Disentangling the splicing factor programs underlying complex molecular phenotypes.

The regulation of exon inclusion through alternative splicing tunes the cell's behavior by increasing the functional diversity of the transcriptome and the proteome. Splicing factors work in concert to generate gene isoform pools that contribute to cell phenotypes yet their activity is controlled by multiple regulatory and signaling layers. This hinders identification of functional, phenotype-specific splicing factors using traditional single-omic measurements, such as their mutational state or expression. To address this challenge, we propose repurposing the virtual inference of protein activity by enriched regulon analysis (VIPER) to measure splicing factor activity solely from their downstream exon transcriptomic inclusion signatures. This approach is effective in assessing the effect of co-occurring splicing factor perturbations, as well as their post-translational regulation. As proof of concept, we dissect recurrent splicing factor programs underlying tumorigenesis including aberrantly activated factors acting as oncogenes and inactivated ones acting as tumor suppressors, which are undetectable by more conventional methodologies. Activation and inactivation of these cancer splicing programs effectively stratifies overall survival, as well as cancer hallmarks such as proliferation and immune evasion. Altogether, repurposing network-based inference of protein activity for splicing factor networks distills common, functionally relevant splicing programs in otherwise heterogeneous molecular contexts.

Detection of differential bait proteoforms through immunoprecipitation-mass spectrometry data analysis.

Proteins are often referred to as the workhorses of cells, and their interactions are necessary to facilitate specific cellular functions. Despite the recognition that protein-protein interactions, and thus protein functions, are determined by proteoform states, such as mutations and post-translational modifications (PTMs), methods for determining the differential abundance of proteoforms across conditions are very limited. Classically, immunoprecipitation coupled with mass spectrometry (IP-MS) has been used to understand how the interactome (preys) of a given protein (bait) changes between conditions to elicit specific cellular functions. Reversing this concept, we present here a new workflow for IP-MS data analysis that focuses on identifying the differential peptidoforms of the bait protein between conditions. This method can provide detailed information about specific bait proteoforms, potentially revealing pathogenic protein states that can be exploited for the development of targeted therapies.

Diffuse large B-cell lymphoma associated with papillary thyroid carcinoma: a case report and systematic review on management and outcomes.

Primary thyroid lymphoma is a rare thyroid cancer, comprising ˂5% of thyroid neoplasms. Most cases are diffuse large B-cell lymphoma (DLBCL). Coexistence with papillary thyroid cancer (PTC) is extremely rare. This study presents a case of a 55-year-old woman with DLBCL and micropapillary thyroid cancer who underwent lobectomy, chemotherapy, and radiotherapy. Additionally, we performed a systematic review of 10 cases, including the reported case. The risk of bias in case reports varied. DLBCL diagnoses were mainly made after surgery, with total thyroidectomy being the most common surgical procedure. Chemotherapy was administered in most cases, and radiotherapy was used in some cases. Long-term outcomes indicated a low recurrence rate. While some debate the role of surgery in thyroid lymphoma, this study suggests that surgery should be considered in selected cases. Further research is needed to determine optimal treatment strategies for DLBCL with PTC.

Changes in EEG Activity and Cognition Related to Physical Activity in Older Adults: A Systematic Review.

Aging is generally associated with a decline in important cognitive functions that can be observed in EEG. Physical activity in older adults should be considered one of the main strategies to promote health and prevent disease in the elderly. The present study aimed to systematically review studies of EEG activity and cognitive function changes associated with physical activity in older adults. Records from PubMed, Scopus, and EBSCO databases were searched and, following the PRISMA guidelines, nine studies were included in the present systematic review. A risk of bias assessment was performed using the National Institute of Health Quality Assessment Tool for Case-control Studies instrument. The studies analyzed used two main strategies to determine the effects of physical activity on cognition and EEG: (1) multiscale entropy and power frequencies; and (2) event-related potentials. In terms of EEG activity, it can be concluded that exercise-induced neuroplasticity underlies improvements in cognitive function in healthy older adults.

Geniposide and Harpagoside Functionalized Cerium Oxide Nanoparticles as a Potential Neuroprotective.

Alzheimer's disease is associated with protein aggregation, oxidative stress, and the role of acetylcholinesterase in the pathology of the disease. Previous investigations have demonstrated that geniposide and harpagoside protect the brain neurons, and cerium nanoparticles (CeO2 NPs) have potent redox and antioxidant properties. Thus, the effect of nanoparticles of Ce NPs and geniposide and harpagoside (GH/CeO2 NPs) on ameliorating AD pathogenesis was established on AlCl3-induced AD in mice and an aggregation proteins test in vitro. Findings of spectroscopy analysis have revealed that GH/CeO2 NPs are highly stable, nano-size, spherical in shape, amorphous nature, and a total encapsulation of GH in cerium. Treatments with CeO2 NPs, GH/CeO2 NPs, and donepezil used as positive control inhibit fibril formation and protein aggregation, protect structural modifications in the BSA-ribose system, have the ability to counteract Tau protein aggregation and amyloid-ß1-42 aggregation under fibrillation condition, and are able to inhibit AChE and BuChE. While the GH/CeO2 NPs, treatment in AD induced by AlCl3 inhibited amyloid-ß1-42, substantially enhanced the memory, the cognition coordination of movement in part AD pathogenesis may be alleviated through reducing amyloidogenic pathway and AChE and BuChE activities. The findings of this work provide important comprehension of the chemoprotective activities of iridoids combined with nanoparticles. This could be useful in the development of new therapeutic methods for the treatment of neurodegenerative diseases.

Developing a platform for secretion of biomolecules in Mycoplasma feriruminatoris.

BACKGROUND: Having a simple and fast dividing organism capable of producing and exposing at its surface or secreting functional complex biomolecules with disulphide bridges is of great interest. The mycoplasma bacterial genus offers a set of relevant properties that make it an interesting chassis for such purposes, the main one being the absence of a cell wall. However, due to their slow growth, they have rarely been considered as a potential platform in this respect. This notion may be challenged with the recent discovery of Mycoplasma feriruminatoris, a species with a dividing time close to that of common microbial workhorses. So far, no tools for heterologous protein expression nor secretion have been described for it. RESULTS: The work presented here develops the fast-dividing M. feriruminatoris as a tool for secreting functional biomolecules of therapeutic interest that could be used for screening functional mutants as well as potentially for protein-protein interactions. Based on RNAseq, quantitative proteomics and promoter sequence comparison we have rationally designed optimal promoter sequences. Then, using in silico analysis, we have identified putative secretion signals that we validated using a luminescent reporter. The potential of the resulting secretion cassette has been shown with set of active clinically relevant proteins (interleukins and nanobodies). CONCLUSIONS: We have engineered Mycoplasma feriruminatoris for producing and secreting functional proteins of medical interest.

Engineering Mycoplasma pneumoniae to bypass the association with Guillain-Barré syndrome.

A non-pathogenic Mycoplasma pneumoniae-based chassis is leading the development of live biotherapeutic products (LBPs) for respiratory diseases. However, reports connecting Guillain-Barré syndrome (GBS) cases to prior M. pneumoniae infections represent a concern for exploiting such a chassis. Galactolipids, especially galactocerebroside (GalCer), are considered the most likely M. pneumoniae antigens triggering autoimmune responses associated with GBS development. In this work, we generated different strains lacking genes involved in galactolipids biosynthesis. Glycolipid profiling of the strains demonstrated that some mutants show a complete lack of galactolipids. Cross-reactivity assays with sera from GBS patients with prior M. pneumoniae infection showed that certain engineered strains exhibit reduced antibody recognition. However, correlation analyses of these results with the glycolipid profile of the engineered strains suggest that other factors different from GalCer contribute to sera recognition, including total ceramide levels, dihexosylceramide (DHCer), and diglycosyldiacylglycerol (DGDAG). Finally, we discuss the best candidate strains as potential GBS-free Mycoplasma chassis.

Bilateral Inferior Rectus Schwannoma and Strabismus: A Case Report.

Schwannomas, also known as neurilemomas, are peripheral nerve sheath neoplasms. They can be sporadic or associated with genetic syndromes including neurofibromatosis type 2 (NF2). Schwannomas may lead to symptoms by exerting pressure on nearby structures, such as nerve and muscle fibers. In this study, we present the case of a 22-year-old female with a history of NF2 who, upon examination, presented with a visibly enlarged salmon-colored mass involving the left inferior rectus that she had since the age of 12 years. Ocular examinations revealed a small left hypertropia and exotropia in all gazes. Magnetic resonance imaging confirmed bilateral involvement of the inferior rectus muscles. She had a partial excisional biopsy of the mass involving the left inferior rectus muscle that confirmed the presence of schwannoma. This case highlights the importance of comprehensive evaluation of sensory and motor functions as well as considering orbital schwannomas in cases of strabismus, especially within the context of neurofibromatosis.

ProTInSeq: transposon insertion tracking by ultra-deep DNA sequencing to identify translated large and small ORFs.

Identifying open reading frames (ORFs) being translated is not a trivial task. ProTInSeq is a technique designed to characterize proteomes by sequencing transposon insertions engineered to express a selection marker when they occur in-frame within a protein-coding gene. In the bacterium Mycoplasma pneumoniae, ProTInSeq identifies 83% of its annotated proteins, along with 5 proteins and 153 small ORF-encoded proteins (SEPs; ≤100 aa) that were not previously annotated. Moreover, ProTInSeq can be utilized for detecting translational noise, as well as for relative quantification and transmembrane topology estimation of fitness and non-essential proteins. By integrating various identification approaches, the number of initially annotated SEPs in this bacterium increases from 27 to 329, with a quarter of them predicted to possess antimicrobial potential. Herein, we describe a methodology complementary to Ribo-Seq and mass spectroscopy that can identify SEPs while providing other insights in a proteome with a flexible and cost-effective DNA ultra-deep sequencing approach.

Unique transcriptomes of sensory and non-sensory neurons: insights from Splicing Regulatory States.

Alternative Splicing (AS) programs serve as instructive signals of cell type specificity, particularly within the brain, which comprises dozens of molecularly and functionally distinct cell types. Among them, retinal photoreceptors stand out due to their unique transcriptome, making them a particularly well-suited system for studying how AS shapes cell type-specific molecular functions. Here, we use the Splicing Regulatory State (SRS) as a novel framework to discuss the splicing factors governing the unique AS pattern of photoreceptors, and how this pattern may aid in the specification of their highly specialized sensory cilia. In addition, we discuss how other sensory cells with ciliated structures, for which data is much scarcer, also rely on specific SRSs to implement a proteome specialized in the detection of sensory stimuli. By reviewing the general rules of cell type- and tissue-specific AS programs, firstly in the brain and subsequently in specialized sensory neurons, we propose a novel paradigm on how SRSs are established and how they can diversify. Finally, we illustrate how SRSs shape the outcome of mutations in splicing factors to produce cell type-specific phenotypes that can lead to various human diseases.

EU-LIFE charter of independent life science research institutes.

The diverse range of organizations contributing to the global research ecosystem is believed to enhance the overall quality and resilience of its output. Mid-sized autonomous research institutes, distinct from universities, play a crucial role in this landscape. They often lead the way in new research fields and experimental methods, including those in social and organizational domains, which are vital for driving innovation. The EU-LIFE alliance was established with the goal of fostering excellence by developing and disseminating best practices among European biomedical research institutes. As directors of the 15 EU-LIFE institutes, we have spent a decade comparing and refining our processes. Now, we are eager to share the insights we've gained. To this end, we have crafted this Charter, outlining 10 principles we deem essential for research institutes to flourish and achieve ground-breaking discoveries. These principles, detailed in the Charter, encompass excellence, independence, training, internationality and inclusivity, mission focus, technological advancement, administrative innovation, cooperation, societal impact, and public engagement. Our aim is to inspire the establishment of new institutes that adhere to these principles and to raise awareness about their significance. We are convinced that they should be viewed a crucial component of any national and international innovation strategies.

Integrating physics in deep learning algorithms: a force field as a PyTorch module.

MOTIVATION: Deep learning algorithms applied to structural biology often struggle to converge to meaningful solutions when limited data is available, since they are required to learn complex physical rules from examples. State-of-the-art force-fields, however, cannot interface with deep learning algorithms due to their implementation. RESULTS: We present MadraX, a forcefield implemented as a differentiable PyTorch module, able to interact with deep learning algorithms in an end-to-end fashion. AVAILABILITY AND IMPLEMENTATION: MadraX documentation, together with tutorials and installation guide, is available at madrax.readthedocs.io.

Indicadores antropométricos como predictores de la masa libre de grasa en basquetbolistas universitarios 3 x 3 / Anthropometric indicators as predictors of fat-free mass in college 3-on-3 basketball players

Introducción: En varios de los deportes la composicióncorporal (CC) es una característica importante que se evalúaperiódicamente en los atletas, al ser considerada un indicadorimportante de la condición física. Objetivo: Identificar los índices antropométricos que permiten predecir la masa libre de grasa (MLG) en seleccionados universitarios de basquetbol 3x3 pertenecientes a Federación Internacional del Deporte Universitario (FISU). Metodología: Se diseñó un estudio descriptivo transversal en jóvenes basquetbolistas de 5 selecciones universitarias pertenecientes a la FISU (Argentina, Brasil, Chile, Colombia, Costa Rica, El Salvador, México y Perú). Participaron de formavoluntaria 46 basquetbolista (24 hombres y 22 mujeres) conun rango de edad de 18 a 23 años. Se evaluó el peso, la es-tatura y la MLG por biompedancia eléctrica. Se calculó el índice de masa corporal (IMC), índice tri-ponderal (IPT), y elárea de superficie corporal (ASC). Resultados: El promedio de edad de los hombres fue21.1±1.9 años y de mujeres 21.3±2.0 años. El poder de ex-plicación entre MLG con el ASC en ambos sexos fueron elevados (hombres R2= 79%, y en mujeres 80<%). El IMC y elITP mostraron valores inferiores que oscilaron desde R2=0.07 hasta R2= 36%). Lolos mejores ajustes del RMSE fueronpara el ASC y en ambos sexos (RMSE= 3,2 hasta 4,3). Conclusión: Los resultados del estudio han evidenciado que el ASC es el mejor predictor de la MLG en relación al IMCe ITP. Estos hallazgos sugieren el uso del ASC para estimar la MLG en jóvenes basquetbolistas 3x3 de ambos sexos.(AU)

Introduction: In several sports, body composition (BC) isan important characteristic that is periodically evaluated inathletes, as it is considered an important indicator of physicalcondition.Objective: To identify the anthropometric indices thatallow predicting fat-free mass (FFM) in selected university 3x3basketball players belonging to the International University Sports Federation (FISU). Methodology: A descriptive cross-sectional study was de-signed in young basketball players from 5 university teamsbelonging to FISU (Argentina, Brazil, Chile, Colombia, Costa Rica, El Salvador, Mexico and Peru). Forty-six basketball pla-yers (24 males and 22 females) with an age range of 18 to 23 years participated voluntarily. Weight, height and FFM wereevaluated by electrical bioimpedance. Body mass index (BMI),tri-ponderal index (TPI), and body surface area (BSA) werecalculated. Results: The mean age of males was 21.1±1.9 years andof females 21.3±2.0 years. The explanatory power betweenFFM with BSA in both sexes were high (males R2= 79%, andin women 80<%). BMI and TPI showed lower values rangingfrom R2= 0.07 to R2= 36%). The best fits of the RMSE werefor BSA and in both sexes (RMSE= 3.2 to 4.3). Conclusion: The results of the study have shown that ASCis the best predictor of FFM in relation to BMI and TPI. Thesefindings suggest the use of BSA to estimate the FFM in young3x3 basketball players of both sexes.(AU)

Nanostructured Cellulose-Based Aerogels: Influence of Chemical/Mechanical Cascade Processes on Quality Index for Benchmarking Dye Pollutant Adsorbents in Wastewater Treatment.

(1) Background: Nanostructured cellulose has emerged as an efficient bio-adsorbent aerogel material, offering biocompatibility and renewable sourcing advantages. This study focuses on isolating (ligno)cellulose nanofibers ((L)CNFs) from barley straw and producing aerogels to develop sustainable and highly efficient decontamination systems. (2) Methods: (Ligno)cellulose pulp has been isolated from barley straw through a pulping process, and was subsequently deconstructed into nanofibers employing various pre-treatment methods (TEMPO-mediated oxidation process or PFI beater mechanical treatment) followed by the high-pressure homogenization (HPH) process. (3) Results: The aerogels made by (L)CNFs, with a higher crystallinity degree, larger aspect ratio, lower shrinkage rate, and higher Young's modulus than cellulose aerogels, successfully adsorb and remove organic dye pollutants from wastewater. (L)CNF-based aerogels, with a quality index (determined using four characterization parameters) above 70%, exhibited outstanding contaminant removal capacity over 80%. The high specific surface area of nanocellulose isolated using the TEMPO oxidation process significantly enhanced the affinity and interactions between hydroxyl and carboxyl groups of nanofibers and cationic groups of contaminants. The efficacy in adsorbing cationic dyes in wastewater onto the aerogels was verified by the Langmuir adsorption isotherm model. (4) Conclusions: This study offers insights into designing and applying advanced (L)CNF-based aerogels as efficient wastewater decontamination and environmental remediation platforms.

Role of the CB2 Cannabinoid Receptor in the Regulation of Food Intake: A Systematic Review.

The CB2 cannabinoid receptor has been found in brain areas that are part of the reward system and has been shown to play a role in food intake regulation. Herein, we conducted a systematic review of studies assessing the role of the CB2 receptor in food intake regulation. Records from the PubMed, Scopus, and EBSCO databases were screened, resulting in 13 studies that were used in the present systematic review, following the PRISMA guidelines. A risk of bias assessment was carried out using the tool of the Systematic Review Center for Laboratory Animal Experimentation (SYRCLE). The studies analyzed used two main strategies: (1) the intraperitoneal or intracerebroventricular administration of a CB2 agonist/antagonist; and (2) depletion of CB2 receptors via knockout in mice. Both strategies are useful in identifying the role of the CB2 receptor in food intake in standard and palatable diets. The conclusions derived from animal models showed that CB2 receptors are necessary for modulating food intake and mediating energy balance.

Interactions between BRD4S, LOXL2, and MED1 drive cell cycle transcription in triple-negative breast cancer.

Triple-negative breast cancer (TNBC) often develops resistance to single-agent treatment, which can be circumvented using targeted combinatorial approaches. Here, we demonstrate that the simultaneous inhibition of LOXL2 and BRD4 synergistically limits TNBC proliferation in vitro and in vivo. Mechanistically, LOXL2 interacts in the nucleus with the short isoform of BRD4 (BRD4S), MED1, and the cell cycle transcriptional regulator B-MyB. These interactions sustain the formation of BRD4 and MED1 nuclear transcriptional foci and control cell cycle progression at the gene expression level. The pharmacological co-inhibition of LOXL2 and BRD4 reduces BRD4 nuclear foci, BRD4-MED1 colocalization, and the transcription of cell cycle genes, thus suppressing TNBC cell proliferation. Targeting the interaction between BRD4S and LOXL2 could be a starting point for the development of new anticancer strategies for the treatment of TNBC.

Bay Leaves Extracts as Active Additive for Food Protective Coatings.

Ethanolic extracts of bay leaves were obtained using the Soxhlet method (extraction yield of 22.3 ± 1.2%) and further analyzed through different methods, thus determining the chemical composition with gas chromatography, phenolic content with the Folin-Ciocalteu technique (11.8 ± 0.4% wt.) and antioxidant power with the radical 2,2'-Azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) method (75.06%). Furthermore, its effect on the growth of two bacteria, Escherichia coli and Bacillus cereus, and on two yeasts, Candida glabrata and Saccharomyces cerevisiae, was determined, showing a minimum inhibitory concentration of 0.65 mg/mL on the growth of B. cereus. Finally, edible films were prepared using different polymers (carboxymethyl cellulose, gum Arabic, polyvinyl pyrrolidone, and polyvinyl alcohol) containing 0, 5, 10, or 15% wt. of bay leaf extract as troubleshooting for perishable fruits, specifically for cultivated strawberry. The prepared composites presented reduced water vapor permeabilities (up to 4.3 × 10-7 g·Pa-1·m-1·h-1), high specific transparencies (≈30%/mm), as well as the effective blocking of ultraviolet radiation (>99.9%). In vivo tests showed that the most suitable treatment for strawberry protection was the impregnation with a composite comprising polyvinyl alcohol and a 15% wt. bay leaf extract, resulting in a noteworthy reduction in mass loss (22% after 6 days). It can be asserted that food packaging with the designed composites would be an effective alternative for the reduction in postharvest losses.

Stepwise emergence of the neuronal gene expression program in early animal evolution.

The assembly of the neuronal and other major cell type programs occurred early in animal evolution. We can reconstruct this process by studying non-bilaterians like placozoans. These small disc-shaped animals not only have nine morphologically described cell types and no neurons but also show coordinated behaviors triggered by peptide-secreting cells. We investigated possible neuronal affinities of these peptidergic cells using phylogenetics, chromatin profiling, and comparative single-cell genomics in four placozoans. We found conserved cell type expression programs across placozoans, including populations of transdifferentiating and cycling cells, suggestive of active cell type homeostasis. We also uncovered fourteen peptidergic cell types expressing neuronal-associated components like the pre-synaptic scaffold that derive from progenitor cells with neurogenesis signatures. In contrast, earlier-branching animals like sponges and ctenophores lacked this conserved expression. Our findings indicate that key neuronal developmental and effector gene modules evolved before the advent of cnidarian/bilaterian neurons in the context of paracrine cell signaling.