A protective vaccine against hepatitis C virus (HCV) remains an unmet clinical need. HCV infects millions of people worldwide and is a leading cause of liver cirrhosis and hepatocellular cancer. ...Animal challenge experiments, immunogenetics studies, and assessment of host immunity during acute infection highlight the critical role that effective T cell immunity plays in viral control. In this first-in-man study, we have induced antiviral immunity with functional characteristics analogous to those associated with viral control in natural infection, and improved upon a vaccine based on adenoviral vectors alone. We assessed a heterologous prime-boost vaccination strategy based on a replicative defective simian adenoviral vector (ChAd3) and modified vaccinia Ankara (MVA) vector encoding the NS3, NS4, NS5A, and NS5B proteins of HCV genotype 1b. Analysis used single-cell mass cytometry and human leukocyte antigen class I peptide tetramer technology in healthy human volunteers. We show that HCV-specific T cells induced by ChAd3 are optimally boosted with MVA, and generate very high levels of both CD8(+) and CD4(+) HCV-specific T cells targeting multiple HCV antigens. Sustained memory and effector T cell populations are generated, and T cell memory evolved over time with improvement of quality (proliferation and polyfunctionality) after heterologous MVA boost. We have developed an HCV vaccine strategy, with durable, broad, sustained, and balanced T cell responses, characteristic of those associated with viral control, paving the way for the first efficacy studies of a prophylactic HCV vaccine.
The ability to perceive the world is not merely a passive process but depends on sensorimotor loops and interactions that guide and actively bias our sensory systems. Understanding which and how ...cognitive processes participate in this active sensing is still an open question. In this context, the auditory system presents itself as an attractive model for this purpose as it features an efferent control network that projects from the cortex to subcortical nuclei and even to the sensory epithelium itself. This efferent system can regulate the cochlear amplifier sensitivity through medial olivocochlear (MOC) neurons located in the brainstem. The ability to suppress irrelevant sounds during selective attention to visual stimuli is one of the functions that have been attributed to this system. MOC neurons are also directly activated by sounds through a brainstem reflex circuit, a response linked to the ability to suppress auditory stimuli during visual attention. Human studies have suggested that MOC neurons are also recruited by other cognitive functions, such as working memory and predictability. The aim of this research was to explore whether cognitive processes related to delayed responses in a visual discrimination task were associated with MOC function. In this behavioral condition, chinchillas held their responses for more than 2.5 s after visual stimulus offset, with and without auditory distractors, and the accuracy of these responses was correlated with the magnitude of the MOC reflex. We found that the animals' performance decreased in presence of auditory distractors and that the results observed in MOC reflex could predict this performance. The individual MOC strength correlated with behavioral performance during delayed responses with auditory distractors, but not without them. These results in chinchillas, suggest that MOC neurons are also recruited by other cognitive functions, such as working memory.
Materials capable of releasing reactive oxygen species (ROS) can display antibacterial and anticancer activity, and may also have anti-oxidant capacity if they suppress intracellular ROS (
e.g.
...nitric oxide, NO) resulting in anti-inflammatory activity. Herein we report silver phosphate (Ag
3
PO
4
)/polyindole (Pln) nanocomposites which display antibacterial, anticancer and anti-inflammatory activity, and have therefore potential for a variety of biomedical applications.
Materials capable of releasing reactive oxygen species (ROS) can display antibacterial and anticancer activity, and may also have antioxidant capacity if they suppress intracellular ROS (
e.g.
nitric oxide, NO) resulting in anti-inflammatory activity.
A trifunctional approach: 3‐hydroxy‐4‐pyridinones that contain phenol groups for antioxidant functionality are further elaborated with pendant glucosyl moieties for improved blood–brain barrier ...targeting (see structure; R=phenyl, 4‐hydroxyphenyl). Glycosidase removal of the carbohydrate substituents gives ligands that are ready to passivate excess metal ions, especially copper and zinc, in the brain. These molecules are potential prodrugs for treatment of neurodegenerative diseases, including Alzheimer's disease.
OBJECTIVES: To assess variation in the association between blood pressure (BP) and risk for dementia across a spectrum of older ages and to examine BP changes before dementia onset.
DESIGN: ...Prospective cohort study.
SETTING: A large health maintenance organization in Seattle, Washington.
PARTICIPANTS: A cohort of 2,356 members of a large health maintenance organization aged 65 and older who were initially without dementia.
MEASUREMENTS: Dementia diagnosis was assessed biennially, and systolic (SBP) and diastolic BP (DBP) were measured at baseline and at four follow‐up assessments. Cox proportional hazards models were used to estimate hazard ratios (HRs) for dementia and Alzheimer's disease (AD) associated with baseline BP in different age groups.
RESULTS: Within the youngest age group (65–74 at enrollment) a greater risk for dementia was found in participants with high SBP (≥160 mmHg) (hazard ratio (HR)=1.60, 95% confidence interval (CI)=1.01–2.55) or borderline‐high DBP (80–89 mmHg) (HR=1.59, 95% CI=1.07–2.35) than for those with normal BP (SBP <140 mmHg and DBP <80 mmHg). The dementia risk associated with SBP declined with increasing age (SBP‐by‐age interaction, P=.01). SBP declined similarly with aging in subjects who developed dementia and those who did not. Thus, in this sample, the association between SBP and dementia risk was not dependent on when BP was measured in relation to onset of dementia.
CONCLUSION: High SBP was associated with greater risk of dementia in the young elderly (<75) but not in older subjects. Adequate control of hypertension in early old age may reduce the risk for dementia.
Silica accumulation in the Yangtze Sea during the Ordovician–Silurian (O–S) transition appears to have coincided with global climatic fluctuations, widespread upwelling, and volcanism. There is a ...need to further evaluate their respective contributions to silica deposition and potential relationships among these factors. The current study selected siliceous deposits in the Wufeng and Longmaxi Formations from four sections spanning the inner to outer Yangtze Sea, South China, to gain a deeper understanding of the climatic and oceanographic evolution associated with silica enrichment. Al/(Al + Fe + Mn) values, the presence of radiolarians, and Si isotope values of samples recovered from the investigated shale successions offer compelling evidence that the silica is largely of biogenic origin with some terrigenous contributions. Further, various productivity and redox proxies suggest that biogenic silica (BSi) accumulated under conditions of enhanced marine productivity and anoxic bottom water conditions. Hg/TOC and Zr/Al2O3 profiles suggest intermittent volcanism during the BSi deposition in the Yangtze Sea. However, the lack of correlation between BSi and Hg/TOC values indicates that volcanic iron fertilization was not responsible for BSi accumulation. Instead, most BSi-rich samples are dominated by low MnEF × CoEF values (<0.5), consistent with BSi deposited in modern upwelling settings. Hydrographic reconstruction based on Mo–U covariation indicates a more open water setting in the outer Yangtze Sea, while the coeval inner Yangtze Sea was relatively restricted. Therefore, upwelling events appear to have been more vigorous in the outer Yangtze Sea. Published and new Chemical Index of Alteration (CIA), BSi, and MnEF × CoEF data for the Wufeng and Longmaxi Formations across the inner to outer Yangtze Sea demonstrate that temporal and spatial variations of BSi were controlled by climate-driven upwelling. In particular, cool-water upwelling contemporaneous with Hirnantian glaciation may have been responsible for the establishment of the cool-water fauna of the shallow-water Guanyinqiao Bed and enhanced silica deposition in deeper water. Moreover, a moderate negative relationship between compiled CIA and BSi contents suggests that enhanced upwelling driving BSi accumulation appears to have been favored during cooling events. Integrated analysis of BSi deposits of the Laurentia and Baltica continental margins further suggests that BSi accumulation on continental margins during the O–S transition was primarily influenced by global cooling. Therefore, we suggest that wind patterns or/and thermohaline circulation, influenced by climate fluctuations, induced widespread cold water upwelling events during the O–S transition. Moreover, elevated BSi production diluted accumulating OM resulting in the observed parabolic relationship of BSi and TOC.
•The O–S siliceous deposits derived from enhanced BSi productivity.•Upwelling was the first-order constraint on BSi distribution.•The upwelling events appeared to correlate with the global cooling.
, a tier 1 select agent and the etiological agent of melioidosis, transitions from soil and aquatic environments to infect a variety of vertebrate and invertebrate hosts. During the transition from ...an environmental saprophyte to a mammalian pathogen,
encounters and responds to rapidly changing environmental conditions. Environmental sensing systems that control cellular levels of cyclic di-GMP promote pathogen survival in diverse environments. Cyclic di-GMP controls biofilm production, virulence factors, and motility in many bacteria. This study is an evaluation of cyclic di-GMP-associated genes that are predicted to metabolize and interact with cyclic di-GMP as identified from the annotated genome of
1026b. Mutants containing transposon disruptions in each of these genes were characterized for biofilm formation and motility at two temperatures that reflect conditions that the bacteria encounter in the environment and during the infection of a mammalian host. Mutants with transposon insertions in a known phosphodiesterase (
) and a predicted hydrolase (Bp1026b_I2285) gene exhibited decreased motility regardless of temperature. In contrast, the phenotypes exhibited by mutants with transposon insertion mutations in a predicted diguanylate cyclase gene (Bp1026b_II2523) were strikingly influenced by temperature and were dependent on a conserved GG(D/E)EF motif. The transposon insertion mutant exhibited enhanced biofilm formation at 37°C but impaired biofilm formation at 30°C. These studies illustrate the importance of studying behaviors regulated by cyclic di-GMP under varied environmental conditions in order to better understand cyclic di-GMP signaling in bacterial pathogens.
This report evaluates predicted cyclic di-GMP binding and metabolic proteins from
1026b, a tier 1 select agent and the etiologic agent of melioidosis. Transposon insertion mutants with disruptions in each of the genes encoding these predicted proteins were characterized in order to identify key components of the
cyclic di-GMP-signaling network. A predicted hydrolase and a phosphodiesterase that modulate swimming motility were identified, in addition to a diguanylate cyclase that modulates biofilm formation and motility in response to temperature. These studies warrant further evaluation of the contribution of cyclic di-GMP to melioidosis in the context of pathogen acquisition from environmental reservoirs and subsequent colonization, dissemination, and persistence within the host.
Redundant and nonoperational buildings at nuclear sites go through the process of ‘decommissioning’, involving decontamination of nuclear waste material and demolition of physical infrastructure. One ...challenging problem currently faced by the nuclear industry during this process is the segregation of redundant waste material into a choice of ‘post-processes’ based upon the nature and extent of its radioactivity that may pose a serious threat to the environment. Following an initial inspection, waste materials are subjected to treatment, disruption and consigned to various types of export containers. To date, the process of objects (waste) classification is performed manually. In order to automate this process, robotic platforms can be deployed that utilise robust and fast vision systems for visual classification of nuclear waste material. This paper proposes a novel solution incorporating a machine vision system for autonomous identification of waste material from decommissioned nuclear plants. Rotation and scale invariant moments are used to describe object shapes in the visual scene whereas a random forest learning algorithm performs object classification. Using nuclear waste simulants (from the nuclear plant decommissioning process), an exhaustive ‘proof-of-concept’ quantitative assessment of the proposed technique is performed, in order to test its applicability within the current problem domain.
•Waste from decommissioned nuclear plants are required to be sorted and segregated.•A vision system for autonomous classification of nuclear waste is proposed.•The lowest possible passive vision sensors are used due to operational constraints.•Proposed system is tested using dataset generated from nonradioactive simulants.•Results are presented using performance metrics with conclusions and future work.
Insulin signaling to the glomerular podocyte via the insulin receptor (IR) is critical for kidney function. In this study we show that near-complete knockout of the closely related insulin-like ...growth factor 1 receptor (IGF1R) in podocytes is detrimental, resulting in albuminuria in vivo and podocyte cell death in vitro. In contrast, partial podocyte IGF1R knockdown confers protection against doxorubicin-induced podocyte injury. Proteomic analysis of cultured podocytes revealed that while near-complete loss of podocyte IGF1R results in the downregulation of mitochondrial respiratory complex I and DNA damage repair proteins, partial IGF1R inhibition promotes respiratory complex expression. This suggests that altered mitochondrial function and resistance to podocyte stress depends on the level of IGF1R suppression, the latter determining whether receptor inhibition is protective or detrimental. Our work suggests that the partial suppression of podocyte IGF1R could have therapeutic benefits in treating albuminuric kidney disease.
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•Near-complete loss of podocyte IGF1R is highly detrimental•Near-complete loss of podocyte IGF1R results in mitochondrial dysfunction•Partial podocyte IGF1R inhibition is beneficial in protecting against oxidative stress
Biological sciences; Molecular biology; Cell biology.
Each additional copy of the apolipoprotein E4 (APOE4) allele is associated with a higher risk of Alzheimer's dementia, while the APOE2 allele is associated with a lower risk of Alzheimer's dementia, ...it is not yet known whether APOE2 homozygotes have a particularly low risk. We generated Alzheimer's dementia odds ratios and other findings in more than 5,000 clinically characterized and neuropathologically characterized Alzheimer's dementia cases and controls. APOE2/2 was associated with a low Alzheimer's dementia odds ratios compared to APOE2/3 and 3/3, and an exceptionally low odds ratio compared to APOE4/4, and the impact of APOE2 and APOE4 gene dose was significantly greater in the neuropathologically confirmed group than in more than 24,000 neuropathologically unconfirmed cases and controls. Finding and targeting the factors by which APOE and its variants influence Alzheimer's disease could have a major impact on the understanding, treatment and prevention of the disease.
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