Real-world complex systems may be mathematically modeled as graphs, revealing properties of the system. Here we study graphs of functional brain organization in healthy adults using resting state ...functional connectivity MRI. We propose two novel brain-wide graphs, one of 264 putative functional areas, the other a modification of voxelwise networks that eliminates potentially artificial short-distance relationships. These graphs contain many subgraphs in good agreement with known functional brain systems. Other subgraphs lack established functional identities; we suggest possible functional characteristics for these subgraphs. Further, graph measures of the areal network indicate that the default mode subgraph shares network properties with sensory and motor subgraphs: it is internally integrated but isolated from other subgraphs, much like a “processing” system. The modified voxelwise graph also reveals spatial motifs in the patterning of systems across the cortex.
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► Areal and modified voxelwise graph definitions are proposed ► Subgraphs reflect known and unknown brain systems ► Default mode, sensory, and motor systems share network properties ► Functional systems are patterned across the cortex with spatial regularities
Adipose tissue (AT) of obese mice and humans accumulates immune cells, which secrete cytokines that can promote insulin resistance. AT macrophages (ATMs) are thought to originate from ...bone-marrow-derived monocytes, which infiltrate the tissue from the circulation. Here, we show that a major fraction of macrophages unexpectedly undergo cell division locally within AT, as detected by Ki67 expression and 5-ethynyl-2′-deoxyuridine incorporation. Macrophages within the visceral AT (VAT), but not those in other tissues (including liver and spleen), displayed increased proliferation in obesity. Importantly, depletion of blood monocytes had no impact on ATM content, whereas their proliferation in situ continued. Treatment with monocyte chemotactic protein 1 (MCP-1) induced macrophage cell division in AT explants, whereas mcp-1 deficiency in vivo decreased ATM proliferation. These results reveal that, in addition to blood monocyte recruitment, in situ proliferation driven by MCP-1 is an important process by which macrophages accumulate in the VAT in obesity.
•Macrophages undergo cell division locally within adipose tissue in mice•Obesity increases the proliferation of macrophages in AT but not other tissues•Macrophage proliferation occurs independently of monocyte recruitment•MCP-1 stimulates adipose tissue macrophage cell division
Insulin resistance in obese humans and animals has been linked to adipose tissue accumulation of immune cells, including macrophages, which are thought to be recruited from blood. Amano et al. show that, surprisingly, macrophages actually divide in the obese adipose tissue and that obesity specifically increases adipose tissue macrophage proliferation.
Mycobacterium tuberculosis (Mtb) infection is initiated in the distal airways, but the bacteria ultimately disseminate to the lung interstitium. Although various cell types, including alveolar ...macrophages (AM), neutrophils, and permissive monocytes, are known to be infected with Mtb, the initially infected cells as well as those that mediate dissemination from the alveoli to the lung interstitium are unknown. In this study, using a murine infection model, we reveal that early, productive Mtb infection occurs almost exclusively within airway-resident AM. Thereafter Mtb-infected, but not uninfected, AM localize to the lung interstitium through mechanisms requiring an intact Mtb ESX-1 secretion system. Relocalization of infected AM precedes Mtb uptake by recruited monocyte-derived macrophages and neutrophils. This dissemination process is driven by non-hematopoietic host MyD88/interleukin-1 receptor inflammasome signaling. Thus, interleukin-1-mediated crosstalk between Mtb-infected AM and non-hematopoietic cells promotes pulmonary Mtb infection by enabling infected cells to disseminate from the alveoli to the lung interstitium.
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•Early M. tuberculosis infection primarily targets lung alveolar macrophages (AM)•Mtb-infected AM selectively relocalize from the airways to the lung interstitium•AM interstitial localization precedes Mtb dissemination to other immune cell types•Relocalization of infected AM is dependent on Mtb ESX-1 and host IL-1R signaling
Using a mouse model, Cohen et al. demonstrate that early Mycobacterium tuberculosis infection predominantly targets alveolar macrophages (AM). Infected AM relocalize from the alveolar space to lung interstitium, preceding bacterial dissemination into migratory myeloid populations. Relocalization requires IL-1R and bacterial ESX-1, highlighting the host-pathogen interplay required to establish infection.
The mature human brain is organized into a collection of specialized functional networks that flexibly interact to support various cognitive functions. Studies of development often attempt to ...identify the organizing principles that guide the maturation of these functional networks. In this report, we combine resting state functional connectivity MRI (rs-fcMRI), graph analysis, community detection, and spring-embedding visualization techniques to analyze four separate networks defined in earlier studies. As we have previously reported, we find, across development, a trend toward 'segregation' (a general decrease in correlation strength) between regions close in anatomical space and 'integration' (an increased correlation strength) between selected regions distant in space. The generalization of these earlier trends across multiple networks suggests that this is a general developmental principle for changes in functional connectivity that would extend to large-scale graph theoretic analyses of large-scale brain networks. Communities in children are predominantly arranged by anatomical proximity, while communities in adults predominantly reflect functional relationships, as defined from adult fMRI studies. In sum, over development, the organization of multiple functional networks shifts from a local anatomical emphasis in children to a more "distributed" architecture in young adults. We argue that this "local to distributed" developmental characterization has important implications for understanding the development of neural systems underlying cognition. Further, graph metrics (e.g., clustering coefficients and average path lengths) are similar in child and adult graphs, with both showing "small-world"-like properties, while community detection by modularity optimization reveals stable communities within the graphs that are clearly different between young children and young adults. These observations suggest that early school age children and adults both have relatively efficient systems that may solve similar information processing problems in divergent ways.
The identification of the H3K4 trimethylase, PRDM9, as the gene responsible for recombination hotspot localization has provided considerable insight into the mechanisms by which recombination is ...initiated in mammals. However, uniquely amongst mammals, canids appear to lack a functional version of PRDM9 and may therefore provide a model for understanding recombination that occurs in the absence of PRDM9, and thus how PRDM9 functions to shape the recombination landscape. We have constructed a fine-scale genetic map from patterns of linkage disequilibrium assessed using high-throughput sequence data from 51 free-ranging dogs, Canis lupus familiaris. While broad-scale properties of recombination appear similar to other mammalian species, our fine-scale estimates indicate that canine highly elevated recombination rates are observed in the vicinity of CpG rich regions including gene promoter regions, but show little association with H3K4 trimethylation marks identified in spermatocytes. By comparison to genomic data from the Andean fox, Lycalopex culpaeus, we show that biased gene conversion is a plausible mechanism by which the high CpG content of the dog genome could have occurred.
Therapeutic cancer vaccines, an exciting development in cancer immunotherapy, share the goal of creating and amplifying tumor-specific T-cell responses, but significant obstacles still remain to ...their success. Here, we briefly outline the principles underlying cancer vaccine therapy with a focus on novel vaccine platforms and antigens, underscoring the renewed optimism. Numerous strategies have been investigated to overcome immunosuppressive mechanisms of the tumor microenvironment (TME) and counteract tumor escape, including improving antigen selection, refining delivery platforms, and use of combination therapies. Several new cancer vaccine platforms and antigen targets are under development. In an effort to amplify tumor-specific T-cell responses, a heterologous prime-boost antigen delivery strategy is increasingly used for virus-based vaccines. Viruses have also been engineered to express targeted antigens and immunomodulatory molecules simultaneously, to favorably modify the TME. Nanoparticle systems have shown promise as delivery vectors for cancer vaccines in preclinical research. T-win is another platform targeting both tumor cells and the TME, using peptide-based vaccines that engage and activate T cells to target immunoregulatory molecules expressed on immunosuppressive and malignant cells. With the availability of next-generation sequencing, algorithms for neoantigen selection are emerging, and several bioinformatic platforms are available to select therapeutically relevant neoantigen targets for developing personalized therapies. However, more research is needed before the use of neoepitope prediction and personalized immunotherapy becomes commonplace. Taken together, the field of therapeutic cancer vaccines is fast evolving, with the promise of potential synergy with existing immunotherapies for long-term cancer treatment.
Solid-state NMR has been used to study mixed-matrix membranes (MMMs) prepared with a metal–organic framework (MOF, UiO-66) and two different high molecular weight polymers (PEO and PVDF). 13C and 1H ...NMR data provide overwhelming evidence that most UiO-66 organic linkers are within 1 nm of PEO, which indicates that PEO is homogeneously distributed throughout the MOF. Systematic changes in MOF 13C NMR peak positions and 1H NMR line widths, as well as dramatic reductions in the MOF 1H T 1ρ relaxation times, are observed as the PEO content increases, and when the pores have been filled, a further increase in PEO results in the formation of semicrystalline PEO outside the UiO-66 particles. In contrast, similar studies on PVDF MMMs show that the polymer contacts only a small fraction (<20%) of the MOF linkers. Simulations confirm that PEO penetrates into UiO-66 more easily than does PVDF. These studies are among the first to provide experimental insights into MOF–polymer interactions in an MMM.
Prior studies suggest that methylphenidate, the primary pharmacological treatment for attention‐deficit/hyperactivity disorder (ADHD), alters functional brain connectivity. As the neurotransmitter ...systems targeted by methylphenidate undergo significant alterations throughout development, the effects of methylphenidate on functional connectivity may also be modulated by age. Therefore, we assessed the effects of a single methylphenidate challenge on brain network connectivity in stimulant‐treatment naïve children and adults with ADHD. We obtained resting‐state functional MRI from 50 boys (10–12 years of age) and 49 men (23–40 years of age) with ADHD (DSM IV, all subtypes), before and after an oral challenge with 0.5 mg/kg methylphenidate; and from 11 boys and 12 men as typically developing controls. Connectivity strength (CS), eigenvector centrality (EC), and betweenness centrality (BC) were calculated for the striatum, thalamus, dorsal anterior cingulate cortex (dACC), and prefrontal cortex (PFC). In line with our hypotheses, we found that methylphenidate decreased measures of connectivity and centrality in the striatum and thalamus in children with ADHD, but increased the same metrics in adults with ADHD. Surprisingly, we found no major effects of methylphenidate in the dACC and PFC in either children or adults. Interestingly, pre‐methylphenidate, participants with ADHD showed aberrant connectivity and centrality compared to controls predominantly in frontal regions. Our findings demonstrate that methylphenidate's effects on connectivity of subcortical regions are age‐dependent in stimulant‐treatment naïve participants with ADHD, likely due to ongoing maturation of dopamine and noradrenaline systems. These findings highlight the importance for future studies to take a developmental perspective when studying the effects of methylphenidate treatment.
We investigated the effects of the stimulant methylphenidate on functional connectivity in stimulant‐treatment naïve children and adults with ADHD, as well as typically developing controls. We found that methylphenidate modulated connectivity metrics primarily in the striatum and thalamus, with little effect on frontal regions. Importantly, opposing effects were found on network connectivity in children and adults in subcortical regions, possibly due to maturation of the dopamine and noradrenaline neurotransmitter systems. As such, our results increase our understanding of the effects of stimulants on brain networks in ADHD and stress the importance of taking a developmental perspective.
As research into metal–organic frameworks (MOFs) enters its third decade, efforts are naturally shifting from fundamental studies to applications, utilizing the unique features of these materials. ...Engineered forms of MOFs, such as membranes and films, are being investigated to transform laboratory-synthesized MOF powders to industrially viable products for separations, chemical sensors and catalysts. Following encouraging demonstrations of gas separations using MOF-based membranes, liquid-phase separations are now being explored in an effort to build effective membranes for these settings. In this Review, we highlight MOF applications that are in their nascent stages, specifically liquid-phase separations using MOF-based mixed-matrix membranes. We also highlight the analytical techniques that provide important insights into these materials, particularly at surfaces and interfaces, to better understand MOFs and their interactions with other materials, which will ultimately lead to their use in advanced technologies.The pores of metal–organic frameworks (MOFs) make them attractive materials for gas- and liquid-phase separations. In this Review, the fabrication of MOF-based membranes and analytical techniques used to characterize them are outlined with a focus on the surfaces and interfaces in these composite materials.
...reductions in malaria morbidity and mortality will require new insights into gaps in the effectiveness of malaria control programs, including evidence on health system performance in the clinical ...management of pediatric malaria. Children with P. falciparum malaria require prompt, appropriate antimalarial treatment in order to prevent progression of the disease to severe morbidity or death 4,5. Since the symptoms of malaria overlap with a number of other common viral and bacterial diseases, blood test confirmation of the disease through microscopy or rapid test is strongly recommended 6,7. ...even children who are seen by a formal provider may not receive appropriate care 28. While a number of studies have assessed quality of care for malaria patients, most are based on interviews with patients or record reviews, though some studies at the national or subnational level also include direct observation of clinical practice 22,24,34–36.
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