Local tumour control and patient survival after ruthenium-106 brachytherapy for small choroidal melanoma.

AIM: To report local tumour control, metastasis and survival rates of patients with small choroidal melanoma (CM) after treatment with ruthenium-106 (Ru-106) plaque brachytherapy. METHODS: Retrospective case series of 353 consecutive eyes with small CM (thickness ≤2.5 mm and largest basal diameter ≤16 mm) treated with Ru-106 brachytherapy at the London Ocular Oncology Service, between October 2004 and May 2019. RESULTS: The final cohort included 310 eyes and tumour recurrence was observed in 52 (17%) eyes. Ocular retention rate was 96%. Metastatic disease and tumour-related death occurred in 18 (5.8%) and 12 (3.9%) patients, respectively. Metastases were diagnosed after a median of 54 (54±35; range 3.6-118) months from initial treatment. Kaplan-Meier estimates for tumour recurrence, melanoma-related metastases and survival were 17% (95% CI 13.3% to 22.9%), 4.8% (95% CI 2.6% to 8.5%) and 98% (95% CI 94.4% to 99.1%) at 5 years and 26% (95% CI 18.3% to 35.3%), 16% (95% CI 8.7% to 27.7%) and 92% (95% CI 84.5% to 95.7%) at 10 years, respectively. On multivariable analysis, factors predictive for tumour recurrence included juxtapapillary location, larger plaque and final tumour thickness, and for metastasis exudative retinal detachment. CONCLUSION: Small CMs treated with Ru-106 brachytherapy show recurrence and death rates of 17% and 2% at 5 years and 26% and 8% at 10 years. As small CMs have better prognosis than large tumours, early treatment is the key for better survival outcomes.

A truncation mutant of adenomatous polyposis coli impairs apical cell extrusion through elevated epithelial tissue tension.

Tissue tension encompasses the mechanical forces exerted on solid tissues within animal bodies, originating from various sources such as cellular contractility, interactions with neighboring cells and the extracellular matrix. Emerging evidence indicates that an imbalance in such forces can influence structural organization, homeostasis, and potentially contribute to disease. For instance, heightened tissue tension can impede apical cell extrusion, leading to the retention of apoptotic or transformed cells. In this study, we investigate the potential role of adenomatous polyposis coli (APC) in modulating tissue tension. Our findings reveal that expression of an APC truncation mutant elevates epithelial tension via the RhoA/ROCK pathway. This elevation induces morphological alterations and hampers apoptotic cell extrusion in cultured epithelial cells and organoids, both of which could be mitigated by pharmacologically restoring the tissue tension. This raises the possibility that APC mutations may exert pathogenetic effects by altering tissue mechanics.

EUFOREUM Berlin 2023: Optimizing care for type 2 inflammatory diseases from clinic to AI: A pediatric focus.

The European Forum for Research and Education in Allergy and Airways diseases (EUFOREA) organized its bi-annual forum EUFOREUM in Berlin in November 2023. The aim of EUFOREUM 2023 was to highlight pediatric action plans for prevention and optimizing care for type 2 inflammatory conditions starting in childhood, with a focus on early-stage diagnosis, ensuring neither under- nor overdiagnosis, optimal care, and suggestions for improvement of care. EUFOREA is an international not-for-profit organization forming an alliance of all stakeholders dedicated to reducing the prevalence and burden of chronic respiratory diseases through the implementation of optimal patient care via educational, research, and advocacy activities. The inclusive and multidisciplinary approach of EUFOREA was reflected in the keynote lectures and faculty of the virtual EUFOREUM 2023 (www.euforea.eu/euforeum) coming from the pediatric, allergology, pulmonology, ENT, dermatology, primary health care fields and patients around the central theme of type 2 inflammation. As most type 2 inflammatory conditions may start in childhood or adolescence, and most children have type 2 inflammation when suffering from a respiratory or skin disease, the moment has come to raise the bar of ambitions of care, including prevention, remission and disease modification at an early stage. The current report provides a comprehensive overview of key statements by the faculty of the EUFOREUM 2023 and the ambitions of EUFOREA allowing all stakeholders in the respiratory field to be updated and ready to join forces in Europe and beyond.

Are Middle- or Older-Aged Adults With a Spinal Cord Injury Engaging in Leisure-Time Physical Activity? A Systematic Review and Meta-Analysis.

Objectives: To investigate the amount of Leisure-Time Physical Activity (LTPA) that people over 45 years with a spinal cord injury (SCI) performed and to determine the frequency, duration, intensity, and modality of LTPA performed. Data Sources: We searched 5 major electronic databases (CINAHL, SCOPUS, EMBASE, MEDLINE, and PubMed) from inception to March 2023. Study Selection: Cross-sectional, longitudinal studies and control arm of controlled trials that assessed LTPA in participants over 45 years old, with a SCI. We included 19 studies in the review and 11 in the meta-analysis. Data Extraction: We followed the PRISMA checklist for Systematic Reviews. Two review authors independently assessed the risk of bias and extracted data on participants' demographics, injury characteristics, and LTPA participation of the included studies. Risk of bias was assessed using the Joanne Briggs Institute critical appraisal tool for cross-sectional studies. Any conflicts were resolved by a third author. Data Synthesis: We found considerable variability in LTPA participation in adults 45 years and older with SCI. An estimated 27%-64% of participants did not take part in any LTPA. A random effects meta-analysis model was completed for studies that reported total or moderate-to-heavy LTPA scores in minutes per week. Overall, participants (n=1675) engaged in 260 [205;329] (mean [95% CI]) mins/week of total LTPA. Those participating in moderate-heavy intensity LTPA (n=364) completed 173 [118; 255] (mean [95% CI]) mins/week. LTPA modalities included walking, wheeling, hand-cycling, basketball, and swimming, among others. Conclusions: While many older adults with SCI seem to be meeting the recommended weekly physical activity volume, many still remain sedentary. There was significant variation in reporting of frequency, intensity, and duration of LTPA and reporting on modality was limited. Because of differences in reporting, it was challenging to compare results across studies. Data constraints prevented subgroup analysis of LTPA disparities between paraplegia and tetraplegia.

Rexinoids Induce Differential Gene Expression in Human Glioblastoma Cells and Protein-Protein Interactions in a Yeast Two-Hybrid System.

Rexinoids are compounds that bind to the rexinoid X receptor (RXR) to modulate gene expression and have been proposed as a new class of therapeutics to treat Alzheimer's disease. Different rexinoids will initiate downstream effects that can be quite marked even though such compounds can be structurally similar and have comparable RXR binding affinities. RXR can both homo- and heterodimerize, and these protein-protein interactions and subsequent transactivating potential lead to differential gene expression, depending on the RXR dimeric partner, additional cofactors recruited, and downstream transcription factors that are up- or downregulated. Expression analysis was performed in the U87 human glioblastoma cell line treated with a panel of rexinoids, and our analysis demonstrated that rexinoids with similar RXR EC50 values can have pronounced differences in differential gene expression. Rexinoid binding likely leads to distinctive RXR conformations that cause major downstream gene expression alterations via modulation of RXR interacting proteins. Yeast two-hybrid analysis of RXR bait with two RXR interacting partners demonstrates that rexinoids drive differential binding of RXR to distinctive protein partners. Physiochemical analysis of the rexinoids reveals that the molecules cluster similarly to their gene expression patterns. Thus, rexinoids with similar RXR binding affinities drive differential gene expression by stimulating additional binding patterns in RXR and its homo- and heteropartners, driven by the physicochemical characteristics of these molecules.

Microphthalmia with multiple ocular abnormalities in a foal.

OBJECTIVE: The aim of this report was to provide a clinical description and clinical, ultrasonographic, and histologic images of a foal with microphthalmia and multiple ocular abnormalities. ANIMALS STUDIED: A 12-h old Friesian-American Paint Horse crossbred filly presented for blindness, microphthalmia and marked ventral strabismus in both eyes. PROCEDURE: A complete ophthalmic examination was performed. Ultrasound biomicroscopy and B-mode ultrasonography were performed. The globes were submitted for histopathology. RESULTS: Ultrasound biomicroscopy demonstrated a hyperechoic cornea void of the typical epithelium, stroma, and Descemet's membrane layers. The anterior chamber was spanned by thick strands of hyperechoic tissue extending from the iris to the cornea. The lens was not visualized. B-mode ultrasound showed aphakia and mild, mottled echogenicity within the vitreous with no evidence of retinal detachment. On histopathology, both globes were microphthalmic with poorly defined corneal tissue. The anterior chambers were poorly formed and contained lacrimal glandular tissue. Portions of iridal tissue were present, but no lenses were noted. The retinas were segmentally detached and markedly atrophied with areas of retina dysplasia noted. CONCLUSIONS: This report provides a clinical, ultrasonographic and histologic description of a rare, congenital condition in a foal characterized by microphthalmia, aphakia, poorly defined corneal tissue, choristomatous differentiation of the anterior segment and retinal dysplasia.

Phospholyl and Arsolyl Triple-Decker Sandwich Complexes of Europium(II) and Strontium(II).

To study the influence of heteroatoms on the photophysical properties of divalent Eu and Sr complexes, the synthesis of the phospholyl and arsolyl compounds [{(Dtp)(thf)M}2{µ-η8:η8-C8H8}] (M = EuII and SrII; Dtp = 3,4-dimethyl-2,5-bis(tert-butyl)phospholyl) and [{(Dtas)(thf)M}2{µ-η8:η8-C8H8}] (M = EuII and SrII; Dtas = 3,4-dimethyl-2,5-bis(tert-butyl)arsolyl) is reported. Organometallic compounds of divalent europium with P and As heterocyclic ligands have not been described previously. They were prepared by salt elimination reactions from potassium phospholyl or arsolyl, K2C8H8, and EuI2(thf)2 or SrI2. Photophysical properties were investigated alongside a reference cyclopentadienyl complex with a comparable structure. Critically, the influence of the heteroatom on the photoluminescence emission and excitation and quantum yields of the complexes is significant. Density functional theory calculations were performed to rationalize the ligand influences.

Fine-scale maps of malaria incidence to inform risk stratification in Laos.

BACKGROUND: Malaria risk maps are crucial for controlling and eliminating malaria by identifying areas of varying transmission risk. In the Greater Mekong Subregion, these maps guide interventions and resource allocation. This article focuses on analysing changes in malaria transmission and developing fine-scale risk maps using five years of routine surveillance data in Laos (2017-2021). The study employed data from 1160 geolocated health facilities in Laos, along with high-resolution environmental data. METHODS: A Bayesian geostatistical framework incorporating population data and treatment-seeking propensity was developed. The models incorporated static and dynamic factors and accounted for spatial heterogeneity. RESULTS: Results showed a significant decline in malaria cases in Laos over the five-year period and a shift in transmission patterns. While the north became malaria-free, the south experienced ongoing transmission with sporadic outbreaks. CONCLUSION: The risk maps provided insights into changing transmission patterns and supported risk stratification. These risk maps are valuable tools for malaria control in Laos, aiding resource allocation, identifying intervention gaps, and raising public awareness. The study enhances understanding of malaria transmission dynamics and facilitates evidence-based decision-making for targeted interventions in high-risk areas.

Population differentiation and dynamics of five pioneer species of Gaultheria from the secondary forests in subtropical China.

BACKGROUND: The influence of native secondary succession associated with anthropogenic disturbance on the biodiversity of the forests in subtropical China remains uncertain. In particular, the evolutionary response of small understory shrubs, particularly pioneer species inhabiting continuously disturbed habitats, to topographic heterogeneity and climate change is poorly understood. This study aimed to address this knowledge gap by focusing on the Gaultheria crenulata group, a clade of small pioneer shrubs in subtropical China. RESULTS: We examined the genetic structure and demographic history of all five species of the G. crenulata group with two maternally inherited chloroplast DNA (cpDNA) fragments and two biparentally inherited low-copy nuclear genes (LCG) over 89 natural populations. We found that the genetic differentiation of this group was influenced by the geomorphological boundary between different regions of China in association with Quaternary climatic events. Despite low overall genetic diversity, we observed an isolation-by-distance (IBD) pattern at a regional scale, rather than isolation-by-environment (IBE), which was attributed to ongoing human disturbance in the region. CONCLUSION: Our findings suggest that the genetic structure of the G. crenulata group reflects the interplay of geological topography, historical climates, and anthropogenic disturbance during the Pliocene-Pleistocene-Holocene periods in subtropical China. The observed IBD pattern, particularly prominent in western China, highlights the role of limited dispersal and gene flow, possibly influenced by physical barriers or decreased connectivity over geographic distance. Furthermore, the east-to-west trend of gene flow, potentially facilitated by the East Asian monsoon system, underscores the complex interplay of biotic and abiotic factors shaping the genetic dynamics of pioneer species in subtropical China's secondary forests. These findings can be used to assess the impact of environmental changes on the adaptation and persistence of biodiversity in subtropical forest ecosystems.

Depicting deterministic variables within directed acyclic graphs (DAGs): An aid for identifying and interpreting causal effects involving derived variables and compositional data.

Deterministic variables are variables that are functionally determined by one or more parent variables. They commonly arise when a variable has been functionally created from one or more parent variables, as with derived variables, and in compositional data, where the 'whole' variable is determined from its 'parts'. This article introduces how deterministic variables may be depicted within directed acyclic graphs (DAGs) to help with identifying and interpreting causal effects involving derived variables and/or compositional data. We propose a two-step approach in which all variables are initially considered, and a choice is made whether to focus on the deterministic variable or its determining parents. Depicting deterministic variables within DAGs brings several benefits. It is easier to identify and avoid misinterpreting tautological associations, i.e., self-fulfilling associations between deterministic variables and their parents, or between sibling variables with shared parents. In compositional data, it is easier to understand the consequences of conditioning on the 'whole' variable, and correctly identify total and relative causal effects. For derived variables, it encourages greater consideration of the target estimand and greater scrutiny of the consistency and exchangeability assumptions. DAGs with deterministic variables are a useful aid for planning and interpreting analyses involving derived variables and/or compositional data.

Adaptive selection at G6PD and disparities in diabetes complications.

Diabetes complications occur at higher rates in individuals of African ancestry. Glucose-6-phosphate dehydrogenase deficiency (G6PDdef), common in some African populations, confers malaria resistance, and reduces hemoglobin A1c (HbA1c) levels by shortening erythrocyte lifespan. In a combined-ancestry genome-wide association study of diabetic retinopathy, we identified nine loci including a G6PDdef causal variant, rs1050828 -T (Val98Met), which was also associated with increased risk of other diabetes complications. The effect of rs1050828 -T on retinopathy was fully mediated by glucose levels. In the years preceding diabetes diagnosis and insulin prescription, glucose levels were significantly higher and HbA1c significantly lower in those with versus without G6PDdef. In the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial, participants with G6PDdef had significantly higher hazards of incident retinopathy and neuropathy. At the same HbA1c levels, G6PDdef participants in both ACCORD and the Million Veteran Program had significantly increased risk of retinopathy. We estimate that 12% and 9% of diabetic retinopathy and neuropathy cases, respectively, in participants of African ancestry are due to this exposure. Across continentally defined ancestral populations, the differences in frequency of rs1050828 -T and other G6PDdef alleles contribute to disparities in diabetes complications. Diabetes management guided by glucose or potentially genotype-adjusted HbA1c levels could lead to more timely diagnoses and appropriate intensification of therapy, decreasing the risk of diabetes complications in patients with G6PDdef alleles.

Characteristics and Outcome in Cardiogenic Shock according to Vascular Access Site for PCI.

BACKGROUND: The optimal vascular access site for percutaneous coronary interventions (PCI) in patients with acute myocardial infarction (AMI) complicated by cardiogenic shock (CS) remains uncertain. While observational data favor transradial access (TRA) due to lower complication rates and mortality, transfemoral (TFA) PCI offers advantages such as shorter access and procedure times, along with quicker escalation to mechanical circulatory support (MCS). In this study, we aimed to investigate factors associated with a transfemoral approach and compare mortality rates between TRA and TFA in AMI-CS patients undergoing PCI. METHODS: Data from a nationwide registry of AMI-CS patients undergoing PCI (2017-2021) were analyzed. We compared patient demographics, procedural details, and outcomes between TRA and TFA groups. Logistic regression identified access site factors and radial-to-femoral cross-over predictors. Propensity score matched (PSM) analysis examined the impact of access site on mortality. RESULTS: Of 1562 patients, 45% underwent TRA PCI, with an increasing trend over time. TFA patients were more often female, had a history of coronary artery bypass grafting (CABG), lower blood pressure, higher resuscitation and intubation rates, and elevated lactate levels. After PSM, 30-day mortality was lower in TRA (33% vs. 46%, p <0.001). Predictors for cross-over included left coronary artery interventions, multivessel PCI, and MCS initiation. CONCLUSION: Significant differences exist between TRA and TFA PCI in AMI-CS. TFA was more common in patients with worse hemodynamics and was associated with higher 30-day mortality compared to TRA. This mortality difference persisted in the propensity score matched analysis.

Mechanistic insights into G-protein coupling with an agonist-bound G-protein-coupled receptor.

G-protein-coupled receptors (GPCRs) activate heterotrimeric G proteins by promoting guanine nucleotide exchange. Here, we investigate the coupling of G proteins with GPCRs and describe the events that ultimately lead to the ejection of GDP from its binding pocket in the Gα subunit, the rate-limiting step during G-protein activation. Using molecular dynamics simulations, we investigate the temporal progression of structural rearrangements of GDP-bound Gs protein (Gs·GDP; hereafter GsGDP) upon coupling to the ß2-adrenergic receptor (ß2AR) in atomic detail. The binding of GsGDP to the ß2AR is followed by long-range allosteric effects that significantly reduce the energy needed for GDP release: the opening of α1-αF helices, the displacement of the αG helix and the opening of the α-helical domain. Signal propagation to the Gs occurs through an extended receptor interface, including a lysine-rich motif at the intracellular end of a kinked transmembrane helix 6, which was confirmed by site-directed mutagenesis and functional assays. From this ß2AR-GsGDP intermediate, Gs undergoes an in-plane rotation along the receptor axis to approach the ß2AR-Gsempty state. The simulations shed light on how the structural elements at the receptor-G-protein interface may interact to transmit the signal over 30 Å to the nucleotide-binding site. Our analysis extends the current limited view of nucleotide-free snapshots to include additional states and structural features responsible for signaling and G-protein coupling specificity.

Dose-Related Visual Outcomes in the Treatment of Choroidal Melanoma with Stereotactic Radiotherapy.

Introduction: Stereotactic radiotherapy (SRT) in the treatment of choroidal melanoma (CM) may be indicated if the tumour is located close to the optic nerve or is unsuitable for a radiotherapeutic plaque. It is thought that the rate of visual decline and ocular sequelae with SRT is influenced by dose and location of radiation in relation to important visual structures. This study therefore aimed to look at these prognoses with respect to localisation and dose of radiation when treatment of CM with SRT occurs. Methods: A retrospective data analysis was conducted on all patients at Dunedin Hospital (DH) from August 2001 to May 2017 who were followed up for 4 years. SRT consisted of 50 Gy divided into five fractions over 5 days to tumours, with 2-mm treatment margins. The primary outcome measure was retention of functional vision - better than hand movements (HMs) within the treated eye. Secondary outcome measures included time to non-functional vision (HM or less) in relation to location, dose and tumour thickness, the presence of radiation retinopathy, local and metastatic tumour progression, enucleation, and disease-specific mortality. Results: Seventy-five patients were identified in this study. Follow-up was incomplete in 10 patients, and 4 patients became deceased within the 4-year study period. Twenty-nine patients (48%) retained visual acuity (VA) better than HMs in the treated eye at 4 years, and thirty-two (52%) of patients did not. Calculated dose to the optic nerve and macula and proximity of the tumour to the optic nerve and macula were not statistically determinative of vision outcomes, although presenting VA was. Fifty-six per cent of patients developed radiation retinopathy involving the macula. The local progression, metastatic progression and enucleation rates were 4.6%, 6%, and 12.3%, representing 3, 4, and 8 patients, respectively. Conclusion: This study demonstrates that approximately half of patients treated with SRT can expect to maintain functional vision better than HM at 4 years. The rate of visual decline and final vision outcome are independent of location of the tumour in relation to the optic nerve and macula. While it affirms that SRT achieves high rates of local tumour control and eye retention, preservation of functional VA remains an unpredictable endpoint for individual cases and highlights the therapeutic challenge of this treatment modality.

Environmental and genetic regulation of Streptococcus pneumoniae galactose catabolic pathways.

Efficient utilization of nutrients is crucial for microbial survival and virulence. The same nutrient may be utilized by multiple catabolic pathways, indicating that the physical and chemical environments for induction as well as their functional roles may differ. Here, we study the tagatose and Leloir pathways for galactose catabolism of the human pathogen Streptococcus pneumoniae. We show that galactose utilization potentiates pneumococcal virulence, the induction of galactose catabolic pathways is influenced differentially by the concentration of galactose and temperature, and sialic acid downregulates galactose catabolism. Furthermore, the genetic regulation and in vivo induction of each pathway differ, and both galactose catabolic pathways can be turned off with a galactose analogue in a substrate-specific manner, indicating that galactose catabolic pathways can be potential drug targets.

Improving Clinician Performance in Classifying EEG Patterns on the Ictal-Interictal Injury Continuum Using Interpretable Machine Learning.

BACKGROUND: In intensive care units (ICUs), critically ill patients are monitored with electroencephalography (EEG) to prevent serious brain injury. EEG monitoring is constrained by clinician availability, and EEG interpretation can be subjective and prone to interobserver variability. Automated deep-learning systems for EEG could reduce human bias and accelerate the diagnostic process. However, existing uninterpretable (black-box) deep-learning models are untrustworthy, difficult to troubleshoot, and lack accountability in real-world applications, leading to a lack of both trust and adoption by clinicians. METHODS: We developed an interpretable deep-learning system that accurately classifies six patterns of potentially harmful EEG activity - seizure, lateralized periodic discharges (LPDs), generalized periodic discharges (GPDs), lateralized rhythmic delta activity (LRDA), generalized rhythmic delta activity (GRDA), and other patterns - while providing faithful case-based explanations of its predictions. The model was trained on 50,697 total 50-second continuous EEG samples collected from 2711 patients in the ICU between July 2006 and March 2020 at Massachusetts General Hospital. EEG samples were labeled as one of the six EEG patterns by 124 domain experts and trained annotators. To evaluate the model, we asked eight medical professionals with relevant backgrounds to classify 100 EEG samples into the six pattern categories - once with and once without artificial intelligence (AI) assistance - and we assessed the assistive power of this interpretable system by comparing the diagnostic accuracy of the two methods. The model's discriminatory performance was evaluated with area under the receiver-operating characteristic curve (AUROC) and area under the precision-recall curve. The model's interpretability was measured with task-specific neighborhood agreement statistics that interrogated the similarities of samples and features. In a separate analysis, the latent space of the neural network was visualized by using dimension reduction techniques to examine whether the ictal-interictal injury continuum hypothesis, which asserts that seizures and seizure-like patterns of brain activity lie along a spectrum, is supported by data. RESULTS: The performance of all users significantly improved when provided with AI assistance. Mean user diagnostic accuracy improved from 47 to 71% (P<0.04). The model achieved AUROCs of 0.87, 0.93, 0.96, 0.92, 0.93, and 0.80 for the classes seizure, LPD, GPD, LRDA, GRDA, and other patterns, respectively. This performance was significantly higher than that of a corresponding uninterpretable black-box model (with P<0.0001). Videos traversing the ictal-interictal injury manifold from dimension reduction (a two-dimensional representation of the original high-dimensional feature space) give insight into the layout of EEG patterns within the network's latent space and illuminate relationships between EEG patterns that were previously hypothesized but had not yet been shown explicitly. These results indicate that the ictal-interictal injury continuum hypothesis is supported by data. CONCLUSIONS: Users showed significant pattern classification accuracy improvement with the assistance of this interpretable deep-learning model. The interpretable design facilitates effective human-AI collaboration; this system may improve diagnosis and patient care in clinical settings. The model may also provide a better understanding of how EEG patterns relate to each other along the ictal-interictal injury continuum. (Funded by the National Science Foundation, National Institutes of Health, and others.).

Reactivities of phosphaalkynes towards diverse bis-silylenes.

Bis-silylenes do not only act as strong chelating σ-donor ligands, but also exhibit cooperative behaviour in the activation of small molecules. Three different P-Si containing molecules were prepared from the reaction between tBuCP and different bis-silylenes, which are bridged by ferrocenediyl, diaminobenzene, or o-carborane.

Geospatial joint modeling of vector and parasite serology to microstratify malaria transmission.

The World Health Organization identifies a strong surveillance system for malaria and its mosquito vector as an essential pillar of the malaria elimination agenda. Anopheles salivary antibodies are emerging biomarkers of exposure to mosquito bites that potentially overcome sensitivity and logistical constraints of traditional entomological surveys. Using samples collected by a village health volunteer network in 104 villages in Southeast Myanmar during routine surveillance, the present study employs a Bayesian geostatistical modeling framework, incorporating climatic and environmental variables together with Anopheles salivary antigen serology, to generate spatially continuous predictive maps of Anopheles biting exposure. Our maps quantify fine-scale spatial and temporal heterogeneity in Anopheles salivary antibody seroprevalence (ranging from 9 to 99%) that serves as a proxy of exposure to Anopheles bites and advances current static maps of only Anopheles occurrence. We also developed an innovative framework to perform surveillance of malaria transmission. By incorporating antibodies against the vector and the transmissible form of malaria (sporozoite) in a joint Bayesian geostatistical model, we predict several foci of ongoing transmission. In our study, we demonstrate that antibodies specific for Anopheles salivary and sporozoite antigens are a logistically feasible metric with which to quantify and characterize heterogeneity in exposure to vector bites and malaria transmission. These approaches could readily be scaled up into existing village health volunteer surveillance networks to identify foci of residual malaria transmission, which could be targeted with supplementary interventions to accelerate progress toward elimination.

Involvement of Endolysosomes and Aurora Kinase A in the Regulation of Amyloid ß Protein Levels in Neurons.

Aurora kinase A (AURKA) is a serine/threonine-protein kinase that regulates microtubule organization during neuron migration and neurite formation. Decreased activity of AURKA was found in Alzheimer's disease (AD) brain samples, but little is known about the role of AURKA in AD pathogenesis. Here, we demonstrate that AURKA is expressed in primary cultured rat neurons, neurons from adult mouse brains, and neurons in postmortem human AD brains. AURKA phosphorylation, which positively correlates with its activity, is reduced in human AD brains. In SH-SY5Y cells, pharmacological activation of AURKA increased AURKA phosphorylation, acidified endolysosomes, decreased the activity of amyloid beta protein (Aß) generating enzyme ß-site amyloid precursor protein cleaving enzyme (BACE-1), increased the activity of the Aß degrading enzyme cathepsin D, and decreased the intracellular and secreted levels of Aß. Conversely, pharmacological inhibition of AURKA decreased AURKA phosphorylation, de-acidified endolysosomes, decreased the activity of cathepsin D, and increased intracellular and secreted levels of Aß. Thus, reduced AURKA activity in AD may contribute to the development of intraneuronal accumulations of Aß and extracellular amyloid plaque formation.