One of the IRDiRC goals for 2017-2027 is to achieve definitive diagnosis for rare undiagnosed diseases within one year, as diagnosis delay remains one of the pending issues in the rare diseases field. The Spanish Undiagnosed Rare Diseases Program (SpainUDP) was created in response to this challenging scenario to cover patients’ needs and after seeing the success of the UDP in USA. SpainUDP offers a multidisciplinary approach to those patients who have long sought a diagnosis without any success. During a first phase of the protocol, undiagnosed cases are sent to SpainUDP by individual patients, patient organizations or hospitals. After a carefully analysis of phenotype, data from sequencing experiments (WES) is processed with a standard pipeline and a detailed standardized phenotypic information (mapped to HPO) is connected to genetic data. In addition, the participation of SpainUDP in international initiatives such as the European projects RD-Connect and Solve RD, the Undiagnosed Diseases Network International (UDNI), and the MatchMaker Exchange platform, allows the establishment of a global data sharing strategy across multiple projects submitting data to these international initiatives. From the official beginning of the program (at the end of 2015) until early 2018, 147 cases were accepted in SpainUDP. During this time, 37 cases (25 %) dropped out the program due to several reasons. The remaining 110 cases are distributed as follows: phenotypic and genotypic (WES) characterization was finished in 30 cases, of which 20 (67 %) were diagnosed; 21 cases are pending on variants validation by Sanger; in 25 cases, WES is ongoing and 34 cases are in a deep phenotypic characterization. As a conclusion, SpainUDP aims to achieve a diagnosis following two recommendations of the IRDiRC: the patients’ diagnosis in a period of time as short as possible and the promotion of data sharing (especially genomic) at the international level.

Congenital Dermatofibrosarcoma Protuberans (DFSP) is an extremely rare low-grade soft tissue sarcoma arising from the dermis. Accounting for less than 0.1% of all malignancies and approximately 1% of soft tissue sarcomas, congenital DFSP presents a significant diagnostic challenge due to its atypical presentation in neonates and infants. Often mimicking benign skin lesions such as hemangiomas, vascular malformations or pigmented moles, it is frequently misdiagnosed, leading to delays in appropriate treatment. This narrative review highlights the importance of early recognition and accurate diagnosis of congenital DFSP to prevent aggressive local growth and reduce the risk of recurrence. We discuss the epidemiology, clinical presentation and diagnostic hurdles associated with this condition. Histopathological examination remains the gold standard for diagnosis, with characteristic findings of spindle-shaped cells in a storiform pattern and strong CD34 positivity on immunohistochemical staining. Imaging modalities such as MRI may be helpful in assessing the extent of the lesion. Surgical excision with clear margins, preferably using Mohs micrographic surgery, is the cornerstone of treatment, balancing oncological control with functional and aesthetic considerations in paediatric patients. A multidisciplinary approach involving dermatologists, paediatric surgeons, oncologists and pathologists is essential for optimal management. We also emphasise the need for clinician vigilance, early biopsy of suspicious lesions, patient education and long-term follow-up to improve outcomes and quality of life for affected children.

Background: Elexacaftor/Tezacaftor/Ivacaftor (ETI) is a CFTR modulator therapy approved for people with cystic fibrosis (pwCF) who have at least one phe508del mutation. However, its approval in the EU for pwCF with non-phe508del mutations is lacking, with limited data on treatment response in this subgroup. Methods: This retrospective study analyzed data from six pwCF (ages 6 to 66) with responsive CFTR mutations (M1101K, R347P, 2789+5G>A, G551D) undergoing off-label ETI therapy. Evaluations were conducted at 0, 3, 6, 9, and 12 months, assessing lung function (FEV1), sweat chloride levels, BMI, quality of life (CFQ-R), medication satisfaction (TSQM), ENT symptoms (SNOT-22), and physical performance. A control group of four pwCF with classic symptoms and no ETI treatment was included. Results: FEV1 improved significantly after 3 and 6 months (p<0.05) and stabilized by 12 months. Sweat chloride levels decreased significantly, with four pwCF achieving levels below 60 mmol/l. Improvements in ENT and respiratory symptoms, medication satisfaction, and increased BMI were noted. Conclusion: ETI demonstrates high efficacy in selected non-phe508del mutations, offering an effective treatment option that warrants further monitoring and evaluation.

A plant’s health and productivity is influenced by its associated microbes. Although the common microbiome is often thought to be the most influential, significant numbers of rare or uncommon microbes (eg. specialized endosymbionts) may also play an important role in the health and productivity of certain plants in certain environments. To help identify rare/specialized bacteria and fungi in the most important angiosperm plants, we contrasted microbiomes of the shoots, roots and rhizospheres of Arabidopsis, Brachypodium, maize, wheat, sugarcane, rice, tomato, coffee, common bean, cassava, soybean, switchgrass, sunflower, Brachiaria, barley, sorghum, and pea. Plants were grown inside sealed jars on sterile sand or field soil. About 95% and 86% of fungal and bacterial diversity inside plants was uncommon, however judging by read abundance, up to half of the mycobiome consists of uncommon fungal cells, while less than 11% of bacterial endophytes are rare. Uncommon seed transmitted microbiomes consisted mostly of Proteobacteria, Firmicutes, Bacteriodetes, Ascomycetes and Basidiomycetes that most heavily colonized shoots, to a lesser extent roots and least of all rhizospheres. Soil served as a more diverse source of rare microbes than seeds, replacing or excluding the majority of the uncommon seed transmitted microbiome. With the rarest microbes, their colonization pattern could either be the result of stringent biotic filtering by most plants, or uneven/stochastic inoculum distribution in seeds or soil. Several strong plant-microbe associations were observed such as seed transmission to shoots, roots and/or rhizospheres of Sarocladium zeae (maize), Penicillium (pea and Phaseolus), and Curvularia (sugarcane), while robust bacterial colonization from cassava field soil occurred with the cyanobacteria Leptolyngbya into Arabidopsis and Panicum roots, and Streptomyces into cassava roots. Some abundant microbes such as Sakaguchia in rice shoots or Vermispora in Arabidopsis roots appeared in no other samples, suggesting they were infrequent, stochastically deposited propagules from either soil or seed (impossible to know based on the available data). Future experiments with culturing and cross inoculation of these microbes between plants may help us better understand host preferences and their role in plant productivity, perhaps leading to their use in crop microbiome engineering and enhancement of agricultural production.

Desmoplastic small round cell tumor (DSRCT) is an extremely rare, aggressive sarcoma affecting adolescents and young adults with male predominance. Generally, it originates from serosal surface of abdominal cavity. The hallmark characteristic of DSRCT is the EWSR1-WT1 gene fusion. This translocation up-regulates the expression of PDGFRα, VEGF and other proteins related to tumor and vascular cell proliferation. Current management of DSRCT includes a combination of chemotherapy, radiation and aggressive cytoreductive surgery plus intra-peritoneal hyperthermic chemotherapy (HIPEC). Despite advances in multimodal therapy, outcomes remain poor since the majority of patients present disease recurrence and die within 3 years. The dismal survival makes DSRCT an orphan disease with urgent need of new drugs. The treatment of advanced and recurrent disease with tyrosine kinase inhibitors, such as pazopanib, sunitinib, and mTOR inhibitors have been evaluated in small studies. Recent works using comprehensive molecular profiling of DSRCT identified potential therapeutic targets. In this review, we aim to describe the current studies conducted to better understand DSRCT biology and to explore the new therapeutic strategies under investigation in preclinical models and in early phase clinical trials.

Seed bank survival underpins plant population persistence but studies on seed bank trait-environment interactions are few. Changes in environmental conditions relevant to seed banks occur in desert ecosystems owing to solar energy development. We developed a conceptual model of seed bank survival to complement methodologies using in-situ seed bank packets. Using this framework, we quantified the seed bank survival of two closely related annual desert plant species, one rare (Eriophyllum mohavense) and one common (Eriophyllum wallacei) and the seed bank-environment interactions of these two species in the Mojave Desert within a system that emulates microhabitat variation associated with solar energy development. We tracked 4,860 seeds buried across 540 seed packets and found, averaged across both species, that seed bank survival was 21% and 6% for the first and second growing seasons, respectively. After two growing seasons, the rare annual had a significantly greater seed bank survival (10%) than the common annual (2%). Seed bank survival, across both species, was significantly greater in Shade (10%) microhabitats compared to Runoff (5%) microhabitats and Control microhabitats (3%). Our study confers insight into this early life-stage across rare and common congeners and their environmental interactions using a novel conceptual framework for seed bank survival.

To understand functions of biomolecules such as proteins, not only structures but their conformational change and kinetics are important to be characterized but its atomistic details are hard to obtain both experimentally and computationally. We review our recent computational studies using novel enhanced sampling techniques for conformational sampling of biomolecules and calculations of their kinetics. For efficiently characterizing the free energy landscape of a biomolecule, we introduce the multiscale enhanced sampling method, which uses a combined system of atomistic and coarse-grained models. Based on the idea of Hamiltonian replica exchange, we can recover the statistical properties of the atomistic model without any biases. We next introduce the string method as a path search method to calculate the minimum free energy pathways along a multidimensional curve in high dimensional space. Finally we introduce novel methods to calculate kinetics of biomolecules based on the ideas of path sampling: One is the Onsager-Machlup action method, and the other is the weighted ensemble method. Some applications of above methods to biomolecular systems are also discussed and illustrated.

The process of developing therapies to treat rare diseases is fraught with financial, regulatory, and logistical challenges that have limited our ability to build effective treatments. Recently, a novel type of therapy called antisense therapy has shown immense potential for the treatment of rare diseases, particularly through single-patient N-of-1 trials. Several N-of-1 antisense therapies have been developed recently for rare diseases, including the landmark study of milasen. In response to the success of N-of-1 antisense therapy, the Food and Drug Administration (FDA) has developed unique guidelines specifically for the development of antisense therapy to treat N-of-1 rare diseases. This policy change establishes a strong foundation for future therapy development, and addresses some of the major limitations that previously hindered the development of therapies for rare diseases.

The altitude of the habitat is one of the important regulators of species survival. Kaçkar Mountains National Park is located in the Eastern Black Sea region of Turkey. This is the first study on the benthic diatom flora of the high mountain lakes in Kaçkar Mountains National Park, which is situated between 2782 and 3075 m a.s.l. A total of 84 diatom species were identified from benthic communities of 15 habitats in summer (19 July, 28 August) and autumn (10 September) months of 2020. The genus Pinnularia (13 species) formed the basis of the taxonomic list followed by Eunotia (5 species), Navicula (5 species), and Frustulia (4 species) genera, respectively. The waters in all the studied lakes were fresh, low-saline, with low-alkaline or circumneutral pH and organically uncontaminated as evidenced by prevailed bioindicator groups. Statistical methods and comparative floristic results confirm the role of the lake altitude for the diatom species distribution. Species richness was higher in lakes with lower altitude, but a statistical approach also revealed a tendency for it to increase with altitude if species richness increased. Further studies will be needed to continue exploring this pattern. In the first round of analysis, diatom species groups were categorized according to IUCN categories, revealing one potentially threatened and one rare species. To protect studied high mountain lakes, their ecological conditions must be constantly monitored in the Kaçkar Mountains National Park.

Background: Hairy cell leukemia (HCL) is a rare indolent B-cell lymphoid malignancy. The majority of patients are asymptomatic and HCL is usually diagnosed incidentally during a routine blood cell counts. In symptomatic patients, typical symptoms are related to pancytope-nia and splenomegaly. In this review we present, rare clinical symptoms in patients with HCL. Methods: A literature search was conducted of PubMed, Web of Science, and Google Scholar for articles concerning hairy cell leukemia, leukemia cutis, bone lesions, neurological manifesta-tions, pulmonary symptoms, ocular manifestations, cardiac manifestation, rare symptoms. Publications from January 1980 to August 2024 were scrutinized. Additional relevant publica-ions were obtained by reviewing the references from the chosen articles. Results: Extra medul-lary and extra nodal manifestations of classic HCL are rare. However, leukemic involvement in the skin, bone, central nervous system, gastrointestinal tract, heart, kidney, liver, lung, ocular and other organs have been reported.

Abstract: Power generation using dielectric elastomer (DE) artificial muscle is attracting attention because of its light weight, low cost, and high efficiency. Since this method is a system that produces electricity without emitting carbon dioxide nor using rare earths, it would contribute to the goal of environmental sustainability. In this paper, the background of DEs, the associated high-efficient wave energy generation (WEG) systems that we developed using DEs, as well as the latest development of its material are summarized. By covering the challenges we face and the achievements that we’ve reached, we can discuss the opportunities to build the foundation of a recycled energy society through the usage of these WEGs. On the other hand, to make these possibilities commercially successful, the advantages of DEs need to be integrated with traditional technologies. To achieve this, we also consider the method of using DEs alone and a system used in combination with an oscillating water column. Finally, the current status and future of DEGs are discussed.

Accurate diagnosis for the 400 million people with rare diseases is critical for healthcare decisions, prognosis, understanding disease mechanisms, and identification of treatments. Despite advances in genome sequencing, barriers such as high interpretation costs, diagnostic expertise, throughput associated delays, and uncertain variant classifications persist, with demand exceeding capacity. Many variant classification methods focus narrowly on specific consequences, leading to the use of complex integrative pipelines that often overlook transcript variability and lack prediction transparency. To overcome these limitations, we introduce DITTO. This transparent, transcript-aware machine-learning method demonstrates superior overall performance in accuracy, recall, and precision when compared to existing tools. DITTO is publicly available at https://github.com/uab-cgds-worthey/DITTO

Most of the commonly used Ionic Liquids (ILs) contain bulky organic cations with suitable anions. With our COMPLET (Concept of Melting Point Lowering due to Ethoxylation), we follow a different approach. We use simple, low-toxic, cheap and commercially available anions of the type Cx(EO)yCH2COO– to liquefy presumably any simple metal ion, independently of its charge. In the simplest case, the cation can be sodium or lithium, but synthesis of Ionic Liquids is also possible with cations of higher valences such as transition or rare earth metals. Anions with longer alkyl chains are surface active and form surface active ionic liquids (SAILs), which combine properties of ionic and nonionic surfactants at room temperature. They show significant structuring even in their pure state, i.e. in the absence of water or any other added solvent.