Bioelectronic DNA detection of human papillomaviruses using eSensor™: a model system for detection of multiple pathogens

BACKGROUND: We used human papillomaviruses (HPV) as a model system to evaluate the utility of a nucleic acid, hybridization-based bioelectronic DNA detection platform (eSensor™) in identifying multiple pathogens. METHODS: Two chips were spotted with capture probes consisting of DNA oligonucleotide sequences specific for HPV types. Electrically conductive signal probes were synthesized to be complementary to a distinct region of the amplified HPV target DNA. A portion of the HPV L1 region that was amplified by using consensus primers served as target DNA. The amplified target was mixed with a cocktail of signal probes and added to a cartridge containing a DNA chip to allow for hybridization with complementary capture probes. RESULTS: Two bioelectric chips were designed and successfully detected 86% of the HPV types contained in clinical samples. CONCLUSIONS: This model system demonstrates the potential of the eSensor platform for rapid and integrated detection of multiple pathogens

Efficacy of melatonin in term neonatal models of perinatal hypoxia-ischaemia

OBJECTIVE: Neonatal encephalopathy (NE) is an important cause of mortality and disability worldwide. Therapeutic hypothermia (HT) is an effective therapy, however not all babies benefit. Novel agents are urgently needed to improve outcomes. Melatonin in preclinical studies has promising neuroprotective properties. This meta-analysis assessed the efficacy of melatonin in term animal models of NE on cerebral infarct size, neurobehavioural tests and cell death. METHODS: A literature search was carried out using Embase, MEDLINE and Web of Science (31 May 2021). We identified 14 studies and performed a meta-analysis with a random effects model using standardised mean difference (SMD) as the effect size. The risk of bias was assessed using the Systematic Review Centre for Laboratory animal Experimentation tool and publication bias was assessed with funnel plots, and adjusted using trim and fill analysis. Subgroup and meta-regression analyses were performed to assess the effects of study design variables. RESULTS: We observed significant reduction in brain infarct size (SMD -2.05, 95% CI [-2.93, -1.16]), improved neurobehavioural outcomes (SMD -0.86, 95% CI [-1.23, -0.53]) and reduction in cell death (SMD -0.60, 95% CI [-1.06, -0.14]) favouring treatment with melatonin. Neuroprotection was evident as a single therapy and combined with HT. Subgroup analysis showed greater efficacy with melatonin given before or immediately after injury and with ethanol excipients. The overall effect size remained robust even after adjustment for publication bias. INTERPRETATION: These studies demonstrate a significant neuroprotective efficacy of melatonin in term neonatal models of hypoxia-ischaemia, and suggest melatonin is a strong candidate for translation to clinical trials in babies with moderate-severe NE

Tau PET and multimodal brain imaging in patients at risk for chronic traumatic encephalopathy.

ObjectiveTo characterize individual and group-level neuroimaging findings in patients at risk for Chronic Traumatic Encephalopathy (CTE).MethodsEleven male patients meeting criteria for Traumatic Encephalopathy Syndrome (TES, median age: 64) underwent neurologic evaluation, 3-Tesla MRI, and PET with [18F]-Flortaucipir (FTP, tau-PET) and [11C]-Pittsburgh compound B (PIB, amyloid-PET). Six patients underwent [18F]-Fluorodeoxyglucose-PET (FDG, glucose metabolism). We assessed imaging findings at the individual patient level, and in group-level comparisons with modality-specific groups of cognitively normal older adults (CN). Tau-PET findings in patients with TES were also compared to a matched group of patients with mild cognitive impairment or dementia due to Alzheimer's disease (AD).ResultsAll patients with TES sustained repetitive head injury participating in impact sports, ten in American football. Three patients met criteria for dementia and eight had mild cognitive impairment. Two patients were amyloid-PET positive and harbored the most severe MRI atrophy, FDG hypometabolism, and FTP-tau PET binding. Among the nine amyloid-negative patients, tau-PET showed either mildly elevated frontotemporal binding, a "dot-like" pattern, or no elevated binding. Medial temporal FTP was mildly elevated in a subset of amyloid-negative patients, but values were considerably lower than in AD. Voxelwise analyses revealed a convergence of imaging abnormalities (higher FTP binding, lower FDG, lower gray matter volumes) in frontotemporal areas in TES compared to controls.ConclusionsMildly elevated tau-PET binding was observed in a subset of amyloid-negative patients at risk for CTE, in a distribution consistent with CTE pathology stages III-IV. FTP-PET may be useful as a biomarker of tau pathology in CTE but is unlikely to be sensitive to early disease stages

The Beneficial Effects of Melatonin Administration Following Hypoxia-Ischemia in Preterm Fetal Sheep

Melatonin (MLT) is an endogenous hormone that controls circadian cycle. MLT has additional important properties that make it appealing as a neuroprotective agent—it is a potent anti-oxidant, with anti-apoptotic and anti-inflammatory properties. MLT is safe for administration during pregnancy or to the newborn after birth, and can reduce white matter brain injury under conditions of chronic fetal hypoxia. Accordingly, in the current study, we examined whether an intermediate dose of MLT could restore white matter brain development when administered after an acute hypoxic ischemic (HI) insult in preterm fetal sheep. Fifteen fetal sheep at 95–98 days gestation were instrumented with femoral artery and vein catheters, and a silastic cuff placed around the umbilical cord. At 102 days gestation, the cuff was inflated, causing complete umbilical cord occlusion for 25 min in 10 fetuses, to induce acute severe HI. Five HI fetuses received intravenous MLT for 24 h beginning at 2 h after HI. The remaining five fetuses were administered saline alone. Ten days after HI, the fetal brain was collected from each animal and white and gray matter neuropathology assessed. HI caused a significant increase in apoptotic cell death (TUNEL+), activated microglia (Iba-1+), and oxidative stress (8-OHdG+) within the subventricular and subcortical white matter. HI reduced the total number of oligodendrocytes and CNPase+ myelin density. MLT administration following HI decreased apoptosis, inflammation and oxidative stress within the white matter. MLT had intermediate benefits for the developing white matter: it increased oligodendrocyte cell number within the periventricular white matter only, and improved CNPase+ myelin density within the subcortical but not the striatal white matter. MLT administration following HI was also associated with improved neuronal survival within the cortex. Neuropathology in preterm infants is complex and mediated by multiple mechanisms, including inflammation, oxidative stress and apoptotic pathways. Treatment with MLT presents a safe approach to neuroprotective therapy in preterm infants but appears to have brain region-specific benefits within the white matter

What sets lower limits to phytoplankton stocks in high-nitrate, low-chlorophyll regions of the open ocean?

Phytoplankton biomass in high-nitrate, low-chlorophyll (HNLC) ocean regions exhibits a pronounced stability: variation occurs only within a narrow range of values. The magnitude of this variation has profound ecological and geochemical consequences. While mechanisms believed to set the upper limits to HNLC phytoplankton biomass (iron limitation, microherbivore grazing) have received much recent attention, mechanisms setting the lower limits are largely unknown. The demonstrated importance of planktonic micrograzers, largely protists, in removing phytoplankton biomass in HNLC regions suggests that micrograzer behavioral and physiological capabilities may hold the key. This will be the case at any level of phytoplankton cell division greater than zero, regardless of the extent of growth rate limitation by resource (e.g. iron, light) availability. Indeed, HNLC plankton dynamics models almost universally include several biological responses that set lower phytoplankton biomass limits and confer temporal stability, including substantial feeding thresholds, zero micrograzer metabolic costs, and no micrograzer mortality at low food levels. Laboratory observations of these same biological responses in protist grazers are equivocal. There are no direct observations of substantive feeding thresholds, and many heterotrophic protists exhibit significant rates of respiration and mortality (cell lysis) at very low food levels. We present several candidate explanations for the discrepancy between laboratory observations and model biological 'requirements'. Firstly, laboratory-derived rate measurements may be biased by use of species and prey concentrations that are not representative of HNLC communities. Secondly, model micrograzer features may be a proxy for other stabilizing phenomena such as spatial heterogeneity ('patchiness') or carnivory (top-down control of rnicroherbivores), though a logical analysis indicates that neither is likely to provide robust stabilization of lower phytoplankton biomass limits. Lastly, the highly plastic feeding capabilities of protist grazers, which include switching between phytoplankton and alternative prey such as bacteria, detritus, and other microherbivores, are a probable locus for stabilization of biomass limits. The extent to which such behavioral plasticity functions on the level of individuals or of species assemblages is unknown. We advocate a coupled modeling and experimental approach to further progress in understanding this key feature of HNLC ecosystems.Keywords: Planktonic food webs, Phytoplankton, Microzooplankton, Plankton dynamics models, Feeding behavior, Grazer

Cultural antecedents to the normative, affective and cognitive effects of domestic versus foreign product purchase behaviour

The paper aims to investigate simultaneous and independent effects of cognitive, affective, and normative (CAN) decision mechanisms and cultural elements on consumer purchase behavior of foreign and domestic products. The study uses a survey to collect data from 5 086 respondents across 19 nations. The findings suggest that CAN factors independently affect purchase decisions for domestic, but not always foreign goods. Collectivism and uncertainty avoidance directly and differentially affect the CAN mechanisms. By explaining the effects of CAN and cultural elements on foreign and domestic purchase behaviour and offering product positioning strategies to internationally operating business managers the study provides important research and practical implications. The originality and value of this research lies in the theoretically proposed and empirically tested model, which incorporates consumer ethnocentrism, quality importance, national identification, cultural antecedents (collectivism and uncertainty avoidance) and domestic/ foreign product purchase behaviour