R21 in Matrix-M adjuvant in UK malaria-naive adult men and non-pregnant women aged 18-45 years: an open-label, partially blinded, phase 1-2a controlled human malaria infection study.

Background: R21 is a novel malaria vaccine, composed of a fusion protein of the malaria circumsporozoite protein and hepatitis B surface antigen. Following favourable safety and immunogenicity in a phase 1 study, we aimed to assess the efficacy of R21 administered with Matrix-M (R21/MM) against clinical malaria in adults from the UK who were malaria naive in a controlled human malaria infection study.

Methods: In this open-label, partially blinded, phase 1-2A controlled human malaria infection study undertaken in Oxford, Southampton, and London, UK, we tested five novel vaccination regimens of R21/MM.

Label-free, non-contact determination of resting membrane potential using dielectrophoresis.

Measurement of cellular resting membrane potential (RMP) is important in understanding ion channels and their role in regulation of cell function across a wide range of cell types. However, methods available for the measurement of RMP (including patch clamp, microelectrodes, and potential-sensitive fluorophores) are expensive, slow, open to operator bias, and often result in cell destruction. We present non-contact, label-free membrane potential estimation which uses dielectrophoresis to determine the cytoplasm conductivity slope as a function of medium conductivity.

Absence of differential protection from extinction in human causal learning.

Elemental models of associative learning typically employ a common prediction-error term. Following a conditioning trial, they predict that the change in the strength of an association between a cue and an outcome is dependent upon how well the outcome was predicted. When multiple cues are present, they each contribute to that prediction.

Continuous flow synthesis enabling reaction discovery.

This article defines the role that continuous flow chemistry can have in new reaction discovery, thereby creating molecular assembly opportunities beyond our current capabilities. Most notably the focus is based upon photochemical, electrochemical and temperature sensitive processes where continuous flow methods and machine assisted processing can have significant impact on chemical reactivity patterns. These flow chemical platforms are ideally placed to exploit future innovation in data acquisition, feed-back and control through artificial intelligence (AI) and machine learning (ML) techniques.

Nitro-sulfinate Reductive Coupling to Access (Hetero)aryl Sulfonamides.

A method to assemble (hetero)aryl sulfonamides via the reductive coupling of aryl sulfinates and nitroarenes is reported. Various reducing conditions with sodium bisulfite and with or without tin(II) chloride in DMSO were developed using an ultrasound bath to improve reaction homogeneity and mixing. A range of (hetero)aryl sulfonamides bearing a selection of functional groups were prepared, and the mechanism of the transformation was investigated.

On the low-frequency dispersion observed in dielectrophoresis spectra.

The foundation of dielectrophoresis (DEP) as a tool for biological investigation is the use of the Clausius-Mossotti (C-M) factor to model the observed behaviour of cells experiencing DEP across a frequency range. Nevertheless, it is also the case that at lower frequencies, the DEP spectrum deviates from predictions; there exists a rise in DEP polarisability, which varies in frequency and magnitude with different cell types and medium conductivities. In order to evaluate the origin of this effect, we have studied DEP spectra from five cell types (erythrocytes, platelets, neurons, HeLa cancer cells and monocytes) in several conditions including medium conductivity and cell treatment.

Photoredox-Catalyzed Preparation of Sulfones Using Bis-Piperidine Sulfur Dioxide - An Underutilized Reagent for SO Transfer.

Sulfonyl groups are widely observed in biologically relevant molecules and consequently, SO capture is an increasingly attractive method to prepare these sulfonyl-containing compounds given the range of SO -surrogates now available as alternatives to using the neat gas. This, along with the advent of photoredox catalysis, has enabled mild radical capture of SO to emerge as an effective route to sulfonyl compounds. Here we report a photoredox-catalyzed cross-electrophile sulfonylation of aryl and alkyl bromides making use of a previously under-used amine-SO surrogate; bis(piperidine) sulfur dioxide (PIPSO).

Neurophysiological evidence of motor preparation in inner speech and the effect of content predictability.

Self-generated overt actions are preceded by a slow negativity as measured by electroencephalogram, which has been associated with motor preparation. Recent studies have shown that this neural activity is modulated by the predictability of action outcomes. It is unclear whether inner speech is also preceded by a motor-related negativity and influenced by the same factor.

An investigation of inattentional blindness using gaze and frequency tagging.

Inattentional blindness (IB) occurs when a salient object presented in plain sight goes unnoticed when its appearance is unexpected. Across two experiments, participants completed a classic dynamic IB task while eye movements and steady-state visual evoked potential (SSVEP) responses were continually recorded. This allowed us to measure the modulation of gaze and brain-based indices of attention during IB.

Disrupted auditory N1, theta power and coherence suppression to willed speech in people with schizophrenia.

The phenomenon of sensory self-suppression - also known as sensory attenuation - occurs when a person generates a perceptible stimulus (such as a sound) by performing an action (such as speaking). The sensorimotor control system is thought to actively predict and then suppress the vocal sound in the course of speaking, resulting in lowered cortical responsiveness when speaking than when passively listening to an identical sound. It has been hypothesized that auditory hallucinations in schizophrenia result from a reduction in self-suppression due to a disruption of predictive mechanisms required to anticipate and suppress a specific, self-generated sound.

Multicomponent Direct Assembly of -Heterospirocycles Facilitated by Visible-Light-Driven Photocatalysis.

-heterospirocycles are interesting structural units found in both natural products and medicinal compounds but have relatively few reliable methods for their synthesis. Here, we enlist the photocatalytic generation of -centered radicals to construct β-spirocyclic pyrrolidines from -allylsulfonamides and alkenes. A variety of β-spirocyclic pyrrolidines have been constructed, including drug derivatives, in moderate to very good yields.

CoVaccine HT™ adjuvant is superior to Freund's in eliciting ovine polyclonal antibodies against human tumor necrosis factor-alpha.

Introduction: Passive immunotherapy using polyclonal antibodies plays an important role in preventing and treating antigenic and pathogenic diseases. Polyclonal antibodies are used for therapeutic, diagnostic and investigational purposes, with adjuvants employed to enhance the immune response against proteins that are poorly antigenic or self-antigens. This study aimed to optimize current immunization methods by evaluating the novel adjuvant CoVaccine HT™ against the established Freund's at producing ovine polyclonal antibodies against pro-inflammatory cytokine human recombinant tumor necrosis factor alpha (TNF-α).

Photoredox-Catalyzed Dehydrogenative Csp-Csp Cross-Coupling of Alkylarenes to Aldehydes in Flow.

Executing photoredox reactions in flow offers solutions to frequently encountered issues regarding reproducibility, reaction time, and scale-up. Here, we report the transfer of a photoredox-catalyzed benzylic coupling of alkylarenes to aldehydes to a flow chemistry setting leading to improvements in terms of higher concentration, shorter residence times, better yields, ease of catalyst preparation, and enhanced substrate scope. Its applicability has been demonstrated by a multi-gram-scale reaction using high-power light-emitting diodes (LEDs), late-stage functionalization of selected active pharmaceutical ingredients (APIs), and also a photocatalyst recycling method.

Movement Planning Determines Sensory Suppression: An Event-related Potential Study.

Sensory suppression refers to the phenomenon that sensory input generated by our own actions, such as moving a finger to press a button to hear a tone, elicits smaller neural responses than sensory input generated by external agents. This observation is usually explained via the internal forward model in which an efference copy of the motor command is used to compute a corollary discharge, which acts to suppress sensory input. However, because moving a finger to press a button is accompanied by neural processes involved in preparing and performing the action, it is unclear whether sensory suppression is the result of movement planning, movement execution, or both.

Sensory attenuation is modulated by the contrasting effects of predictability and control.

Self-generated stimuli have been found to elicit a reduced sensory response compared with externally-generated stimuli. However, much of the literature has not adequately controlled for differences in the temporal predictability and temporal control of stimuli. In two experiments, we compared the N1 (and P2) components of the auditory-evoked potential to self- and externally-generated tones that differed with respect to these two factors.

Outcome unpredictability affects outcome-specific motivation to learn.

Outcome predictability effects in associative learning paradigms describe better learning about outcomes with a history of greater predictability in a similar but unrelated task compared with outcomes with a history of unpredictability. Inspired by the similarities between this phenomenon and the effect of uncontrollability in learned helplessness paradigms, here, we investigate whether learning about unpredictability decreases outcome-specific motivation to learn. We used a modified version of the allergy task, in which participants first observe the foods eaten by a fictitious patient, followed by allergic reactions that he subsequently suffers, some of which are perfectly predictable and others unpredictable.

Reinforcement history shapes primary visual cortical responses: An SSVEP study.

Efficient learning requires allocating limited attentional resources to meaningful stimuli and away from irrelevant stimuli. This prioritization may occur via covert attention, evident in the activity of the visual cortex. We used steady-state visual evoked potentials (SSVEPs) to assess whether associability-driven changes in stimulus processing were evident in visuocortical responses.

Schizotypy is associated with difficulty maintaining multiple hypotheses.

Among neurocognitive accounts of delusions, there is a growing consensus that it is the certainty with which delusions are held, rather than their content that defines some beliefs as delusional. On a continuum model of psychosis, this inappropriate certainty ought to be present (albeit in an attenuated form) in healthy adults who score highly in schizotypy. It was hypothesised that this might be most evident in circumstances where the environment provides incomplete or probabilistic information, which thereby forces the participant to hold two imperfectly supported, concurrent hypotheses in mind.

Inflammatory bowel disease and targeted oral anti-TNFα therapy.

Antibodies have provided invaluable treatment options for many diseases, with immunotherapy revolutionising the treatment of several inflammatory disorders including inflammatory bowel disease (IBD). Accumulating evidence suggests that IBD results from an inappropriate response to intestinal microbes and environmental factors in genetically susceptible individuals, with overactivity of the pro-inflammatory pathways. On a pathophysiological level, IBD is a complex disease with intestinal fibrosis, stenosis and an increased incidence of cancer observed in those whose disease is inadequately controlled over time.

The outcome predictability bias is evident in overt attention.

Previous studies of human associative learning have demonstrated that people's experience with a cueing stimulus will change how that cue is treated during subsequent learning. Typically, studies have shown that people pay more attention to cues that were informative in the past, and learn new information about these cues more rapidly (these cues are said to have a higher associability). It has recently been shown that to-be-predicted events (outcomes) can also differ in their associability as a consequence of prior experience.

Learned biases in the processing of outcomes: A brief review of the outcome predictability effect.

Much empirical work and theoretical discussion in the associative learning literature has focused on when and how a cue changes in its associability. A series of new findings in human learning preparations (collectively referred to as the "outcome predictability" effect) appear to show that outcomes vary in their capacity to enter into novel associations as a product of their associative history. This effect is reminiscent of how cues change in associability as a consequence of their reinforcement history.

Safety and Immunogenicity of a Heterologous Prime-Boost Ebola Virus Vaccine Regimen in Healthy Adults in the United Kingdom and Senegal.

Background: The 2014 West African outbreak of Ebola virus disease highlighted the urgent need to develop an effective Ebola vaccine.

Methods: We undertook 2 phase 1 studies assessing safety and immunogenicity of the viral vector modified vaccinia Ankara virus vectored Ebola Zaire vaccine (MVA-EBO-Z), manufactured rapidly on a new duck cell line either alone or in a heterologous prime-boost regimen with recombinant chimpanzee adenovirus type 3 vectored Ebola Zaire vaccine (ChAd3-EBO-Z) followed by MVA-EBO-Z. Adult volunteers in the United Kingdom (n = 38) and Senegal (n = 40) were vaccinated and an accelerated 1-week prime-boost regimen was assessed in Senegal.

Semantic prediction-errors are context-dependent: An ERP study.

The human brain is an efficient, adaptive, and predictive machine, constructing a generative model of the environment that we then perceive and become conscious of. Here, we show that different types of prediction-errors - the discrepancies between top-down expectations and bottom-up sensory input - are integrated across processing levels and sensory modalities of the cortical hierarchy. We designed a novel, hybrid protocol in which five prediction-establishing sounds were played in rapid succession (e.

Superstition predicts perception of illusory control.

Superstitions are common, yet we have little understanding of the cognitive mechanisms that bring them about. This study used a laboratory-based analogue for superstitious beliefs that involved people monitoring the relationship between undertaking an action (pressing a button) and an outcome occurring (a light illuminating). The task was arranged such that there was no objective contingency between pressing the button and the light illuminating - the light was just as likely to illuminate whether the button was pressed or not.