and starting materials alternative to harmful alkyl halides. In this study, a simple, benign and efficient pathway was developed to synthesize 1,3‐diphenylpropan‐1‐ols via the β‐alkylation of 1‐phenylethanol with benzyl alcohols. Unlike conventional borrowing hydrogen processes in which alcohols were activated by transition‐metal catalyzed dehydrogenation, in this work, t‐BuONa was suggested to be a dual‐role reagent, namely, both base and radical initiator, for the radical coupling of aromatic alcohols. The cross‐coupling reaction readily proceeded under transition metal‐free conditions and an inert atmosphere, affording 1,3‐diphenylpropan‐1‐ol with an excellent yield. A good functional group tolerance in benzyl alcohols was observed, leading to the production of various phenyl‐substituted propan‐1‐ol derivatives in moderate‐to‐good yields. The mechanistic studies proposed that the reaction could involve the formation of reactive radical anions by base‐mediated deprotonation and single electron transfer. Insert text for Table of Contents here. A series of 1,3‐diphenylpropan‐1‐ol derivatives were successfully obtained via the t‐BuONa‐mediated radical coupling of stable and available substrates involving 1‐phenylethanol and benzyl alcohols without the need of any external oxidants and transition metal catalysts. The experimental results demonstrated the crucial role of a strong base in the steps of the conversion to the desired product. From the viewpoint of green chemistry, the applied‐here pathway is simple, less toxic, step‐ and cost‐efficient.