Selective Agonism of Liver and Gut FXR Prevents Cholestasis and Intestinal Atrophy in Parenterally Fed Neonatal Pigs.

BACKGROUND & AIMS: We aimed to investigate the relative efficacy of feeding different bile acids in preventing PNALD in neonatal pigs. METHODS: Newborn pigs given total parenteral nutrition (TPN) combined with minimal enteral feeding of chenodeoxycholic acid (CDCA), or increasing doses of obeticholic acid (OCA) for 19 days. RESULTS: Enteral OCA (5 and 15 mg/kg), but not CDCA (30 mg/kg) reduced blood cholestasis markers compared to TPN controls and increased bile acids in the gallbladder and intestine. Major bile acids in the liver and distal intestine were CDCA, HCA, HDCA and OCA, and their relative proportions were increased by the type of bile acid (CDCA or OCA) given enterally. High doses of OCA increased the total NR1H4-agonistic bile acid profile in the liver and intestine above 50% total bile acids. Both CDCA and OCA treatments suppressed hepatic cyp7a1 expression, but only OCA increased hepatobiliary transporters, ABCB11, ABCC$ and ABCB1. Plasma phytosterol levels were reduced and biliary levels were increased by CDCA and OCA and hepatic sterol transporters, abcg5/8, expression were increased by OCA. Both CDCA and OCA increased plasma FGF19 and OCA increased intestinal FGF19, FABP6, and SLC51A. Both CDCA and OCA increased intestinal mucosal growth, whereas CDCA increased the plasma GLP-2, GLP-1 and GIP. CONCLUSIONS: Enteral OCA prevented cholestasis and phytosterolemia by increased hepatic bile acid and sterol transport via induction of hepatobiliary transporter FXR target genes and not by suppression of bile acid synthesis genes. We also showed an intestinal trophic action of OCA that demonstrates a dual clinical benefit of FXR agonism in the prevention of PNALD in piglets.

Optimization of TiO2-natural hydrogels for paracetamol and ibuprofen degradation in wastewaters.

Agarose/micrometer titanium dioxide (TiO2) beads were essayed to test the photocatalytic capacity of two of the most widely prescribed drugs worldwide: paracetamol and ibuprofen. Although the initial tests demonstrated promising degradation rates for both drugs, the presence of turbidity, due to TiO2 leakage, during the photocatalytic essays induced to improve the stability of the photocatalytic composites. Among the different strategies adopted to strengthen such materials, crosslinking with citric acid and the use of alternative gelling agents: gellan, agargel™, and agar were chosen. Composites obtained by merging both strategies were characterized and employed to degrade both drugs under a simulated light that mimics the solar spectrum (indoor). Considering the superior degradation rates obtained when agar and agarose were used to shape the titanium oxide particles (up to 70-75% of drug destruction), such composites were subjected to a more realistic experiment (outdoor): solar illumination, tap water, and higher volumes, that should facilitate its ulterior scale up as a real wastewater depollution procedure. Degradation rates between 80 and 90% are attained under such conditions for both drugs.

Cost-Effectiveness of a Telemedicine Optometric-Based Assessment for Screening Diabetic Retinopathy in a Country with a Universal Public Health System.

Objective: To determine the cost-effectiveness of a new telemedicine optometric-based screening program of diabetic retinopathy (DR) compared with traditional models' assessments in a universal European public health system. Methods: A new teleophthalmology program for DR based on the assessment of retinographies (3-field Joslin Vision Network by a certified optometrist and a reading center [IOBA-RC]) was designed. This program was first conducted in a rural area 40 km from the referral hospital (Medina de Rioseco, Valladolid, Spain). The cost-effectiveness was compared with telemedicine based on evaluations by primary care physicians and general ophthalmologists, and to face-to-face examinations conducted by ophthalmologists. A decision tree model was developed to simulate the cost-effectiveness of both models, considering public and private costs. The effectiveness was measured in terms of quality of life. Results: A total of 261 patients with type 2 diabetes were included (42 had significant DR and required specific surveillance by the RC; 219 were undiagnosed). The sensitivity and specificity of the detection of DR were 100% and 74.1%, respectively. The telemedicine-based DR optometric screening model demonstrated similar utility to models based on physicians and general ophthalmologists and traditional face-to-face evaluations (0.845) at a lower cost/patient (€51.23, €71.65, and €86.46, respectively). Conclusions: The telemedicine-based optometric screening program for DR in a RC demonstrated cost savings even in a developed country with a universal health care system. These results support the expansion of this kind of teleophthalmology program not only for screening but also for the follow-up of diabetic patients.

Stress and sleep deprivation-related biomarkers in saliva in patients with retinitis pigmentosa.

PURPOSE: Patients with Retinitis Pigmentosa (RP) commonly experience sleep-related issues and are susceptible to stress. Moreover, variatiaons in their vision are often linked to anxiety, stress and drowsiness, indicating that stress and sleep deprivation lead to a decline in vision, and vision improves when both are mitigated. The objective of this study was to investigate the utility of salivary biomarkers as biochemical indicators of anxiety and sleep deprivation in RP patients. METHODS: Seventy-eight RP patients and 34 healthy controls were included in this observational study. Anxiety and sleep-quality questionnaires, a complete ophthalmological exam for severity grading and, the collection of salivary samples from participants were assessed for participants. The activity of biomarkers was estimated by ELISA, and statistical analysis was performed to determine associations between the parameters. Associations between underlying psychological factors, grade of disease severity, and biomarkers activity were also examined. RESULTS: Fifty-two (67%) of patients had a severe RP, and 26 (33%) had a mild-moderate grade. Fifty-eight (58,9%) patients reported severe levels of anxiety and 18 (23.,1%) a high level. Forty-six (59%) patients obtained pathological values in sleep-quality questionaries and 43 (55.1%) in sleepiness. Patients with RP exhibited significant differences in testosterone, cortisol, sTNFαRII, sIgA and melatonin as compared to controls and patients with a mild-moderate and advanced stage of disease showed greater differences. In covariate analysis, patients with a severe anxiety level also showed greater differences in mean salivary cortisol, sTNFαRII and melatonin and male patients showed lower IgA levels than female. CONCLUSIONS: The present findings suggest that salivary biomarkers could be suitable non-invasive biochemical markers for the objective assessment of sleep deprivation and anxiety in RP patients. Further research is needed to characterize the effects of untreated negative psychological states and sleep deprivation on increased variability of vision and disease progression, if any.

Vision loss associated with silicone oil endotamponade in vitreoretinal surgery - a review.

PURPOSE: To clarify the definition, prevalence and classification of different types of unexplained vision loss associated with silicone oil (SO) endotamponades (SO in situ (SOIS) or after removal of SO (ROSO)) in vitreoretinal surgery and identifying the most specific clinical findings and suggesting possible causes. METHODS: Review of the literature regarding randomized clinical trials (RCTs), retrospective case-control, cohort studies and case series evaluating the risk of using SO, published in English between 1994 and 2023, conducting a computer-based search of the following databases: PubMed, Web of Science, Scopus and Embase. The search was supplemented using the Medline option 'Related Articles' and consulting review articles on the topic. RESULTS: Findings from reported clinical examinations in SOIS and ROSO are analyzed and finally different theories regarding the underlying pathophysiology are described. From the clinical point of view, findings have been found in OCT, OCTA, microperimetry and electrophysiological studies. Other clearly identifiable causes of vision loss related to the use of SO are listed and commented as differential diagnosis. Finally, the different physiopathological theories of the two types of causes of unexplained vision have been analyzed. CONCLUSION: Unexpected vision loss under or after SO tamponade (SOIS and ROSO) is a significant concern which is probably underestimated because it is not a clearly defined and known entity. The most frequently described changes were in the ganglion cell complex but this unexpected vision loss remains a serious and unexplained concern for vitreoretinal surgeons and should be identified by clinicians, addressed by manufacturers and reported to Health Authorities as a serious incident according to the new regulation.

Enhancing Sleep Quality in Pediatric Intensive Care: A Chronobiological Perspective.

Biologic synchronized rhythmicity is a critical physiologic process. The lack of synchronized rhythms, mainly those showing a circadian basis, like sleep, heart rate, and arterial pressure, often leads to several organic challenges usually associated with adverse outcomes. Sleep itself, as an independent regulator of many crucial body functions, should preferentially occur with minimum interferences to optimize its plastic role toward structural and functional recovery and regeneration. Hence, patients will mostly benefit from both circadian and sleep-related optimized functions in order to improve prognosis and reduce patients' discharge times.

Unearthing the soil-borne microbiome of land plants.

Plant-soil biodiversity interactions are fundamental for the functioning of terrestrial ecosystems. Yet, the existence of a set of globally distributed topsoil microbial and small invertebrate organisms consistently associated with land plants (i.e., their consistent soil-borne microbiome), together with the environmental preferences and functional capabilities of these organisms, remains unknown. We conducted a standardized field survey under 150 species of land plants, including 58 species of bryophytes and 92 of vascular plants, across 124 locations from all continents. We found that, despite the immense biodiversity of soil organisms, the land plants evaluated only shared a small fraction (less than 1%) of all microbial and invertebrate taxa that were present across contrasting climatic and soil conditions and vegetation types. These consistent taxa were dominated by generalist decomposers and phagotrophs and their presence was positively correlated with the abundance of functional genes linked to mineralization. Finally, we showed that crossing environmental thresholds in aridity (aridity index of 0.65, i.e., the transition from mesic to dry ecosystems), soil pH (5.5; i.e., the transition from acidic to strongly acidic soils), and carbon (less than 2%, the lower limit of fertile soils) can result in drastic disruptions in the associations between land plants and soil organisms, with potential implications for the delivery of soil ecosystem processes under ongoing global environmental change.

Structure and dispersion of the conjugative mobilome in surface ocean bacterioplankton.

Mobile genetic elements (MGEs), collectively referred to as the "mobilome", can have a significant impact on the fitness of microbial communities and therefore on ecological processes. Marine MGEs have mainly been associated with wide geographical and phylogenetic dispersal of adaptative traits. However, whether the structure of this mobilome exhibits deterministic patterns in the natural community is still an open question. The aim of this study was to characterize the structure of the conjugative mobilome in the ocean surface bacterioplankton by searching the publicly available marine metagenomes from the TARA Oceans survey, together with molecular markers, such as relaxases and type IV coupling proteins of the type IV secretion system (T4SS). The T4SS machinery was retrieved in more abundance than relaxases in the surface marine bacterioplankton. Moreover, among the identified MGEs, mobilizable elements were the most abundant, outnumbering self-conjugative sequences. Detection of a high number of incomplete T4SSs provides insight into possible strategies related to trans-acting activity between MGEs, and accessory functions of the T4SS (e.g. protein secretion), allowing the host to maintain a lower metabolic burden in the highly dynamic marine system. Additionally, the results demonstrate a wide geographical dispersion of MGEs throughout oceanic regions, while the Southern Ocean appears segregated from other regions. The marine mobilome also showed a high similarity of functions present in known plasmid databases. Moreover, cargo genes were mostly related to DNA processing, but scarcely associated with antibiotic resistance. Finally, within the MGEs, integrative and conjugative elements showed wider marine geographic dispersion than plasmids.

Short-Wavelength Light-Blocking Filters and Oral Melatonin Administration in Patients With Retinitis Pigmentosa: Protocol for a Randomized Controlled Trial.

BACKGROUND: The medical community is beginning to recognize that retinitis pigmentosa (RP), due to its disabling progression, eventually leads to a reduction in the patient´s quality of life, a direct economic impact, and an increase in the burden on the health care system. There is no curative treatment for the origin of the disease, and most of the current interventions fail in reducing the associated negative psychological states, such as anxiety and depression, which lead to increased variability of vision and pose a continuous threat to the patient's independence. OBJECTIVE: The aim of this study is to assess the effect of oral melatonin (OM) administration alone and combined with short-wavelength light (SWL)-blocking filters on patients with RP and test their effectiveness in improving the level of stress and sleep problems in many of these patients. METHODS: We have developed a low-cost therapy protocol for patients with RP with sleep disorders and negative psychological stress. Patients will be randomized to receive a combined intervention with SWL-blocking filters and OM, SWL-blocking filters alone, or OM alone. There will also be a nonintervention arm as a control group. This study will be conducted across 2 retinal units in patients with RP with sleep disorders and high perceived stress and anxiety score reports. Patients will be assessed in the preintervention period, weekly during the 4 weeks of intervention, and then at 6 months postintervention. The primary outcomes are the differences in changes from baseline to postintervention in hormone release (α-amylase, cortisol, and melatonin) and sleep quality, as measured with the visual analog scale. Secondary outcome measures include clinical macular changes, as measured with optical coherence tomography and optical coherence tomography angiography; retinal function, as measured using the visual field and best-corrected visual acuity; sleep data collected from personal wearables; and several patient-reported variables, such as self-recorded sleep diaries, quality of life, perceived stress, and functional status. RESULTS: This project is still a study protocol and has not yet started. Bibliographic research for information for its justification began in 2020, and this working group is currently seeking start-up funding. As soon as we have the necessary means, we will proceed with the registration and organization prior to the preliminary phase. CONCLUSIONS: In this feasibility randomized clinical controlled trial, we will compare the effects of SWL blocking alone, administration of OM alone, and a combined intervention with both in patients with RP. We present this study so that it may be replicated and incorporated into future studies at other institutions, as well as applied to additional inherited retinal dystrophies. The goal of presenting this protocol is to aid recent efforts in reducing the impact of sleeping disorders and other psychological disorders on the quality of life in patients with RP and recovering their self-autonomy. In addition, the results of this study will represent a significant step toward developing a novel low-cost therapy for patients with RP and validating a novel therapeutic target. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): PRR1-10.2196/49196.

Deep Learning Application to Detect Glaucoma with a Mixed Training Approach: Public Database and Expert-Labeled Glaucoma Population.

INTRODUCTION: Artificial intelligence has real potential for early identification of ocular diseases such as glaucoma. An important challenge is the requirement for large databases properly selected, which are not easily obtained. We used a relatively original strategy: a glaucoma recognition algorithm trained with fundus images from public databases and then tested and retrained with a carefully selected patient database. METHODS: The study's supervised deep learning method was an adapted version of the ResNet-50 architecture previously trained from 10,658 optic head images (glaucomatous or non-glaucomatous) from seven public databases. A total of 1,158 new images labeled by experts from 616 patients were added. The images were categorized after clinical examination including visual fields in 304 (26%) control images or those with ocular hypertension and 347 (30%) images with early, 290 (25%) with moderate, and 217 (19%) with advanced glaucoma. The initial algorithm was tested using 30% of the selected glaucoma database and then re-trained with 70% of this database and tested again. RESULTS: The results in the initial sample showed an area under the curve (AUC) of 76% for all images, and 66% for early, 82% for moderate, and 84% for advanced glaucoma. After retraining the algorithm, the respective AUC results were 82%, 72%, 89%, and 91%. CONCLUSION: Using combined data from public databases and data selected and labeled by experts facilitated improvement of the system's precision and identified interesting possibilities for obtaining tools for automatic screening of glaucomatous eyes more affordably.

The potential of a combination of pungent spices as a novel supplement in gilthead seabream (Sparus aurata) diets to aid in the strategic use of fish oil in aquafeeds: a holistic perspective.

This work studied the potential of a combination of pungent spices (capsicum, black pepper, ginger, and cinnamaldehyde) to be used as a supplement in diets of gilthead seabream (Sparus aurata; 44.1 ± 4.2 g). During 90 days, fish were fed three experimental diets with low inclusion of fish oil and containing poultry fat as the main source of lipids, supplemented with graded levels of the tested supplement: 0 (control), 0.1 (SPICY0.1%), and 0.15% (SPICY0.15%). As a result, the pungent spices enhanced the growth performance, the activity of the bile-salt-activated lipase in the intestine, and decreased fat deposit levels within enterocytes. The SPICY0.1% diet reduced the feed conversion ratio and the perivisceral fat index and lipid deposits in the liver. Moreover, the ratio of docosahexaenoic acid/eicosapentaenoic acid in fillet increased in fish fed the SPICY0.1% diet, while the hepatic levels of docosahexaenoic acid and total n-3 polyunsaturated fatty acids increased in fish fed the SPICY0.15% diet. Furthermore, there was an effect on the expression of some biomarkers related to lipid metabolism in 2-h postprandial fish (fasn, elovl6, scd1b, cyp7a1, lpl, and pparß), and in 48 h fasted-fish fed with the SPICY0.1% diet, a regulation of the intestinal immune response was indicated. However, no significant differences were found in lipid apparent digestibility and proximate macronutrient composition. The spices did not affect biomarkers of hepatic or oxidative stress. No differences in microbial diversity were found, except for an increase in Simpson's Index in the posterior intestine of fish fed the SPICY0.1% diet, reflected in the increased relative abundance of the phylum Chloroflexi and lower relative abundances of the genera Campylobacter, Corynebacterium, and Peptoniphilus. In conclusion, the supplementation of gilthead seabream diets with pungent spices at an inclusion of 0.1% was beneficial to enhance growth performance and feed utilization; reduce fat accumulation in the visceral cavity, liver, and intestine; and improve the fish health status and condition. Results suggest that the tested supplement can be used as part of a nutritional strategy to promote a more judicious use of fish oil in fish diets due to its decreasing availability and rising costs.

The holocentric chromosome microevolution: From phylogeographic patterns to genomic associations with environmental gradients.

Geographic isolation and chromosome evolution are two of the major drivers of diversification in eukaryotes in general, and specifically, in plants. On one hand, range shifts induced by Pleistocene glacial oscillations deeply shaped the evolutionary trajectories of species in the Northern Hemisphere. On the other hand, karyotype variability within species or species complexes may have adaptive potential as different karyotypes may represent different recombination rates and linkage groups that may be associated with locally adapted genes or supergenes. Organisms with holocentric chromosomes are ideal to study the link between local adaptation and chromosome evolution, due to their high cytogenetic variability, especially when it seems to be related to environmental variation. Here, we integrate the study of the phylogeography, chromosomal evolution and ecological requirements of a plant species complex distributed in the Western Euro-Mediterranean region (Carex gr. laevigata, Cyperaceae). We aim to clarify the relative influence of these factors on population differentiation and ultimately on speciation. We obtained a well-resolved RADseq phylogeny that sheds light on the phylogeographic patterns of molecular and chromosome number variation, which are compatible with south-to-north postglacial migration. In addition, landscape genomics analyses identified candidate loci for local adaptation, and also strong significant associations between the karyotype and the environment. We conclude that karyotype distribution in C. gr. laevigata has been constrained by both range shift dynamics and local adaptation. Our study demonstrates that chromosome evolution may be responsible, at least partially, for microevolutionary patterns of population differentiation and adaptation in Carex.

Exploring the relationship between personality and chronic pain in adults with osteogenesis imperfecta: A cross-sectional study.

Despite the growing body of research on chronic pain in adults with osteogenesis imperfecta (OI), there is still a lack of comprehensive understanding of the influence of psychological factors on pain experienced by individuals with this condition. This study aims to delve into the correlation between personality traits and various aspects of pain, such as frequency, intensity, appraisal, and coping mechanisms, in a significant sample of adults with OI. Additionally, the investigation seeks to identify whether certain personality profiles may be more susceptible to chronic pain within this specific population. A descriptive cross-sectional study was conducted on a sample of 418 adults diagnosed with OI. Participants completed an online survey that assessed sociodemographic and clinical variables, pain parameters, personality traits, pain appraisal, and coping strategies. Subsequently, descriptive, correlational, cluster and comparative analyses were performed. Up to 83% of the participants reported experiencing pain on a regular basis. Regarding personality dimensions, moderate scores were obtained, with no significant differences compared to the general population. Neuroticism emerged as the trait showing the most robust relationships with the evaluated variables. It positively correlated with pain intensity, frequency, and the perception of pain as threatening (P < .001). Conversely, higher levels of extraversion were associated with a reduction in pain and its threatening perception (P < .001). Finally, the cluster analysis revealed a personality profile that showed greater vulnerability in pain adaptation, characterized by high levels of neuroticism and low levels of extraversion, agreeableness, and conscientiousness. Chronic pain is prevalent in adults with OI. Personality dimensions maintain a significant relationship with this pain, acting as vulnerability or protective factors. Consequently, specific personality profiles are associated with poorer adaptation. Understanding these profiles would allow for a deeper comprehension of the pain experience in adults with OI.

Intravitreal allogeneic mesenchymal stem cells: a non-randomized phase II clinical trial for acute non-arteritic optic neuropathy.

BACKGROUND: An effective treatment for acute non-arteritic ischemic optic neuropathy (NA-AION) has not been known or proven yet. Previous studies have suggested a neuroprotective effect of allogeneic bone marrow-derived mesenchymal stem cells. This study aims to report the results of a clinical trial on patients with acute non-arteritic optic neuropathy (NA-AION) treated with an intravitreal injection of allogeneic bone marrow-derived mesenchymal stem cells (BM-MSCs) (MSV®). METHODS: We conducted a prospective, non-randomized, clinical phase-II study (Eudra CT number 2016-003029-40; ClinicalTrials.gov Registry NCT03173638) that included 5 patients with acute unilateral NA-AION diagnosed within 2 weeks after symptom onset and who received an intravitreal injection of allogeneic BM-MSCs (0.05 ml; cell concentration: 1.5 × 106cells/mL). The patients underwent regular ophthalmological examinations and were followed for one year. RESULTS: In this trial, allogeneic BM-MSCs appeared to be safe as no patients developed signs of acute nor chronic intraocular inflammation or a significant change in intraocular pressure, although an epiretinal membrane was developed in one patient. A retrolental aggregate formed shortly after the injection spontaneously disappeared within a few weeks in another phakic patient, leaving a subcapsular cataract. Visual improvement was noted in 4 patients, and amplitudes of P100 on the visually evoked potentials recordings increased in three patients. The retinal nerve fiber layer and macular ganglion cell layer thicknesses significantly decreased during the follow-up. CONCLUSIONS: Besides the development of an epiretinal membrane in one patient, the intravitreal application of allogeneic BM-MSCs appeared to be intraocularly well tolerated. Consequently, not only NA-AION but also BM-MSCs deserve more clinical investigational resources and a larger randomized multicenter trial that would provide stronger evidence both about safety and the potential therapeutic efficacy of intravitreally injected allogeneic BM-MSCs in acute NA-AION. TRIAL REGISTRATION: Safety Assessment of Intravitreal Mesenchymal Stem Cells for Acute Non-Arteritic Anterior Ischemic Optic Neuropathy (NEUROSTEM). NCT03173638. Registered June 02, 2017 https://clinicaltrials.gov/ct2/show/NCT03173638 .

tRNA queuosine modification is involved in biofilm formation and virulence in bacteria.

tRNA modifications are crucial for fine-tuning of protein translation. Queuosine (Q) modification of tRNAs is thought to modulate the translation rate of NAU codons, but its physiological role remains elusive. Therefore, we hypothesize that Q-tRNAs control those physiological processes involving NAU codon-enriched genes (Q-genes). Here, we report a novel bioinformatic strategy to predict Q-genes, revealing a widespread enrichment in functions, especially those related to biofilm formation and virulence in bacteria, and particularly in human pathogens. Indeed, we experimentally verified that these processes were significantly affected by altering the degree of tRNA Q-modification in different model bacteria, representing the first report of a general mechanism controlling biofilm formation and virulence in Gram-positive and Gram-negative bacteria possibly through the coordination of the expression of functionally related genes. Furthermore, we propose that changes in Q availability in a microbiome would affect its functionality. Our findings open the door to the control of bacterial infections and biofilm formation by inhibition of tRNA Q-modification.

Deep learning and support vector machines for transcription start site identification.

Recognizing transcription start sites is key to gene identification. Several approaches have been employed in related problems such as detecting translation initiation sites or promoters, many of the most recent ones based on machine learning. Deep learning methods have been proven to be exceptionally effective for this task, but their use in transcription start site identification has not yet been explored in depth. Also, the very few existing works do not compare their methods to support vector machines (SVMs), the most established technique in this area of study, nor provide the curated dataset used in the study. The reduced amount of published papers in this specific problem could be explained by this lack of datasets. Given that both support vector machines and deep neural networks have been applied in related problems with remarkable results, we compared their performance in transcription start site predictions, concluding that SVMs are computationally much slower, and deep learning methods, specially long short-term memory neural networks (LSTMs), are best suited to work with sequences than SVMs. For such a purpose, we used the reference human genome GRCh38. Additionally, we studied two different aspects related to data processing: the proper way to generate training examples and the imbalanced nature of the data. Furthermore, the generalization performance of the models studied was also tested using the mouse genome, where the LSTM neural network stood out from the rest of the algorithms. To sum up, this article provides an analysis of the best architecture choices in transcription start site identification, as well as a method to generate transcription start site datasets including negative instances on any species available in Ensembl. We found that deep learning methods are better suited than SVMs to solve this problem, being more efficient and better adapted to long sequences and large amounts of data. We also create a transcription start site (TSS) dataset large enough to be used in deep learning experiments.

Towards the international interoperability of clinical research networks for rare diseases: recommendations from the IRDiRC Task Force.

BACKGROUND: Many patients with rare diseases are still lacking a timely diagnosis and approved therapies for their condition despite the tremendous efforts of the research community, biopharmaceutical, medical device industries, and patient support groups. The development of clinical research networks for rare diseases offers a tremendous opportunity for patients and multi-disciplinary teams to collaborate, share expertise, gain better understanding on specific rare diseases, and accelerate clinical research and innovation. Clinical Research Networks have been developed at a national or continental level, but global collaborative efforts to connect them are still lacking. The International Rare Diseases Research Consortium set a Task Force on Clinical Research Networks for Rare Diseases with the objective to analyse the structure and attributes of these networks and to identify the barriers and needs preventing their international collaboration. The Task Force created a survey and sent it to pre-identified clinical research networks located worldwide. RESULTS: A total of 34 responses were received. The survey analysis demonstrated that clinical research networks are diverse in their membership composition and emphasize community partnerships including patient groups, health care providers and researchers. The sustainability of the networks is mostly supported by public funding. Activities and research carried out at the networks span the research continuum from basic to clinical to translational research studies. Key elements and infrastructures conducive to collaboration are well adopted by the networks, but barriers to international interoperability are clearly identified. These hurdles can be grouped into five categories: funding limitation; lack of harmonization in regulatory and contracting process; need for common tools and data standards; need for a governance framework and coordination structures; and lack of awareness and robust interactions between networks. CONCLUSIONS: Through this analysis, the Task Force identified key elements that should support both developing and established clinical research networks for rare diseases in implementing the appropriate structures to achieve international interoperability worldwide. A global roadmap of actions and a specific research agenda, as suggested by this group, provides a platform to identify common goals between these networks.

Soil contamination in nearby natural areas mirrors that in urban greenspaces worldwide.

Soil contamination is one of the main threats to ecosystem health and sustainability. Yet little is known about the extent to which soil contaminants differ between urban greenspaces and natural ecosystems. Here we show that urban greenspaces and adjacent natural areas (i.e., natural/semi-natural ecosystems) shared similar levels of multiple soil contaminants (metal(loid)s, pesticides, microplastics, and antibiotic resistance genes) across the globe. We reveal that human influence explained many forms of soil contamination worldwide. Socio-economic factors were integral to explaining the occurrence of soil contaminants worldwide. We further show that increased levels of multiple soil contaminants were linked with changes in microbial traits including genes associated with environmental stress resistance, nutrient cycling, and pathogenesis. Taken together, our work demonstrates that human-driven soil contamination in nearby natural areas mirrors that in urban greenspaces globally, and highlights that soil contaminants have the potential to cause dire consequences for ecosystem sustainability and human wellbeing.