Search

High-throughput Structural Genomics yields many new protein structures without known molecular function. This study aims to uncover these missing annotations by globally comparing select functional residues across the structural proteome. First, Evolutionary Trace Annotation, or ETA, identifies which proteins have local evolutionary and structural features in common; next, these proteins are linked together into a proteomic network of ETA similarities; then, starting from proteins with known functions, competing functional labels diffuse link-by-link over the entire network. Every node is thus assigned a likelihood z-score for every function, and the most significant one at each node wins and defines its annotation. In high-throughput controls, this competitive diffusion process recovered enzyme activity annotations with 99% and 97% accuracy at half-coverage for the third and fourth Enzyme Commission (EC) levels, respectively. This corresponds to false positive rates 4-fold lower than nearest-neighbor and 5-fold lower than sequence-based annotations. In practice, experimental validation of the predicted carboxylesterase activity in a protein from Staphylococcus aureus illustrated the effectiveness of this approach in the context of an increasingly drug-resistant microbe. This study further links molecular function to a small number of evolutionarily important residues recognizable by Evolutionary Tracing and it points to the specificity and sensitivity of functional annotation by competitive global network diffusion. A web server is at http://mammoth.bcm.tmc.edu/networks.

Background: Among diarrheal children, injudicious use of antibiotics is a major public health concern particularly in low- and middle-income countries. There are evidence-based guidelines by the World Health Organization (WHO) to prescribe antibiotics for bloody diarrhea in children. There is a scarcity of published data regarding the judicious use of antibiotics for bloody diarrhea in children. So, we aimed to evaluate the presenting features of bloody diarrhea at hospital with prior antibiotic use at home and the prevalence of injudicious antibiotic use for bloody diarrhea in children., Methods: We screened 7,289 children aged 24-59 months with diarrhea (≥3 loose stools in the last 24 h) at Dhaka Hospital, International Centre for Diarrheal Disease Research, Bangladesh (icddr,b), from December 5, 2021 to February 16, 2023. Antibiotic intake at home due to current diarrheal illness was evaluated and confirmed by direct observation of a prescription, the bottle of antibiotics, or asking the caregiver about the name of antibiotics., Results: Out of 7,289 children presented with diarrhea, 3,823 (52.45%) children consumed antibiotics before visiting hospital. 254 (3.48%) children presented with bloody diarrhea, among which 162 ingested antibiotics. Among 162 children, 88 (54.32%) received inappropriate antibiotics due to bloody diarrhea, according to the WHO guidelines. The most prevalent single antibiotic consumed in bloody diarrhea was metronidazole (n = 45, 27.78%), followed by ciprofloxacin (n = 39, 24.07%) and azithromycin (n = 32, 19.75%). After adjusting for relevant covariates like age, sex, presence of straining/tenesmus, fever during admission, history of cough, stunting, wasting, and underweight; children suffering from bloody diarrhea had 1.55 times higher odds of using metronidazole alone or in combination with other antibiotics (aOR:1.55, 95% CI: 1.10-2.19, p-value = 0.012) and 1.93 times higher odds of using multiple antibiotics (aOR:1.93, 95% CI: 1.23-3.02, p-value = 0.004) compared to children with non-bloody diarrhea., Conclusion: The study underscores the excessive use of antimicrobials among children with diarrheal illnesses. It is also evident that metronidazole use and multiple antibiotic use are increasing among children due to bloody diarrhea, which is alarming and calls for antibiotic stewardship by regulating bodies in the country., Competing Interests: The authors declare that they have no competing interests other than Amy Newlands, who is an employee of GSK and owns shares in it. This does not alter our adherence to PLOS ONE policies on sharing data and materials., (Copyright: © 2024 Bashar et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background/aim: Obesity and related metabolic abnormalities in adults are associated with peripheral neuropathy. Acanthosis nigricans (AN) is associated with insulin resistance, fatty liver, hyperlipidemia and glucose intolerance, all of which are risk factors for neuropathy. The aim of this study was to investigate if obese adolescents with AN have evidence of small nerve fiber damage., Material and Methods: Adolescents with obesity with and without AN underwent body composition analysis, assessment of vibration perception threshold (VPT), monofilament sensitivity and corneal confocal microscopy (CCM) to quantify corneal nerve fiber density (CNFD), branch density (CNBD), length (CNFL) and inferior whorl length (IWL)., Results: Forty-six participants with obesity with (n = 31) and without (n = 15) AN aged 15(14-17) years were compared to 20 healthy controls aged 13(12-14) years. There was no difference in VPT, monofilament sensitivity and CCM measures between adolescents with obesity and controls. However, adolescents with AN had a significantly higher weight (P = 0.022), fat% (P = 0.029) and fat-muscle ratio (P = 0.012) with a lower CNFD (P = 0.045) compared to those with obesity without AN., Conclusion: Adolescents with obesity and acanthosis nigricans have a higher fat mass and small nerve fibre loss, indicative of a sub-clinical neuropathy., Competing Interests: NO authors have competing interests., (Copyright: © 2024 Gad et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Anomaly detection in time series data is essential for fraud detection and intrusion monitoring applications. However, it poses challenges due to data complexity and high dimensionality. Industrial applications struggle to process high-dimensional, complex data streams in real time despite existing solutions. This study introduces deep ensemble models to improve traditional time series analysis and anomaly detection methods. Recurrent Neural Networks (RNNs) and Long Short-Term Memory (LSTM) networks effectively handle variable-length sequences and capture long-term relationships. Convolutional Neural Networks (CNNs) are also investigated, especially for univariate or multivariate time series forecasting. The Transformer, an architecture based on Artificial Neural Networks (ANN), has demonstrated promising results in various applications, including time series prediction and anomaly detection. Graph Neural Networks (GNNs) identify time series anomalies by capturing temporal connections and interdependencies between periods, leveraging the underlying graph structure of time series data. A novel feature selection approach is proposed to address challenges posed by high-dimensional data, improving anomaly detection by selecting different or more critical features from the data. This approach outperforms previous techniques in several aspects. Overall, this research introduces state-of-the-art algorithms for anomaly detection in time series data, offering advancements in real-time processing and decision-making across various industrial sectors., Competing Interests: The author have declared that no competing interest exit., (Copyright: © 2024 Iqbal et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Depression is a serious mental health disorder affecting millions of individuals worldwide. Timely and precise recognition of depression is vital for appropriate mediation and effective treatment. Electroencephalography (EEG) has surfaced as a promising tool for inspecting the neural correlates of depression and therefore, has the potential to contribute to the diagnosis of depression effectively. This study presents an EEG-based mental depressive disorder detection mechanism using a publicly available EEG dataset called Multi-modal Open Dataset for Mental-disorder Analysis (MODMA). This study uses EEG data acquired from 55 participants using 3 electrodes in the resting-state condition. Twelve temporal domain features are extracted from the EEG data by creating a non-overlapping window of 10 seconds, which is presented to a novel feature selection mechanism. The feature selection algorithm selects the optimum chunk of attributes with the highest discriminative power to classify the mental depressive disorders patients and healthy controls. The selected EEG attributes are classified using three different classification algorithms i.e., Best- First (BF) Tree, k-nearest neighbor (KNN), and AdaBoost. The highest classification accuracy of 96.36% is achieved using BF-Tree using a feature vector length of 12. The proposed mental depressive classification scheme outperforms the existing state-of-the-art depression classification schemes in terms of the number of electrodes used for EEG recording, feature vector length, and the achieved classification accuracy. The proposed framework could be used in psychiatric settings, providing valuable support to psychiatrists., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Khan et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Large carnivores face numerous threats, including habitat loss and fragmentation, direct killing, and prey depletion, leading to significant global range and population declines. Despite such threats, leopards (Panthera pardus) persist outside protected areas throughout most of their range, occupying diverse habitat types and land uses, including peri-urban and rural areas. Understanding of leopard population dynamics in mixed-use landscapes is limited, especially in South Africa, where the majority of leopard research has focused on protected areas. We use spatially explicit capture-recapture models to estimate leopard density across a mixed-use landscape of protected areas, farmland, and urban areas in the Overberg region of the Western Cape, South Africa. Data from 86 paired camera stations provided 221 independent captures of 25 leopards at 50 camera trap stations with a population density estimate of 0.64 leopards per 100 km2 (95% CI: 0.55-0.73). Elevation, terrain ruggedness, and vegetation productivity were important drivers of leopard density in the landscape, being highest on elevated remnants of natural land outside of protected areas. These results are similar to previous research findings in other parts of the Western Cape, where high-lying natural vegetation was shown to serve as both a refuge and a corridor for leopard movement in otherwise transformed landscapes. Given the low leopard density and the prevalence of transformed land intermixed with patches of more suitable leopard habitat, prioritising and preserving connectivity for leopards is vital in this shared landscape. Ecological corridors should be developed in partnership with private landowners through an inclusive and multifaceted conservation strategy which also incorporates monitoring of and rapid mitigation of emerging threats to leopards., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Hinde et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Introduction: Our study aimed to evaluate whether assessing α-synuclein expression levels in blood samples could provide a reliable and straightforward alternative to existing diagnostic and prognostic methods for neurodegenerative disorders, including multiple sclerosis (MS). We specifically investigated if α-synuclein and IL-6 expression levels from serum and peripheral blood mononuclear cells (PBMCs) could accurately predict MS severity in patients using a two-dimensional approach., Methods: We designed a case-control study to analyze the expression of α-synuclein and IL-6 in the peripheral blood of an MS patient group (n = 51) and a control group (n = 51). We statistically evaluated the PBMCs and serum profiles of α-synuclein and IL-6 in MS patients, along with their age of onset, disease duration, tobacco exposure, and Expanded Disability Status Scale (EDSS) score, using SPSS V22.0 software and GraphPad Prism V9.0., Results: Our findings indicate that α-synuclein production was significantly downregulated in MS patients. Principal component analysis also revealed distinct profiles between MS patients and controls. PBMCs and serum profiles of α-synuclein correlated with the EDSS score, suggesting that disease severity can be predicted using α-synuclein profiles. Moreover, α-synuclein showed a significant correlation with IL-6 and age of onset. Lastly, receiver operating characteristic curves of PBMCs and serum activity of α-synuclein profiles displayed discrimination with area under the curve values of 0.856 and 0.705, respectively., Conclusion: Our results imply that measuring α-synuclein levels in both serum and PBMCs could be a valuable method for diagnosing and predicting MS severity, potentially serving as a non-invasive biomarker for the disease., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Razia et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Globally, leopards are the most widespread large felid. However, mounting anthropogenic threats are rapidly reducing viable leopard populations and their range. Despite the clear pressures facing this species, there is a dearth of robust and reliable population and density estimates for leopards across their range, which is particularly important in landscapes that consist of protected and non-protected areas. We conducted a camera trapping survey between 2017 and 2018 in the Western Cape, South Africa to estimate the occupancy, density, and population size of a leopard population. Leopards were recorded at 95% of camera trapping sites, which resulted in a high occupancy that showed no significant variation between seasons, habitat types, or along an altitudinal gradient. Our results indicated a low leopard density in the study area, with an estimated 1.53 leopards/100 km2 in summer and 1.62 leopards/100 km2 in winter. Mean leopard population size was therefore estimated at 107 and 113 individuals in the winter and summer respectively. Leopard activity centres for female ranges were centred in the core study area and could be predicted with good certainty, while males appeared to move out of the study area during winter which resulted in a higher uncertainty in locations of activity centres. Interestingly, livestock depredation events in the surrounding farmlands were significantly higher in winter, which coincides with male leopards moving outside the core protected area into the surrounding farmlands. To reduce livestock losses and retaliatory leopard killings, we suggest that human-carnivore conflict mitigation measures be intensely monitored during the winter months in the study area. We also suggest that future leopard conservation efforts should focus on privately-owned land as these non-protected areas contain the majority of the remaining suitable leopard habitat and may provide important dispersal corridors and buffer zones on which the long-term sustainability of leopard populations depends., Competing Interests: The authors have declared that no competing interests exist.

Background: Xerosis cutis or dry skin is a highly prevalent dermatological disorder especially in the elderly and in patients with underlying health conditions. In the past decades, numerous molecular markers have been investigated for their association with the occurrence or severity of skin dryness. The aim of this review was to summarize the molecular markers used in xerosis cutis research and to describe possible associations with different dry skin etiologies., Methods: We conducted a systematic review of molecular markers of xerosis cutis caused by internal or systemic changes. References published between 1990 and September 2020 were searched using 'MEDLINE', 'EMBASE' and 'Biological abstracts' databases. Study results were summarized and analyzed descriptively. The review protocol was registered in PROSPERO database (CRD42020214173)., Results: A total of 21 study reports describing 72 molecules were identified including lipids, natural moisturizing factors (NMFs), proteins including cytokines and metabolites or metabolic products. Most frequently reported markers were ceramides, total free fatty acids, triglycerides and selected components of NMFs. Thirty-one markers were reported only once. Although, associations of these molecular markers with skin dryness were described, reports of unclear and/or no association were also frequent for nearly every marker., Conclusion: An unexpectedly high number of various molecules to quantify xerosis cutis was found. There is substantial heterogeneity regarding molecular marker selection, tissue sampling and laboratory analyses. Empirical evidence is also heterogeneous regarding possible associations with dry skin. Total free fatty acids, total ceramide, ceramide (NP), ceramide (NS), triglyceride, total free amino acids and serine seem to be relevant, but the association with dry skin is inconsistent. Although the quantification of molecular markers plays an important role in characterizing biological processes, pathogenic processes or pharmacologic responses, it is currently unclear which molecules work best in xerosis cutis., Competing Interests: The authors have declared that no competing interests exist.

Background: Clinical practice guidelines (CPGs) are representative methods for promoting the standardization of healthcare and improvement of its quality. Few studies have investigated changes in the quality of CPGs published in a country over time. Our aim was to investigate changes in the quality of CPGs over time in the context of the available infrastructure for CPG development, public interest in healthcare quality, and healthcare providers' responses to this interest., Methods: All CPGs pertaining to evidence-based medicine (EBM) issued between 2000 and 2014 in Japan (n = 373) were evaluated using the Japanese version of the Appraisal of Guidelines for Research and Evaluation (AGREE) I. Additionally, time trends in quality were analyzed. Using a cut-off point based on the publication year of CPG development literature, the evaluated CPGs were classified into those published until 2008 (pre-2008) and those published since 2009 (post-2008). Subsequently, we compared these groups in terms of 1) first edition CPGs and its second editions, and 2) patients' version of CPGs., Results: Scores on all six domains of AGREE I improved each year. A comparison of the first- and second-edition of CPGs (n = 64) showed that scores on all domains improved significantly after revision. Significant improvement was observed in three domains (#2 stakeholder involvement, #3 rigor of development, and #4 clarity of presentation) in the pre-2008 group and in all domains in the post-2008 group. The comparison between the pre- and post-2008 groups in terms of CPGs for patients showed that the score increased in only one domain (#1 scope and purpose)., Conclusions: The number of published CPGs has been increasing and the quality of CPGs, as assessed using the AGREE I instrument, has been improving. These changes seem to be influenced by improvements in social infrastructure, such as the publication of CPG development procedures, availability of CPG preparation methodology training, and increase in CPG-related skills., Competing Interests: The authors have declared that no competing interests exist.

Background: Population trends of disease prevalence and incidence over time measure burden of disease and inform healthcare planning. Neuromuscular disorders (NMD) affect muscle and nerve function with varying degrees of severity and disease progression., Objective: Using health administrative databases we described trends in incidence, prevalence, and mortality of adults and children with NMD. We also explored place of death and use of palliative care., Methods: Population-based (Ontario, Canada) cohort study (2003 to 2014) of adults and children with NMD identified using International Classification of Disease and health insurance billing codes within administrative health databases., Results: Adult disease prevalence increased on average per year by 8% (95% confidence interval (CI) 6% to 10%, P <.001), with the largest increase in adults18-39 years. Childhood disease prevalence increased by 10% (95% CI 8% to 11%, P <.0001) per year, with the largest increase in children 0 to 5 years. Prevalence increased across all diagnoses except amyotrophic lateral sclerosis and spinal muscular atrophy for adults and all diagnoses for children. Adult incidence decreased by 3% (95% CI -4% to -2%, P <.0001) but incidence remained stable in children. Death occurred in 34,336 (18.5%) adults; 21,236 (61.8%) of whom received palliative care. Death occurred in 1,009 (5.6%) children; 507 (50.2%) of whom received palliative care. Mortality decreased over time in adults (odds ratio (OR) 0.86, 95% CI 0.86-0.87, P <.0001) and children (OR 0.79, 95% CI 0.76-0.82, P <.0001). Use of palliative care over time increased for adults (OR 1.18, 95% CI 1.09 to 1.28, P <.0001) and children (OR 1.22, 95% CI 1.20 to 1.23, P <.0001)., Conclusions: In both adults and children, NMD prevalence is rising and mortality rates are declining. In adults incidence is decreasing while in children it remains stable. This confirms on a population-based level the increased survival of children and adults with NMD., Competing Interests: The authors have declared that no competing interests exist.

Honokiol (poly-phenolic lignan from Magnolia grandiflora) is a Sirtuin-3 (SIRT3) activator which exhibit antioxidant activity and augment mitochondrial functions in several experimental models. Modern evidence suggests the critical role of SIRT3 in the progression of several metabolic and neurodegenerative diseases. Amyloid beta (Aβ), the precursor to extracellular senile plaques, accumulates in the brains of patients with Alzheimer's disease (AD) and is related to the development of cognitive impairment and neuronal cell death. Aβ is generated from amyloid-β precursor protein (APP) through sequential cleavages, first by β-secretase and then by γ-secretase. Drugs modulating this pathway are believed to be one of the most promising strategies for AD treatment. In the present study, we found that Honokiol significantly enhanced SIRT3 expression, reduced reactive oxygen species generation and lipid peroxidation, enhanced antioxidant activities, and mitochondrial function thereby reducing Aβ and sAPPβ levels in Chinese Hamster Ovarian (CHO) cells (carrying the amyloid precursor protein-APP and Presenilin PS1 mutation). Mechanistic studies revealed that Honokiol affects neither protein levels of APP nor α-secretase activity. In contrast, Honokiol increased the expression of AMPK, CREB, and PGC-1α, thereby inhibiting β-secretase activity leading to reduced Aβ levels. These results suggest that Honokiol is an activator of SIRT3 capable of improving antioxidant activity, mitochondrial energy regulation, while decreasing Aβ, thereby indicating it to be a lead compound for AD drug development.

Aims: To synthesise evidence from UK-based randomised trials of psycho-educational interventions in children and young people (CYP) with Type 1 Diabetes (T1D) to inform the evidence-base for adoption of such interventions into the NHS., Methods: We searched Medline, Embase, Cochrane, PsycINFO, CINAHL, and Web of Science up to March 2016. Two reviewers independently selected UK-based randomised trials comparing psycho-educational interventions for improving management of T1D for CYP with a control group of usual care or attention control. The main outcome was glycaemic control measured by percentage of glycated haemoglobin (HbA1c); secondary outcomes included psychosocial functioning, diabetes knowledge, adverse and other clinical outcomes. A narrative synthesis and meta-analysis were conducted. Pooled effect sizes of standardised mean difference (SMD) were calculated., Results: Ten eligible trials of three educational and seven psycho-educational interventions were identified. Most interventions were delivered by non-psychologists and targeted adolescents with more than one year duration of diabetes. Meta-analysis of nine of these trials (N = 1,838 participants) showed a non-significant reduction in HbA1c attributable to the intervention (pooled SMD = -0.06, 95% CI: -0.21 to 0.09). Psycho-educational interventions aiming to increase children's self-efficacy had a moderate, beneficial effect (SMD = 0.50, 95% CI: 0.13 to 0.87). No benefits on diabetes knowledge and other indicators of psychosocial functioning were identified., Conclusions: There is insufficient evidence to recommend the use of particular psycho-educational programme for CYP with T1D in the UK. Further trials with sufficient power and reporting standards are needed. Future trials could consider active involvement of psychological specialists in the delivery of psychologically informed interventions and implementation of psycho-educational interventions earlier in the course of the disease., Systematic Review Registration: PROSPERO CRD42015010701.

Multiple lines of evidence implicate the endocannabinoid signaling system in the modulation of metabolic disease. Genetic or pharmacological inactivation of CB1 in rodents leads to reduced body weight, resistance to diet-induced obesity, decreased intake of highly palatable food, and increased energy expenditure. Cannabinoid agonists stimulate feeding in rodents and increased levels of endocannabinoids can disrupt lipid metabolism. Therefore, the hypothesis that sustained endocannabinoid signaling can lead to obesity and diabetes was examined in this study using S426A/S430A mutant mice expressing a desensitization-resistant CB1 receptor. These mice display exaggerated and prolonged responses to acute administration of phytocannabinoids, synthetic cannabinoids, and endocannabinoids. As a consequence these mice represent a novel model for determining the effect of enhanced endocannabinoid signaling on metabolic disease. S426A/S430A mutants consumed equivalent amounts of both high fat (45%) and low fat (10%) chow control diet compared to wild-type littermate controls. S426A/S430A mutants and wild-type mice fed either high or low fat control diet displayed similar fasting blood glucose levels and normal glucose clearance following a 2 g/kg glucose challenge. Furthermore, S426A/S430A mutants and wild-type mice consumed similar amounts of chow following an overnight fast. While both THC and JZL195 significantly increased food intake two hours after injection, this increase was similar between the S426A/S430A mutant and wildtype control mice Our results indicate that S426A/S430A mutant mice expressing the desensitization-resistant form of CB1 do not exhibit differences in body weight, food intake, glucose homeostasis, or re-feeding following a fast.

Objective: Health related quality of life (HRQL) of children using medical technology at home is largely unknown. Our aim was to examine the HRQL in children on long-term ventilation at home (LTHV) in comparison to a cohort using an enterostomy tube., Study Design: Participants were divided into three groups: 1) LTHV without an enterostomy tube (LTHV cohort); 2) Enterostomy tube (GT cohort); 3) LTHV with an enterostomy tube (LTHV+GT cohort). Caregivers of children ≥ 5 years and followed at SickKids, Toronto, Canada, completed three questionnaires: Health Utilities Index 2/3 (HUI2/3), Caregiver Priorities Caregiver Health Index (CPCHILD), and the Paediatric Quality of Life Inventory (PedsQL). The primary outcome was the difference in utility (HUI2/3) scores between the cohorts., Results: One hundred and nineteen children were enrolled; 47 in the LTHV cohort, 44 in the GT cohort, and 28 in the LTHV+GT cohort. In univariate analysis, HUI2 mean (SE) scores were lowest for the GT cohort, 0.4 (0.04) followed by the LTHV+GT, 0.42 (0.05) and then the LTHV cohort, 0.7 (0.04), p = 0.001. A similar trend was seen for the HUI3 mean (SE) scores: GT cohort, 0.1 (0.06), followed by the LTHV +GT cohort, 0.2 (0.08) and then the LTHV cohort, 0.5 (0.06), p = 0.0001. Technology cohort, nursing hours and the severity of health care needs predicted HRQL as measured by the HUI2/3., Conclusion: The HRQL of these children is low. Children on LTHV had higher HRQL than children using enterostomy tubes. Further work is needed to identify modifiable factors that can improve HRQL.

Recent studies support a role for FGF23 and its co-receptor Klotho in cardiovascular pathology, yet the underlying mechanisms remain largely elusive. Herein, we analyzed the expression of Klotho in mouse arteries and generated a novel mouse model harboring a vascular smooth muscle cell specific deletion of Klotho (Sm22-KL(-/-) ). Arterial Klotho expression was detected at very low levels with quantitative real-time PCR; Klotho protein levels were undetectable by immunohistochemistry and Western blot. There was no difference in arterial Klotho between Sm22-KL(-/-) and wild-type mice, as well as no changes in serum markers of mineral metabolism. Intravenous delivery of FGF23 elicited a rise in renal (0.005; p<0.01) but not arterial Egr-1 expression, a marker of Klotho-dependent FGF23 signaling. Further, the impact of FGF23 on vascular calcification and endothelial response was evaluated in bovine vascular smooth muscle cells (bVSMC) and in a murine ex vivo model of endothelial function, respectively. FGF23 treatment (0.125-2 ng/mL) did not modify calcification in bVSMCs or dilatory, contractile and structural properties in mice arterial specimen ex vivo. Collectively, these results demonstrate that FGF23-Klotho signaling is absent in mouse arteries and that the vascular response was unaffected by FGF23 treatment. Thus, our data do not support Klotho-mediated FGF23 effects in the vasculature although confirmative studies in humans are warranted.

The Red List Index uses information from the IUCN Red List to track trends in the projected overall extinction risk of sets of species. It has been widely recognised as an important component of the suite of indicators needed to measure progress towards the international target of significantly reducing the rate of biodiversity loss by 2010. However, further application of the RLI (to non-avian taxa in particular) has revealed some shortcomings in the original formula and approach: It performs inappropriately when a value of zero is reached; RLI values are affected by the frequency of assessments; and newly evaluated species may introduce bias. Here we propose a revision to the formula, and recommend how it should be applied in order to overcome these shortcomings. Two additional advantages of the revisions are that assessment errors are not propagated through time, and the overall level extinction risk can be determined as well as trends in this over time.