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Many industries rely on heavy-duty machinery such as cranes, pipelines, motors, which are subject to wear and tear. Milling of such parts using conventional machine tools presents many drawbacks and is impossible in some cases. In such situations, mobile machine tools can be used to machine directly on site. However, mobile machines are flexible, and are prone to detrimental vibrations during cutting operations. Vibrational stability in the surfacing process has been extensively studied in conventional milling. However, the focus of this article is an original study on a mobile milling machine used for on-site surfacing operations. An experimental investigation into the vibrational behavior of the machine is carried out and a sensorless method is used to detect the onset of chatter. Machine flexibility is discussed using a tool-point frequency response function and references from the literature. Milling operations are carried out over a range machining parameter to determine an experimental stability limit. Internal sensors for spindle motor consumption and spindle motor encoder are monitored during the machining process. A threshold is established for determining the appearance of chatter using only the machine’s internal sensors.

Acknowledgements: The authors thank Prof. Duer for helpful discussions, and Prof. Wales for providing access to computational facilities. KR was funded by a Henslow Research Fellowship from the Cambridge Philosophical Society., Collagen fibres are the main constituent of the extracellular matrix, and fulfil an important role in the structural stability of living multicellular organisms. An open question is how collagen absorbs pulling forces, and if the applied forces are strong enough to break bonds, what mechanisms underlie this process. As experimental studies on this topic are challenging, simulations are an important tool to further our understanding of these mechanisms. Here, we present pulling simulations of collagen triple helices, revealing the molecular mechanisms induced by tensile stress. At lower forces, pulling alters the configuration of proline residues leading to an effective absorption of applied stress. When forces are strong enough to introduce bond ruptures, these are located preferentially in X-position residues. Reduced backbone flexibility, for example through mutations or cross linking, weakens tensile resistance, leading to localised ruptures around these perturbations. In fibre-like segments, a significant overrepresentation of ruptures in proline residues compared to amino acid contents is observed. This study confirms the important role of proline in the structural stability of collagen, and adds detailed insight into the molecular mechanisms underlying this observation.

Impaired social cognition is a core deficit of frontotemporal dementia (FTD). It is most commonly associated with the behavioural-variant of FTD, with atrophy of the orbitofrontal and ventromedial prefrontal cortex. However, social cognitive changes are also common in semantic dementia, with atrophy centred on the anterior temporal lobes. The impairment of social behaviour in FTD has typically been attributed to damage to the orbitofrontal cortex and/or temporal poles and/or the uncinate fasciculus that connects them. However, the relative contribution of each region is unresolved. In this review, we present a unified neurocognitive model of controlled social behaviour that not only explains the observed impairment of social behaviours in FTD, but also assimilates findings from other patient groups, comparative neurology, and normative cognitive neuroscience. We propose that impaired social behaviour results from damage to two cognitively- and anatomically-distinct components. The first component is social-semantic knowledge, supported by the anterior temporal lobes bilaterally. The second component is social control, supported by the orbitofrontal cortex, medial frontal cortex and ventrolateral frontal cortex, which interact with social-semantic knowledge to guide and shape social behaviour.

Maintaining good cognitive function is crucial for well-being across the lifespan. We proposed that the degree of cognitive maintenance is determined by the functional interactions within and between large-scale brain networks. Such connectivity can be represented by the white matter architecture of structural brain networks that shape intrinsic neuronal activity into integrated and distributed functional networks. We explored how the function-structure connectivity convergence, and the divergence of functional connectivity from structural connectivity, contribute to the maintenance of cognitive function across the adult lifespan. Multivariate analyses were used to investigate the relationship between function-structure connectivity convergence and divergence with multivariate cognitive profiles, respectively. Cognitive function was increasingly dependent on function-structure connectivity convergence as age increased. The dependency of cognitive function on connectivity was particularly strong for high-order cortical networks and subcortical networks. The results suggest that brain functional network integrity sustains cognitive functions in old age, as a function of the integrity of the brain’s structural connectivity.

Plant roots exhibit plasticity in their branching patterns to forage efficiently for heterogeneously distributed resources, such as soil water. The xerobranching response represses lateral root formation when roots lose contact with water. Here, we show that xerobranching is regulated by radial movement of the phloem-derived hormone abscisic acid, which disrupts intercellular communication between inner and outer cell layers through plasmodesmata. Closure of these intercellular pores disrupts the inward movement of the hormone signal auxin, blocking lateral root branching. Once root tips regain contact with moisture, the abscisic acid response rapidly attenuates. Our study reveals how roots adapt their branching pattern to heterogeneous soil water conditions by linking changes in hydraulic flux with dynamic hormone redistribution.

The transformation from perception to action requires a set of decisions about the nature of the percept, identification and selection of response options, and execution of the appropriate motor response. The unfolding of such decisions is mediated by distributed representations of the decision variables - evidence and intentions – that are represented through oscillatory activity across the cortex. Here we combine magneto-electroencephalography and linear ballistic accumulator models of decision-making to reveal the impact of Parkinson’s disease during the selection and execution of action. We used a visuomotor task in which we independently manipulated uncertainty in sensory and action domains. A generative accumulator model was optimized to single-trial neurophysiological correlates of human behaviour, mapping the cortical oscillatory signatures of decision-making, and relating these to separate processes accumulating sensory evidence and selecting a motor action. We confirmed the role of widespread beta oscillatory activity in shaping the feed-forward cascade of evidence accumulation from resolution of sensory inputs to selection of appropriate responses. By contrasting the spatiotemporal dynamics of evidence accumulation in age-matched healthy controls and people with Parkinson’s disease, we identified disruption of the beta-mediated cascade of evidence accumulation as the hallmark of atypical decision-making in Parkinson’s disease. In frontal cortical regions, there was inefficient processing and transfer of perceptual information. Our findings emphasize the intimate connection between abnormal visuomotor function and pathological oscillatory activity in neurodegenerative disease. We propose that disruption of the oscillatory mechanisms governing fast and precise information exchanges between the sensory and motor systems contributes to behavioural changes in people with Parkinson’s disease.

The plant hormone abscisic acid (ABA) accumulates under abiotic stress to recast water relations and development. To overcome a lack of high-resolution, sensitive reporters, we developed ABACUS2s, next-generation FRET biosensors for ABA with high affinity, signal-to-noise ratio and orthogonality, that reveal endogenous ABA patterns in Arabidopsis thaliana. We mapped stress-induced ABA dynamics in high-resolution to reveal the cellular basis for local and systemic ABA functions. At reduced foliar humidity, roots cells accumulated ABA in the elongation zone, the site of phloem transported ABA unloading. Phloem ABA and root ABA signalling were both essential to maintain root growth at low humidity. ABA coordinates a robust system to maintain root growth in response to foliar stresses, enabling plants to maintain foraging of deeper soil for water uptake

There is a pressing need to accelerate therapeutic strategies against the syndromes caused by frontotemporal lobar degeneration, including symptomatic treatments. One approach is for experimental medicine, coupling neurophysiological studies of the mechanisms of disease with pharmacological interventions aimed at restoring neurochemical deficits. Here we consider the role of glutamatergic deficits and their potential as targets for treatment. We performed a double-blind placebo-controlled crossover pharmaco-magnetoencephalography study in 20 people with symptomatic frontotemporal lobar degeneration (10 behavioral variant frontotemporal dementia, 10 progressive supranuclear palsy) and 20 healthy age- and gender- matched controls. Both magnetoencephalography sessions recorded a roving auditory oddball paradigm: on placebo or following 10mg memantine, an uncompetitive NMDA-receptor antagonist. Ultrahigh-field magnetic resonance spectroscopy confirmed lower concentrations of GABA in the right inferior frontal gyrus of people with frontotemporal lobar degeneration. There was no overall effect of memantine on the magnitude of the mismatch negativity response in right frontotemporal cortex in patients, or controls. However, the change in right auditory cortex response to memantine (vs. placebo) in patients correlated with individuals’ prefrontal GABA concentration. There was no moderating effect of glutamate concentration, or cortical atrophy. This proof-of-concept study demonstrates the potential for baseline-dependency in pharmacological restoration of neurotransmitter deficits, to influence cognitive neurophysiology in neurodegenerative disease. With changes to multiple neurotransmitters in frontotemporal lobar degeneration, we suggest that individuals’ balance of excitation and inhibition may determine drug efficacy, with implications for drug selection and patient stratification in future clinical trials.

Serine/arginine-rich (SR) proteins are conserved splicing regulators that play important roles in plant stress responses, namely those mediated by the abscisic acid (ABA) hormone. The Arabidopsis thaliana SR-like protein SR45 is a described negative regulator of the ABA pathway during early seedling development. How the inhibition of growth by ABA signaling is counteracted to maintain plant development under stress conditions remains largely unknown. Here, we show that SR45 overexpression reduces Arabidopsis sensitivity to ABA during early seedling development. Biochemical and confocal microscopy analyses of transgenic plants expressing fluorescently tagged SR45 revealed that exposure to ABA dephosphorylates the protein at multiple amino acid residues and leads to its accumulation, due to SR45 stabilization via reduced ubiquitination and proteasomal degradation. Using phosphomutant and phosphomimetic transgenic Arabidopsis lines, we demonstrate the functional relevance of ABA-mediated dephosphorylation of a single SR45 residue, T264, in antagonizing SR45 ubiquitination and degradation to promote its function as a repressor of seedling ABA sensitivity. Our results reveal a mechanism that negatively autoregulates ABA signaling and allows early plant growth under stress via posttranslational control of the SR45 splicing factor.

Vascular, cardiovascular and neurovascular ageing processes contribute to cognitive impairment. However, the unique and synergistic contributions of cardiovascular factors to cognitive function remain unclear because they are often condensed into a single composite score or examined in isolation of each other. We hypothesized that vascular risk factors, electrocardiographic features and blood pressure indices reveal multiple latent vascular factors, with independent contributions to age differences in cognition. In a population-based deep-phenotyping study of cognition across the lifespan (n=708, age 18-88), path analysis revealed three latent vascular factors dissociating the autonomic nervous system response from two components of blood pressure. These three factors made unique and additive contributions to the variability in crystallized and fluid intelligence. The discrepancy in fluid relative to crystallized intelligence, indicative of cognitive decline, was associated with a latent vascular factor predominantly expressing pulse pressure, suggesting that higher pulse pressure is associated with cognitive decline from expected performance. This association varied with age, such that higher factor scores predicted a greater cognitive discrepancy in older individuals. Controlling pulse pressure may help to preserve cognitive function, particularly in older adults. Our findings highlight the need to better understand the multifactorial nature of vascular aging, its effects on neurocognitive function, and the modifiable risks of cognitive decline.

Background: Neurodegeneration in the locus coeruleus (LC) contributes to neuropsychiatric symptoms in both Parkinson's disease (PD) and progressive supranuclear palsy (PSP). Spatial precision of LC imaging is improved with ultrahigh field 7 T magnetic resonance imaging. Objectives: This study aimed to characterize the spatial patterns of LC pathological change in PD and PSP and the transdiagnostic relationship between LC signals and neuropsychiatric symptoms. Methods: Twenty-five people with idiopathic PD, 14 people with probable PSP-Richardson's syndrome, and 24 age-matched healthy controls were recruited. Participants underwent clinical assessments and high-resolution (0.08 mm3 ) 7 T-magnetization-transfer imaging to measure LC integrity in vivo. Spatial patterns of LC change were obtained using subregional mean contrast ratios and significant LC clusters; we further correlated the LC contrast with measures of apathy and cognition, using both mixed-effect models and voxelwise analyses. Results: PSP and PD groups showed significant LC degeneration in the caudal subregion relative to controls. Mixed-effect models revealed a significant interaction between disease-group and apathy-related correlations with LC degeneration (? = 0.46, SE [standard error] = 0.17, F(1, 35) = 7.46, P = 0.01), driven by a strong correlation in PSP (? = -0.58, SE = 0.21, t(35) = -2.76, P = 0.009). Across both disease groups, voxelwise analyses indicated that lower LC integrity was associated with worse cognition and higher apathy scores. Conclusions: The relationship between LC and nonmotor symptoms highlights a role for noradrenergic dysfunction across both PD and PSP, confirming the potential for noradrenergic therapeutic strategies to address transdiagnostic cognitive and behavioral features in neurodegenerative disease. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Brain ageing is a complex process which requires a multimodal approach. Neuroimaging can provide insights into brain morphology, functional organization and vascular dynamics. However, most neuroimaging studies of ageing have focused on each imaging modality separately, limiting the understanding of interrelations between processes identified by different modalities and their relevance to cognitive decline in ageing. Here, we used a data-driven multimodal approach, linked independent component analysis (ICA), to jointly analyze magnetic resonance imaging of grey matter volume, cerebrovascular, and functional network topographies in relation to measures of fluid intelligence. Neuroimaging and cognitive data from the Cambridge Centre for Ageing and Neuroscience study were used, with healthy participants aged 18 to 88 years (main dataset n = 215; secondary dataset n = 433). Using linked ICA, functional network activities were characterized in independent components but not captured in the same component as structural and cerebrovascular patterns. Split-sample (n = 108/107) and out-of-sample (n = 433) validation analyses using linked ICA were also performed. Global grey matter volume with regional cerebrovascular changes and the right frontoparietal network activity were correlated with age-related and individual differences in fluid intelligence. This study presents the insights from linked ICA to bring together measurements from multiple imaging modalities, with independent and additive information. We propose that integrating multiple neuroimaging modalities allows better characterization of brain pattern variability and changes associated with healthy ageing.

Kurzfassung Um spanende Werkzeugmaschinen möglichst profitabel betreiben zu können, muss der aktuelle Verschleißzustand der Maschinen hinreichend genau bekannt sein. Dies kann durch kontinuierliche Zustandsüberwachung erreicht werden. Neuartige, direkt in die Komponenten des Antriebsstranges von Werkzeugmaschinen integrierte Sensoren bieten die Möglichkeit, dies auf einfache und kostengünstige Weise durchzuführen. Als Indikator für Verschleiß kann dabei direkt das dynamische Verhalten des Antriebsstranges herangezogen und so eine hohe Anlagenverfügbarkeit sichergestellt werden.

My ABN fellowship focusses on the syndromes caused by frontotemporal lobar degeneration. Despite distinctive pathological causes, these highly heterogeneous syndromes overlap in clinical manifesta- tions and pathophysiology. This is both a challenge and an opportunity for future trials aimed at slowing the diseases or treating their symptoms. By modelling phenotypic data and long-term outcomes, I will determine the features of blood, brain and behaviour that predict survival. The “PIck’s disease and Pro- gressive supranuclear palsy Prevalence and INcidence” study (PiPPIN), has 440 participants from previous recruitment phases, of whom 318 have died. I have recruited 91 from an expected 220-250 patients in this 3rd phase. My initial analysis of existing samples will test the hypothesis that metabolic signatures dif- ferentiate disorders (PSP, FTD, controls). Preliminary results from N=269 samples confirm multiple metabolic differences between patients and controls, focussing within the lipid pathways. This will be analysed in relation to clinical severity, phenotype, and survival outcomes. Subsequent analysis will integrate cognitive/behavioural profiles, magnetic resonance imaging and spectroscopy, and blood biomarkers (including metabolites) in multivariate models of survival. Prediction of survival does not indicate causation but will generate hypotheses of promising targets for intervention and tools for risk-based stratification.

AimsStudies of thalamic structure and function in Progressive Supranuclear Palsy (PSP) suggest it may play a role in key aspects of the clinical syndrome. This study examined thalamic changes across PSP phenotypes investigating (i) thalamic atrophy (ii) thalamic functional connectivity and (iii) the relationship between thalamic structural and functional connectivity changes with clinical severity.MethodsParticipants92 participants with PSP [63 PSP-Richardson's Syndrome (RS), 24 PSP-cortical, 5 PSP-subcortical] and 104 age-matched controls were recruited from the Cambridge Centre for Parkinson's Plus Disorders cohort. Clinical assessments and imaging were conducted within 1 year of diagnosis.Structural AnalysisThalamic volumes (TVs) were obtained using FreeSurfer. Bayesian multiple regression (brms, R) was used to model (i) mean TVs (ii) group differences in mean TVs (iii) relationships between Z-standardised clinical scores and TVs with age, gender, and total grey matter as covariates.Functional AnalysisVoxel-wise seed-based functional connectivity of the thalamus used the Functional Magnetic Resonance Imaging Expert Analysis Tool (FEAT) in FMRIB's Software Library (FSL). Inter-group differences and relationships between clinical scores and functional connectivity for each group were assessed using a general linear model with age and gender as covariates.ResultsStructural AnalysisTVs for all PSP subgroups were smaller than controls. No differences between PSP subgroups were detected. There was evidence for a relationship between TVs for the entire PSP group and Revised Addenbrooke's Cognitive Examination (ACER) scores [ß = 0.28, 95% credible interval (CI) = 0.04–0.53]. Subgroup analysis showed evidence for a relationship between ACER scores and TVs in PSP-RS [ß = 0.33, 95% CI = 0.09–0.57] and PSP-cortical [ß = 0.46, 95% CI = 0.12–0.83] phenotypes. A negative influence of TVs on total PSP rating scale scores was found for the PSP cohort a whole [ß = −0.51, 95% CI = −1.00 – −0.02].Functional AnalysisPSP patients as a group showed decreased thalamic functional connectivity in higher cortical regions. Subgroup analysis revealed decreased connectivity in those areas compared to controls but in distinct distributions and magnitude. Increased thalamic connectivity with the middle temporal gyrus correlated with ACER scores for PSP patients as a group and in the PSP-cortical subtype.ConclusionThalamic volume loss is a prominent aspect of PSP and is associated with a wide network of changes in functional connectivity that may be distinct between PSP subtypes. Changes in thalamic structure and function predict clinical severity, particularly in PSP-RS and PSP-cortical subtypes.

This paper poses the question whether insider trading should be legalized. The paper proceeds to introduce the work of the academic father of insider trading, Henry G. Manne, and proceeds to introduce his critics arguments before ending with a surprising conclusion. There is no right or wrong answer to the prudence of legalizing insider trading; rather, it’s a choice society must make by weighing its preferences for market efficiency versus market fairness.

This research was designed to examine the growth in popularity of Special Purpose Acquisition Companies, particularly the U.S. Federal Government’s responsibility for such growth and their concerns and proposed solutions. I will attempt to answer the following questions: (1) What characteristics of SPACs or the market operating environment led to the explosion in SPAC transactions, (2) What was the U.S. Government’s role in igniting SPAC growth, (3) What concerns the U.S. Government has communicated regarding SPACs, (4) What solutions is the U.S. Government proposing to address their concerns, and finally, (5) My analysis of the aforementioned questions. I rely on qualitative research methods to support my argument. Additionally, I incorporated quantitative data from SpacInsider.com to buttress my arguments. Future research papers will require primary research as well as multivariable regression analyses to better understand which factors are pushing SPAC growth, and which policy options have the desired impact of reducing the use of SPACs for going public and increasing the use of traditional IPOs. My qualitative research uncovered an outsized role played by the U.S. Government in the growth and popularity of SPACs. Additionally, precedent research demonstrated that the U.S. Federal Government’s proposed solution of additional regulations will not work and will, instead, create a new alternative investment vehicle in the same fashion that overregulation of IPOs led to SPACs. To solve the concerns regulators have voiced, officials charged with developing and altering the IPO regulatory framework must loosen the grip of listing-crushing regulations. If smaller businesses were able to access the markets via an IPO, they would do so because there is more certainty in the legal grounding of an IPO, and the process is an established one familiar to the business world. Any actions, on the government’s part, to tighten already strangling regulations will lead to more of the same.

The Consumer Financial Protection Bureau was created in the wake of the Global Financial Crisis of 2008 to protect consumers from the predatory practices of businesses involved in the provision of consumer finance, whether that be a retail bank making housing loans to individual debtors, or retail stores providing store credit to customers. Concerns exist about the Bureau’s insulation from the checks and balances to which other government agencies are subject, including budget checks via the congressional appropriations process and command and control by the President via his or her authority over the executive branch of government. The judiciary is the only branch of government from which the CFPB was not insulated by the law creating the Bureau, and they have already acted, via the Supreme Court, to limit the Bureau’s independence by requiring that the director of the CFPB be required to serve at the President’s sole will and discretion. The Bureau serves a valiant and critical purpose, but as a government agency staffed with human beings, it is not immune from abusing its power when carrying out its mission. As a result, it must be subject to restrictions to protect the public, which includes businesses, from what James Madison termed “government tyranny” at the time of the formation of our government.

This study reports on the stability of United States Pharmacopeia-grade metronidazole powder and commercially available metronidazole tablets in two dye-free oral suspending vehicles, namely Oral Mix and Oral Mix Sugar-Free. Metronidazole at 50 mg/mL was prepared individually in Oral Mix and Oral Mix Sugar-Free suspension vehicles and placed in 50-mL amber polyethyleneterephthalate bottles and 3-mL amber plastic syringes and stored at 4°C or 25°C/60% relative humidity for 90 days. The solutions were analyzed at the time of preparation and at 7 days, 14 days, 30 days, 45 days, 60 days, 75 days, and 90 days, with the concentration of metronidazole measured by high-performance liquid chromatography with photodiode array detection. The oral solutions were also monitored for pH, homogeneity, color, and odor. Except for the Oral Mix suspension of metronidazole prepared from the United States Pharmacopeia-grade powder and from the commercial tablet, when stored in pre-filled syringes, all the other preparations were stable at 4°C or 25°C/60% relative humidity for 90 days, with the metronidazole remaining within ± 10% of the initial concentration. The pH, color, odor, and resuspendability remained essentially unchanged. Metronidazole in Oral Mix and Oral Mix Sugar-Free oral suspensions, compounded from United States Pharmacopeia-grade powder or commercially available tablets, are a suitable alternative as an extemporaneously prepared medication.

Litigation finance is a relatively new financial product that has the potential to unlock the justice system for an unmeasurable number of people in the United States who have suffered injustices that would represent meritorious claims if the victims could afford to bring a civil case. Unfortunately, the costs of litigation are so high, that many cannot. Litigation finance is quickly becoming the key to the justice system for those people. The relative lack of familiarity with third-party litigation finance, and the lack of a regulatory regime are still roadblocks to the widespread use of the product, but it’s only a matter of time before that issue fades. Fortunately, these impediments to litigation finance’s emergence as a mainstream product are being actively addressed. Multiple countries have developed regulatory regimes, while the United States has thus far deferred to state governments to develop their own rules regarding litigation finance. This process will eventually lead to a federal standard that will provide clarity and stability for litigation finance to expand. Additionally, litigation finance is increasingly becoming a known financial product. Using traditional marketing techniques and the spread by word of mouth from friends and family members who have used the product, litigation finance is moving into the mainstream. This paper will explore litigation finance and follow its evolution from its ancient beginnings to its current state as a new financial product designed to provide the financial means for unlocking justice which has always been a cornerstone of our democracy.

To examine the role of repeat expansions in the pathogenesis of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS), we performed repeat sizing of ten genetic loci previously implicated in neurodegenerative diseases. We examined whole-genome sequence data from 2,442 FTD/ALS patients, 2,599 Lewy body dementia (LBD) patients, and 3,158 neurologically healthy subjects. Pathogenic expansions (range: 40 to 64 CAG repeats) in the huntingtin (HTT) gene were found in three (0.12%) patients diagnosed with pure FTD/ALS syndromes but were not present in the LBD or healthy cohorts. We replicated our findings in an independent cohort, and identified five (0.14%) out of 3,674 FTD/ALS patients harboring pathogenic HTT CAG expansions. Postmortem evaluations of two patients revealed huntingtin-positive, as well as TDP43- and ubiquitin-positive aggregates, predominantly in the frontal cortex, without neostriatal atrophy. Our findings reveal an etiological relationship between HTT repeat expansions and FTD/ALS syndromes, and indicate that genetic screening of FTD/ALS patients for HTT repeat expansions should be considered.

The United States Department of Justice recently announced an antitrust lawsuit against the search and search advertising giant, Google. Referencing anticompetitive practices that restrict competition and harm consumers, the DOJ, by attempting to break up Google’s control of the search market due to harm it is inflicting upon consumers as a result of its monopoly power, is continuing a policy of ensuring competitive markets that goes back more than a century to President Theodore Roosevelt and his crusade against trusts, and in particular, John D. Rockefeller’s Standard Oil Monopoly. Monopolistic behavior can take many forms, but opponents of monopolies, of which there are many, share the common criticism that monopolies are toxic for the economy and commit an injustice against individual consumers. Their solution to these harmful effects includes robust regulation and providing readily available detailed information to the public demonstrating the extent to which industry in the United States is concentrated. Unfortunately, while it is true that monopolies have the power to cause harm through the market power possessed by monopolies, it is equally true that monopolies are uniquely capable of taking actions that benefit the country, the economy, and consumers. The benefits of monopoly do not receive a lot of publicity because it’s not politically valuable and goes against the traditions of thought to which Americans have been subjected for well over a century. The fact that 10 percent of the world’s public companies generate 80 percent of all profits and the United States’ 100 largest companies have increased their share of GDP creation by 13 percentage points to 46 percent in two decades, it’s urgent to discuss monopolies more expansively and focus on the facts rather than political talking points.1 This paper will make the argument that monopolies are overregulated, which harms the economy and its consumers more so than it helps. Monopolies should be subject to less scrutiny in the U.S. economy to perform their functions more efficiently. Regulators have alternative means of guarding against the negative effects of monopoly while allowing for the positive effects.

Financial institutions are indirectly exposed to risks associated with the impacts and dependencies on natural capital and ecosystem services of the companies that they invest in, lend to, and insure. This is particularly true for banks lending to agriculture: a sector with both significant impacts and critical dependencies on natural capital. Bank lending is a vital source of new finance for the sector, which is essential to achieve sustainable intensification targets. Yet current credit decision-making practice is still based on conventional financial and management indicators, lacking any systematic assessment of natural capital risks, especially those associated with dependencies. Operationalising natural capital risk assessment requires practicable indicators and data to evaluate the most material natural capital risks for a given sub-sector and geography, but it is unclear to what extent these are available. We assess the practicability of natural capital dependency risk indicators and data sources for a critical case study of Australian sheep production. We find that at least moderately practicable indicators and data sources are available to assess the 11 major dependency risks that are material for this industry. Challenges remain in determining risk thresholds for most indicators, and quantifying risk impacts on profitability.

Purpose: To compare registration strategies to align arterial spin labeling (ASL) with 3D T1-weighted (T1w) images, with the goal of reducing the between-subject variability of cerebral blood flow (CBF) images. Materials and Methods: Multi-center 3T ASL data were collected at eight sites with four different sequences in the multi-center GENetic Frontotemporal dementia Initiative (GENFI) study. In a total of 48 healthy controls, we compared the following image registration options: (I) which images to use for registration (perfusion-weighted images [PWI] to the segmented gray matter (GM) probability map (pGM) (CBF-pGM) or M0 to T1w (M0-T1w); (II) which transformation to use (rigid-body or non-rigid); and (III) whether to mask or not (no masking, M0-based FMRIB software library Brain Extraction Tool [BET] masking). In addition to visual comparison, we quantified image similarity using the Pearson correlation coefficient (CC), and used the Mann-Whitney U rank sum test. Results: CBF-pGM outperformed M0-T1w (CC improvement 47.2% ± 22.0%; P < 0.001), and the non-rigid transformation outperformed rigid-body (20.6% ± 5.3%; P < 0.001). Masking only improved the M0-T1w rigid-body registration (14.5% ± 15.5%; P = 0.007). Conclusion: The choice of image registration strategy impacts ASL group analyses. The non-rigid transformation is promising but requires validation. CBF-pGM rigid-body registration without masking can be used as a default strategy. In patients with expansive perfusion deficits, M0-T1w may outperform CBF-pGM in sequences with high effective spatial resolution. BET-masking only improves M0-T1w registration when the M0 image has sufficient contrast. Level of Evidence: 1. Technical Efficacy: Stage 1. J. Magn. Reson. Imaging 2018;47:131–140.

Mitochondrial complex 1 is involved in maintaining brain bioenergetics; σ-1 receptor responds to neuronal stress; and synaptic vesicle protein 2A reflects synaptic integrity. Expression of each of these proteins is altered in neurodegenerative diseases. Here, we characterize the kinetic behavior of 3 PET radioligands

As the sophistication of genomic technologies increases and their cost continues to decrease, they are becoming routine tools in livestock breeding programs and production systems. The convergence of electronic measurement systems, cloud-based computing and fast internet enable the use of powerful decision support to help automate and manage livestock production, animal welfare and quality control. The complexity of livestock production systems, combined with the challenges of producing top-quality discretionary products for consumers, means that no single organisation has the range of expertise to support coordinated development of innovation in the relevant supply chains. Collaboration between a broad spectrum of scientists and industry partners is essential to ensure well integrated input to the design and implementation of programs to deliver improvements in efficiency, quality and profit. The need for collaboration among researchers, among research organisations and with end-users has never been more important. Collaboration brings together the skills needed to manage complex problems and enables the sharing of facilities and scarce resources within Australia and internationally. However, the most important component of effective collaboration is the early engagement of end-users to contribute to the design of programs of innovation, to ensure that investment is well targeted and that there is ownership of the problem as well as the solutions delivered through research. Although the potential benefits of effective collaboration are clear, it often takes more than logic to get individuals and organisations to work together. There needs to be a significant financial incentive combined with strong industry leadership and agreed common goals. Allocating resources to establish these foundations for effective collaboration should precede any major research and development funding initiative. The present paper argues that the new face of animal science in Australia should be structured around coordinated programs of research and development, on the basis of effective collaboration.

Cognitive impairment is integral to the syndrome of progressive supranuclear palsy. It is most commonly described as a frontal dysexecutive syndrome but other impairments include apathy, impulsivity, visuospatial and memory functions. Cognitive dysfunction may be exacerbated by mood disturbance, medication and communication problems. In this review we advocate an individualized approach to managing cognitive impairment in progressive supranuclear palsy with the education of caregivers as a central component. Specific cognitive and behavioral treatments are complemented by treatment of mood disturbances, rationalizing medications and a patient-centered approach to communication. This aims to improve patients' quality of life, reduce carer burden and assist people with progressive supranuclear palsy in decisions about their life and health, including discussions of feeding and end-of-life issues.

Introduction Delivery of vardenafil (for improvement of erectile function) via the inhaled route of administration may be advantageous in that this avoids extensive first pass metabolism and may therefore increase the bioavailability (hence the reliability of absorption) and shorten the time of pharmacological onset of activity. A unique nebulizer design has been developed by the sponsor (Advanced Medical Institute Pty Ltd) that is capable of delivering relatively large volumes of drug. Aim The primary objective of the Phase 1 study was to assess and compare the pharmacokinetics of a single dose of vardenafil 10-mg tablet and a single dose of vardenafil solution administered via inhalation using an ultrasonic nebulizer device. Secondary objective was to assess the safety of vardenafil administered via inhalation using an ultrasonic nebuliser device. Methods Two-part study in healthy volunteers. Dose-ranging study was performed in two subjects to determine the appropriate inhalational dose, followed by an open, randomized, crossover, single dose pharmacokinetic study in 12 subjects, which compared a single 10-mg oral dose to the inhalation dose. Main Outcome Measures C max , C max /Dose, T max , k e , t 1/2 , AUC 0–t , AUC t–∞ , AUC 0–∞ , AUC 0–∞ , AUC 0–∞ /Dose, and % area extrapolated. Results The two treatments are not bioequivalent, with vardenafil absorbed and eliminated faster and with less variability using the nebulizer for drug delivery. Administration via the inhalational route was not associated with any clinically significant changes in blood pressure or heart rate, and no serious adverse events were recorded, demonstrating an acceptable safety profile. Conclusion To our knowledge, this is the first report of the administration of vardenafil HCl via the pulmonary route of administration. This trial demonstrates that vardenafil HCl may be administered using the ultrasonic nebulizer to reach blood levels comparable with those produced by a vardenafil 10-mg oral tablet, faster and using less drug. This new route of administration may potentially improve the onset of action, reliability, and safety for this class of drug.

The refurbishment of the Simon Building, University of Manchester, included the removal of four columns from the basement of this multi-storey structure. This complex task was conducted safely and without damage to the existing building (a monolithic concrete frame structure). An innovative clamping system was used, in combination with a series of hydraulic jacks, to lift the structure above the point of demolition. This relieved the column of load and allowed the demolition to be conducted in a controlled manner. This paper details the design and implementation phases of this project.

This study examines variability across the age span in cognitive performance in a cross-sectional, population-based, adult lifespan cohort from the Cambridge Centre for Ageing and Neuroscience (Cam-CAN) study (n = 2680). A key question we highlight is whether using measures that are designed to detect age-related cognitive pathology may not be sensitive to, or reflective of, individual variability among younger adults. We present three issues that contribute to the debate for and against age-related increases in variability. Firstly, the need to formally define measures of central tendency and measures of variability. Secondly, in addition to the commonly addressed location-confounding (adjusting for covariates) there may exist changes in measures of variability due to confounder sub-groups. Finally, that increases in spread may be a result of floor or ceiling effects, where the measure is not sensitive enough at all ages. From the Cam-CAN study, a large population-based dataset, we demonstrate the existence of variability-confounding for the immediate episodic memory task, and show that increasing variance with age in our general cognitive measures is driven by a ceiling effect in younger age groups.

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper.

Physical activity has positive effects on brain health and cognitive function throughout the life span. Thus far, few studies have examined the effects of physical activity on white matter microstructure and psychomotor speed within the same, population-based sample (critical if conclusions are to extend to the wider population). Here, using diffusion tensor imaging and a simple reaction time task within a relatively large population-derived sample (N = 399; 18–87 years) from the Cambridge Centre for Ageing and Neuroscience (Cam-CAN), we demonstrate that physical activity mediates the effect of age on white matter integrity, measured with fractional anisotropy. Higher self-reported daily physical activity was associated with greater preservation of white matter in several frontal tracts, including the genu of corpus callosum, uncinate fasciculus, external capsule, and anterior limb of the internal capsule. We also show that the age-related slowing is mediated by white matter integrity in the genu. Our findings contribute to a growing body of work, suggesting that a physically active lifestyle may protect against age-related structural disconnection and slowing.

Frontotemporal dementia (FTD) is a neurodegenerative disorder predominantly affecting the frontal and temporal lobes. Genome-wide association studies (GWAS) on FTD identified only a few risk loci. One of the possible explanations is that FTD is clinically, pathologically, and genetically heterogeneous. An important open question is to what extent epigenetic factors contribute to FTD and whether these factors vary between FTD clinical subgroup. We compared the DNA-methylation levels of FTD cases (n = 128), and of FTD cases with Amyotrophic Lateral Sclerosis (FTD-ALS; n = 7) to those of unaffected controls (n = 193), which resulted in 14 and 224 candidate genes, respectively. Cluster analysis revealed significant class separation of FTD-ALS from controls. We could further specify genes with increased susceptibility for abnormal gene-transcript behavior by jointly analyzing DNA-methylation levels with the presence of mutations in a GWAS FTD-cohort. For FTD-ALS, this resulted in 9 potential candidate genes, whereas for FTD we detected 1 candidate gene (ELP2). Independent validation-sets confirmed the genes DLG1, METTL7A, KIAA1147, IGHMBP2, PCNX, UBTD2, WDR35, and ELP2/SLC39A6 among others. We could furthermore demonstrate that genes harboring mutations and/or displaying differential DNA-methylation, are involved in common pathways, and may therefore be critical for neurodegeneration in both FTD and FTD-ALS.