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Abstract Background Compensatory movements frequently emerge in the process of motor recovery after a stroke. Given their potential for unfavorable long-term effects, it is crucial to assess and document compensatory movements throughout rehabilitation. However, clinically applicable assessment tools are currently limited. Deep learning methods have shown promising potential for assessing movement quality and addressing this gap. A crucial prerequisite for developing an accurate measurement tool is ensuring reliability in assessing compensatory movements, which is essential for establishing a valid ground truth. Objective The study aimed to assess inter- and intra-rater reliability of occupational and physical therapists’ visual assessment of compensatory movements based on video analysis. Methods Experienced therapists evaluated video-recorded performances of a standardized drinking task through an online labeling system. The standardized drinking task was performed by seven individuals with mild to moderate upper limb motor impairments after a stroke. The therapists rated compensatory movements in predetermined body segments and movement phases using a slider with a continuous scale ranging from 0 (no compensation) to 100 (maximum compensation). The collected data were analyzed using a generalized-linear mixed effects model with zero-inflated beta regression to estimate variance components. Intraclass correlation coefficients (ICC) were calculated to assess inter- and intra-rater reliability. Results Twenty-two therapists participated in this study. Inter-rater reliability was good for the phases of reaching, drinking, and returning (ICC ≥ .0.75), and moderate for both phases of transporting. Intra-rater reliability was excellent for the drinking phase (ICC > 0.9) and moderate to good for the phases of reaching, transporting, and returning of our cohort. ICCs for smoothness and interjoint coordination were poor for both inter- and intra-rater reliability. The data analysis unveiled a wide range of credible intervals for the ICCs across all domains examined in this study. Conclusions While this study shows promising inter- and intra-rater reliability for the drinking phases within our sample, the wide credible intervals raise the possibility that these results may have occurred by chance. Consequently, we cannot recommend the establishment of a ground truth for the automatic assessment of compensatory movements during a drinking task based on therapists’ ratings alone.

Despite effective knowledge transfer being a primary goal among post-secondary instructors, scholars, and administrators, students still have difficulty adapting their skills to novel contexts. This challenge is especially salient in writing pedagogy, where the transfer of writing-related knowledge is not guaranteed (Driscoll, 2011; Perkins & Salomon, 2012). To investigate possibilities for catalyzing writing transfer, this paper reports on a collaborative autoethnography project (Chang et al., 2013) carried out by two undergraduate students and a faculty member based at a large Ontario university. Their experiences on the editorial team of a first-year writing journal provide insight into how mentorship within journal environments can contribute to post-secondary students’ literacy development, and, concurrently, help them to transfer what they know to new contexts. We consider how similar learning opportunities may contribute to undergraduate skill development outside traditional classroom contexts.

ABSTRACT Integrating whole genome sequencing (WGS) of the Mycobacterium tuberculosis complex into routine care, surveillance, and research in high tuberculosis burden settings remains challenging due to limited resources and skills. While technological platforms for scaling WGS are emerging, scaling wet lab and analytic components often depends on partnerships where such skills have been established. To address this, a virtual training program was developed. Over 12 weeks, 21 trainees from five Southern African institutes engaged in learning from curated theoretical content and interactive virtual meetings with experienced instructors. The training program, developed by a diverse team of experts in molecular biology, biomedical research, microbiology, and tuberculosis research, provided comprehensive coverage aligned with the latest advancements. Teaching strategies included interactive mentor-led sessions and real-time feedback, together with facilitated knowledge exchange and understanding. The virtual training program yielded several successes. Of note, trainees submitted three scientific articles for peer review, based on their acquired knowledge and its application in research. The program also fostered collaborations on Mycobacterium tuberculosis WGS among participants, showcasing the potential for networking and future joint projects. While the virtual training program encountered challenges related to the pandemic, limited resources, trainee engagement, and language barriers, these were creatively mitigated. To improve future training sessions, a platform assessing participant engagement and information retention is recommended. Wider collaborative efforts among experts and institutions in collating resources will lead to more comprehensive training programs. Addressing challenges such as internet connectivity issues and language barriers is crucial for ensuring inclusivity and enhancing the overall learning experience. In conclusion, the virtual training program successfully provided knowledge and skill training in WGS to trainees, leading to scientific article submissions and collaborations. Furthermore, content creators benefited from improved science communication and training opportunities.

Abstract Background Harms associated with the use of alcohol and other drugs (AOD) in licensed entertainment settings (LES) and outdoor music festivals (OMF) are ongoing public health and criminal justice concerns. This systematic review provides a comprehensive, synthesized report on the evidence base of interventions that impact harm in these settings, and how they affect health, behavioral, and criminal justice outcomes. Methods Nine databases were searched for experimental and observational studies published between 2010 and 2021. Studies were included if they were peer-reviewed, published in English, described interventions which could impact AOD-related harms in LES or OMF (and were delivered in these environments), and reported on health, criminal justice and/or behavioral outcomes. Methodological quality was assessed using the Effective Public Health Practice Project’s Quality Assessment Tool for Quantitative Studies and the Critical Appraisal Skills Program for qualitative studies. A narrative synthesis was conducted to synthesize outcomes across studies. The review protocol was registered in PROSPERO (CRD42020140004). Results Of the 48,303 studies screened, 100 met the inclusion criteria. 86 focused solely on reducing alcohol-related harm, 7 on reducing illicit drug-related harm, and 7 on both. Most (n = 88) focused on LES and evaluated changes in laws and regulations (n = 28) and/or multicomponent interventions/policies (n = 41). Multicomponent interventions showed the best results for both health (62% positive) and criminal justice (84% positive) outcomes, with 71% of studies being rated as strong quality. There was also good evidence to support the careful application of trading hour restrictions and limited but promising evidence to support medical services and drug checking. Conclusion The breadth, quality and volume of evidence regarding what works in reducing AOD-related harm in recreational settings have increased in the past decade, particularly regarding LES. Findings support onsite medical services (reducing ambulance transfer rates), multicomponent interventions targeting alcohol accessibility and availability (reducing assaults), and drug checking services, but suggest other interventions such as drug detection dogs may exacerbate harm. Further, higher quality research is required to address identified gaps in the evidence base, particularly on optimal interventions within OMF, around illicit drugs more broadly and in the Global South.

Abstract Many bacterial species use Type VI secretion systems (T6SSs) to deliver anti-bacterial effector proteins into neighbouring bacterial cells, representing an important mechanism of inter-bacterial competition. Specific immunity proteins protect bacteria from the toxic action of their own effectors, whilst orphan immunity proteins without a cognate effector may provide protection against incoming effectors from non-self competitors. T6SS-dependent Rhs effectors contain a variable C-terminal toxin domain (CT), with the cognate immunity protein encoded immediately downstream of the effector. Here, we demonstrate that Rhs1 effectors from two strains of Serratia marcescens, the model strain Db10 and clinical isolate SJC1036, possess distinct CTs which both display NAD(P)+ glycohydrolase activity but belong to different subgroups of NADase from each other and other T6SS-associated NADases. Comparative structural analysis identifies conserved functions required for NADase activity and reveals that unrelated NADase immunity proteins utilise a common mechanism of effector inhibition. By replicating a natural recombination event, we show successful functional exchange of CTs and demonstrate that Db10 encodes an orphan immunity protein which provides protection against T6SS-delivered SJC1036 NADase. Our findings highlight the flexible use of Rhs effectors and orphan immunity proteins during inter-strain competition and the repeated adoption of NADase toxins as weapons against bacterial cells.

Abstract Background Antimicrobial resistance (AMR) is a major global health threat caused by the inappropriate use of antimicrobials in healthcare and other settings. Antimicrobial stewardship (AMS) is a broad multi-component health services intervention that promotes and monitors the judicious use of antimicrobials to preserve their future effectiveness. A main component of AMS is education and training (E&T). However, there are often discrepancies in how such interventions are implemented and delivered in hospital-based care. The aim of this study was to explore the factors influencing the implementation of AMS E&T in UK hospitals. Methods Semi-structured interviews were carried out with AMS E&T trainers in UK hospitals. The interview schedule was developed using the Capability, Opportunity, Motivation = Behaviour (COM-B) model. Participants were identified via professional networks and social media. Interviews were analysed using inductive thematic analysis, followed by deductive analysis using the COM-B model as a framework. Results A total of 34 participants (26 antimicrobial pharmacists, 3 nurses, 1 advanced clinical practitioner, 2 infectious disease consultants, 1 microbiologist and 1 clinical scientist). responsible for designing, implementing and evaluating AMS E&T in UK hospitals (five from Northern Ireland, four from Wales, two from Scotland and 23 from England) took part in virtual interviews. Key themes were: (1) The organisational context, including system-level barriers to AMS included competing organisational targets (Reflective motivation and physical opportunity) and the impact of the COVID-19 pandemic on activity (Physical opportunity); (2) Healthcare professionals’ roles and the wider multi-disciplinary team, such that AMS roles were defined and addressed poorly in E&T (Social opportunity); and (3) The individual perception of the need for AMS E&T in hospital-based care, manifest in a perceived lack of conviction of the wider threat of AMR and the resulting need for AMS E&T (Reflective motivation). Conclusion This study has identified factors influencing implementation of AMS E&T in UK hospitals and further identified where implemented, AMS E&T did not address real-world challenges. Current AMS E&T needs to be optimised to elicit practice change, with recommendations including training and engaging the wider work-force and drawing upon theoretically-informed intervention development frameworks to inform AMS E&T to better target AMS behaviour change.

This essay examines a case study that investigated how students learned and how they applied their writing skills as they pursued publication in an undergraduate scientific journal at a Canadian university. As we conducted a genre analysis of student drafts submitted to the journal and interviewed students who published in the journal’s inaugural year, we noted the desire and eagerness that students had to publish at the undergraduate level. We also noticed certain barriers to students fully participating in research for their discourse communities, including challenges accessing publication opportunities and revising their work for new audiences and contexts. Undergraduate journals offer a tremendous space for them to hone a variety of skills in a supportive environment while also taking the first steps to fully participating in scholarly practice.

Abstract Obstructive sleep apnea (OSA) is characterized by collapse of the upper airways during sleep. The contribution of alterations in effort perception is not understood. This study investigated the response of inspiratory and quadriceps muscles to repetitive loading on effort perception in OSA patients, pre and post continuous positive airway pressure (CPAP) treatment, and in healthy individuals. Twenty‐one OSA patients and 40 healthy participants completed protocols for repetitive inspiratory and leg muscle loading combined with intermittent rating of perceived exertion (RPE 14—somewhat hard/hard) to assess effort sensitivity. Electromyography, inspiratory pressure and isometric force were measured. OSA patients reported higher fatiguability of respiratory and leg muscles than controls. OSA patients revealed lower effort sensitivity in the leg muscles compared with controls, while repetitive loading led to a decline in force production. In the respiratory system, OSA patients revealed similar effort sensitivity at baseline compared with controls, but a large reduction in effort sensitivity after loading. Baseline effort sensitivity was correlated with apnea‐hypopnea index (AHI). After CPAP treatment, OSA patients revealed a decreased baseline effort sensitivity with a missing loading response. Effort sensitivity was differentially affected in the respiratory and leg systems with outcomes of CPAP treatment suggesting a full reversibility. Outcomes suggest that reversible adaptive response of effort perception in the respiratory system might contribute to the severity of OSA.

Abstract Leg movements during sleep occur in patients with sleep pathology and healthy individuals. Some (but not all) leg movements during sleep are related to cortical arousals which occur without conscious awareness but have a significant effect of sleep fragmentation. Detecting leg movements during sleep that are associated with cortical arousals can provide unique insight into the nature and quality of sleep. In this study, a novel leg movement monitor that uses a unique capacitive displacement sensor and 6-axis inertial measurement unit, is used in conjunction with polysomnography to understand the relationship between leg movement and electroencephalogram (EEG) defined cortical arousals. In an approach that we call neuro-extremity analysis, directed connectivity metrics are used to interrogate causal linkages between EEG and leg movements measured by the leg movement sensors. The capacitive displacement measures were more closely related to EEG-defined cortical arousals than inertial measurements. Second, the neuro-extremity analysis reveals a temporally evolving connectivity pattern that is consistent with a model of cortical arousals in which brainstem dysfunction leads to near-instantaneous leg movements and a delayed, filtered signal to the cortex leading to the cortical arousal during sleep.

Abstract Peptidoglycan (PG) is the exoskeleton of bacterial cells and is required for their viability, growth, and cell division. Unlike most bacteria, mycobacteria possess an atypical PG characterized by a high degree of unique linkages and chemical modifications which most likely serve as important determinants of virulence and pathogenesis in mycobacterial diseases. Despite this important role, the chemical composition and molecular architecture of mycobacterial PG have yet to be fully determined. Here we determined the chemical composition of PG from Mycobacterium smegmatis using high-resolution liquid chromatography-mass spectrometry. Purified cell walls from the stationary phase were digested with mutanolysin and compositional analysis was performed on 130 muropeptide ions that were identified using an in silico PG library. The relative abundance for each muropeptide ion was measured by integrating the extracted-ion chromatogram. The percentage of crosslink per PG subunit was measured at 45%. While both 3→3 and 4→3 transpeptide cross-linkages were found in PG dimers, a high abundance of 3→3 linkages was found associated with the trimers. Approximately 43% of disaccharides in the PG of M. smegmatis showed modifications by acetylation or deacetylation. A significant number of PG trimers are found with a loss of 41.00 amu that is consistent with N-deacetylation, whereas the dimers show a gain of 42.01 amu corresponding to O-acetylation of the PG disaccharides. This suggests a possible role of PG acetylation in the regulation of cell wall homeostasis in M. smegmatis. Collectively, these data report important novel insights into the ultrastructure of mycobacterial PG.

Study region: This is study of the Rio Conchos Watershed, Chihuahua, Mexico. Study focus: This study provides assessment of climate variability from analysis of instrumental climate and reservoir operations data, plus nearby tree-ring indices in Chihuahua, Mexico. Water demand include international treaty deliveries, growing agricultural land use, and intensified crop production. Analysis of climate cycles includes frequency analysis of local multidecadal instrumental hydrologic time series and multi-century tree-ring indices. In addition, tree-ring indices were compared with 14C content in tree rings to assess the presence of the millennial solar cycle. New hydrological insights for the region: Most of the climate variability within inter-annual to interdecadal periods are aligned with Pacific Decadal Oscillation (PDO)-like climate cycles. New multi-century climate cycles were discovered from tree-ring indices that have a profound impact on sustainability of food and water security. Historical droughts of 8-year average duration within PDO-like cycles that span longer (12–43 year) periods were newly identified which are longer than the 5-year delivery cycles used in the 1944 International Treaty of the Rivers. Mega-droughts were discovered to occur within multi-century climate cycles. Multi-century cycles identified in tree-ring indices were likely driven by solar luminosity changes from the millennial solar cycle and not just recent anthropogenic climate change. Climate variability and temperature increases will further amplify cycles of supply and demand and exacerbate sustainability, mitigation, and management strategies. Conjunctive use combined with reservoir operations will broaden sustainability portfolio of options, reducing demand effects as well as enhance supply options and replenishment effects.

Understanding the pathology and immunological response to SARS CoV2 infection in specific patient groups is essential for informing the scientific and clinical handling of infections within these patient populations. Here the authors characterise the adaptive immune response to SARS-CoV2 infection in people living with HIV.

Artificial neural networks (ANNs) have been successfully trained to perform a wide range of sensory-motor behaviors. In contrast, the performance of spiking neuronal network (SNN) models trained to perform similar behaviors remains relatively suboptimal. In this work, we aimed to push the field of SNNs forward by exploring the potential of different learning mechanisms to achieve optimal performance. We trained SNNs to solve the CartPole reinforcement learning (RL) control problem using two learning mechanisms operating at different timescales: (1) spike-timing-dependent reinforcement learning (STDP-RL) and (2) evolutionary strategy (EVOL). Though the role of STDP-RL in biological systems is well established, several other mechanisms, though not fully understood, work in concert during learning in vivo. Recreating accurate models that capture the interaction of STDP-RL with these diverse learning mechanisms is extremely difficult. EVOL is an alternative method and has been successfully used in many studies to fit model neural responsiveness to electrophysiological recordings and, in some cases, for classification problems. One advantage of EVOL is that it may not need to capture all interacting components of synaptic plasticity and thus provides a better alternative to STDP-RL. Here, we compared the performance of each algorithm after training, which revealed EVOL as a powerful method for training SNNs to perform sensory-motor behaviors. Our modeling opens up new capabilities for SNNs in RL and could serve as a testbed for neurobiologists aiming to understand multi-timescale learning mechanisms and dynamics in neuronal circuits.

Abstract Rapid detection of tuberculosis (TB) infection is paramount to curb further transmission. The gold standard for this remains mycobacterial culture, however emerging evidence confirms the presence of differentially culturable tubercle bacteria (DCTB) in clinical specimens. These bacteria do not grow under standard culture conditions and require the presence of culture filtrate (CF), from axenic cultures of Mycobacterium tuberculosis (Mtb), to emerge. It has been hypothesized that molecules such as resuscitation promoting factors (Rpfs), fatty acids and cyclic-AMP (cAMP) present in CF are responsible for the growth stimulatory activity. Herein, we tested the ability of CF from the non-pathogenic bacterium Mycobacterium smegmatis (Msm) to stimulate the growth of DCTB, as this organism provides a more tractable source of CF. We also interrogated the role of Mtb Rpfs in stimulation of DCTB by creating recombinant strains of Msm that express Mtb rpf genes in various combinations. CF derived from this panel of strains was tested on sputum from individuals with drug susceptible TB prior to treatment. CF from wild type Msm did not enable detection of DCTB in a manner akin to Mtb CF preparations and whilst the addition of RpfAB Mtb and RpfABCDE Mtb to an Msm mutant devoid of its native rpfs did improve detection of DCTB compared to the no CF control, it was not statistically different to the empty vector control. To further investigate the role of Rpfs, we compared the growth stimulatory activity of CF from Mtb, with and without Rpfs and found these to be equivalent. Next, we tested chemically diverse fatty acids and cAMP for growth stimulation and whilst some selective stimulatory effect was observed, this was not significantly higher than the media control and not comparable to CF. Together, these data indicate that the growth stimulatory effect observed with Mtb CF is most likely the result of a combination of factors. Future work aimed at identifying the nature of these growth stimulatory molecules may facilitate improvement of culture-based diagnostics for TB.

Background: Young people living with 22q11.2 Deletion Syndrome (22q11.2DS) are at increased risk of schizophrenia, intellectual disability, attention-deficit hyperactivity disorder (ADHD) and autism spectrum disorder (ASD). In common with these conditions, 22q11.2DS is also associated with sleep problems. We investigated whether abnormal sleep or sleep-dependent network activity in 22q11.2DS reflects convergent, early signatures of neural circuit disruption also evident in associated neurodevelopmental conditions. Methods: In a cross-sectional design, we recorded high-density sleep EEG in young people (6–20 years) with 22q11.2DS (n=28) and their unaffected siblings (n=17), quantifying associations between sleep architecture, EEG oscillations (spindles and slow waves) and psychiatric symptoms. We also measured performance on a memory task before and after sleep. Results: 22q11.2DS was associated with significant alterations in sleep architecture, including a greater proportion of N3 sleep and lower proportions of N1 and REM sleep than in siblings. During sleep, deletion carriers showed broadband increases in EEG power with increased slow-wave and spindle amplitudes, increased spindle frequency and density, and stronger coupling between spindles and slow-waves. Spindle and slow-wave amplitudes correlated positively with overnight memory in controls, but negatively in 22q11.2DS. Mediation analyses indicated that genotype effects on anxiety, ADHD and ASD were partially mediated by sleep EEG measures. Conclusions: This study provides a detailed description of sleep neurophysiology in 22q11.2DS, highlighting alterations in EEG signatures of sleep which have been previously linked to neurodevelopment, some of which were associated with psychiatric symptoms. Sleep EEG features may therefore reflect delayed or compromised neurodevelopmental processes in 22q11.2DS, which could inform our understanding of the neurobiology of this condition and be biomarkers for neuropsychiatric disorders. Funding: This research was funded by a Lilly Innovation Fellowship Award (UB), the National Institute of Mental Health (NIMH 5UO1MH101724; MvdB), a Wellcome Trust Institutional Strategic Support Fund (ISSF) award (MvdB), the Waterloo Foundation (918-1234; MvdB), the Baily Thomas Charitable Fund (2315/1; MvdB), MRC grant Intellectual Disability and Mental Health: Assessing Genomic Impact on Neurodevelopment (IMAGINE) (MR/L011166/1; JH, MvdB and MO), MRC grant Intellectual Disability and Mental Health: Assessing Genomic Impact on Neurodevelopment 2 (IMAGINE-2) (MR/T033045/1; MvdB, JH and MO); Wellcome Trust Strategic Award ‘Defining Endophenotypes From Integrated Neurosciences’ Wellcome Trust (100202/Z/12/Z MO, JH). NAD was supported by a National Institute for Health Research Academic Clinical Fellowship in Mental Health and MWJ by a Wellcome Trust Senior Research Fellowship in Basic Biomedical Science (202810/Z/16/Z). CE and HAM were supported by Medical Research Council Doctoral Training Grants (C.B.E. 1644194, H.A.M MR/K501347/1). HMM and UB were employed by Eli Lilly & Co during the study; HMM is currently an employee of Boehringer Ingelheim Pharma GmbH & Co KG. The views and opinions expressed are those of the author(s), and not necessarily those of the NHS, the NIHR or the Department of Health funders.

This paper comes from narrative research that I did with ten former students who reflected on their experiences with writing both in a first-year writing class and beyond. As the participants and I worked together, it became clear that there was the tension between the way they described process and skill building in writing pedagogy. They emphasized that process and scaffolding were integral to their learning, but they equally emphasized the one-off, skills-oriented components of our work. Many conversations in Canadian writing studies have focused on dismantling or resisting the skills narrative, but the tension in the participants’ responses prompted me to think about this differently. The paper explores the tension between skills and process to argue that perhaps skill building has its place in our contexts, and that we as writing teachers and scholars must think about it differently in order to articulate the value of the work that we do. If we can use the skills-oriented components of our courses to open spaces to discuss the less quantifiable elements of our work that often get overlooked (i.e., scaffolding), then we may put ourselves in a better position to advocate for increased resources and funding.

Current understanding of the dynamic and slow flow paths that support streamflow in mountain headwater catchments is inhibited by the lack of long-term hydrogeochemical data and the frequent use of short residence time age tracers. To address this, the current study combined the traditional mean transit time and the state-of-the-art fraction of young water (Fyw) metrics with stable water isotopes and tritium tracers to characterize the dynamic and slow flow paths at Marshall Gulch, a sub-humid headwater catchment in the Santa Catalina Mountains, Arizona, USA. The results show that Fyw varied significantly with period when using sinusoidal curve fitting methods (e.g., iteratively re-weighted least squares or IRLS), but not when using the transit time distribution (TTD)-based method. Therefore, Fyw estimates from TTD-based methods may be particularly useful for intercomparison of dynamic flow behavior between catchments. However, the utility of 3H to determine Fyw in deeper groundwater was limited due to both data quality and inconsistent seasonal cyclicity of the precipitation 3H time series data. Although a Gamma-type TTD was appropriate to characterize deep groundwater, there were large uncertainties in the estimated Gamma TTD shape parameter arising from the short record length of 3H in deep groundwater. This work demonstrates how co-application of multiple metrics and tracers can yield a more complete understanding of the dynamic and slow flow paths and observable deep groundwater storage volumes that contribute to streamflow in mountain headwater catchments.

Diagnosis of tuberculosis in pediatric patients remains challenging due to inherent difficulties associated with obtaining respiratory samples for molecular and culture-based testing. To address this, recent studies have highlighted the utility of tongue swabs to detect Mycobacterium tuberculosis genomic DNA in the oral epithelia of tuberculosis infected adults. It is unknown whether tongue swabs have similar utility for diagnosis of childhood tuberculosis and if the presence of DNA in these swabs was associated with whole bacilli. We therefore sought to conduct a preliminary assessment of the utility of tongue swabs to detect tubercle bacilli and their associated genetic material in young children. For this, we recruited hospitalized children with clinically diagnosed tuberculosis (n = 26) or lower respiratory tract infection (LRTI, n = 9). These categories were blinded for downstream laboratory tests, which included PCR, spoligotyping, smear microscopy, and culture. Mtb genomic DNA was detected by PCR only in clinically diagnosed TB cases [11/26 (31.4%)] and not in cases with LRTI. Of these, 5/11 [45.5%] were associated with a spoligotype. Spoligotyping also detected an additional six specimens that were negative by PCR. Using smear microscopy, 19/26 [73.1%] and 4/9 [44.4] were Mtb positive in the tuberculosis or LRTI categories respectively. We noted positive results on all three tests in 5/26 [19.2%] in the tuberculosis category and 0/9 in the LRTI category. All specimens were culture negative. Collectively, these preliminary data present a compelling case for broader testing of tongue swabs to diagnose tuberculosis in children where obtaining standard sputum specimens is not easy.

Mycobacterium tuberculosis, the causative agent of tuberculosis remains a global health concern, further compounded by the high rates of HIV-TB co-infection and emergence of multi- and extensive drug resistant TB, all of which have hampered efforts to eradicate this disease. As a result, novel anti-tubercular interventions are urgently required, with the peptidoglycan component of the M. tuberculosis cell wall emerging as an attractive drug target. Peptidoglycan M23 endopeptidases can function as active cell wall hydrolases or degenerate activators of hydrolases in a variety of bacteria, contributing to important processes such as bacterial growth, division and virulence. Herein, we investigate the function of the Rv0950-encoded putative M23 endopeptidase in M. tuberculosis. In silico analysis revealed that this protein is conserved in mycobacteria, with a zinc-binding catalytic site predictive of hydrolytic activity. Transcript analysis indicated that expression of Rv0950c was elevated during lag and log phases of growth and reduced in stationary phase. Deletion of Rv0950c yielded no defects in growth, colony morphology, antibiotic susceptibility or intracellular survival but caused a reduction in cell length. Staining with a monopeptide-derived fluorescent D-amino acid, which spatially reports on sites of active PG biosynthesis or repair, revealed an overall reduction in uptake of the probe in ΔRv0950c. When stained with a dipeptide probe in the presence of cell wall damaging agents, the ΔRv0950c mutant displayed reduced sidewall labelling. As bacterial peptidoglycan metabolism is important for survival and pathogenesis, the role of Rv0950c and other putative M23 endopeptidases in M. tuberculosis should be explored further.

Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB), remains the leading cause of death from an infectious bacterium and is responsible for 1.8 million deaths annually. The emergence of drug resistance, together with the need for a shorter more effective regimen, has prompted the drive to identify novel therapeutics with the bacterial cell surface emerging as a tractable area for drug development. Mtb assembles a unique, waxy, and complex cell envelope comprised of the mycolyl-arabinogalactan-peptidoglycan complex and an outer capsule like layer, which are collectively essential for growth and pathogenicity while serving as an inherent barrier against antibiotics. A detailed understanding of the biosynthetic pathways required to assemble the polymers that comprise the cell surface will enable the identification of novel drug targets as these structures provide a diversity of biochemical reactions that can be targeted. Herein, we provide an overview of recently described mycobacterial cell wall targeting compounds, novel drug combinations and their modes of action. We anticipate that this summary will enable prioritization of the best pathways to target and triage of the most promising molecules to progress for clinical assessment.

Sulfate isotopes (δ34S, δ18OSO4) interpreted in conjunction with sulfate concentrations show that sulfate of both agricultural and geologic sources is present in groundwater and surface water in the Rio Grande flood plain within the Hueco Bolsón. From previous studies, water isotopes (δ2H, δ18O) in the study area indicate groundwater age relative to dam construction upstream. Surface water entering the Hueco Bolsón contains a mixture of soil-amendment sulfate and sulfate from deep-basin groundwater seeps at the terminus of Mesilla Valley. In the shallow Rio Grande alluvial aquifer within the Hueco Bolsón, ranges of δ34S in pre-dam (+2 to +9‰) and post-dam (0 to +6‰) groundwater overlap; the range for post-dam water coincides with common high-sulfate soil amendments used in the area. Most post-dam groundwater, including discharge into agricultural drains, has higher sulfate than pre-dam groundwater. In surface water downstream of Fabens, high-δ34S (>+10‰) sulfate, resembling Middle Permian gypsum, mixes with sulfate from upstream sources and agriculture. The high- δ34S sulfate probably represents discharge from the regional Hueco Bolsón aquifer. In surface water downstream of Fort Hancock, soil-amendment sulfate predominates, probably representing discharge from the Rio Grande alluvial aquifer near the basin terminus. The δ18OSO4 dataset is consistent with sulfate origins determined from the larger δ34S dataset.

Determining the degradation pathways in lead halide perovskites is key to its development as a viable solar technology. Aristidouet al. identify iodide vacancies as the preferred sites in mediating the photo-induced formation of superoxide species from intercalated oxygen.

Abstract Mycobacteria possess a multi-layered cell wall that requires extensive remodelling during cell division. We investigated the role of an amidase_3 domain-containing N-acetylmuramyl-L-alanine amidase, a peptidoglycan remodelling enzyme implicated in cell division. We demonstrated that deletion of MSMEG_6281 (Ami1) in Mycobacterium smegmatis resulted in the formation of cellular chains, illustrative of cells that were unable to complete division. Suprisingly, viability in the Δami1 mutant was maintained through atypical lateral branching, the products of which proceeded to form viable daughter cells. We showed that these lateral buds resulted from mislocalization of DivIVA, a major determinant in facilitating polar elongation in mycobacterial cells. Failure of Δami1 mutant cells to separate also led to dysregulation of FtsZ ring bundling. Loss of Ami1 resulted in defects in septal peptidoglycan turnover with release of excess cell wall material from the septum or newly born cell poles. We noted signficant accumulation of 3-3 crosslinked muropeptides in the Δami1 mutant. We further demonstrated that deletion of ami1 leads to increased cell wall permeability and enhanced susceptiblity to cell wall targeting antibiotics. Collectively, these data provide novel insight on cell division in actinobacteria and highlights a new class of potential drug targets for mycobacterial diseases.

The present work discusses capabilities within the finite element library CU-BENs. CU-BENs focuses on applying the finite element method to structural mechanics problems encountered within the context of inverse problems and partitioned fluid–structure interaction; thus element formulations are primarily of a structural type — truss, frame, and triangular discrete Kirchhoff theory shells. CU-BENs defaults to the skyline sparse storage scheme for the system matrix, but also supports other storage schemes when using external libraries such as LAPACK and UMFPACK. CU-BENs includes built-in nonlinear solution strategies, such as the Newton Raphson method and modified spherical arc length method, that are available within static analyses as well within the context of transient dynamic analyses involving a generalized-α implementation of the Newmark implicit time integration scheme.

Conventional and plasmacytoid dendritic cells (cDCs and pDCs) are the two populations of DCs that can be readily identified in human blood. Conventional DCs have been subdivided into CD1c+, or blood dendritic cells antigen (BDCA) 1 and CD141+, or BDCA-3, DCs, each having both unique gene expression profiles and functions. BDCA-3 DCs express high levels of toll-like receptor (TLR) 3 and upon stimulation with Poly:IC secrete IFN-β, CXCL10, and IL-12p70. In this article, we show that activation of human BDCA-3 DCs with Poly:IC induces the expression of activation markers (CD40, CD80, and CD86) and immunoglobulin-like transcript (ILT) 3 and 4. This Poly:IC stimulation results in four populations identifiable by flow cytometry based on their expression of ILT3 and ILT4. We focused our efforts on profiling the ILT4- and ILT4+ DCs. These ILT-expressing BDCA3 populations exhibit similar levels of activation as measured by CD40, CD80, and CD86; however they exhibit differential cytokine secretion profiles, unique gene signatures, and vary in their ability to prime allogenic naïve T cells. Taken together, these data illustrate that within a pool of BDCA-3 DCs there are cells poised to respond differently to a given input stimulus with unique output of immune functions.

Eye movements are generated by different premotor pathways. Damage to them can cause specific deficits of eye movements, such as saccades. For correlative clinico-anatomical post-mortem studies of cases with eye movement disorders it is essential to identify the functional cell groups of the oculomotor system in the human brain by marker proteins. Based on monkey studies, the premotor neurons of the saccadic system can be identified by the histochemical markers parvalbumin and perineuronal nets in humans. These areas involve the interstitial nucleus of Cajal (INC) and the rostral interstitial nucleus of the medial longitudinal fascicle (RIMLF), which both contain premotor neurons for upgaze and downgaze. Recent monkey and human studies revealed a selective excitatory calretinin-positive input to the motoneurons mediating upgaze, but not to those for downgaze. Three premotor regions were identified as sources of calretinin input in monkey: y-group, INC and RIMLF. These findings suggest that the expression pattern of parvalbumin and calretinin may help to identify premotor neurons involved in up- or downgaze. In a post-mortem study of five human cases without neurological diseases we investigated the y-group, INC and RIMLF for the presence of parvalbumin and calretinin positive neurons including their co-expression. Adjacent thin paraffin sections were stained for the aggrecan component of perineuronal nets, parvalbumin or calretinin and glutamate decarboxylase. The comparative analysis of scanned thin sections of INC and RIMLF revealed medium-sized parvalbumin positive neurons with and without calretinin coexpression, which were intermingled. The parvalbumin/calretinin positive neurons in both nuclei are considered as excitatory premotor upgaze neurons. Accordingly, the parvalbumin-positive neurons lacking calretinin are considered as premotor downgaze neurons in RIMLF, but may in addition include inhibitory premotor upgaze neurons in the INC as indicated by co-expression of glutamate decarboxylase in a subpopulation. Calretinin-positive neurons ensheathed by perineuronal nets in the human y-group are considered as the homologue premotor neurons described in monkey, projecting to superior rectus and inferior oblique motoneurons. In conclusion, combined immunostaining for parvalbumin, perineuronal nets and calretinin may well be suited for the specific identification and subsequent analysis of premotor upgaze pathways in clinical cases of isolated up- or downgaze deficits.

Introduction: Handcycling is a relatively new wheelchair sport that has gained increased popularity for people with lower limb disabilities. The aim of this study was to examine the effect of three different grip positions on physical parameters during handcycling in a laboratory setting.Methods: Twenty one able-bodied participants performed three maximum incremental handcycling tests until exhaustion, each with a different grip angle. The angle between the grip and the crank was randomly set at 90° (horizontal), 0° (vertical) or 10° (diagonal). The initial load was 20 W and increased by 20 W each five minutes. In addition, participants performed a 20 s maximum effort.Results: The relative peak functional performance (W/kg), peak heart rate (bpm), associated lactate concentrations (mmol/l) and peak oxygen uptake per kilogram body weight (ml.min-1.kg-1) for the different grip positions during the stage test were: (a) Horizontal: 1.43 ± 0.21 W/kg, 170.14 ± 12.81 bpm, 9.54 ± 1.93 mmol/l, 30.86 ± 4.57 ml/kg; (b) Vertical: 1.38 ± 0.20 W/kg, 171.81 ± 13.87 bpm, 9.91 ± 2.29 mmol/l, 29.75 ± 5.13 ml/kg; (c) Diagonal: 1.40 ± 0.22 W/kg, 169.19 ± 13.31 bpm, 9.34 ± 2.36 mmol/l, 29.39 ± 4.70 ml/kg. Statistically significant (p

The liver is involved in a variety of critical biological functions including the homeostasis of glucose, fatty acids, amino acids and the synthesis of proteins that are secreted in the blood. It is also at the forefront in the detoxification of noxious metabolites that would otherwise upset the functioning of the body. As such, this vital component of the mammalian system is exposed to a notable quantity of toxicants on a regular basis. It therefore comes as no surprise that there are over a hundred disparate hepatic disorders, encompassing such afflictions as fatty liver disease, hepatitis and liver cancer. Most if not all of liver functions are dependent on energy, an ingredient that is primarily generated by the mitochondrion, the power house of all cells. This organelle is indispensable in providing adenosine triphosphate (ATP), a key effector of most biological processes. Dysfunctional mitochondria lead to a shortage in ATP, the leakage of deleterious reactive oxygen species (ROS) and the excessive storage of fats. Here we examine how incapacitated mitochondrial bioenergetics triggers the pathogenesis of various hepatic diseases. Exposure of liver cells to detrimental environmental hazards such as oxidative stress, metal toxicity and various xenobiotics results in the inactivation of crucial mitochondrial enzymes and decreased ATP levels. The contribution of the latter to hepatic disorders and potential therapeutic cues to remedy these conditions are elaborated.

Survey rating scale: In Brief: Recent content analyses of LIS literature show that, by far, the most popular data collection method employed by librarians and library researchers is the survey. The authors of this article, all participants in the 2014 Institute for Research Design in Librarianship, recognize that there are sound reasons for using a […]

Listeria monocytogenes is a bacterial pathogen capable of causing severe infections in humans, often with fatal outcomes. Many different animal models exist to study L. monocytogenes pathogenicity, and we have investigated the chicken embryo as an infection model: What are the benefits and possible drawbacks? We have compared a defined wild-type strain with its isogenic strains lacking well-characterized virulence factors. Our results show that wild-type L. monocytogenes, already at a relatively low infection dose (~5 x 102 cfu), caused death of the chicken embryo within 36 hours, in contrast to strains lacking the main transcriptional activator of virulence, PrfA, or the cytolysin LLO. Surprisingly, strains lacking the major adhesins InlA and InlB caused similar mortality as the wild-type strain. In conclusion, our results suggest that the chicken embryo is a practical model to study L. monocytogenes infections, especially when analyzing alternative virulence pathways independent of the InlA and InlB adhesins. However, the route of infection might be different from a human infection. The chicken embryo model and other Listeria infection models are discussed.

The amygdala has been implicated in the processing of emotion and animacy information and to be responsivity to novelty. However, the way in which these functions interact is poorly understood. Subjects (N= 30) viewed threatening or neutral images that could be either animate (facial expressions) or inanimate (objects) in the context of a dot probe task. The amygdala showed responses to both emotional and animacy information, but no emotion by stimulus-type interaction; i.e., emotional face and object stimuli, when matched for arousal and valence, generate comparable amygdala activity relative to neutral face and object stimuli. Additionally, a habituation effect was not seen in amygdala; however, increased amygdala activity was observed for incongruent relative to congruent negative trials in second vs. first exposures. Furthermore, medial fusiform gyrus showed increased response to inanimate stimuli, while superior temporal sulcus showed increased response to animate stimuli. Greater functional connectivity between bilateral amygdala and medial fusiform gyrus was observed to negative vs. neutral objects, but to fearful vs. neutral faces. The current data suggest that the amygdala is responsive to animate and emotional stimuli. Additionally, these data suggest that the interaction between the various functions of the amygdala may need to be considered simultaneously to fully understand how they interact. Moreover, they suggest category-specific modulation of medial fusiform cortex as a function of emotion.

Educating researchers in sound data management skills is a hot topic in today’s data intensive research world. Librarians across the country and the world are taking the lead in offering this training to their campus research communities. In Fall, 2013, the Data Curation Librarian at the University of Tennessee, Knoxville, held a one-day “Data Management Basics” Workshop geared towards graduate students in engineering and science disciplines based on the New England Collaborative Data Management Curriculum. Students were asked to complete a pre-workshop survey and a series of seven post-module surveys throughout the day. This article discusses the results of the survey feedback, the planning process, and elaborates on important variables in planning data management training initiatives, such as disciplinary adjustments and time constraints. The article concludes with a discussion of the author’s future plans for providing training initiatives based on the feedback he received.

Stress activates the hypothalamic-pituitary-adrenal (HPA) axis, which then modulates the degree of adaptation and response to a later stressor. It is known that early life stress can impact on later health but less is known about how early life stress impairs HPA axis activity, contributing to maladaptation of the stress response system. Early life stress exposure (either prenatally or in the early postnatal period) can impact developmental pathways resulting in lasting structural and regulatory changes that predispose to adulthood disease. Epidemiological, clinical and experimental studies have demonstrated that early life stress produces long-term hyper responsiveness to stress with exaggerated circulating glucocorticoids, and enhanced anxiety and depression-like behaviours. Recently, evidence has emerged on early life stress induced metabolic derangements, for example hyperinsulinemia and altered insulin sensitivity on exposure to a high energy diet later in life. This draws our attention to the contribution of later environment to disease vulnerability. Early life stress can alter the expression of genes in peripheral tissues, such as the glucocorticoid receptor and 11-beta hydroxysteroid dehydrogenase (11β-HSD1). We propose that interactions between altered HPA axis activity and liver 11β-HSD1 modulates both tissue and circulating glucocorticoid availability, with adverse metabolic consequences. This review discusses the potential mechanisms underlying early life stress induced maladaptation of the HPA axis, and its subsequent effects on energy utilisation and expenditure. The effects of positive later environments as a means of ameliorating early life stress induced health deficits, and proposed mechanisms underpinning the interaction between early life stress and subsequent detrimental environmental exposures on metabolic risk will be outlined. Limitations in current methodology linking early life stress and later health outcomes will also be addressed.

BACKGROUND: Compound 48/80 is widely used in animal and tissue models as a "selective" mast cell activator. With this study we demonstrate that compound 48/80 also directly activates enteric neurons and visceral afferents. METHODOLOGY/PRINCIPAL FINDINGS: We used in vivo recordings from extrinsic intestinal afferents together with Ca(++) imaging from primary cultures of DRG and nodose neurons. Enteric neuronal activation was examined by Ca(++) and voltage sensitive dye imaging in isolated gut preparations and primary cultures of enteric neurons. Intraluminal application of compound 48/80 evoked marked afferent firing which desensitized on subsequent administration. In egg albumen-sensitized animals, intraluminal antigen evoked a similar pattern of afferent activation which also desensitized on subsequent exposure to antigen. In cross-desensitization experiments prior administration of compound 48/80 failed to influence the mast cell mediated response. Application of 1 and 10 µg/ml compound 48/80 evoked spike discharge and Ca(++) transients in enteric neurons. The same nerve activating effect was observed in primary cultures of DRG and nodose ganglion cells. Enteric neuron cultures were devoid of mast cells confirmed by negative staining for c-kit or toluidine blue. In addition, in cultured enteric neurons the excitatory action of compound 48/80 was preserved in the presence of histamine H(1) and H(2) antagonists. The mast cell stabilizer cromolyn attenuated compound 48/80 and nicotine evoked Ca(++) transients in mast cell-free enteric neuron cultures. CONCLUSIONS/SIGNIFICANCE: The results showed direct excitatory action of compound 48/80 on enteric neurons and visceral afferents. Therefore, functional changes measured in tissue or animal models may involve a mast cell independent effect of compound 48/80 and cromolyn.

We study the number of encryptions necessary to revoke a set of users in the complete subtree scheme (CST) and the subset-difference scheme (SD). These are well-known tree based broadcast encryption schemes. Park and Blake in: Journal of Discrete Algorithms, vol. 4, 2006, pp. 215―238, give the mean number of encryptions for these schemes. We continue their analysis and show that the limiting distribution of the number of encryptions for these schemes is normal. This implies that the mean numbers of Park and Blake are good estimates for the number of necessary encryptions used by these schemes.

Background: Micro- and nanoplastics (MNPs) are emerging pollutants of concern with ubiquitous presence in global ecosystems. MNPs pose potential implications for human health; however, the health impacts of MNP exposures are not yet understood. Recent evidence suggests that MNPs can cross the placental barrier, underlying the urgent need to understand their impact on reproductive health and development., Objective: The Actionable eUropean ROadmap for early-life health Risk Assessment of micro- and nanoplastics (AURORA) project will investigate MNP exposures and their biological and health effects during pregnancy and early life, which are critical periods due to heightened vulnerability to environmental stressors. The AURORA project will enhance exposure assessment capabilities for measuring MNPs, MNP-associated chemicals, and plastic additives in human tissues, including placenta and blood., Methods: In this interdisciplinary project, we will advance methods for in-depth characterization and scalable chemical analytical strategies, enabling high-resolution and large-scale toxicological, exposure assessment, and epidemiological studies. The AURORA project performs observational studies to investigate determinants and health impacts of MNPs by including 800 mother-child pairs from 2 existing birth cohorts and 110 women of reproductive age from a newly established cohort. This will be complemented by toxicological studies using a tiered-testing approach and epidemiological investigations to evaluate associations between maternal and prenatal MNP exposures and health perturbations, such as placental function, immune-inflammatory responses, oxidative stress, accelerated aging, endocrine disruption, and child growth and development. The ultimate goal of the AURORA project is to create an MNP risk assessment framework and identify the remaining knowledge gaps and priorities needed to comprehensively assess the impact of MNPs on early-life health., Results: In the first 3 years of this 5-year project (2021-2026), progress was made toward all objectives. This includes completion of recruitment and data collection for new and existing cohorts, development of analytical methodological protocols, and initiation of the toxicological tiered assessments. As of September 2024, data analysis is ongoing and results are expected to be published starting in 2025., Conclusions: As plastic pollution increases globally, it is imperative to understand the impact of MNPs on human health, particularly during vulnerable developmental stages such as early life. The contributions of the AURORA project will inform future risk assessment., International Registered Report Identifier (irrid): DERR1-10.2196/63176., (©Amanda M Durkin, Runyu Zou, Justin M Boucher, Matthew SP Boyles, Jeske van Boxel, Mariona Bustamante, Emily A Christopher, Payam Dadvand, Hanna M Dusza, Majorie van Duursen, Markus M Forsberg, Karen S Galea, Juliette Legler, Laurens DB Mandemaker, Florian Meirer, Jane Muncke, Tim S Nawrot, Petra Přibylová, Anna R Robuck, Nelly D Saenen, Barbara M Scholz-Böttcher, Kuanliang Shao, Martine Vrijheid, Douglas I Walker, Lisa Zimmermann, Laura M Zoutendijk, Virissa Lenters, Roel Vermeulen. Originally published in JMIR Research Protocols (https://www.researchprotocols.org), 08.10.2024.)

Remembering to complete goals-termed prospective memory (PM)-is critical for success in everyday life, yet minimal empirical work has been dedicated to examining PM within an educational setting. The main goal of this study was to investigate students' ability to complete numerous future-oriented academic intentions (PM tasks) while simultaneously paying attention to a lecture and to see if working memory (WM) capacity and adding subtle contextual information would support the students' likelihood of completing their PM tasks. Participants took part in a 2-hr session of college course-like activities. Throughout the session, there was occasionally the opportunity to complete one of several naturalistic PM tasks. The following findings are based on the results of our Bayesian models. Providing subtle contextual clues about when PM tasks could be completed was found to likely increase performance. The number of PM intentions to be remembered (i.e., load) produced no discernable effect on ongoing task performance or PM performance. Furthermore, individual differences in WM capacity were likely to be predictive of a near-zero change in PM performance. The current findings hold meaningful implications for educators, wherein providing context, even at a subtle level, can enhance students' ability to remember to complete tasks, without altering their ability to focus on the tasks at hand. Moreover, it appears that asking students to remember to complete multiple, prospective in-class tasks is not likely to hinder task completion or their ability to focus on other ongoing tasks., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: Pick's disease is a rare and predominantly sporadic form of frontotemporal dementia that is classified as a primary tauopathy. Pick's disease is pathologically defined by the presence in the frontal and temporal lobes of Pick bodies, composed of hyperphosphorylated, three-repeat tau protein, encoded by the MAPT gene. MAPT has two distinct haplotypes, H1 and H2; the MAPT H1 haplotype is the major genetic risk factor for four-repeat tauopathies (eg, progressive supranuclear palsy and corticobasal degeneration), and the MAPT H2 haplotype is protective for these disorders. The primary aim of this study was to evaluate the association of MAPT H2 with Pick's disease risk, age at onset, and disease duration., Methods: In this genetic association study, we used data from the Pick's disease International Consortium, which we established to enable collection of data from individuals with pathologically confirmed Pick's disease worldwide. For this analysis, we collected brain samples from individuals with pathologically confirmed Pick's disease from 35 sites (brainbanks and hospitals) in North America, Europe, and Australia between Jan 1, 2020, and Jan 31, 2023. Neurologically healthy controls were recruited from the Mayo Clinic (FL, USA, or MN, USA between March 1, 1998, and Sept 1, 2019). For the primary analysis, individuals were directly genotyped for the MAPT H1-H2 haplotype-defining variant rs8070723. In a secondary analysis, we genotyped and constructed the six-variant-defined (rs1467967-rs242557-rs3785883-rs2471738-rs8070723-rs7521) MAPT H1 subhaplotypes. Associations of MAPT variants and MAPT haplotypes with Pick's disease risk, age at onset, and disease duration were examined using logistic and linear regression models; odds ratios (ORs) and β coefficients were estimated and correspond to each additional minor allele or each additional copy of the given haplotype., Findings: We obtained brain samples from 338 people with pathologically confirmed Pick's disease (205 [61%] male and 133 [39%] female; 338 [100%] White) and 1312 neurologically healthy controls (611 [47%] male and 701 [53%] female; 1312 [100%] White). The MAPT H2 haplotype was associated with increased risk of Pick's disease compared with the H1 haplotype (OR 1·35 [95% CI 1·12 to 1·64], p=0·0021). MAPT H2 was not associated with age at onset (β -0·54 [95% CI -1·94 to 0·87], p=0·45) or disease duration (β 0·05 [-0·06 to 0·16], p=0·35). Although not significant after correcting for multiple testing, associations were observed at p less than 0·05: with risk of Pick's disease for the H1f subhaplotype (OR 0·11 [0·01 to 0·99], p=0·049); with age at onset for H1b (β 2·66 [0·63 to 4·70], p=0·011), H1i (β -3·66 [-6·83 to -0·48], p=0·025), and H1u (β -5·25 [-10·42 to -0·07], p=0·048); and with disease duration for H1x (β -0·57 [-1·07 to -0·07], p=0·026)., Interpretation: The Pick's disease International Consortium provides an opportunity to do large studies to enhance our understanding of the pathobiology of Pick's disease. This study shows that, in contrast to the decreased risk of four-repeat tauopathies, the MAPT H2 haplotype is associated with an increased risk of Pick's disease in people of European ancestry. This finding could inform development of isoform-related therapeutics for tauopathies., Funding: Wellcome Trust, Rotha Abraham Trust, Brain Research UK, the Dolby Fund, Dementia Research Institute (Medical Research Council), US National Institutes of Health, and the Mayo Clinic Foundation., Competing Interests: Declarations of interest WJS declares funding from a Wellcome Trust Clinical PhD Fellowship (220582/Z/20/Z) and from the Rotha Abraham Trust; and has received conference travel funding from the Guarantors of Brain. NT declares funding from the 2023 Diana Jacobs Kalman-American Federation for Aging Research Scholarship for Pre-Doctoral Research on the biology of aging. KM declares funding from the Michael J Fox Foundation, Innovation and Technology Commission, Hong Kong Government, and the Chow Tai Fook Charity Foundation; affiliations with the Hong Kong University of Science and Technology and University College London; employment with the Hong Kong Center for Neurodegenerative Diseases; and support for speaker and educational activity from the National Taiwan University, Yonsei University, and the Movement Disorder Society. WWS declares funding from the National Institutes of Health (NIH), Tau Consortium, Bluefield Project to Cure Frontotemporal Dementia, and the Chan-Zuckerberg Initiative. EBL declares funding from the NIH and personal honorarium from University of Toronto, Mayo Clinic, St Louis University, Haverford, University of Oslo, NIH, and the Association of Frontotemporal Dementia. LM-P declares personal honorarium from the Galician Society of Neurology and the Spanish Society of Neurology. JBR declares funding from the NIH Research Biomedical Research Centre, the Medical Research Council, Wellcome Trust, Cambridge Centre for Parkinson-plus, PSP association, and Alzheimer's UK; and has received consulting fees from Asceneuron, Astronautx, Astex, Curasen, CumulusNeuro, Wave, Prevail, and SVHealth. TGB declares funding from the NIH, Michael J Fox Foundation, and Life Molecular Imaging; personal consulting fees from Aprinoia Therapeutics; and stock options in Vivid Genomics. S-HJW declares funding from NIH and personal honorarium from the American Society of Clinical Pathology. CG declares funding from the Swedish Frontotemporal Dementia Inititative-Schörling Foundation, EU Joint Programme-Neurodegenerative Disease Research-Prefrontals, EU Joint Programme-Neurodegenerative Disease Research-Genetic Frontotemporal Dementia Initiative-Proximity, the Alzheimer Foundation, Brain Foundation, Dementia Foundation, Region Karolinska Institutet-StratNeuro Strategiska forskningsområden, Centre for Innovative Medicine, and Karolinska Institutet-Region Stockholm Core facility; personal honoraria from Demensdagarna Örebro, Diakonia Ersta sjukhus, and Göteborgsregionen. GGK declares funding from Edmond J Safra Philanthropic Foundation, Michael J Fox Foundation, Parkinson Canada, Canada, Canada Foundation for Innovation, MSA Coalition, and the NIH; and royalties from a patent for 5G4 synuclein antibody (DE102011008153B4); and personal honoraria from the Movement Disorders Society. MN declares funding from Deutsche Forschungsgemeinschaft and Alzheimer Forschungsinitiative. HRM declares funding from the PSP Association, CBD Solutions, the Drake Foundation, the Cure Parkinson's Trust, the Michael J Fox Foundation, and Parkinson's UK; consulting fees from Roche, Amylyx, and Aprinoia; personal honoraria from Kyowa-Kirin, BMJ, and the Movement Disorders Society; travel support from the Michael J Fox Foundation; is a co-applicant on a patent application related to C9ORF72 method for diagnosing a neurodegenerative disease (PCT/GB2012/052140); and serves on the Cure PSP Association Advisory Board, the Association of British Neurologists Movement Disorders Special Interest Group, and the Association of British Neurologists Neurogenetics Advisory Group. RRa declares consulting fees from Arkuda Therapeutics and is on the advisory board for the Kissick Family Foundation. JAH declares funding from the Dolby Charities, and consulting fees from Eli Lilly and Eisai. JDR declares funding from the Bluefied project and the Alzheimer's Associaton; and consulting fees from Novartis, Wave Life Sciences, Prevail, Alector, Aviado Bio, Takeda, Arkuda Therapeutics, and Denali Therapeutics. OAR declares internal funding from the Mayo Clinic Foundation. All other authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Background: Pick's disease (PiD) is a rare and predominantly sporadic form of frontotemporal dementia that is classified as a primary tauopathy. PiD is pathologically defined by argyrophilic inclusion Pick bodies and ballooned neurons in the frontal and temporal brain lobes. PiD is characterised by the presence of Pick bodies which are formed from aggregated, hyperphosphorylated, 3-repeat tau proteins, encoded by the MAPT gene. The MAPT H2 haplotype has consistently been associated with a decreased disease risk of the 4-repeat tauopathies of progressive supranuclear palsy and corticobasal degeneration, however its role in susceptibility to PiD is unclear. The primary aim of this study was to evaluate the association between MAPT H2 and risk of PiD., Methods: We established the Pick's disease International Consortium (PIC) and collected 338 (60.7% male) pathologically confirmed PiD brains from 39 sites worldwide. 1,312 neurologically healthy clinical controls were recruited from Mayo Clinic Jacksonville, FL (N=881) or Rochester, MN (N=431). For the primary analysis, subjects were directly genotyped for MAPT H1-H2 haplotype-defining variant rs8070723. In secondary analysis, we genotyped and constructed the six-variant MAPT H1 subhaplotypes (rs1467967, rs242557, rs3785883, rs2471738, rs8070723, and rs7521)., Findings: Our primary analysis found that the MAPT H2 haplotype was associated with increased risk of PiD (OR: 1.35, 95% CI: 1.12-1.64 P=0.002). In secondary analysis involving H1 subhaplotypes, a protective association with PiD was observed for the H1f haplotype (0.0% vs. 1.2%, P=0.049), with a similar trend noted for H1b (OR: 0.76, 95% CI: 0.58-1.00, P=0.051). The 4-repeat tauopathy risk haplotype MAPT H1c was not associated with PiD susceptibility (OR: 0.93, 95% CI: 0.70-1.25, P=0.65)., Interpretation: The PIC represents the first opportunity to perform relatively large-scale studies to enhance our understanding of the pathobiology of PiD. This study demonstrates that in contrast to its protective role in 4R tauopathies, the MAPT H2 haplotype is associated with an increased risk of PiD. This finding is critical in directing isoform-related therapeutics for tauopathies., Competing Interests: M.A.N. and D.V.’s participation in this project was part of a competitive contract awarded to Data Tecnica International LLC by the National Institutes of Health to support open science research. M.A.N. also currently serves on the scientific advisory board for Character Bio Inc. and Neuron23 Inc.

Background: Mutations in the leucine-rich repeat kinase 2 gene (LRRK2) are the most common genetic cause of Parkinson's disease (PD). Unexpectedly, tau pathology has been reported in a subset of LRRK2 mutation carriers., Methods: To estimate the frequency of pathogenic LRRK2 mutations and to evaluate the association of common LRRK2 variants with risk of primary tauopathies, we studied 1039 progressive supranuclear palsy (PSP) and 145 corticobasal degeneration patients from the Mayo Clinic Florida brain bank and 1790 controls ascertained at Mayo Clinic. Sanger sequencing of LRRK2 exons 30, 31, 35, and 41 was performed in all patients, and genotyping of all 17 known exonic variants with minor allele frequency >0.5% was performed in patients and controls., Results: LRRK2 mutational screening identified 2 known pathogenic mutations (p.G2019S and p.R1441C), each in 1 PSP patient, the novel p.A1413T mutation in a PSP patient and the rare p.R1707K mutation in a corticobasal degeneration patient. Both p.A1413T and p.R1707K mutations were predicted damaging by at least 2 of 3 prediction programs and affect evolutionary conserved sites of LRRK2. Association analysis using common LRRK2 variants only showed nominal association of the p.L153L variant with PSP., Conclusions: Our study confirms the presence of pathogenic and potentially pathogenic LRRK2 mutations in pathologically confirmed primary tauopathies, albeit with low frequency. In contrast to PD, common LRRK2 variants do not appear to play a major role in determining PSP and corticobasal degeneration risk. © 2016 International Parkinson and Movement Disorder Society., (© 2016 International Parkinson and Movement Disorder Society.)

Remembering to complete one's future intentions is termed prospective memory. We employed a new eyetracking paradigm to concretely observe the impact of environmental cues on strategic monitoring within a visual prospective memory task. Participants worked on a continuous living-count task comprising images, while simultaneously being asked to respond to a prospective memory target when it appeared. Importantly, the prospective memory target appeared in a different area of the participant's visual field than did the continuous task, which is consistent with prospective memory in many real-world situations, and further allows for a clear index of strategic monitoring processes. Subtle cues in the form of semantically related images were embedded in the continuous task to prompt monitoring for the prospective memory target. Overt strategic monitoring was operationalized as the number of times participants fixated on the designated target area, and cue-driven monitoring was defined by the number of fixations on the prospective memory target region directly after fixating on a related cue. Overt strategic monitoring for the prospective memory target was directly observed for participants in the prospective memory condition, and cue-driven monitoring was also observed in these participants, since they were more likely to initiate monitoring immediately after fixating on a semantically related cue, relative to an unrelated cue. This psychophysiological approach afforded precise measurement of the strategic monitoring process and revealed how contextual cues in the environment interact with the cognitive mechanisms supporting prospective memory.

The apolipoprotein E (apoE) genotype is an important genetic risk factor for Alzheimer's disease (AD). In the central nervous system (CNS), most apoE is produced by astrocytes and is present in unique high-density lipoprotein (HDL)-like particles that have distinct properties from apoE derived from other sources. To develop an efficient system to produce astrocyte-derived apoE in large quantities, we produced and characterized immortalized cell lines from primary astrocyte cultures derived from human APOE knock-in mice. APOE2, APOE3, and APOE4 expressing cell lines were established that secrete apoE in HDL-like particles at similar levels, cholesterol composition, and size as those produced by primary astrocytes. In physiological buffers, astrocyte-secreted apoE3 and E4 associated equally well with amyloid-beta. Under the same conditions, only a small fraction of A beta formed sodium dodecyl sulfate (SDS)-stable complexes with apoE (E3 > E4). These immortalized astrocytes will be useful for studying mechanisms underlying the isoform-specific effects of apoE in the CNS.

Carbon-13 CP/MAS spectra have been obtained for seven polymorphic and solvated forms of cortisone acetate. For signals in the high-frequency region, the spinning sideband manifolds of the spectra recorded under slow-spinning conditions have been analysed to obtain the shielding tensor components for the five resonances at the highest frequency. These show characteristic values for given types of carbon and have enabled assignments of the C5 and C22 signals to be made with some certainty, providing firm evidence of cross-over between the shifts for these carbons between different polymorphs. Assignments are suggested more tentatively for the resonances from C3, C11 and C20. Comparison of chemical shifts for those forms with published X-ray structures enables conclusions to be drawn regarding hydrogen bonding in the remaining forms. Hydrogen bonding induces a high-frequency change in the isotropic chemical shift of approximately 3 ppm.