Search

Abstract Background Sepsis remains a major global health concern due to its high prevalence and mortality. Changes in body temperature (Tb), such as hypothermia or fever, are diagnostic indicators and play a crucial role in the pathophysiology of sepsis. This study aims to characterize the thermoregulatory mechanisms during sepsis using the cecal ligation and puncture (CLP) model and explore how sepsis severity and ambient temperature (Ta) influence Tb regulation and mortality. Rats were subjected to mild or severe sepsis by CLP while housed at thermoneutral (28 °C) or subthermoneutral (22 °C) Ta, and their Tb was monitored for 12 h. Blood and hypothalamus were collected for cytokines and prostaglandin E2 (PGE2) analysis. Results At 28 °C, febrile response magnitude correlated with sepsis severity and inflammatory response, with tail vasoconstriction as the primary heat retention mechanism. At 22 °C, Tb was maintained during mild sepsis but dropped during severe sepsis, linked to reduced UCP1 expression in brown adipose tissue and less effective vasoconstriction. Despite differences in thermoregulatory responses, both Ta conditions induced a persistent inflammatory response and increased hypothalamic PGE2 production. Notably, mortality in severe sepsis was significantly higher at 28 °C (80%) compared to 22 °C (0%). Conclusions Our findings reveal that ambient temperature and the inflammatory burden critically influence thermoregulation and survival during early sepsis. These results emphasize the importance of considering environmental factors in preclinical sepsis studies. Although rodents in experimental settings are often adapted to cold environments, these conditions may not fully translate to human sepsis, where cold adaptation is rare. Thus, researchers should carefully consider these variables when designing experiments and interpreting translational implications. Graphical Abstract Graphical representation of the thermoregulatory and inflammatory responses to mild and severe sepsis in rats housed at thermoneutral (28 °C) and subthermoneutral (22 °C) ambient temperatures (Ta). The model highlights distinct body temperature outcomes: fever and hypothermia. At thermoneutral Ta, severe sepsis induces a high fever, associated with increased hypothalamic PGE2, cytokine levels, and mortality, while mild sepsis leads to a moderate fever. In contrast, at subthermoneutral Ta, severe sepsis results in hypothermia with decreased UCP1 expression and lower mortality, whereas mild sepsis maintains normal body temperature. The impact of Ta on sepsis severity, thermoregulatory mechanisms, and survival is emphasized.

Abstract Chronic limb-threatening ischemia (CLTI) significantly increases the risk of major adverse limb events (MALE) and major adverse cardiac events (MACE) after lower extremity revascularization (LER). This study aims to identify novel biomarkers that help to further reduce the risk of postoperative cardiovascular complications. In this prospective, nonrandomized, observational study, baseline serum levels of sirtuin 1 (SIRT1) were assessed in 147 diabetic patients scheduled for LER due to CLTI, and participants were followed for the occurrence of MALE and MACE over 12 months. Fifty-three patients experienced MALE, and 33 experienced MACE within the follow-up period. Lower baseline SIRT1 levels were significantly associated with an increased risk of MALE and MACE, independent of other risk factors. The ROC curve analysis identified a SIRT1 cutoff of 3.79 ng/mL for predicting the risk of MALE. Moreover, incorporating SIRT1 into predictive models significantly enhanced the accuracy of predicting adverse outcomes. Results suggest serum SIRT1 is a potential independent marker for predicting MALE and MACE in diabetic patients with CLTI undergoing LER. Further research is needed to clarify the mechanistic pathways in which SIRT1 may influence cardiovascular outcomes, and the role of this novel biomarker in the management of PAD and CLTI among patients with diabetes.

Abstract Background Manually bent, standard-of-care, Ti–6Al–4V, mandibular graft fixation devices are associated with a significant post-operative failure rate. These failures require the patient to endure stressful and expensive re-operation. The approach recommended in this report demonstrates the optimization of graft fixation device mechanical properties via “stiffness-matching” by varying the fixation device’s location, shape, and material composition through simulation of the device’s post-operative performance. This provides information during pre-operative planning that may avoid future device failure. Optimized performance may combine translation of all loading into compression of the bone graft with the adjacent bone segments and elimination or minimization of post-healing interruption of normal stress–strain (loading) trajectories. Results This study reports a sheep mandibular graft model where four animals received virtually optimized, experimental nickel–titanium (NiTi) fixation plates fabricated using laser beam powder bed fusion (LPBF) additive manufacturing (AM). The last animal, our control, received a standard-of-care, manually bent, Ti–6Al–4V (aka Ti64) fixation plate. A 17.5-mm mandibular graft healed completely in all four animals receiving the experimental device. Experimental NiTi-implanted sheep experienced mandibular bone healing and restoration. The Ti64 plate, in the control animal, fractured and dislocated shortly after being implanted. Conclusion The use of stiffness-matched implants, by means of plate material (NiTi) and geometry (porosity) enhanced bone healing and promoted better load transfer to the healed bone when compared to the bulk Ti64 found in the fixation plate that the Control animal received. The design technique and screw orientation and depth planning improved throughout the study leading to more rapid healing. The large animal model reported here provides data useful for a follow-on clinical trial. Graphical Abstract

Abstract Background SARS-CoV-2 infection has become a major international issue, not only from a medical point of view, but also social, economic and political. Most of the available information comes from the United States, Europe, and China, where the population and the socioeconomic status are very different from Latin American countries. This study evaluates the effect of regional socioeconomic characteristics on mortality due SARS-CoV-2 infection in patients with immune-mediated rheumatic diseases (IMRD) from Argentina, Mexico and Brazil. Methods Data from three national registries, SAR-COVID (Argentina), CMR-COVID (Mexico) and ReumaCoV-Brasil (Brazil), were combined. Adult IMRD patients with SARS-CoV-2 infection were recruited. National data for each province/state, including population density, number of physicians per inhabitant, income, unemployment, GINI index, Municipal Human Development Index (MHDI), stringency index, vaccination rate and most frequent viral strains per period were assessed as risk factors for mortality due to COVID-19. Results A total of 4744 patients were included, 2534 (53.4%) from SAR-COVID, 1166 (24.6%) from CMRCOVID and 1044 (22.0%) from ReumaCoV-Brasil. Mortality due to COVID-19 was 5.4%. In the multivariable analysis, higher number of physicians per 1000 inhabitants and being infected during the vaccination period of each country were associated with lower mortality. After adjustment for socioeconomic factors, there was no association with country of residence and mortality. Conclusion These findings corroborate the complex interplay between socioeconomic factors, rheumatic disease activity, and regional disparities as determinants of death due to COVID-19 in Argentina, Brazil and Mexico. Thus, this research provides valuable insights for guiding public health policies and clinical practice in the ongoing fight against the COVID-19 pandemic.

Abstract Nuclear receptors (NRs) play a crucial role as biological targets in drug discovery. However, determining which compounds can act as endocrine disruptors and modulate the function of NRs with a reduced amount of candidate drugs is a challenging task. Moreover, the computational methods for NR-binding activity prediction mostly focus on a single receptor at a time, which may limit their effectiveness. Hence, the transfer of learned knowledge among multiple NRs can improve the performance of molecular predictors and lead to the development of more effective drugs. In this research, we integrate graph neural networks (GNNs) and Transformers to introduce a few-shot GNN-Transformer, Meta-GTNRP to predict the binding activity of compounds using the combined information of different NRs and identify potential NR-modulators with limited data. The Meta-GTNRP model captures the local information in graph-structured data and preserves the global-semantic structure of molecular graph embeddings for NR-binding activity prediction. Furthermore, a few-shot meta-learning approach is proposed to optimize model parameters for different NR-binding tasks and leverage the complementarity among multiple NR-specific tasks to predict binding activity of compounds for each NR with just a few labeled molecules. Experiments with a compound database containing annotations on the binding activity for 11 NRs shows that Meta-GTNRP outperforms other graph-based approaches. The data and code are available at: https://github.com/ltorres97/Meta-GTNRP . Scientific contribution The proposed few-shot GNN-Transformer model, Meta-GTNRP captures the local structure of molecular graphs and preserves the global-semantic information of graph embeddings to predict the NR-binding activity of compounds with limited available data; A few-shot meta-learning framework adapts model parameters across NR-specific tasks for different NRs in a joint learning procedure to predict the binding activity of compounds for each NR with just a few labeled molecules in highly imbalanced data scenarios; Meta-GTNRP is a data-efficient approach that combines the strengths of GNNs and Transformers to predict the NR-binding properties of compounds through an optimized meta-learning procedure and deliver robust results valuable to identify potential NR-based drug candidates.

Insectivorous bats of the family Vespertilionidae have been grouped into eight tribes, with Lasiurini showing an extensive distribution in South America. In Bolivia, three species of lasiurine bats have been reported: Lasiurus blossevillii (Lesson & Garnot, 1826), L. ega (Gervais, 1856), and L. villosissimus (É. Geoffroy St.-Hilaire, 1806). The morphological analyses of specimens of this genus deposited in Bolivian scientific collections and comparisons with specimens from other countries (including holotypes) prompt us to report the first records of three species: Lasiurus atratus Handley 1996, L. castaneus Handley 1960, and L. egregius (Peters, 1870) in Bolivia, expanding their known geographic ranges to the southwestern part of the Amazon.

Abstract Background A prediction model can be a useful tool to quantify the risk of a patient developing dementia in the next years and take risk-factor-targeted intervention. Numerous dementia prediction models have been developed, but few have been externally validated, likely limiting their clinical uptake. In our previous work, we had limited success in externally validating some of these existing models due to inadequate reporting. As a result, we are compelled to develop and externally validate novel models to predict dementia in the general population across a network of observational databases. We assess regularization methods to obtain parsimonious models that are of lower complexity and easier to implement. Methods Logistic regression models were developed across a network of five observational databases with electronic health records (EHRs) and claims data to predict 5-year dementia risk in persons aged 55–84. The regularization methods L1 and Broken Adaptive Ridge (BAR) as well as three candidate predictor sets to optimize prediction performance were assessed. The predictor sets include a baseline set using only age and sex, a full set including all available candidate predictors, and a phenotype set which includes a limited number of clinically relevant predictors. Results BAR can be used for variable selection, outperforming L1 when a parsimonious model is desired. Adding candidate predictors for disease diagnosis and drug exposure generally improves the performance of baseline models using only age and sex. While a model trained on German EHR data saw an increase in AUROC from 0.74 to 0.83 with additional predictors, a model trained on US EHR data showed only minimal improvement from 0.79 to 0.81 AUROC. Nevertheless, the latter model developed using BAR regularization on the clinically relevant predictor set was ultimately chosen as best performing model as it demonstrated more consistent external validation performance and improved calibration. Conclusions We developed and externally validated patient-level models to predict dementia. Our results show that although dementia prediction is highly driven by demographic age, adding predictors based on condition diagnoses and drug exposures further improves prediction performance. BAR regularization outperforms L1 regularization to yield the most parsimonious yet still well-performing prediction model for dementia.

Outer membrane vesicles (OMVs) are spherical structures that contain a small fraction of the periplasm of Gram-negative bacteria, surrounded by its outer membrane. They are naturally produced and detached from the bacterial surface, participate in diverse biological processes, and their diameter size is in the range of 10–300 nm. OMVs have gained interest in different applications, such as the development of biosensors, vaccines, protein chips, and the encapsulation of heterologous proteins and peptides expressed by these microorganisms. However, the use of OMVs in these applications is limited due to the low yields and high purification costs. In this study, we produced green fluorescent protein (GFP) encapsulated into OMVs using Escherichia coli JC8031 transformed with pTRC99A-ssTorA-GFP to establish the production and purification route. Results showed that the motility of the strain prevents its immobilization in alginate, which hampers the purification of OMVs. To address this issue, a zeolite-based column was used to chromatographically separate the OMVs from smaller particles. Further experiments will be focused on standardizing the production and purification of OMVs at a scalable level.

In-situ laser fenestration (ISLF) has been described as a viable option for urgent thoracic aortic aneurysm cases involving supra-aortic vessels. There are, however, limited data on its durability. Here, we present a case of a 70-year-old man with a symptomatic 13-cm thoracic aortic aneurysm extending proximally to the origin of the left subclavian artery (LSA). Emergent thoracic endovascular aortic repair with chimney stenting of the left common carotid artery and ISLF for the LSA was successfully performed. During the follow-up, a compression of the bridging stent to the LSA progressed to a stent fracture needing realignment. Despite ISLF’s reported technical success, this case highlights the risk of bridging stent complications, emphasizing the need for a close follow-up.

Abstract Phages play an essential role in controlling bacterial populations. Those infecting Pelagibacterales (SAR11), the dominant bacteria in surface oceans, have been studied in silico and by cultivation attempts. However, little is known about the quantity of phage-infected cells in the environment. Using fluorescence in situ hybridization techniques, we here show pelagiphage-infected SAR11 cells across multiple global ecosystems and present evidence for tight community control of pelagiphages on the SAR11 hosts in a case study. Up to 19% of SAR11 cells were phage-infected during a phytoplankton bloom, coinciding with a ~90% reduction in SAR11 cell abundance within 5 days. Frequently, a fraction of the infected SAR11 cells were devoid of detectable ribosomes, which appear to be a yet undescribed possible stage during pelagiphage infection. We dubbed such cells zombies and propose, among other possible explanations, a mechanism in which ribosomal RNA is used as a resource for the synthesis of new phage genomes. On a global scale, we detected phage-infected SAR11 and zombie cells in the Atlantic, Pacific, and Southern Oceans. Our findings illuminate the important impact of pelagiphages on SAR11 populations and unveil the presence of ribosome-deprived zombie cells as part of the infection cycle.

Abstract Cells in obligately multicellular organisms by definition have aligned fitness interests, minimum conflict, and cannot reproduce independently. However, some cells eat other cells within the same body, sometimes called cell cannibalism. Such cell-in-cell events have not been thoroughly discussed in the framework of major transitions to multicellularity. We performed a systematic screening of 508 articles, from which we chose 115 relevant articles in a search for cell-in-cell events across the tree of life, the age of cell-in-cell-related genes, and whether cell-in-cell events are associated with normal multicellular development or cancer. Cell-in-cell events are found across the tree of life, from some unicellular to many multicellular organisms, including non-neoplastic and neoplastic tissue. Additionally, out of the 38 cell-in-cell-related genes found in the literature, 14 genes were over 2.2 billion years old, i.e., older than the common ancestor of some facultatively multicellular taxa. All of this suggests that cell-in-cell events may have originated before the origins of obligate multicellularity. Thus, our results show that cell-in-cell events exist in obligate multicellular organisms, but are not a defining feature of them. The idea of eradicating cell-in-cell events from obligate multicellular organisms as a way of treating cancer, without considering that cell-in-cell events are also part of normal development, should be abandoned.

IntroductionParkinson’s disease (PD) presents a significant challenge in medical science, as current treatments are limited to symptom management and often carry significant side effects. Our study introduces an innovative approach to evaluate the effects of gdnf overexpression mediated by CRISPRa in an in vitro model of Parkinson’s disease. The expression of gdnf can have neuroprotective effects, being related to the modulation of neuroinflammation and pathways associated with cell survival, differentiation, and growth.MethodsWe have developed a targeted delivery system using a magnetite nanostructured vehicle for the efficient transport of genetic material. This system has resulted in a substantial increase, up to 200-fold) in gdnf expression in an In vitro model of Parkinson’s disease using a mixed primary culture of astrocytes, neurons, and microglia.Results and DiscussionThe delivery system exhibits significant endosomal escape of more than 56%, crucial for the effective delivery and activation of the genetic material within cells. The increased gdnf expression correlates with a notable reduction in MAO-B complex activity, reaching basal values of 14.8 μU/μg of protein, and a reduction in reactive oxygen species. Additionally, there is up to a 34.6% increase in cell viability in an In vitro Parkinson’s disease model treated with the neurotoxin MPTP. Our study shows that increasing gdnf expression can remediate some of the cellular symptoms associated with Parkinson’s disease in an in vitro model of the disease using a novel nanostructured delivery system.

IntroductionAdvancements in endovascular therapy, especially in complex aortic procedures, underscore the need for additional post-certification training. Dedicated post-residency vascular fellowship programs offer exposure to diverse cases, research opportunities, and professional networking. The study aims to describe and present outcomes from the complex aortic fellowship program at the Vascular Surgery Department of the Uppsala University Hospital.MethodsNine former fellows who completed the aortic fellowship program at the Uppsala University Hospital from 2018 to 2023 were invited to take part in an anonymous 29-question survey through email. Demographic data, information about the existence of local aortic programs as well as on the types of aortic procedures performed were gained. The overall experience and impact of the fellowship were assessed using multiple interval scale questions, with a rating scale (1 excellent to 5 very poor). Finally, we provided the option to the participants to share additional feedback.ResultsMedian age of participants was 34 years (IQR, 30.5–36), with 44.4% being women (4/9). There was a significant variation in the number of publications produced during the fellowship, with an overall mean of 4 papers (IQR, 2–10). Regarding the long-term impact of the fellowship, 5/9 (55.6%) of the fellows have contributed to the implementation of a complex aortic program after finishing the fellowship, providing a broad range of complex aortic procedures. All fellows (9/9, 100%) stated that the quality of the fellowship was excellent. The clinical experience 7/9 (77.8%), the academic environment 7/9 (77.8%) and the research opportunities 7/9 (77.8%) together with the mentorship 9/9 (100%) and the work environment 8/9 (88.9%), were considered of most value among the fellows. In general, the survey participants agreed that the fellowship atmosphere was suitable for learning, 9/9 (100%), and that it had a positive impact on their current practice, 7/9 (77.8%). Currently, 5/9 (55.5%) of the fellows hold a position including academic involvement.ConclusionsThere is a universal need for additional post-certification training. The current study showed that a balanced clinical and scientific exposure to complex aortic diseases is broadly welcomed among young vascular surgeons. The extension of the fellowship to cover other disciplines dealing with complex aortic procedures can be of value.

Antecedentes: Los aneurismas y los divertículos del ventrículo izquierdo son afecciones raras en la infancia, con una prevalencia menor del 0.1%. Descritos desde 1886, constituyen una enfermedad grave que puede ser fatal en caso de no corregirse, debido principalmente a la presencia de anomalías asociadas y al riesgo de ruptura. Objetivo: Dar a conocer otras opciones de manejo de divertículos ventriculares, diferentes a las opciones quirúrgicas, usando materiales alternativos, que no se usan muy a menudo en la práctica diaria. Método: Se realiza una descripción detallada de un caso manejado de forma exitosa con estas nuevas modalidades de tratamiento. Resultados: El manejo endovascular del divertículo ventricular izquierdo, diagnosticado de forma prenatal en el paciente presentado, fue exitoso luego del fracaso inicial con el manejo quirúrgico. Conclusiones: El manejo endovascular de divertículos ventriculares, usando materiales alternativos a los que se usan comúnmente, es una opción atractiva y con resultados satisfactorios en estos pacientes.

Mucopolysaccharidosis IVA (MPS IVA) is a lysosomal storage disease caused by mutations in the gene encoding the lysosomal enzyme N-acetylgalactosamine-6-sulfate sulfatase (GALNS), resulting in the accumulation of keratan sulfate (KS) and chondroitin-6-sulfate (C6S). Previously, it was reported the production of an active human recombinant GALNS (rGALNS) in E. coli BL21(DE3). However, this recombinant enzyme was not taken up by HEK293 cells or MPS IVA skin fibroblasts. Here, we leveraged a glyco-engineered E. coli strain to produce a recombinant human GALNS bearing the eukaryotic trimannosyl core N-glycan, Man3GlcNAc2 (rGALNSoptGly). The N-glycosylated GALNS was produced at 100 mL and 1.65 L scales, purified and characterized with respect to pH stability, enzyme kinetic parameters, cell uptake, and KS clearance. The results showed that the addition of trimannosyl core N-glycans enhanced both protein stability and substrate affinity. rGALNSoptGly was capture through a mannose receptor-mediated process. This enzyme was delivered to the lysosome, where it reduced KS storage in human MPS IVA fibroblasts. This study demonstrates the potential of a glyco-engineered E. coli for producing a fully functional GALNS enzyme. It may offer an economic approach for the biosynthesis of a therapeutic glycoprotein that could prove useful for MPS IVA treatment. This strategy could be extended to other lysosomal enzymes that rely on the presence of mannose N-glycans for cell uptake.

Laboratory-scale experiments were conducted on Carboniferous Limestone gravels from the Mendip Hills area, England; sandstones from the Pirambóia and Botucatu formations, Paraná sedimentary basin, Brazil; samples of schist and quartzite from Caldas Novas Hydrothermal Complex, Brazil; and the minerals tantalite, cassiterite, and columbite from mining areas at Rio Grande do Norte State, Brazil, with the purpose of evaluating the release of 222Rn to the water phase. The specific surface area of the samples corresponded to 1.69–81.36 cm2g−1, which provided values of 0.001–1.68 dpm/g and 3.18 × 10−6 to 0.59 for the radon released and radon emanation coefficient, respectively. These results allowed us to calculate the radon flux with respect to the radon leakage, which corresponded to values of 0.00016–0.00158 Bq/m2/d for the denser materials and 0.018–0.43 Bq/m2/d for limestones and sandstones. They also permitted us to find an inverse, significant relationship between the radon generated by the minerals/rocks and the radon flux into the water phase, which was tested for sediments in coastal and inland Brazilian areas, demonstrating utility for evaluating the diffusive radon flux from the sediments, which is an important parameter to monitor submarine groundwater discharge (SGD) by means of radon as a natural tracer.

The E3 ubiquitin ligase Smurf1 catalyzes the ubiquitination and proteasomal degradation of several protein substrates related to inflammatory responses and antiviral signaling. This study investigated the role of Smurf1 in modulating inflammation induced by Betacoronavirus infection. Bone marrow-derived macrophages (BMDMs) from C57BL/6 (wild-type) or Smurf1-deficient (Smurf1−/−) mice were infected with MHV-A59 to evaluate the inflammatory response in vitro. Smurf1 was found to be required to downregulate the macrophage production of pro-inflammatory mediators, including TNF, and CXCL1; to control viral release from infected cells; and to increase cell viability. To assess the impact of Smurf 1 in vivo, we evaluated the infection of mice with MHV-A59 through the intranasal route. Smurf1−/− mice infected with a lethal inoculum of MHV-A59 succumbed earlier to infection. Intranasal inoculation with a 10-fold lower dose of MHV-A59 resulted in hematological parameter alterations in Smurf1−/− mice suggestive of exacerbated systemic inflammation. In the lung parenchyma, Smurf1 expression was essential to promote viral clearance, downregulating IFN-β mRNA and controlling the inflammatory profile of macrophages and neutrophils. Conversely, Smurf1 did not affect IFN-β mRNA regulation in the liver, but it was required to increase TNF and iNOS expression in neutrophils and decrease TNF expression in macrophages. In addition, Smurf1−/− mice exhibited augmented liver injuries, accompanied by high serum levels of alanine aminotransferase (ALT). These findings suggest that Smurf1 plays a critical role in regulating the inflammatory response in macrophages and attenuating systemic inflammation during Betacoronavirus infection.

Abstract One of the major paradigms in ecology is the understanding of processes and patterns related to the structure of biological communities. Reef ecosystems, with their high productivity, habitat heterogeneity, and fish diversity provide a model for studying these processes. We sampled four sites three times during the season associated with the California Current and two times associated with the North Equatorial Current using video-transects on the coast of Zihuatanejo, Guerrero, Mexico to determine the relationship between the habitat characteristics and the structure of the fish assemblage. We recorded a total of 26 families and 54 species and estimated fish richness and abundance. In addition to measuring local water variables such as temperature (°C), salinity (PPT), pH and dissolved oxygen (O2%), we determined habitat heterogeneity by processing photographs of the substrate and calculated rugosity using the tape chain. Oxygen and temperature were the variables associated to sea water conditions that differentiated the sampled sites. The fish community structure presented high correlations with temperature, salinity, and dissolved oxygen, followed by the heterogeneity components such as rugosity and substrate diversity. Our results showed that seasonal changes in water conditions and physical components in the coast of Zihuatanejo promotes changes in the fish community.

The importance of radiology in modern medicine is acknowledged for its non-invasive diagnostic capabilities, yet the manual formulation of unstructured medical reports poses time constraints and error risks. This study addresses the common limitation of Artificial Intelligence applications in medical image captioning, which typically focus on classification problems, lacking detailed information about the patient's condition. Despite advancements in AI-generated medical reports that incorporate descriptive details from X-ray images, which are essential for comprehensive reports, the challenge persists. The proposed solution involves a multimodal model utilizing Computer Vision for image representation and Natural Language Processing for textual report generation. A notable contribution is the innovative use of the Swin Transformer as the image encoder, enabling hierarchical mapping and enhanced model perception without a surge in parameters or computational costs. The model incorporates GPT-2 as the textual decoder, integrating cross-attention layers and bilingual training with datasets in Portuguese PT-BR and English. Promising results are noted in the proposed database with ROUGE-L 0.748, METEOR 0.741, and NIH CHEST X-ray with ROUGE-L 0.404 and METEOR 0.393.

Superparamagnetic iron oxide micro- and nanoparticles have significant applications in biomedical and chemical engineering. This study presents the development and evaluation of a novel low-cost microfluidic device for the purification and hyperconcentration of these magnetic particles. The device, fabricated using laser ablation of polymethyl methacrylate (PMMA), leverages precise control over fluid dynamics to efficiently separate magnetic particles from non-magnetic ones. We assessed the device’s performance through Multiphysics simulations and empirical tests, focusing on the separation of magnetite nanoparticles from blue carbon dots and magnetite microparticles from polystyrene microparticles at various total flow rates (TFRs). For nanoparticle separation, the device achieved a recall of up to 93.3 ± 4% and a precision of 95.9 ± 1.2% at an optimal TFR of 2 mL/h, significantly outperforming previous models, which only achieved a 50% recall. Microparticle separation demonstrated an accuracy of 98.1 ± 1% at a TFR of 2 mL/h in both simulations and experimental conditions. The Lagrangian model effectively captured the dynamics of magnetite microparticle separation from polystyrene microparticles, with close agreement between simulated and experimental results. Our findings underscore the device’s robust capability in distinguishing between magnetic and non-magnetic particles at both micro- and nanoscales. This study highlights the potential of low-cost, non-cleanroom manufacturing techniques to produce high-performance microfluidic devices, thereby expanding their accessibility and applicability in various industrial and research settings. The integration of a continuous magnet, as opposed to segmented magnets in previous designs, was identified as a key factor in enhancing magnetic separation efficiency.

(1) Background: There is increasing interest in the use of platelet-rich plasma and related orthobiologics for the treatment of chronic musculoskeletal disorders in horses; however, there is no information on the bibliometric impact of the literature published in this area. (2) Methods: A bibliometric analysis was performed using the bibliometrix R package by analyzing the documents registered in the WOS and Scopus databases from 2000 to 2024. The included registers were evaluated according to the menu of results from the biblioshiny web app (overview, sources, authors, documents, words, trending topics, clustering, conceptual structure, and social structure). (3) Conclusions: The documents produced were mainly published in Frontiers in Veterinary Science, Journal of Equine Veterinary Science, BMC Veterinary Research, and the American Journal of Veterinary Research). The most productive institutions were Universidad de Caldas, Colorado State University, University of California-Davis, and University of Leipzig, and the most productive countries were the USA, Brazil, and Colombia. Horse, platelet-rich plasma, equine, osteoarthritis, and autologous conditioned serum were the most frequently used keywords. The trending topics in this area are platelet lysates and orthobiologics. The collaboration network of authors, institutions, and countries shows an isolated development of individual author networks with modest collaboration between institutions and countries.

Microfluidic separators play a pivotal role in the biomedical and chemical industries by enabling precise fluid manipulations. Traditional fabrication of these devices typically requires costly cleanroom facilities, which limits their broader application. This study introduces a novel microfluidic device that leverages the passive Zweifach–Fung principle to overcome these financial barriers. Through Lagrangian computational simulations, we optimized an eleven-channel Zweifach–Fung configuration that achieved a perfect 100% recall rate for particles following a specified normal distribution. Experimental evaluations determined 2 mL/h as the optimal total flow rate (TFR), under which the device showcased exceptional performance enhancements in precision and recall for micrometer-sized particles, achieving an overall accuracy of 94% ± 3%. Fabricated using a cost-effective, non-cleanroom method, this approach represents a significant shift from conventional practices, dramatically reducing production costs while maintaining high operational efficacy. The cost of each chip is less than USD 0.90 cents and the manufacturing process takes only 15 min. The development of this device not only makes microfluidic technology more accessible but also sets a new standard for future advancements in the field.

In this work, the cell line SW620-GFP has been used in a complete magnetic hyperthermia assay, from the preparation of the ferrofluid with folate-coated iron oxide nanoparticles to in vivo experiments. The physical and chemical characterization of the nanoparticles evidenced their superparamagnetic behaviour, an average diameter of 12 ± 4 nm, a 2 nm coat thickness, and a high-power loss density. The main innovation of the work is the exclusive capability of viable SW620-GFP cells to emit fluorescence, enabling fast analysis of both, cell viability in vitro with an epifluorescence microscope and tumour size and shape in vivo in a non-invasive manner using the iBox technology. Moreover, with this imaging technique, it was possible to demonstrate the successful tumour size reduction in mice applying magnetic hyperthermia three times a week over 3 weeks.

We review the taxonomic identities of museum specimens of three bat species previously reported from Bolivia. We comment on some erroneously reported taxa, or taxa either not represented by voucher materials or based on insufficient data (including acoustic detections) to verify their taxonomic affinities. As result of this review, the list of bat species known to occur in Bolivia is updated to eight families and 133 species, unlike the nine families and 146 species of previous lists. Some recommendations for future research and a brief historical revision of bat inventories in the country are included.

Abstract Background Lower-extremity endovascular revascularization (LER) is often required for diabetic patients with chronic limb threatening ischemia (CLTI). During the post-revascularization period patients may unpredictably experience major adverse cardiac events (MACE) and major adverse limb events (MALE). Several families of cytokines are involved in the inflammatory process that underlies the progression of atherosclerosis. According to current evidence, we have identified a panel of possible biomarkers related with the risk of developing MACE and MALE after LER. The aim was to study the relationship between a panel of biomarkers - Interleukin-1 (IL-1) and 6 (IL-6), C-Reactive Protein (CRP), Tumor Necrosis Factor-α (TNF-α), High-Mobility Group Box-1 (HMGB-1), Osteoprotegerin (OPG), Sortilin and Omentin-1- at baseline, with cardiovascular outcomes (MACE and MALE) after LER in diabetic patients with CLTI. Methods In this prospective non-randomized study, 264 diabetic patients with CLTI undergoing endovascular revascularization were enrolled. Serum levels of each biomarker were collected before revascularization and outcomes’ incidence was evaluated after 1, 3, 6 and 12 months. Results During the follow-up period, 42 cases of MACE and 81 cases of MALE occurred. There was a linear association for each biomarker at baseline and incident MACE and MALE, except Omentin-1 levels that were inversely related to the presence of MACE or MALE. After adjusting for traditional cardiovascular risk factors, the association between each biomarker baseline level and outcomes remained significant in multivariable analysis. Receiver operating characteristics (ROC) models were constructed using traditional clinical and laboratory risk factors and the inclusion of biomarkers significantly improved the prediction of incident events. Conclusions Elevated IL-1, IL-6, CRP, TNF-α, HMGB-1, OPG and Sortilin levels and low Omentin-1 levels at baseline correlate with worse vascular outcomes in diabetic patients with CLTI undergoing LER. Assessment of the inflammatory state with this panel of biomarkers may support physicians to identify a subset of patients more susceptible to the procedure failure and to develop cardiovascular adverse events after LER.

Antecedentes: Los aneurismas de la aorta ascendente son patologías poco frecuentes en la infancia, sobre todo en ausencia de enfermedades previas como el síndrome de Marfan. Objetivo: Dar a conocer la posibilidad del manejo endovascular exitoso de los aneurismas de grandes vasos, usando stent y micro catéter con embolización del saco aneurismático. Método: Presentamos el caso de una paciente de 10 años y 2 meses, previamente sana, en quien se documentó un pseudoaneurisma entre el origen de la arteria carótida común izquierda y la arteria subclavia izquierda, que logró manejarse de forma endovascular, inicialmente con un stent cubriendo el cuello del aneurisma con el fin de remodelarlo y posteriormente por medio de microcatéter se realizó embolización del saco del aneurisma con coils, con resultado exitoso. Resultados: Los aneurismas de los grandes vasos, como la arteria carótida común y la arteria subclavia, tienen riesgo de ruptura con complicaciones devastadoras; el manejo endovascular se plantea como una opción poco invasiva de manejo, con resultados favorables. Conclusión: El manejo de aneurismas de grandes vasos, por vía endovascular usando stent y microcatéter con embolización del saco aneurismático, es una opción novedosa de manejo que logra resultados exitosos.

ABSTRACTLarge-scale surveys of prokaryotic communities (metagenomes), as well as isolate genomes, have revealed that their diversity is predominantly organized in sequence-discrete units that may be equated to species. Specifically, genomes of the same species commonly show genome-aggregate average nucleotide identity (ANI) >95% among themselves and ANI 99.99% proposed). Collectively, our results should facilitate future micro-diversity studies across clinical or environmental settings because they provide a more natural definition of intra-species units of diversity.IMPORTANCEBacterial strains and clonal complexes are two cornerstone concepts for microbiology that remain loosely defined, which confuses communication and research. Here we identify a natural gap in genome sequence comparisons among isolate genomes of all well-sequenced species that has gone unnoticed so far and could be used to more accurately and precisely define these and related concepts compared to current methods. These findings advance the molecular toolbox for accurately delineating and following the important units of diversity within prokaryotic species and thus should greatly facilitate future epidemiological and micro-diversity studies across clinical and environmental settings.

Although microparticles are frequently used in chemistry and biology, their effectiveness largely depends on the homogeneity of their particle size distribution. Microfluidic devices to separate and purify particles based on their size have been developed, but many require expensive cleanroom manufacturing processes. A cost-effective, passive microfluidic separator is presented, capable of efficiently sorting and purifying particles spanning the size range of 15 µm to 40 µm. Fabricated from Polymethyl Methacrylate (PMMA) substrates using laser ablation, this device circumvents the need for cleanroom facilities. Prior to fabrication, rigorous optimization of the device's design was carried out through computational simulations conducted in COMSOL Multiphysics. To gauge its performance, chitosan microparticles were employed as a test case. The results were notably promising, achieving a precision of 96.14 %. This quantitative metric underscores the device's precision and effectiveness in size-based particle separation.This low-cost and accessible microfluidic separator offers a pragmatic solution for laboratories and researchers seeking precise control over particle sizes, without the constraints of expensive manufacturing environments. This innovation not only mitigates the limitations tied to traditional cleanroom-based fabrication but also widens the horizons for various applications within the realms of chemistry and biology.

Abstract Background Over the past years, sequencing technologies have expanded our ability to examine novel microbial metabolisms and diversity previously obscured by isolation approaches. Long-read sequencing promises to revolutionize the metagenomic field and recover less fragmented genomes from environmental samples. Nonetheless, how to best benefit from long-read sequencing and whether long-read sequencing can provide recovered genomes of similar characteristics as short-read approaches remains unclear. Results We recovered metagenome-assembled genomes (MAGs) from the free-living fraction at four-time points during a spring bloom in the North Sea. The taxonomic composition of all MAGs recovered was comparable between technologies. However, differences consisted of higher sequencing depth for contigs and higher genome population diversity in short-read compared to long-read metagenomes. When pairing population genomes recovered from both sequencing approaches that shared ≥ 99% average nucleotide identity, long-read MAGs were composed of fewer contigs, a higher N50, and a higher number of predicted genes when compared to short-read MAGs. Moreover, 88% of the total long-read MAGs carried a 16S rRNA gene compared to only 23% of MAGs recovered from short-read metagenomes. Relative abundances for population genomes recovered using both technologies were similar, although disagreements were observed for high and low GC content MAGs. Conclusions Our results highlight that short-read technologies recovered more MAGs and a higher number of species than long-read due to an overall higher sequencing depth. Long-read samples produced higher quality MAGs and similar species composition compared to short-read sequencing. Differences in the GC content recovered by each sequencing technology resulted in divergences in the diversity recovered and relative abundance of MAGs within the GC content boundaries.

Abstract Cardiovascular complications after lower extremity revascularization (LER) are common in diabetic patients with peripheral arterial disease (PAD) and chronic limb threatening ischemia (CLTI). The Klotho-fibroblast growth factor 23 (FGF23) axis is associated with endothelial injury and cardiovascular risk. We aimed to analyze the relationship between Klotho and FGF23 serum levels and the incidence of major adverse cardiovascular events (MACE) and major adverse limb events (MALE) after LER in diabetic patients with PAD and CLTI. Baseline levels of Klotho and FGF23, and their association with subsequent incidence of MACE and MALE were analyzed in a prospective, non-randomized study in a population of diabetic patients with PAD and CLTI requiring LER. A total of 220 patients were followed for 12 months after LER. Sixty-three MACE and 122 MALE were recorded during follow-up period. Baseline lower Klotho serum levels (295.3 ± 151.3 pg/mL vs. 446.4 ± 171.7 pg/mL, p

In the cognitive and neural sciences, Bayesianism refers to a collection of concepts and methods stemming from various implementations of Bayes’ theorem, which is a formal way to calculate the conditional probability of a hypothesis being true based on prior expectations and updating priors in the face of errors. Bayes’ theorem has been fruitfully applied to describe and explain a wide range of cognitive and neural phenomena (e.g., visual perception and neural population activity) and is at the core of various theories (e.g., predictive processing). Despite these successes, we claim that Bayesianism has two interrelated shortcomings: its calculations and models are predominantly linear and noise is assumed to be random and unstructured versus deterministic. We outline ways that Bayesianism can address those shortcomings: first, by making more central the nonlinearities characteristic of biological cognitive systems, and second, by treating noise not as random and unstructured dynamics, but as the kind of structured nonlinearities of complex dynamical systems (e.g., chaos and fractals). We provide bistable visual percepts as an example of a real-world phenomenon that demonstrates the fruitfulness of integrating complex dynamical systems theory in Bayesian treatments of perception. Doing so facilitates a Bayesianism that is more capable of explaining a number of currently out-of-reach natural phenomena on their own, biologically realistic terms.

La conservación y tratamiento adecuado de las frutas postcosecha es fundamental para su comercialización en mercados internacionales. Este proceso permite mantener la calidad, frescura y atractivo de los productos asegurando su competitividad en el mercado global, que además exige el cumplimiento de normas de calidad estrictas, como las Buenas Prácticas Agrícolas (BPA) y las regulaciones fitosanitarias. El tratamiento postcosecha incluye una serie de prácticas y tecnologías que se aplican a las frutas después de su cosecha, con el fin de prolongar su vida útil y mantener sus características organolépticas. Entre estas prácticas se encuentran el control de la temperatura, la humedad, la atmósfera y el uso de recubrimientos comestibles, que garantizan una menor pérdida de peso, mejor apariencia y reducción de enfermedades y desórdenes fisiológicos. Además, el tratamiento postcosecha es crucial para reducir las pérdidas y el desperdicio de alimentos, contribuyendo a la sostenibilidad y a la seguridad alimentaria. El manejo postcosecha también es relevante para mantener la inocuidad alimentaria, al reducir la presencia de patógenos y contaminantes químicos. Finalmente es de suma importancia que las investigaciones se orienten para dar respuesta a los problemas reales a los que se enfrentan los distintos actores de la cadena frutihortícola.

Summary: Background: While vaccines have established utility against COVID-19, phase 3 efficacy studies have generally not comprehensively evaluated protection provided by previous infection or hybrid immunity (previous infection plus vaccination). Individual patient data from US government-supported harmonized vaccine trials provide an unprecedented sample population to address this issue. We characterized the protective efficacy of previous SARS-CoV-2 infection and hybrid immunity against COVID-19 early in the pandemic over three-to six-month follow-up and compared with vaccine-associated protection. Methods: In this post-hoc cross-protocol analysis of the Moderna, AstraZeneca, Janssen, and Novavax COVID-19 vaccine clinical trials, we allocated participants into four groups based on previous-infection status at enrolment and treatment: no previous infection/placebo; previous infection/placebo; no previous infection/vaccine; and previous infection/vaccine. The main outcome was RT-PCR-confirmed COVID-19 >7–15 days (per original protocols) after final study injection. We calculated crude and adjusted efficacy measures. Findings: Previous infection/placebo participants had a 92% decreased risk of future COVID-19 compared to no previous infection/placebo participants (overall hazard ratio [HR] ratio: 0.08; 95% CI: 0.05–0.13). Among single-dose Janssen participants, hybrid immunity conferred greater protection than vaccine alone (HR: 0.03; 95% CI: 0.01–0.10). Too few infections were observed to draw statistical inferences comparing hybrid immunity to vaccine alone for other trials. Vaccination, previous infection, and hybrid immunity all provided near-complete protection against severe disease. Interpretation: Previous infection, any hybrid immunity, and two-dose vaccination all provided substantial protection against symptomatic and severe COVID-19 through the early Delta period. Thus, as a surrogate for natural infection, vaccination remains the safest approach to protection. Funding: National Institutes of Health.

This paper presents a properly designed branch current based state estimator (BCBSE) used as the main core of an accurate fault location approach (FLA) devoted to distribution networks. Contrary to the approaches available in the literature, it uses only a limited set of conventional measurements obtained from smart meters to accurately locate faults at buses or branches without requiring measurements provided by phasor measurement units (PMUs). This is possible due to the methods used to model the angular reference and the faulted bus, in addition to the proper choice of the weights in the state estimator (SE). The proposed approach is based on a searching procedure composed of up to three stages: ① the identification of the faulted zones; ② the identification of the bus closest to the fault; and ③ the location of the fault itself, searching on branches connected to the bus closest to the fault. Furthermore, this paper presents a comprehensive assessment of the proposed approach, even considering the presence of distributed generation, and a sensitivity study on the proper weights required by the SE for fault location purposes, which can not be found in the literature. Results show that the proposed BCBSE-based FLA is robust, accurate, and aligned with the requirements of the traditional and active distribution networks.

Background and Aims: Sugammadex (SUG) has been associated with changes in coagulation studies. Most reports have concluded a lack of clinical significance based on surgical blood loss with SUG use at the end of surgery. Previous reports have not measured its use intraoperatively during ongoing blood loss. Our hypothesis was that the use of SUG intraoperatively may increase bleeding. Material and Methods: This was a single site retrospective study. Inclusion criteria were patients undergoing a primary posterior cervical spine fusion, aged over 18 years, between July 2015 and June 2021. The primary outcomes compared were intraoperative estimated blood loss (EBL) and postoperative drain output (PDO) between patients receiving SUG, neostigmine (NEO) and no NMB reversal agent. The objective was to determine if there was a difference in primary endpoints between patients administered SUG, NEO or no paralytic reversal agent. Primary endpoints were compared using analysis of variance with a P value of 0.05 used to determine statistical significance. Groups were compared using the Chi-squared test, rank sum or student's t test. A logistic regression model was constructed to account for differences between the groups. Results: There was no difference in median EBL or PDO between groups. The use of SUG was not associated with an increase in odds for >500 milliliters (ml) of EBL. Increasing duration of surgery and chronic kidney disease were both associated with an increased risk for EBL >500 ml. Conclusion: Intraoperative use of SUG was not associated with increased bleeding. Any coagulation laboratory abnormalities previously noted did not appear to have an associated clinical significance.

Abstract Background Many dementia prediction models have been developed, but only few have been externally validated, which hinders clinical uptake and may pose a risk if models are applied to actual patients regardless. Externally validating an existing prediction model is a difficult task, where we mostly rely on the completeness of model reporting in a published article. In this study, we aim to externally validate existing dementia prediction models. To that end, we define model reporting criteria, review published studies, and externally validate three well reported models using routinely collected health data from administrative claims and electronic health records. Methods We identified dementia prediction models that were developed between 2011 and 2020 and assessed if they could be externally validated given a set of model criteria. In addition, we externally validated three of these models (Walters’ Dementia Risk Score, Mehta’s RxDx-Dementia Risk Index, and Nori’s ADRD dementia prediction model) on a network of six observational health databases from the United States, United Kingdom, Germany and the Netherlands, including the original development databases of the models. Results We reviewed 59 dementia prediction models. All models reported the prediction method, development database, and target and outcome definitions. Less frequently reported by these 59 prediction models were predictor definitions (52 models) including the time window in which a predictor is assessed (21 models), predictor coefficients (20 models), and the time-at-risk (42 models). The validation of the model by Walters (development c-statistic: 0.84) showed moderate transportability (0.67–0.76 c-statistic). The Mehta model (development c-statistic: 0.81) transported well to some of the external databases (0.69–0.79 c-statistic). The Nori model (development AUROC: 0.69) transported well (0.62–0.68 AUROC) but performed modestly overall. Recalibration showed improvements for the Walters and Nori models, while recalibration could not be assessed for the Mehta model due to unreported baseline hazard. Conclusion We observed that reporting is mostly insufficient to fully externally validate published dementia prediction models, and therefore, it is uncertain how well these models would work in other clinical settings. We emphasize the importance of following established guidelines for reporting clinical prediction models. We recommend that reporting should be more explicit and have external validation in mind if the model is meant to be applied in different settings.

Abstract Background Up to 40% of patients with estrogen receptor-positive (ER+) breast cancer experience relapse. This can be attributed to breast cancer stem cells (BCSCs), which are known to be involved in therapy resistance, relapse, and metastasis. Therefore, there is an urgent need to identify genes/pathways that drive stem-like cell properties in ER+ breast tumors. Methods Using single-cell RNA sequencing and various bioinformatics approaches, we identified a unique stem-like population and established its clinical relevance. With follow-up studies, we validated our bioinformatics findings and confirmed the role of ER and NFĸB in the promotion of stem-like properties in breast cancer cell lines and patient-derived models. Results We identified a novel quiescent stem-like cell population that is driven by ER and NFĸB in multiple ER+ breast cancer models. Moreover, we found that a gene signature derived from this stem-like population is expressed in primary ER+ breast tumors, endocrine therapy-resistant and metastatic cell populations and predictive of poor patient outcome. Conclusions These findings indicate a novel role for ER and NFĸB crosstalk in BCSCs biology and understanding the mechanism by which these pathways promote stem properties can be exploited to improve outcomes for ER+ breast cancer patients at risk of relapse.

Esta investigación presenta un enfoque alternativo para calcular el contenido de carbono orgánico total utilizando registros de cable y técnicas de aprendizaje automático; específicamente, imágenes resistivas de pozo, su resistividad promedio y registro de rayos gamma son empleados para entrenar un modelo regresivo. La metodología se aplicó en la Formación La Luna, la cual ha sido reportada como una de las principales rocas generadoras de Colombia y el oeste de Venezuela. El objetivo de este trabajo es enseñar a una máquina como reconocer patrones entre rasgos fractales en imágenes de pozo y su contenido de carbono orgánico total. El aprendizaje automático implementado se basa en técnicas de aprendizaje por conjuntos, en este caso, un conjunto de árboles de decisión conocido como bosques aleatorios. Los datos empleados tienen un total de 960 mediciones de registros, los cuales fueron divididos aleatoriamente en 80% para entrenamiento y 20% para validación. El resultado es equivalente a la curva obtenida con una regresión semilogarítmica del carbono orgánico medido en el núcleo contra valores de registro de densidad. La precisión de este método es suficientemente alta para ser considerada durante evaluaciones petrofísicas, mostrando un error medio cuadrático de 0.44% y un coeficiente de correlación de Pearson de 0.88. La metodología depende de la calidad de la imagen y cualquier anomalía en estos datos aumentará el error. El modelo generado debe ser recalibrado para otras formaciones, pozos horizontales, desviados y cuando se empleen registro de imágenes durante la perforación.

Colobomas of the globe and microphthalmia are congenital conditions that can strongly affect vision. Etiologies are varied and include embryonic and hereditary origins. We report what is, to the best of our knowledge, the first case of a SIX6 gene pathogenic variant associated with a phenotype of both bilateral microphthalmia and extensive colobomas of the globes. A 3-week-old boy presented with bilateral microphthalmia and iris, optic nerve, and chorioretinal colobomas. Genetic analysis was performed on a panel of 78 genes (microphthalmia, anophthalmia, and coloboma panel), and a homozygous likely pathogenic variant was identified in the SIX6 gene, resulting in the loss of the initiator methionine. Thus, our report expands the phenotypic spectrum of SIX6-related disorders.

Abstract Background Peripheral arterial disease (PAD) is one of the most disabling cardiovascular complications of type 2 diabetes mellitus and is indeed associated with a high risk of cardiovascular and limb adverse events. High mobility group box-1 (HMGB-1) is a nuclear protein involved in the inflammatory response that acts as a pro-inflammatory cytokine when released into the extracellular space. HMBG-1 is associated with PAD in diabetic patients. The aim of this study was to evaluate the association between serum HMGB-1 levels and major adverse cardiovascular events (MACE) and major adverse limb events (MALE) after lower-extremity endovascular revascularization (LER) in a group of diabetic patients with chronic limb-threatening ischemia (CLTI). Methods We conducted a prospective observational study of 201 diabetic patients with PAD and CLTI requiring LER. Baseline serum HMGB-1 levels were determined before endovascular procedure. Data on cardiovascular and limb outcomes were collected in a 12-month follow-up. Results During the follow-up period, 81 cases of MACE and 93 cases of MALE occurred. Patients who subsequently developed MACE and MALE had higher serum HMGB-1 levels. Specifically, 7.5 ng/mL vs 4.9 ng/mL (p

Abstract Mucopolysaccharidosis IV A (MPS IVA) is a lysosomal disorder caused by mutations in the GALNS gene. Consequently, the glycosaminoglycans (GAGs) keratan sulfate and chondroitin 6-sulfate accumulate in the lysosomal lumen. Although enzyme replacement therapy has shown essential advantages for the patients, several challenges remain to overcome, such as the limited impact on the bone lesion and recovery of oxidative profile. Recently, we validated a CRISPR/nCas9-based gene therapy with promising results in an in vitro MPS IVA model. In this study, we have expanded the use of this CRISPR/nCas9 system to several MPS IVA fibroblasts carrying different GALNS mutations. Considering the latent need to develop more safety vectors for gene therapy, we co-delivered the CRISPR/nCas9 system with a novel non-viral vector based on magnetoliposomes (MLPs). We found that the CRISPR/nCas9 treatment led to an increase in enzyme activity between 5 and 88% of wild-type levels, as well as a reduction in GAGs accumulation, lysosomal mass, and mitochondrial-dependent oxidative stress, in a mutation-dependent manner. Noteworthy, MLPs allowed to obtain similar results to those observed with the conventional transfection agent lipofectamine. Overall, these results confirmed the potential of CRISPR/nCas9 as a genome editing tool for treating MPS IVA. We also demonstrated the potential use of MLPs as a novel delivery system for CRISPR/nCas9-based therapies.

Background: Chronic Kidney Disease (CKD) is a global public health problem with increasing prevalence and a substantial burden on healthcare systems. The characteristics of rapid progressors and factors that may predict accelerated CKD progression require further exploration, especially since there are no published studies about this topic in Colombia. Purpose: To identify the clinical and sociodemographic factors associated with the rapid progression of CKD in a large cohort of Colombian patients. Methods: This retrospective observational study included two cohorts of G1 to G4 stage CKD patients without dialysis from the Colombian North Coast. Follow-up was conducted for 18 months (n=14,420) and 24 months (n=10,042). Patients were divided into rapid progressors and stable progressors based on the glomerular filtration rate (GFR) slope 5 mL/min/1.73m2/year or ?-5 mL/min/1.73 m2/year, respectively. Results: 37.68% of the cohort was classified as rapid progressors at 24 months and 28.41% at 18 months. An R2=0.77 was found in both cohorts for GFR measurements, indicating a linear trend toward loss. Furthermore, accelerated progression was observed in younger patients and those with higher diastolic blood pressure values. Conclusion: In two large cohorts of renal patients, approximately 4 out of 10 patients were classified as rapid progressors at 24 months of follow-up and 3 out of 10 at 18 months of follow-up. It is important to identify patients at higher risk of accelerated CKD progression in the short term to provide them with personalized and effective care.

Abstract Venous aneurysms are rare and have a prevalence of 0.1 to 0.2% in the reported series. Typically, patients do not present any symptoms, but are prone to develop deep venous thrombosis (DVT) and the most feared complication, pulmonary embolism (PE). We present the case of a previously healthy 36-year-old man who presented at the emergency department with tachycardia, dyspnea, and pleuritic pain. A thoracic computed tomography angiography (CTA) confirmed the diagnosis of acute pulmonary embolism. He was treated with systemic thrombolysis and anticoagulation. In the further workup of the cause of the embolism, computed tomography revealed a fusiform dilation of the left popliteal vein measuring 3 by 3 centimeters (cm) with an incomplete filling defect because of thrombus presence. The patient underwent open surgical repair. At one month follow-up, he was asymptomatic, and an ultrasound revealed complete patency of the popliteal vein without dilatation or thrombus.

ABSTRACT Net growth of microbial populations, that is, changes in abundances over time, can be studied using 16S rRNA fluorescence in situ hybridization (FISH). However, this approach does not differentiate between mortality and cell division rates. We used FISH-based image cytometry in combination with dilution culture experiments to study net growth, cell division, and mortality rates of four bacterial taxa over two distinct phytoplankton blooms: the oligotrophs SAR11 and SAR86, and the copiotrophic phylum Bacteroidetes, and its genus Aurantivirga. Cell volumes, ribosome content, and frequency of dividing cells (FDC) co-varied over time. Among the three, FDC was the most suitable predictor to calculate cell division rates for the selected taxa. The FDC-derived cell division rates for SAR86 of up to 0.8/day and Aurantivirga of up to 1.9/day differed, as expected for oligotrophs and copiotrophs. Surprisingly, SAR11 also reached high cell division rates of up to 1.9/day, even before the onset of phytoplankton blooms. For all four taxonomic groups, the abundance-derived net growth (−0.6 to 0.5/day) was about an order of magnitude lower than the cell division rates. Consequently, mortality rates were comparably high to cell division rates, indicating that about 90% of bacterial production is recycled without apparent time lag within 1 day. Our study shows that determining taxon-specific cell division rates complements omics-based tools and provides unprecedented clues on individual bacterial growth strategies including bottom–up and top–down controls. IMPORTANCE The growth of a microbial population is often calculated from their numerical abundance over time. However, this does not take cell division and mortality rates into account, which are important for deriving ecological processes like bottom–up and top–down control. In this study, we determined growth by numerical abundance and calibrated microscopy-based methods to determine the frequency of dividing cells and subsequently calculate taxon-specific cell division rates in situ. The cell division and mortality rates of two oligotrophic (SAR11 and SAR86) and two copiotrophic (Bacteroidetes and Aurantivirga) taxa during two spring phytoplankton blooms showed a tight coupling for all four taxa throughout the blooms without any temporal offset. Unexpectedly, SAR11 showed high cell division rates days before the bloom while cell abundances remained constant, which is indicative of strong top–down control. Microscopy remains the method of choice to understand ecological processes like top–down and bottom–up control on a cellular level.

The concept of representation is commonly treated as indispensable to research on brains, behavior, and cognition. Nevertheless, systematic evidence about the ways the concept is applied remains scarce. We present the results of an experiment aimed at elucidating what researchers mean by “representation.” Participants were an international group of psychologists, neuroscientists, and philosophers (N = 736). Applying elicitation methodology, participants responded to a survey with experimental scenarios aimed at invoking applications of “representation” and five other ways of describing how the brain responds to stimuli. While we find little disciplinary variation in the application of “representation” and other expressions (e.g., “about” and “carry information”), the results suggest that researchers exhibit uncertainty about what sorts of brain activity involve representations or not; they also prefer non-representational, causal characterizations of the brain’s response to stimuli. Potential consequences of these findings are explored, such as reforming or eliminating the concept of representation from use.

There is a growing demand for nutritional, functional, and eco-friendly dairy products, which has increased the need for research regarding alternative and sustainable protein sources. Plant-based, single-cell (SCP), and recombinant proteins are being explored as alternatives to dairy proteins. Plant-Based Proteins (PBPs) are commonly used to replace total dairy protein. However, PBPs are generally mixed with dairy proteins to improve their functional properties, which makes them dependent on animal protein sources. In contrast, single-Cell Proteins (SCPs) and recombinant dairy proteins are promising alternatives for dairy protein replacement since they provide nutritional components, essential amino acids, and high protein yield and can use industrial and agricultural waste as carbon sources. Although alternative protein sources offer numerous advantages over conventional dairy proteins, several technical and sensory challenges must be addressed to fully incorporate them into cheese and yogurt products. Future research can focus on improving the functional and sensory properties of alternative protein sources and developing new processing technologies to optimize their use in dairy products. This review highlights the current status of alternative dairy proteins in cheese and yogurt, their functional properties, and the challenges of their use in these products.

Extracranial carotid artery aneurysms (CAAs) are extremely rare and often require surgical intervention to avoid complications such as local compression symptoms and thrombo-embolization. We present the case of a 63-year-old man with a history of hypertension, meningioma, and an incidental finding of a right saccular internal carotid artery aneurysm at the base of the skull. He underwent open surgical repair; nonetheless, end-to-end anastomosis was not feasible. As bailout, the internal carotid artery was successfully reconstructed with a novel Viabahn-assisted sutureless anastomosis technique (GORE, Viabahn). Postoperative clinical assessment revealed no complications, postoperative computed tomography angiography revealed a patent reconstruction, and the patient was discharged home uneventfully with 1-year clinical and computed tomography angiography follow-up without remarks. Hybrid procedure is a viable option for technically challenging carotid anastomoses near the skull base.