UDP-glycosyltransferases act as key determinants of host plant range in generalist and specialist Spodoptera species.

Phytophagous insects have evolved sophisticated detoxification systems to overcome the antiherbivore chemical defenses produced by many plants. However, how these biotransformation systems differ in generalist and specialist insect species and their role in determining insect host plant range remains an open question. Here, we show that UDP-glucosyltransferases (UGTs) play a key role in determining the host range of insect species within the Spodoptera genus. Comparative genomic analyses of Spodoptera species that differ in host plant breadth identified a relatively conserved number of UGT genes in generalist species but high levels of UGT gene pseudogenization in the specialist Spodoptera picta. CRISPR-Cas9 knockouts of the three main UGT gene clusters of Spodoptera frugiperda revealed that UGT33 genes play an important role in allowing this species to utilize the poaceous plants maize, wheat, and rice, while UGT40 genes facilitate utilization of cotton. Further functional analyses in vivo and in vitro identified the UGT SfUGT33F32 as the key mechanism that allows generalist S. frugiperda to detoxify the benzoxazinoid DIMBOA (2,4-dihydroxy-7-methoxy-2H-1,4-benzoxazin-3(4H)-one), a potent insecticidal phytotoxin produced by poaceous plants. However, while this detoxification capacity is conserved in several generalist Spodoptera species, Spodoptera picta, which specializes on Crinum plants, is unable to detoxify DIMBOA due to a nonfunctionalizing mutation in SpUGT33F34. Collectively, these findings provide insight into the role of insect UGTs in host plant adaptation, the mechanistic basis of evolutionary transitions between generalism and specialism and offer molecular targets for controlling a group of notorious insect pests.

Function and contribution of two putative Enterococcus faecalis glycosaminoglycan degrading enzymes to bacteremia and catheter-associated urinary tract infection.

Enterococcus faecalis is a common cause of healthcare-acquired bloodstream infections and catheter-associated urinary tract infections (CAUTIs) in both adults and children. Treatment of E. faecalis infection is frequently complicated by multi-drug resistance. Based on protein homology, E. faecalis encodes two putative hyaluronidases, EF3023 (HylA) and EF0818 (HylB). In other Gram-positive pathogens, hyaluronidases have been shown to contribute to tissue damage and immune evasion, but the function in E. faecalis has yet to be explored. Here, we show that both hylA and hylB contribute to E. faecalis pathogenesis. In a CAUTI model, ΔhylA exhibited defects in bladder colonization and dissemination to the bloodstream, and ΔhylB exhibited a defect in kidney colonization. Furthermore, a ΔhylAΔhylB double mutant exhibited a severe colonization defect in a model of bacteremia while the single mutants colonized to a similar level as the wild-type strain, suggesting potential functional redundancy within the bloodstream. We next examined enzymatic activity, and demonstrate that HylB is capable of digesting both hyaluronic acid (HA) and chondroitin sulfate in vitro, while HylA exhibits only a very modest activity against heparin. Importantly, HA degradation by HylB provided a modest increase in cell density during the stationary phase and also contributed to dampening of lipopolysaccharide-mediated NF-κB activation. Overall, these data demonstrate that glycosaminoglycan degradation is important for E. faecalis pathogenesis in the urinary tract and during bloodstream infection.

Clock-Line-Mediated Sisyphus Cooling.

We demonstrate subrecoil Sisyphus cooling using the long-lived ^{3}P_{0} clock state in alkaline-earth-like ytterbium. A 1388-nm optical standing wave nearly resonant with the ^{3}P_{0}→^{3}D_{1} transition creates a spatially periodic light shift of the ^{3}P_{0} clock state. Following excitation on the ultranarrow clock transition, we observe Sisyphus cooling in this potential, as the light shift is correlated with excitation to ^{3}D_{1} and subsequent spontaneous decay to the ^{1}S_{0} ground state. We observe that cooling enhances the loading efficiency of atoms into a 759-nm magic-wavelength one-dimensional (1D) optical lattice, as compared to standard Doppler cooling on the ^{1}S_{0}→^{3}P_{1} transition. Sisyphus cooling yields temperatures below 200 nK in the weakly confined, transverse dimensions of the 1D optical lattice. These lower temperatures improve optical lattice clocks by facilitating the use of shallow lattices with reduced light shifts while retaining large atom numbers to reduce the quantum projection noise. This Sisyphus cooling can be pulsed or continuous and is applicable to a range of quantum metrology applications.

Aberrant splicing of a nicotinic acetylcholine receptor alpha 6 subunit is associated with spinosad tolerance in the thrips predator Orius laevigatus.

Susceptibility to insecticides is one of the limiting factors preventing wider adoption of natural enemies to control insect pest populations. Identification and selective breeding of insecticide tolerant strains of commercially used biological control agents (BCAs) is one of the approaches to overcome this constraint. Although a number of beneficial insects have been selected for increased tolerance to insecticides the molecular mechanisms underpinning these shifts in tolerance are not well characterised. Here we investigated the molecular mechanisms of enhanced tolerance of a lab selected strain of Orius laevigatus (Fieber) to the commonly used biopesticide spinosad. Transcriptomic analysis showed that spinosad tolerance is not a result of overexpressed detoxification genes. Molecular analysis of the target site for spinosyns, the nicotinic acetylcholine receptor (nAChR), revealed increased expression of truncated transcripts of the nAChR α6 subunit in the spinosad selected strain, a mechanism of resistance which was described previously in insect pest species. Collectively, our results demonstrate the mechanisms by which some beneficial biological control agents can evolve insecticide tolerance and will inform the development and deployment of insecticide-tolerant natural enemies in integrated pest management strategies.

Preferential catabolism of l- vs d-serine by Proteus mirabilis contributes to pathogenesis and catheter-associated urinary tract infection.

Proteus mirabilis is a common cause of urinary tract infection, especially in catheterized individuals. Amino acids are the predominant nutrient for bacteria during growth in urine, and our prior studies identified several amino acid import and catabolism genes as fitness factors for P. mirabilis catheter-associated urinary tract infection (CAUTI), particularly those for d- and l-serine. In this study, we sought to determine the hierarchy of amino acid utilization by P. mirabilis and to examine the relative importance of d- vs l-serine catabolism for critical steps in CAUTI development and progression. Herein, we show that P. mirabilis preferentially catabolizes l-serine during growth in human urine, followed by d-serine, threonine, tyrosine, glutamine, tryptophan, and phenylalanine. Independently disrupting catabolism of either d- or l-serine has minimal impact on in vitro phenotypes while completely disrupting both pathways decreases motility, biofilm formation, and fitness due to perturbation of membrane potential and cell wall biosynthesis. In a mouse model of CAUTI, loss of either serine catabolism system decreased fitness, but disrupting l-serine catabolism caused a greater fitness defect than disrupting d-serine catabolism. We, therefore, conclude that the hierarchical utilization of amino acids may be a critical component of P. mirabilis colonization and pathogenesis within the urinary tract.

Quantum Spin Hall Edge States and Interlayer Coupling in Twisted Bilayer WTe2.

The quantum spin Hall (QSH) effect, characterized by topologically protected spin-polarized edge states, was recently demonstrated in monolayers of the transition metal dichalcogenide (TMD) WTe2. However, the robustness of this topological protection remains largely unexplored in van der Waals heterostructures containing one or more layers of a QSH insulator. In this work, we use scanning tunneling microscopy and spectroscopy (STM/STS) to explore the topological nature of twisted bilayer (tBL) WTe2. At the tBL edges, we observe the characteristic spectroscopic signatures of the QSH edge states. For small twist angles, a rectangular moiré pattern develops, which results in local modifications of the band structure. Using first-principles calculations, we quantify the interactions in tBL WTe2 and its topological edge states as a function of interlayer distance and conclude that it is possible to engineer the topology of WTe2 bilayers via the twist angle as well as interlayer interactions.

Tunneling Spectroscopy of Two-Dimensional Materials Based on Via Contacts.

We introduce a novel planar tunneling architecture for van der Waals heterostructures based on via contacts, namely, metallic contacts embedded into through-holes in hexagonal boron nitride (hBN). We use the via-based tunneling method to study the single-particle density of states of two different two-dimensional (2D) materials, NbSe2 and graphene. In NbSe2 devices, we characterize the barrier strength and interface disorder for barrier thicknesses of 0, 1, and 2 layers of hBN and study the dependence on the tunnel-contact area down to (44 ± 14)2 nm2. For 0-layer hBN devices, we demonstrate a crossover from diffusive to point contacts in the small-contact-area limit. In graphene, we show that reducing the tunnel barrier thickness and area can suppress effects due to phonon-assisted tunneling and defects in the hBN barrier. This via-based architecture overcomes limitations of other planar tunneling designs and produces high-quality, ultraclean tunneling structures from a variety of 2D materials.

Nontypeable Haemophilus influenzae Infection Impedes Pseudomonas aeruginosa Colonization and Persistence in Mouse Respiratory Tract.

Patients with cystic fibrosis (CF) experience lifelong respiratory infections, which are a significant cause of morbidity and death. These infections are polymicrobial in nature, and the predominant bacterial species undergo a predictable series of changes as patients age. Young patients have populations dominated by opportunists that are typically found within the microbiome of the human nasopharynx, such as nontypeable Haemophilus influenzae (NTHi); these are eventually supplanted, and the population within the CF lung is later dominated by pathogens such as Pseudomonas aeruginosa. In this study, we investigated how initial colonization with NTHi impacts colonization and persistence of P. aeruginosa in the respiratory tract. Analysis of polymicrobial biofilms in vitro by confocal microscopy revealed that NTHi promoted greater P. aeruginosa biofilm volume and diffusion. However, sequential respiratory infection of mice with NTHi followed by P. aeruginosa resulted in significantly lower levels of P. aeruginosa, compared to infection with P. aeruginosa alone. Coinfected mice also had reduced airway tissue damage and lower levels of inflammatory cytokines, compared with P. aeruginosa-infected mice. Similar results were observed after instillation of heat-inactivated NTHi bacteria or purified NTHi lipooligosaccharide endotoxin prior to P. aeruginosa introduction. Based on these results, we conclude that NTHi significantly reduces susceptibility to subsequent P. aeruginosa infection, most likely due to priming of host innate immunity rather than a direct competitive interaction between species. These findings have potential significance with regard to therapeutic management of early-life infections in patients with CF.

Charged Bosons Made of Fermions in Bilayer Structures with Strong Metallic Screening.

Two-dimensional monolayer structures of transition metal dichalogenides (TMDs) have been shown to allow many higher-order excitonic bound states, including trions (charged excitons), biexcitons (excitonic molecules), and charged biexcitons. We report here experimental evidence and the theoretical basis for a new bound excitonic complex, consisting two free carriers bound to an exciton in a bilayer structure. Our experimental measurements on structures made using two different materials show a new spectral line at the predicted energy with two different TMD materials (MoSe2 and WSe2) with both n- and p-doping if and only if all the required theoretical conditions for this complex are fulfilled, in particular, only in the presence of a parallel metal layer that significantly screens the repulsive interaction between the like-charge carriers. Because these four-carrier bound states are charged bosons, they could eventually be the basis for a new path to superconductivity without Cooper pairing.

Adaptation of Helicoverpa armigera to Soybean Peptidase Inhibitors Is Associated with the Transgenerational Upregulation of Serine Peptidases.

Molecular phenotypes induced by environmental stimuli can be transmitted to offspring through epigenetic inheritance. Using transcriptome profiling, we show that the adaptation of Helicoverpa armigera larvae to soybean peptidase inhibitors (SPIs) is associated with large-scale gene expression changes including the upregulation of genes encoding serine peptidases in the digestive system. Furthermore, approximately 60% of the gene expression changes induced by SPIs persisted in the next generation of larvae fed on SPI-free diets including genes encoding regulatory, oxidoreductase, and protease functions. To investigate the role of epigenetic mechanisms in regulating SPI adaptation, the methylome of the digestive system of first-generation larvae (fed on a diet with and without SPIs) and of the progeny of larvae exposed to SPIs were characterized. A comparative analysis between RNA-seq and Methyl-seq data did not show a direct relationship between differentially methylated and differentially expressed genes, while trypsin and chymotrypsin genes were unmethylated in all treatments. Rather, DNA methylation potential epialleles were associated with transcriptional and translational controls; these may play a regulatory role in the adaptation of H. armigera to SPIs. Altogether, our findings provided insight into the mechanisms of insect adaptation to plant antiherbivore defense proteins and illustrated how large-scale transcriptional reprograming of insect genes can be transmitted across generations.

The effect of DNA methylation on bumblebee colony development.

BACKGROUND: Although around 1% of cytosines in bees' genomes are known to be methylated, less is known about methylation's effect on bee behavior and fitness. Chemically altered DNA methylation levels have shown clear changes in the dominance and reproductive behavior of workers in queen-less colonies, but the global effect of DNA methylation on caste determination and colony development remains unclear, mainly because of difficulties in controlling for genetic differences among experimental subjects in the parental line. Here, we investigated the effect of the methylation altering agent decitabine on the developmental rate of full bumblebee colonies. Whole genome bisulfite sequencing was used to assess differences in methylation status. RESULTS: Our results showed fewer methylated loci in the control group. A total of 22 CpG loci were identified as significantly differentially methylated between treated and control workers with a change in methylation levels of 10% or more. Loci that were methylated differentially between groups participated in pathways including neuron function, oocyte regulation and metabolic processes. Treated colonies tended to develop faster, and therefore more workers were found at a given developmental stage. However, male production followed the opposite trend and it tended to be higher in control colonies. CONCLUSION: Overall, our results indicate that altered methylation patterns resulted in an improved cooperation between workers, while there were no signs of abnormal worker dominance or caste determination.

The developing relations between networks of cortical myelin and neurophysiological connectivity.

Recent work identified that patterns of distributed brain regions sharing similar myeloarchitecture are related to underlying functional connectivity, demonstrating cortical myelin's plasticity to changes in functional demand. However, the changing relations between functional and structural architecture throughout child and adulthood are poorly understood. We show that structural covariance connectivity (T1-weighted/T2-weighted ratio) and functional connectivity (magnetoencephalography) exhibit nonlinear developmental changes. We then show significant relations between structural and functional connectivity, which have shared and distinct characteristics dependent on the neural oscillatory frequency. Increases in structure-function coupling are visible during the protracted myelination observed throughout childhood and adolescence and are followed by decreases near the onset of adulthood. Our work lays the foundation for understanding the mechanisms by which myeloarchitecture supports brain function, enabling future investigations into how clinical populations may deviate from normative patterns.

Ignore the faces: Neural characterisation of emotional inhibition from childhood to adulthood using MEG.

The ability to effectively and automatically regulate one's response to emotional information is a basic, fundamental skill for social functioning. The neural mechanisms underlying emotion regulation processing have been assessed, however few investigations have leveraged neurophysiological techniques, particularly magnetoencephalography (MEG) to determine the development of this critical ability. The current MEG study is the first to examine developmental changes in the neural mechanisms supporting automatic emotion regulation. We used an emotional go/no-go task with happy and angry faces in a single-site cohort of 97 healthy participants, 4-40 years of age. We found age-related changes as a function of emotion and condition in brain regions key to emotion regulation, including the right inferior frontal gyrus, orbitofrontal cortices and primarily right-lateralized temporal areas. Interaction effects, including an age by emotion and condition, were also found in the left angular gyrus, an area critical in emotion regulation and attention. Findings demonstrate protracted and nonlinear development, due to the adolescent group, of emotion regulation processing from child to adulthood, and highlight that age-related differences in emotion regulation are modulated by emotional face type.

The role of transient spectral 'bursts' in functional connectivity: A magnetoencephalography study.

Neural oscillations dominate electrophysiological measures of macroscopic brain activity and fluctuations in these rhythms offer an insightful window on cortical excitation, inhibition, and connectivity. However, in recent years the 'classical' picture of smoothly varying oscillations has been challenged by the idea that many 'oscillations' may actually be formed from the recurrence of punctate high-amplitude bursts in activity, whose spectral composition intersects the traditionally defined frequency ranges (e.g. alpha/beta band). This finding offers a new interpretation of measurable brain activity, however neither the methodological means to detect bursts, nor their link to other findings (e.g. connectivity) have been settled. Here, we use a new approach to detect bursts in magnetoencephalography (MEG) data. We show that a time-delay embedded Hidden Markov Model (HMM) can be used to delineate single-region bursts which are in agreement with existing techniques. However, unlike existing techniques, the HMM looks for specific spectral patterns in timecourse data. We characterise the distribution of burst duration, frequency of occurrence and amplitude across the cortex in resting state MEG data. During a motor task we show how the movement related beta decrease and post movement beta rebound are driven by changes in burst occurrence. Finally, we show that the beta band functional connectome can be derived using a simple measure of burst overlap, and that coincident bursts in separate regions correspond to a period of heightened coherence. In summary, this paper offers a new methodology for burst identification and connectivity analysis which will be important for future investigations of neural oscillations.

Multi-channel whole-head OPM-MEG: Helmet design and a comparison with a conventional system.

Magnetoencephalography (MEG) is a powerful technique for functional neuroimaging, offering a non-invasive window on brain electrophysiology. MEG systems have traditionally been based on cryogenic sensors which detect the small extracranial magnetic fields generated by synchronised current in neuronal assemblies, however, such systems have fundamental limitations. In recent years, non-cryogenic quantum-enabled sensors, called optically-pumped magnetometers (OPMs), in combination with novel techniques for accurate background magnetic field control, have promised to lift those restrictions offering an adaptable, motion-robust MEG system, with improved data quality, at reduced cost. However, OPM-MEG remains a nascent technology, and whilst viable systems exist, most employ small numbers of sensors sited above targeted brain regions. Here, building on previous work, we construct a wearable OPM-MEG system with 'whole-head' coverage based upon commercially available OPMs, and test its capabilities to measure alpha, beta and gamma oscillations. We design two methods for OPM mounting; a flexible (EEG-like) cap and rigid (additively-manufactured) helmet. Whilst both designs allow for high quality data to be collected, we argue that the rigid helmet offers a more robust option with significant advantages for reconstruction of field data into 3D images of changes in neuronal current. Using repeat measurements in two participants, we show signal detection for our device to be highly robust. Moreover, via application of source-space modelling, we show that, despite having 5 times fewer sensors, our system exhibits comparable performance to an established cryogenic MEG device. While significant challenges still remain, these developments provide further evidence that OPM-MEG is likely to facilitate a step change for functional neuroimaging.

Relationships Between Neuronal Oscillatory Amplitude and Dynamic Functional Connectivity.

Event-related fluctuations of neural oscillatory amplitude are reported widely in the context of cognitive processing and are typically interpreted as a marker of brain "activity". However, the precise nature of these effects remains unclear; in particular, whether such fluctuations reflect local dynamics, integration between regions, or both, is unknown. Here, using magnetoencephalography, we show that movement induced oscillatory modulation is associated with transient connectivity between sensorimotor regions. Further, in resting-state data, we demonstrate a significant association between oscillatory modulation and dynamic connectivity. A confound with such empirical measurements is that increased amplitude necessarily means increased signal-to-noise ratio (SNR): this means that the question of whether amplitude and connectivity are genuinely coupled, or whether increased connectivity is observed purely due to increased SNR is unanswered. Here, we counter this problem by analogy with computational models which show that, in the presence of global network coupling and local multistability, the link between oscillatory modulation and long-range connectivity is a natural consequence of neural networks. Our results provide evidence for the notion that connectivity is mediated by neural oscillations, and suggest that time-frequency spectrograms are not merely a description of local synchrony but also reflect fluctuations in long-range connectivity.

Molecularly Thin Electrolyte for All Solid-State Nonvolatile Two-Dimensional Crystal Memory.

A molecularly thin electrolyte is developed to demonstrate a nonvolatile, solid-state, one-transistor (1T) memory based on an electric-double-layer (EDL) gated WSe2 field-effect transistor (FET). The custom-designed monolayer electrolyte consists of cobalt crown ether phthalocyanine and lithium ions, which are positioned by field-effect at either the surface of the WSe2 channel or an h-BN capping layer to achieve "1" or "0", respectively. Bistability in the monolayer electrolyte memory is significantly improved by the h-BN cap with density functional theory (DFT) calculations showing enhanced trapping of Li+ near h-BN due to a ∼1.34 eV increase in the absolute value of the adsorption energy compared to vacuum. The threshold voltage shift between the two states corresponds to a change in charge density of ∼2.5 × 1012 cm-2, and an On/Off ratio exceeding 104 at a back gate voltage of 0 V. The On/Off ratio remains stable after 1000 cycles and the retention time for each state exceeds 6 h (max measured). When the write time approaches 1 ms, the On/Off ratio remains >102, showing that the monolayer electrolyte-gated FET can respond on time scales similar to existing flash memory. The data suggest that faster switching times and lower switching voltages could be feasible by top gating.

Electron Transport in Multidimensional Fuzzy Graphene Nanostructures.

Atomically thin two-dimensional (2D) materials offer a range of superlative electronic and electrochemical properties that facilitate applications in sensing, energy conversion, and storage. Graphene, a 2D allotrope of carbon, has exceptional surface area per unit mass and highly catalytic edges. To leverage these properties, efforts have been made to synthesize complex three-dimensional (3D) geometries of graphene, with an eye toward integration into functional electronic devices. However, the electronic transport properties of such complex 3D structures are not well understood at a microscopic level. Here, we report electron transport in a 3D arrangement of free-standing 2D graphene flakes along an isolated one-dimensional Si nanowire. We show that transport through the free-standing graphene network is dominated by variable-range hopping and leads to negative magnetoresistance, from cryogenic conditions up to room temperature. Our findings lay the foundation for studying transport mechanisms in 2D material-based multidimensional nanostructures.

A biophysical model of dynamic balancing of excitation and inhibition in fast oscillatory large-scale networks.

Over long timescales, neuronal dynamics can be robust to quite large perturbations, such as changes in white matter connectivity and grey matter structure through processes including learning, aging, development and certain disease processes. One possible explanation is that robust dynamics are facilitated by homeostatic mechanisms that can dynamically rebalance brain networks. In this study, we simulate a cortical brain network using the Wilson-Cowan neural mass model with conduction delays and noise, and use inhibitory synaptic plasticity (ISP) to dynamically achieve a spatially local balance between excitation and inhibition. Using MEG data from 55 subjects we find that ISP enables us to simultaneously achieve high correlation with multiple measures of functional connectivity, including amplitude envelope correlation and phase locking. Further, we find that ISP successfully achieves local E/I balance, and can consistently predict the functional connectivity computed from real MEG data, for a much wider range of model parameters than is possible with a model without ISP.

Reflections on the Life and Career of Émigré German-Canadian Psychiatrist Sebastian Klaus Littmann (1931-1986).

OBJECTIVE: This article explores the life and career of Sebastian K. Littmann. He was a foundational figure of the University of Calgary's Department of Psychiatry in his role as its second chair and, before this, as an influential administrator at Toronto's Queen Street Mental Health Centre and Clarke Institute during a transitional period in the 1970s-1980s. According to McGill University's Heinz Lehmann, this transitional period was when the field of psychiatry underwent an identity crisis that threatened to dissolve the discipline and see its functions increasingly filled by counsellors, neurologists, and primary physicians. Littmann's professional background and training in Edinburgh was followed by periods of community work in New York, which-by the time he immigrated to Canada-predisposed him to favour a humane and community-based approach to psychiatric work; this approach encompassed the cultural variations that were increasingly characterizing North America's urban social landscape. His compassionate and progressive approach to treatment was remarkable in light of his troubled and deprived upbringing in Nazi-era Germany. CONCLUSIONS: The present sketch of Littmann's personal and professional biography serves to highlight the ways that major historical events and large-scale migration movements, which affected Central Europe, impacted the development of Canadian psychiatry and, by extension, individual Canadians in the twentieth century.