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Anxiety disorders are a significant problem in the community, and recent neuroimaging research has focused on determining the brain circuits that underlie them. Research on the neurocircuitry of anxiety disorders has its roots in the study of fear circuits in animal models and the study of brain responses to emotional stimuli in healthy humans. We review this research, as well as neuroimaging studies of anxiety disorders. In general, these studies have reported relatively heightened amygdala activation in response to disorder-relevant stimuli in post-traumatic stress disorder, social phobia, and specific phobia. Activation in the insular cortex appears to be heightened in many of the anxiety disorders. Unlike other anxiety disorders, post-traumatic stress disorder is associated with diminished responsivity in the rostral anterior cingulate cortex and adjacent ventral medial prefrontal cortex. Additional research will be needed to (1) clarify the exact role of each component of the fear circuitry in the anxiety disorders, (2) determine whether functional abnormalities identified in the anxiety disorders represent acquired signs of the disorders or vulnerability factors that increase the risk of developing them, (3) link the findings of functional neuroimaging studies with those of neurochemistry studies, and (4) use functional neuroimaging to predict treatment response and assess treatment-related changes in brain function.

Epidemiological studies reveal significant associations between periodontitis and oral cancer. However, knowledge about the contribution of periodontal pathogens to oral cancer and potential regulatory mechanisms involved is limited. Previously, we showed that nisin, a bacteriocin and commonly used food preservative, reduced oral cancer tumorigenesis and extended the life expectancy in tumor-bearing mice. In addition, nisin has antimicrobial effects on key periodontal pathogens. Thus, the purpose of this study was to test the hypothesis that key periodontal pathogens (Porphyromonas gingivalis, Treponema denticola, and Fusobacterium nucleatum) promote oral cancer via specific host-bacterial interactions, and that bacteriocin/nisin therapy may modulate these responses. All three periodontal pathogens enhanced oral squamous cell carcinoma (OSCC) cell migration, invasion, tumorsphere formation, and tumorigenesis in vivo, without significantly affecting cell proliferation or apoptosis. In contrast, oral commensal bacteria did not affect OSCC cell migration. Pathogen-enhanced OSCC cell migration was mediated via integrin alpha V and FAK activation, since stably blocking alpha V or FAK expression abrogated these effects. Nisin inhibited these pathogen-mediated processes. Further, Treponema denticola induced TLR2 and 4 and MyD88 expression. Stable suppression of MyD88 significantly inhibited Treponema denticola-induced FAK activation and abrogated pathogen-induced migration. Together, these data demonstrate that periodontal pathogens contribute to a highly aggressive cancer phenotype via crosstalk between TLR/MyD88 and integrin/FAK signaling. Nisin can modulate these pathogen-mediated effects, and thus has therapeutic potential as an antimicrobial and anti-tumorigenic agent.

Membrane-free synthetic DNA-based condensates enable programmable control of dynamic behaviors as shown by phase-separated condensates in biological cells. We demonstrate remote-controlled microflow using photocontrollable state transitions of DNA condensates, assembled from multi-branched DNA nanostructures via sticky-end (SE) hybridization. Introducing azobenzene into SEs enables their photoswitchable binding affinity, which underlies photoreversible fluidity of the resulting condensates that transition between gel/liquid/dissociated states in a wavelength-dependent manner. Leveraging base-sequence programmability, spatially coupled orthogonal DNA condensates with divergent photoresponsive capabilities perform multi-modal mechanical actions that depend on azobenzene insertion sites in the SE, including switching flows radially expanding and converging under photoswitching. Localizing photoswitching within a DNA liquid condensate generates two distinct directional motions, whose contrasting morphology, direction, and lifetime are determined by switching frequency. Numerical simulations reveal its regulatory role in weight-adjusting energy-exchanging and energy-dissipative interactions between the photoirradiated and unirradiated domains. Membrane-free synthetic DNA-based condensates enable programmable control of dynamic behaviors as shown by phase-separated condensates in biological cells. Here, the authors demonstrate remote-controlled microflow using photocontrollable state transitions of DNA condensates, using an azobenzene motif.

Gold nanorods (AuNRs)-assisted plasmonic photothermal therapy (AuNRs-PPTT) is a promising strategy for combating cancer in which AuNRs absorb near-infrared light and convert it into heat, causing cell death mainly by apoptosis and/or necrosis. Developing a valid PPTT that induces cancer cell apoptosis and avoids necrosis in vivo and exploring its molecular mechanism of action is of great importance. Furthermore, assessment of the long-term fate of the AuNRs after treatment is critical for clinical use. We first optimized the size, surface modification [rifampicin (RF) conjugation], and concentration (2.5 nM) of AuNRs and the PPTT laser power (2 W/cm²) to achieve maximal induction of apoptosis. Second, we studied the potential mechanism of action of AuNRs-PPTT using quantitative proteomic analysis in mouse tumor tissues. Several death pathways were identified, mainly involving apoptosis and cell death by releasing neutrophil extracellular traps (NETs) (NETosis), which were more obvious upon PPTT using RF-conjugated AuNRs (AuNRs@RF) than with polyethylene glycol thiol-conjugated AuNRs. Cytochrome c and p53-related apoptosis mechanisms were identified as contributing to the enhanced effect of PPTT with AuNRs@RF. Furthermore, Pin1 and IL18-related signaling contributed to the observed perturbation of the NETosis pathway by PPTT with AuNRs@RF. Third, we report a 15-month toxicity study that showed no long-term toxicity of AuNRs in vivo. Together, these data demonstrate that our AuNRs-PPTT platform is effective and safe for cancer therapy in mouse models. These findings provide a strong framework for the translation of PPTT to the clinic.

Cell-sized liposomes and droplets coated with lipid layers have been used as platforms for understanding live cells, constructing artificial cells, and implementing functional biomedical tools such as biosensing platforms and drug delivery systems. However, these systems are very fragile, which results from the absence of cytoskeletons in these systems. Here, we construct an artificial cytoskeleton using DNA nanostructures. The designed DNA oligomers form a Y-shaped nanostructure and connect to each other with their complementary sticky ends to form networks. To undercoat lipid membranes with this DNA network, we used cationic lipids that attract negatively charged DNA. By encapsulating the DNA into the droplets, we successfully created a DNA shell underneath the membrane. The DNA shells increased interfacial tension, elastic modulus, and shear modulus of the droplet surface, consequently stabilizing the lipid droplets. Such drastic changes in stability were detected only when the DNA shell was in the gel phase. Furthermore, we demonstrate that liposomes with the DNA gel shell are substantially tolerant against outer osmotic shock. These results clearly show the DNA gel shell is a stabilizer of the lipid membrane akin to the cytoskeleton in live cells.

Emotional stress is associated with increased risk of cardiovascular disease. We imaged the amygdala, a brain region involved in stress, to determine whether its resting metabolic activity predicts risk of subsequent cardiovascular events. Individuals aged 30 years or older without known cardiovascular disease or active cancer disorders, who underwent 18F-fluorodexoyglucose PET/CT at Massachusetts General Hospital (Boston, MA, USA) between Jan 1, 2005, and Dec 31, 2008, were studied longitudinally. Amygdalar activity, bone-marrow activity, and arterial inflammation were assessed with validated methods. In a separate cross-sectional study we analysed the relation between perceived stress, amygdalar activity, arterial inflammation, and C-reactive protein. Image analyses and cardiovascular disease event adjudication were done by mutually blinded researchers. Relations between amygdalar activity and cardiovascular disease events were assessed with Cox models, log-rank tests, and mediation (path) analyses. 293 patients (median age 55 years [IQR 45·0–65·5]) were included in the longitudinal study, 22 of whom had a cardiovascular disease event during median follow-up of 3·7 years (IQR 2·7–4·8). Amygdalar activity was associated with increased bone-marrow activity (r=0·47; p<0·0001), arterial inflammation (r=0·49; p<0·0001), and risk of cardiovascular disease events (standardised hazard ratio 1·59, 95% CI 1·27–1·98; p<0·0001), a finding that remained significant after multivariate adjustments. The association between amygdalar activity and cardiovascular disease events seemed to be mediated by increased bone-marrow activity and arterial inflammation in series. In the separate cross-sectional study of patients who underwent psychometric analysis (n=13), amygdalar activity was significantly associated with arterial inflammation (r=0·70; p=0·0083). Perceived stress was associated with amygdalar activity (r=0·56; p=0·0485), arterial inflammation (r=0·59; p=0·0345), and C-reactive protein (r=0·83; p=0·0210). In this first study to link regional brain activity to subsequent cardiovascular disease, amygdalar activity independently and robustly predicted cardiovascular disease events. Amygdalar activity is involved partly via a path that includes increased bone-marrow activity and arterial inflammation. These findings provide novel insights into the mechanism through which emotional stressors can lead to cardiovascular disease in human beings. None.

Recent developments in nanotechnology have provided researchers with new tools for cancer imaging and treatment. This technology has enabled the development of nanoscale devices that can be conjugated with several functional molecules simultaneously, including tumor-specific ligands, antibodies, anticancer drugs, and imaging probes. Since these nanodevices are 100 to 1,000-fold smaller than cancer cells, they can be easily transferred through leaky blood vessels and interact with targeted tumor-specific proteins both on the surface of and inside cancer cells. Therefore, their application as cancer cell-specific delivery vehicles will be a significant addition to the currently available armory for cancer therapeutics and imaging. [PUBLICATION ABSTRACT]

Key Points Nanoparticles are emerging as a new class of therapeutics for cancer because they can perform in ways that other therapeutic modalities cannot. Newer nanoparticle therapeutics are showing enhanced efficacy with lower side effects than traditional small-molecule chemotherapeutics in early clinic studies, and are doing so without creating additional new side effects due to the nanoparticle. Although there are many types of nanoparticles, few will have the proper attributes to reach clinical use because of the issues involved in translating research grade nanoparticles to clinic grade nanoparticles. Newer nanoparticle therapeutics have a greater degree of multifunctionality and involve not only delivery to the tumour but intracellular delivery so that multidrug resistance can be bypassed and therapeutic agents such as siRNA that require intracellular delivery can be utilized. Nanoparticles that contain cancer cell-surface targeting ligands are now in the clinic. Several nanoscaled systems for cancer therapy are approved or in clinical trials. Here, Davis and colleagues discuss the key properties of nanotherapeutics for cancer, summarize clinical findings with first- and second-generation nanoparticles, and discuss the issues involved in translating experimental nanotherapeutics to the clinic. Nanoparticles — particles in the size range 1–100 nm — are emerging as a class of therapeutics for cancer. Early clinical results suggest that nanoparticle therapeutics can show enhanced efficacy, while simultaneously reducing side effects, owing to properties such as more targeted localization in tumours and active cellular uptake. Here, we highlight the features of nanoparticle therapeutics that distinguish them from previous anticancer therapies, and describe how these features provide the potential for therapeutic effects that are not achievable with other modalities. While large numbers of preclinical studies have been published, the emphasis here is placed on preclinical and clinical studies that are likely to affect clinical investigations and their implications for advancing the treatment of patients with cancer.

Ammonia-oxidizing archaea are ubiquitous in marine and terrestrial environments and now thought to be significant contributors to carbon and nitrogen cycling. The isolation of Candidatus \"Nitrosopumilus maritimus\" strain SCM1 provided the opportunity for linking its chemolithotrophic physiology with a genomic inventory of the globally distributed archaea. Here we report the 1,645,259-bp closed genome of strain SCM1, revealing highly copper-dependent systems for ammonia oxidation and electron transport that are distinctly different from known ammonia-oxidizing bacteria. Consistent with in situ isotopic studies of marine archaea, the genome sequence indicates N. maritimus grows autotrophically using a variant of the 3-hydroxypropionate/4-hydroxybutryrate pathway for carbon assimilation, while maintaining limited capacity for assimilation of organic carbon. This unique instance of archaeal biosynthesis of the osmoprotectant ectoine and an unprecedented enrichment of multicopper oxidases, thioredoxin-like proteins, and transcriptional regulators points to an organism responsive to environmental cues and adapted to handling reactive copper and nitrogen species that likely derive from its distinctive biochemistry. The conservation of N. maritimus gene content and organization within marine metagenomes indicates that the unique physiology of these specialized oligophiles may play a significant role in the biogeochemical cycles of carbon and nitrogen.

Treatment of advanced locoregional head and neck cancer with high-dose radiotherapy plus cetuximab was superior to radiotherapy alone in improving local control and overall survival. Treatment of advanced locoregional head and neck cancer with high-dose radiotherapy plus cetuximab was superior to radiotherapy alone in improving local control and overall survival. The treatment of locoregionally advanced squamous-cell carcinoma of the head and neck (hereafter called head and neck cancer) has evolved gradually from surgery as the mainstay of treatment to radiotherapy as the principal treatment. 1 – 6 More recently, additional benefit has been obtained with altered-fractionation radiotherapy (i.e., accelerated fractionation or hyperfractionated radiotherapy) and with radiotherapy combined with chemotherapy (chemoradiotherapy). 5 – 11 The value of chemoradiotherapy is, however, counterbalanced by increased and often prohibitive toxicity, particularly among patients with coexisting medical conditions and decreased performance status. 6 , 12 The epidermal growth factor receptor (EGFR), a member of the ErbB family of receptor tyrosine kinases, . . .