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Design of a basigin-mimicking inhibitor targeting the malaria invasion protein RH5.
Many human pathogens use host cell-surface receptors to attach and invade cells. Often, the host-pathogen interaction affinity is low, presenting opportunities to block invasion using a soluble, high-affinity mimic of the host protein. The Plasmodium falciparum reticulocyte-binding protein homolog 5 (RH5) provides an exciting candidate for mimicry: it is highly conserved and its moderate affinity binding to the human receptor basigin (KD ≥1 μM) is an essential step in erythrocyte invasion by this malaria parasite. We used deep mutational scanning of a soluble fragment of human basigin to systematically characterize point mutations that enhance basigin affinity for RH5 and then used Rosetta to design a variant within the sequence space of affinity-enhancing mutations. The resulting seven-mutation design exhibited 1900-fold higher affinity (KD approximately 1 nM) for RH5 with a very slow binding off rate (0.23 h-1 ) and reduced the effective Plasmodium growth-inhibitory concentration by at least 10-fold compared to human basigin. The design provides a favorable starting point for engineering on-rate improvements that are likely to be essential to reach therapeutically effective growth inhibition.
Identification of an assimilatory nitrate reductase in mutants of Paracoccus denitrificans GB17 deficient in nitrate respiration
A Paracoccus denitrificans strain (M6Omega) unable to use nitrate as a terminal electron acceptor was constructed by insertional inactivation of the periplasmic and membrane-bound nitrate reductases. The mutant strain was able to grow aerobically with nitrate as the sole nitrogen source. It also grew anaerobically with nitrate as sole nitrogen source when nitrous oxide was provided as a respiratory electron acceptor. These growth characteristics are attributed to the presence of a third, assimilatory nitrate reductase. Nitrate reductase activity was detectable in intact cells and soluble fractions using nonphysiological electron donors. The enzyme activity was not detectable when ammonium was included in the growth medium. The results provide an unequivocal demonstration that P. denitrificans can express an assimilatory nitrate reductase in addition to the well-characterised periplasmic and membrane-bound nitrate reductases.
Structures of influenza A virus RNA polymerase offer insight into viral genome replication.
Influenza A viruses are responsible for seasonal epidemics, and pandemics can arise from the transmission of novel zoonotic influenza A viruses to humans1,2. Influenza A viruses contain a segmented negative-sense RNA genome, which is transcribed and replicated by the viral-RNA-dependent RNA polymerase (FluPolA) composed of PB1, PB2 and PA subunits3-5. Although the high-resolution crystal structure of FluPolA of bat influenza A virus has previously been reported6, there are no complete structures available for human and avian FluPolA. Furthermore, the molecular mechanisms of genomic viral RNA (vRNA) replication-which proceeds through a complementary RNA (cRNA) replicative intermediate, and requires oligomerization of the polymerase7-10-remain largely unknown. Here, using crystallography and cryo-electron microscopy, we determine the structures of FluPolA from human influenza A/NT/60/1968 (H3N2) and avian influenza A/duck/Fujian/01/2002 (H5N1) viruses at a resolution of 3.0-4.3 Å, in the presence or absence of a cRNA or vRNA template. In solution, FluPolA forms dimers of heterotrimers through the C-terminal domain of the PA subunit, the thumb subdomain of PB1 and the N1 subdomain of PB2. The cryo-electron microscopy structure of monomeric FluPolA bound to the cRNA template reveals a binding site for the 3' cRNA at the dimer interface. We use a combination of cell-based and in vitro assays to show that the interface of the FluPolA dimer is required for vRNA synthesis during replication of the viral genome. We also show that a nanobody (a single-domain antibody) that interferes with FluPolA dimerization inhibits the synthesis of vRNA and, consequently, inhibits virus replication in infected cells. Our study provides high-resolution structures of medically relevant FluPolA, as well as insights into the replication mechanisms of the viral RNA genome. In addition, our work identifies sites in FluPolA that could be targeted in the development of antiviral drugs.
Lipid-Dependent Regulation of Ion Channels and G Protein-Coupled Receptors: Insights from Structures and Simulations.
Ion channels and G protein-coupled receptors (GPCRs) are regulated by lipids in their membrane environment. Structural studies combined with biophysical and molecular simulation investigations reveal interaction sites for specific lipids on membrane protein structures. For K channels, PIP2 plays a key role in regulating Kv and Kir channels. Likewise, several recent cryo-EM structures of TRP channels have revealed bound lipids, including PIP2 and cholesterol. Among the pentameric ligand-gated ion channel family, structural and biophysical studies suggest the M4 TM helix may act as a lipid sensor, e.g., forming part of the binding sites for neurosteroids on the GABAA receptor. Structures of GPCRs have revealed multiple cholesterol sites, which may modulate both receptor dynamics and receptor oligomerization. PIP2 also interacts with GPCRs and may modulate their interactions with G proteins. Overall, it is evident that multiple lipid-binding sites exist on channels and receptors that modulate their function allosterically and are potential druggable sites. Expected final online publication date for the Annual Review of Pharmacology and Toxicology, Volume 60 is January 6, 2020. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.
Dynamic sustained attention markers differentiate atypical development: The case of Williams syndrome and Down's syndrome.
Impaired sustained attention is considered an important factor in determining poor functional outcomes across multiple cognitive and behavioural disorders. Sustained attention is compromised for both children with Williams syndrome (WS) and Down's syndrome (DS), but specific difficulties remain poorly understood because of limitations in how sustained attention has been assessed thus far. In the current study, we compared the performance of typically developing children (N = 99), children with WS (N = 25), and children with DS (N = 18), on a Continuous Performance Task - a standard tool for measuring sustained attention. In contrast to previous studies, primarily focused on overall differences in mean performance, we estimated the extent to which performance changed over time on task, thus focusing directly on the sustained element of performance. Children with WS and children with DS performed more poorly overall compared to typically developing children. Importantly, measures specific to changes over time differentiated between children with the two syndromes. Children with WS showed a decrement in performance, whereas children with Down's syndrome demonstrated non-specific poor performance. In addition, our measure of change in performance predicted teacher-rated attention deficits symptoms across the full sample. An approach that captures dynamic changes in performance over assessments may be fruitful for investigating similarities and differences in sustained attention for other atypically developing populations.
Recommendations for the Nonpharmacological Treatment of Apathy in Brain Disorders
© 2019 American Association for Geriatric Psychiatry Apathy is a common neuropsychiatric syndrome observed across many neurocognitive and psychiatric disorders. Although there are currently no definitive standard therapies for the treatment of apathy, nonpharmacological treatment (NPT) is often considered to be at the forefront of clinical management. However, guidelines on how to select, prescribe, and administer NPT in clinical practice are lacking. Furthermore, although new Information and Communication Technologies (ICT) are beginning to be employed in NPT, their role is still unclear. The objective of the present work is to provide recommendations for the use of NPT for apathy, and to discuss the role of ICT in this domain, based on opinions gathered from experts in the field. The expert panel included 20 researchers and healthcare professionals working on brain disorders and apathy. Following a standard Delphi methodology, experts answered questions via several rounds of web-surveys, and then discussed the results in a plenary meeting. The experts suggested that NPT are useful to consider as therapy for people presenting with different neurocognitive and psychiatric diseases at all stages, with evidence of apathy across domains. The presence of a therapist and/or a caregiver is important in delivering NPT effectively, but parts of the treatment may be performed by the patient alone. NPT can be delivered both in clinical settings and at home. However, while remote treatment delivery may be cost and time-effective, it should be considered with caution, and tailored based on the patient's cognitive and physical profile and living conditions.
Sexual Networks
© 2016 Elsevier Inc. All rights reserved. Sexual networks define a quantitative framework developed from an integration of social network analysis and selection theory with the aim of providing a toolkit to examine how the complexity of social and competitive sexual interactions determine the strength and shape of sexual selection in populations characterized by nonrandom mating patterns.
Grandmothers' mental health is associated with grandchildren's emotional and behavioral development: a three-generation prospective study in Brazil.
BACKGROUND: Maternal mental health is associated with an increased risk of emotional and behavioural problems in children, and the risk is partly explained by the negative impact of maternal depression on caregiving. The role of mental health in other family members, who in many contexts also provide substantial caregiving, has received far less attention. We examined the impact of grandmothers' emotional symptoms, whose role in child care is increasing across the world, on internalizing and externalizing symptoms in grandchildren from a three-generation birth cohort study. METHODS: Prospective data from three generations in two birth cohorts 22 years apart (1982 and 2004) in Pelotas, Brazil, were used (n = 92). Mental health in grandmothers and parents was assessed using the Self-Reported Questionnaire (SRQ-20). Grandchildren were members of the 2004 birth cohort, and behavioural and emotional problems were measured using the Child-Behaviour Checklist (CBCL) at age 4 years. RESULTS: Grandmothers' symptoms were associated with more emotional and behavioural problems in grandchildren after adjustment for confounding factors. The size of the associations between grandmothers' and grandchildren mental health symptoms was comparable to the associations between maternal emotional symptoms and children emotional and behavioural problems. There was no evidence for associations with paternal symptoms. These effects were substantially stronger for maternal compared to paternal grandmothers. CONCLUSIONS: In some contexts, grandmothers' mental health may be as important to grandchild emotional and behavioural development as maternal mental health. Interventions to improve the mental health of grandmothers, as well as parents, may be important to child mental health.
Establishing boundary conditions for multiple design elements congruent with taste expectations
© 2019 Elsevier Ltd Over the past two decades, a burgeoning literature has demonstrated the robust associations that exist between visual elements (‘cues’) on product packaging in the food and beverage category and consumer expectations regarding the taste of a product. However, to date, little research has examined if/how the individual effects demonstrated for such visual cues combine when multiple cues are presented together. Therefore, two experiments were designed to investigate whether manipulating the number (Experiment 1), and congruency (i.e., an association with a particular taste as identified by previous literature; Experiment 2) of word, colour, and background pattern angularity cues would influence people's taste expectations and associated evaluations. The results of Experiment 1 demonstrated that increasing the number of congruent cues on product packaging increased the strength of people's expectations concerning the relevant basic taste, with an apparent ‘ceiling effect’ hinted at. Experiment 2 extended this novel empirical finding by demonstrating that when colour and background pattern cues were associated with different basic tastes (i.e., the cues were, in some sense, ‘incongruent’), rather than counteracting one another, colour tended to dominate over background pattern in terms of determining the expected taste of the product. Taken together, these results suggest that stronger, or at least more salient, design cues dominate over weaker ones when they conflict in terms of their meaning (or corresponding taste).
Selective Attention in Vision, Audition, and Touch
© 2017 Elsevier Ltd. All rights reserved. Given that our perceptual capacity is limited, it is important that we are able to focus our attention selectively on certain stimuli at the expense of others to behave effectively in a world filled with sensory information. Here, we review evidence from behavioral and neuroscientific studies of this process of selective attention in vision, hearing, and touch. Our particular focus in this chapter is on the enduring debate over the stage of processing at which unattended information is excluded from further processing. This chapter describes the origins of this debate and highlights some of the most important empirical and theoretical work that have emerged from studies of this issue in recent years.