GET: a foundation model of transcription across human cell types.

Transcriptional regulation, involving the complex interplay between regulatory sequences and proteins, directs all biological processes. Computational models of transcription lack generalizability to accurately extrapolate in unseen cell types and conditions. Here, we introduce GET, an interpretable foundation model designed to uncover regulatory grammars across 213 human fetal and adult cell types. Relying exclusively on chromatin accessibility data and sequence information, GET achieves experimental-level accuracy in predicting gene expression even in previously unseen cell types. GET showcases remarkable adaptability across new sequencing platforms and assays, enabling regulatory inference across a broad range of cell types and conditions, and uncovering universal and cell type specific transcription factor interaction networks. We evaluated its performance on prediction of regulatory activity, inference of regulatory elements and regulators, and identification of physical interactions between transcription factors. Specifically, we show GET outperforms current models in predicting lentivirus-based massive parallel reporter assay readout with reduced input data. In fetal erythroblasts, we identify distal (>1Mbp) regulatory regions that were missed by previous models. In B cells, we identified a lymphocyte-specific transcription factor-transcription factor interaction that explains the functional significance of a leukemia-risk predisposing germline mutation. In sum, we provide a generalizable and accurate model for transcription together with catalogs of gene regulation and transcription factor interactions, all with cell type specificity.

The Microalgae Chlamydomonas for Bioremediation and Bioproduct Production.

The extensive metabolic diversity of microalgae, coupled with their rapid growth rates and cost-effective production, position these organisms as highly promising resources for a wide range of biotechnological applications. These characteristics allow microalgae to address crucial needs in the agricultural, medical, and industrial sectors. Microalgae are proving to be valuable in various fields, including the remediation of diverse wastewater types, the production of biofuels and biofertilizers, and the extraction of various products from their biomass. For decades, the microalga Chlamydomonas has been widely used as a fundamental research model organism in various areas such as photosynthesis, respiration, sulfur and phosphorus metabolism, nitrogen metabolism, and flagella synthesis, among others. However, in recent years, the potential of Chlamydomonas as a biotechnological tool for bioremediation, biofertilization, biomass, and bioproducts production has been increasingly recognized. Bioremediation of wastewater using Chlamydomonas presents significant potential for sustainable reduction in contaminants and facilitates resource recovery and valorization of microalgal biomass, offering important economic benefits. Chlamydomonas has also established itself as a platform for the production of a wide variety of biotechnologically interesting products, such as different types of biofuels, and high-value-added products. The aim of this review is to achieve a comprehensive understanding of the potential of Chlamydomonas in these aspects, and to explore their interrelationship, which would offer significant environmental and biotechnological advantages.

Face-brain correlates as potential sex-specific biomarkers for schizophrenia and bipolar disorder.

Given the shared ectodermal origin and integrated development of the face and the brain, facial biomarkers emerge as potential candidates to assess vulnerability for disorders in which neurodevelopment is compromised, such as schizophrenia (SZ) and bipolar disorder (BD). The sample comprised 188 individuals (67 SZ patients, 46 BD patients and 75 healthy controls (HC)). Using a landmark-based approach on 3D facial reconstructions, we quantified global and local facial shape differences between SZ/BD patients and HC using geometric morphometrics. We also assessed correlations between facial and brain cortical measures. All analyses were performed separately by sex. Diagnosis explained 4.1 % - 5.9 % of global facial shape variance in males and females with SZ, and 4.5 % - 4.1 % in BD. Regarding local facial shape, we detected 43.2 % of significantly different distances in males and 47.4 % in females with SZ as compared to HC, whereas in BD the percentages decreased to 35.8 % and 26.8 %, respectively. We detected that brain area and volume significantly explained 2.2 % and 2 % of facial shape variance in the male SZ - HC sample. Our results support facial shape as a neurodevelopmental marker for SZ and BD and reveal sex-specific pathophysiological mechanisms modulating the interplay between the brain and the face.

Oxysterol-binding protein like 7 deficiency leads to ER stress mediated apoptosis in podocytes and proteinuria.

Chronic kidney disease (CKD) is associated with renal lipid dysmetabolism among a variety of other pathways. We recently demonstrated that oxysterol-binding protein like 7 (OSBPL7) modulates the expression and function of ATP Binding Cassette Subfamily A Member 1 (ABCA1) in podocytes, a specialized type of cell essential for kidney filtration. Drugs that target OSBPL7 lead to improved renal outcomes in several experimental models of CKD. However, the role of OSBPL7 in podocyte injury remains unclear. Employing mouse models and cellular assays, we investigated the influence of OSBPL7 deficiency on podocytes. We demonstrated that reduced renal OSBPL7 levels as observed in two different models of experimental CKD are linked to increased podocyte apoptosis, primarily mediated by heightened endoplasmic reticulum (ER) stress. While as expected the absence of OSBPL7 also resulted in lipid dysregulation (increased lipid droplets and triglycerides content), OSBPL7-deficiency related lipid dysmetabolism did not contribute to podocyte injury. Similarly, we demonstrated that the decreased autophagic flux we observed in OSBPL7-deficient podocytes was not the mechanistic link between OSBPL7-deficiency and apoptosis. In a complementary zebrafish model, osbpl7 knockdown was sufficient to induce proteinuria and morphological damage to the glomerulus, underscoring its physiological relevance. Our study shed new light on the mechanistic link between OSBPL7 deficiency and podocyte injury in glomerular diseases associated with CKD, and it strengthen the role of OSBPL7 as a novel therapeutic target.

Preliminary insights of the genetic diversity and invasion pathways of Cedrela odorata in the Galapagos Islands, Ecuador.

Cedrela odorata is considered the second most invasive tree species of the Galapagos Islands. Although it is listed in CITES Appendix II and there are population losses in mainland Ecuador, in Galapagos it is paradoxically a species of concern due to its invasive potential. Genetic studies can shed light on the invasion history of introduced species causing effects on unique ecosystems like the Galapagos. We analyzed nine microsatellite markers in C. odorata individuals from Galapagos and mainland Ecuador to describe the genetic diversity and population structure of C. odorata in the Galapagos and to explore the origin and invasion history of this species. The genetic diversity found for C. odorata in Galapagos (H e = 0.55) was lower than reported in the mainland (H e = 0.81), but higher than other invasive insular plant species, which could indicate multiple introductions. Our results suggest that Ecuador's northern Coastal region is the most likely origin of the Galapagos C. odorata, although further genomic studies, like Whole Genome Sequencing, Rad-Seq, and/or Whole Genome SNP analyses, are needed to confirm this finding. Moreover, according to our proposed pathway scenarios, C. odorata was first introduced to San Cristobal and/or Santa Cruz from mainland Ecuador. After these initial introductions, C. odorata appears to have arrived to Isabela and Floreana from either San Cristobal or Santa Cruz. Here, we report the first genetic study of C. odorata in the Galapagos and the first attempt to unravel the invasion history of this species. The information obtained in this research could support management and control strategies to lessen the impact that C. odorata has on the islands' local flora and fauna.

Cedrela odorata es considerada la segunda especie más invasora de árboles en las Islas Galápagos. Esta especie está catalogada en el Apéndice II de CITES y sus poblaciones se encuentran amenazadas en Ecuador continental, pero paradójicamente en Galápagos es una especie de preocupación por su potencial invasor. Estudios genéticos pueden ayudar a entender la historia de invasión de especies introducidas que causan efectos en ecosistemas únicos como Galápagos. En este estudio, analizamos 9 marcadores microsatélites en individuos de Galápagos y Ecuador continental para describir la diversidad genética y estructura poblacional de C. odorata en Galápagos y explorar el origen e historia de invasión de esta especie. La diversidad genética encontrada para C. odorata en Galápagos (H e = 0.55) fue menor que la reportada en continente (H e = 0.81), pero mayor que la de otras especies de plantas insulares invasoras, lo que podría sugerir múltiples introducciones de esta especie a Galápagos. Nuestros resultados sugieren que la costa norte ecuatoriana es el origen más probable de C. odorata en Galápagos, aunque más estudios, como secuenciación del genoma completo, Rad­Seq y/o análisis de SNPs, son necesarios para confirmar este hecho. Además, de acuerdo con los escenarios propuestos, es posible que C. odorata haya sido introducida primero a San Cristóbal y/o Santa Cruz desde Ecuador continental. Después de estas introducciones iniciales, parece haber llegado a Isabela y Floreana desde San Cristóbal o Santa Cruz. Este es el primer estudio genético de C. odorata en Galápagos y el primer intento de esclarecer la historia de invasión de esta especie. La información obtenida en esta investigación podría apoyar estrategias de manejo para disminuir el impacto que C. odorata tiene sobre la flora y fauna nativa de estas islas.

Assessment of the quality of interdisciplinary communication (CritCom): evaluation and refinement of a center summary report.

Communication failures among clinicians in the ICU (intensive care unit) often lead to worse patient outcomes. CritCom is a bilingual (English and Spanish) tool to evaluate the quality of interdisciplinary communication around patient deterioration for pediatric oncology patients. The use of reports, such as the CritCom report, as dissemination methods lead to quicker knowledge translation and implementation of research findings into policy. Nurses and physicians at participating centers who care for patients at risk of deterioration completed the CritCom survey and center-specific reports were generated to communicate CritCom results. Focus groups were conducted with clinicians receiving CritCom reports in both English and Spanish to evaluate report clarity and usability. Participants found the reports to be useful and described the writing and design as clear and specific. Participants provided feedback to improve report design and requested actionable steps to improve communication at their center. Feedback illustrated that the report was easy to interpret and a useful way to disseminate information. Participants noted the utility of the report, illustrating that the use of reports can be a useful method to disseminate research findings back to participants in a way that is applicable to the local context. Communicating research findings through reports can minimize the significant time lag in knowledge translation and provide participants with actionable steps to implement in their setting.

Concepts for the development of person-centred, digitally-enabled, Artificial Intelligence-assisted ARIA care pathways (ARIA 2024).

The traditional healthcare model is focused on diseases (medicine and natural science) and does not acknowledge patients' resources and abilities to be experts in their own life based on their lived experiences. Improving healthcare safety, quality and coordination, as well as quality of life, are important aims in the care of patients with chronic conditions. Person-centred care needs to ensure that people's values and preferences guide clinical decisions. This paper reviews current knowledge to develop (i) digital care pathways for rhinitis and asthma multimorbidity and (ii) digitally-enabled person-centred care (1). It combines all relevant research evidence, including the so-called real-world evidence, with the ultimate goal to develop digitally-enabled, patient-centred care. The paper includes (i) Allergic Rhinitis and its Impact on Asthma (ARIA), a two-decade journey, (ii) Grading of Recommendations, Assessment, Development and Evaluation (GRADE), the evidence-based model of guidelines in airway diseases, (iii) mHealth impact on airway diseases, (iv) from guidelines to digital care pathways, (v) embedding Planetary Health, (vi) novel classification of rhinitis and asthma, (vi) embedding real-life data with population-based studies, (vii) the ARIA-EAACI strategy for the management of airway diseases using digital biomarkers, (viii) Artificial Intelligence, (ix) the development of digitally-enabled ARIA Person-Centred Care and (x) the political agenda. The ultimate goal is to propose ARIA 2024 guidelines centred around the patient in order to make them more applicable and sustainable.

Genome Report: First reference genome of Vaccinium floribundum Kunth, an emblematic Andean species.

Vaccinium floribundum Kunth, known as "mortiño, " is an endemic shrub species of the Andean region adapted to harsh conditions in high-altitude ecosystems. It plays an important ecological role as a pioneer species in the aftermath of deforestation and human-induced fires within paramo ecosystems, emphasizing its conservation value. While previous studies have offered insights into the genetic diversity of mortiño, comprehensive genomic studies are still missing to fully understand the unique adaptations of this species and its population status, highlighting the importance of generating a reference genome for this plant. ONT and Illumina sequencing were used to establish a reference genome for this species. Three different de novo genome assemblies were generated and compared for quality, continuity and completeness. The Flye assembly was selected as the best and refined by filtering out short ONT reads, screening for contaminants and genome scaffolding. The final assembly has a genome size of 529 MB, containing 1,317 contigs and 97% complete BUSCOs, indicating a high level of integrity of the genome. Additionally, the LAI Index of 12.93, further categorizes this assembly as a reference genome. The genome of V. floribundum reported in this study is the first reference genome generated for this species, providing a valuable tool for further studies. This high-quality genome, based on the quality and completeness parameters obtained, will not only help uncover the genetic mechanisms responsible for its unique traits and adaptations to high-altitude ecosystems, but will also contribute to conservation strategies for a species endemic to the Andes.

The Role of Defendant Gender and PTSD Diagnosis in a Battered Spouse Case.

A quarter of women and 11% of men report being survivors of intimate partner violence (IPV) during their lifetimes in the United States. Despite being victims themselves, people who kill their IPV abuser can still be subject to criminal proceedings. Given this complexity, the law has employed battered spouse syndrome (BSS) as a tool used in some jurisdictions to support a claim that an IPV survivor killed in self-defense. A defendant who is attempting to claim self-defense using BSS may introduce testimony of post-traumatic stress disorder (PTSD). However, a diagnosis of PTSD can pose problems in admission during litigation as the occurrence of a traumatic event is often what is being decided. The present study examined how college students, living on the U.S.-México border, perceive survivors-turned-defendants in a BSS mock trial. Specifically, we had each participant read a written trial transcript of a mock trial where gender of the defendant and clinical diagnosis of PTSD were manipulated. The current study hypothesized that jurors would be more lenient toward female defendants than male defendants (Hypothesis 1), jurors would be influenced by a PTSD diagnosis of the defendant (Hypothesis 2a-b), and female jurors would be more lenient than male jurors (Hypothesis 3). We also wanted to examine the impact of victim blaming, sexism, stigma of PTSD, and prior exposure to IPV on decision-making (Hypothesis 4a-d). Findings showed jurors were more lenient with female defendants than male defendants, however there was no effect of clinical diagnosis except on difficulty of decision. Implications of the role defendant gender has in decision-making is discussed.

The prognostic relevance of a gene expression signature in MRI-defined highly vascularized glioblastoma.

Background: The vascular heterogeneity of glioblastomas (GB) remains an important area of research, since tumor progression and patient prognosis are closely tied to this feature. With this study, we aim to identify gene expression profiles associated with MRI-defined tumor vascularity and to investigate its relationship with patient prognosis. Methods: The study employed MRI parameters calculated with DSC Perfusion Quantification of ONCOhabitats glioma analysis software and RNA-seq data from the TCGA-GBM project dataset. In our study, we had a total of 147 RNA-seq samples, which 15 of them also had MRI parameter information. We analyzed the gene expression profiles associated with MRI-defined tumor vascularity using differential gene expression analysis and performed Log-rank tests to assess the correlation between the identified genes and patient prognosis. Results: The findings of our research reveal a set of 21 overexpressed genes associated with the high vascularity pattern. Notably, several of these overexpressed genes have been previously implicated in worse prognosis based on existing literature. Our log-rank test further validates that the collective upregulation of these genes is indeed correlated with an unfavorable prognosis. This set of genes includes a variety of molecules, such as cytokines, receptors, ligands, and other molecules with diverse functions. Conclusions: Our findings suggest that the set of 21 overexpressed genes in the High Vascularity group could potentially serve as prognostic markers for GB patients. These results highlight the importance of further investigating the relationship between the molecules such as cytokines or receptors underlying the vascularity in GB and its observation through MRI and developing targeted therapies for this aggressive disease.

Cardiopulmonary phenotype in systemic sclerosis associated pulmonary hypertension.

INTRODUCTION: Pulmonary hypertension (PH) associated with systemic sclerosis (SSc) increases morbidity and mortality. Cardiopulmonary comorbidities, as per the 2021 PH consensus, play a role in the choice of therapy between monotherapy and combination therapy. METHODS: A cross-sectional study was conducted in patients with SSc based on the 2013 ACR/EULAR criteria or very early disease (VEDOSS 2011). PH was considered if they met the following criteria: pulmonary artery systolic pressure (PASP)>39mmHg or peak tricuspid regurgitation velocity (PTRV)>3.4m/s, PASP between 33 and 39mmHg or PTRV between 2.9 and 3.4m/s plus two additional findings suggestive of PH. PH was classified as type 2 if LVEF<50% or moderate to severe diastolic dysfunction was present; type 3 if extensive interstitial disease on tomography>20% or forced vital capacity (FVC)<75%; type 4 if abnormalities related to embolism were detected on scintigraphy or tomography. If patients did not meet these criteria, they were classified as type 1 PH. Complete data on cardiopulmonary risk factors and other factors were required. The frequency of these factors in the population and differences between groups based on risk factors were estimated. RESULTS: A total of 228 patients were selected. Three had type 2 PH, 24 had type 3, and 40 had type 1 PH, with the majority (75%) having at least one cardiopulmonary risk factor, and 47.5% having more than one. Mild diastolic dysfunction (25%) and hypertension (35%) were the most prevalent. In the type 1 PH group, those with risk factors experienced an increase in the number of years with Raynaud's phenomenon, anticentromere antibodies, and gastrointestinal symptoms (p<0.05). CONCLUSION: In patients with PH, 75% have one, and 45% have two or more risk factors.

Excess weight and changes in body composition in boys and girls from La Plata district (Buenos Aires, Argentina) - a study with a secular perspective.

The aim of the present study was to advance knowledge of the secular changes in the prevalence of excess weight (overweight and obesity) and body composition of children living in different localities of La Plata district (Buenos Aires province, Argentina) over the last two decades. For this purpose, anthropometric data and information on the socioeconomic and environmental context of residence of schoolchildren aged 4.0-12.9 years collected during 2005-2009 (Cohort 1, n = 1 233) and 2016-2019 (Cohort 2, n = 1 499) were analysed and compared. From a secular perspective, the current analysis showed that the socioeconomic and environmental conditions of families living in La Plata district have deteriorated in recent decades. In this context, child excess weight increased by 13% and body composition was altered, mainly as a result of an increase in fat mass, without observing changes in the muscle component.

Severely compromised supply of patch test allergens in Europe hampers adequate diagnosis of occupational and non-occupational contact allergy. A European Society of Contact Dermatitis (ESCD), European Academy of Allergy and Clinical Immunology (EAACI), European Academy of Dermatology and Venereology (EADV) task forces 'Contact Dermatitis' and 'Occupational Skin Disease' position paper.

Patch testing is the only clinically applicable diagnostic method for Type IV allergy. The availability of Type IV patch test (PT) allergens in Europe, however, is currently scarce. This severely compromises adequate diagnostics of contact allergy, leading to serious consequences for the affected patients. Against this background, the European Society of Contact Dermatitis (ESCD) has created a task force (TF) (i) to explore the current availability of PT substances in different member states, (ii) to highlight some of the unique characteristics of Type IV vs. other allergens and (iii) to suggest ways forward to promote and ensure availability of high-quality patch testing substances for the diagnosis of Type IV allergies throughout Europe. The suggestions of the TF on how to improve the availability of PT allergens are supported by the ESCD, the European Academy of Allergy and Clinical Immunology, and the European Academy of Dermatology and Venereology and intend to provide potential means to resolve the present medical crisis.

Earlier detection of gestational diabetes impacts on medication requirements, neonatal and maternal outcomes.

AIM: Gestational diabetes (GD) is a global health concern with significant implications for maternal and neonatal outcomes. This study investigates the association between early GD (eGD) diagnosis (<24 weeks), pharmacotherapy requirements and adverse neonatal outcomes. MATERIALS AND METHODS: A cohort of 369 pregnant women underwent a 75-g oral glucose tolerance test. Maternal variables, pharmacotherapy prescriptions and neonatal outcomes were analysed employing t-tests, χ2 tests, and logistic regression. A p < .05 was considered significant. RESULTS: Early GD increased the odds of neonatal hypoglycaemia [odds ratio (OR): 18.57, p = .013] and respiratory distress syndrome (OR: 4.75, p = .034). Nutritional therapy prescription by an accredited nutritionist was the most common treatment in women diagnosed after 24 weeks, but those with eGD required more frequently specialized nutritional consulting + metformin to achieve glycaemic control (p = .027). eGD was associated with a higher requirement of nutritional therapy prescription + metformin (OR: 2.26, 95% confidence interval: 1.25-4.09, p = .007) and with maternal hyperglycaemia during the post-partum period at 2 h of the oral glucose tolerance test (OR: 1.03, 95% confidence interval: 1.02-1.13, p = .024). CONCLUSION: Timely diagnosis and personalized treatment of GD are desirable because an earlier presentation is related to a higher risk of adverse neonatal and maternal outcomes.

Safety and Efficacy of Atezolizumab/Bevacizumab in Patients with Hepatocellular Carcinoma and Impaired Liver Function: A Systematic Review and Meta-Analysis.

Background: Safety and outcome of atezolizumab/bevacizumab in Child-Pugh B patients with hepatocellular carcinoma (HCC) have not been completely characterized. Objectives: In this study, we aimed at addressing safety and efficacy of atezolizumab/bevacizumab in Child-Pugh B patients by reviewing the available data and analyzing them by meta-analysis. Methods: We compared the safety and efficacy of atezolizumab/becavizumab treatment in patients with unresectable HCC and various degrees of liver dysfunction. A total of 8 retrospective, non-randomized, cohort studies were included in this meta-analysis, for a total of 1,071 Child-Pugh A and 225 Child-Pugh B patients. The albumin-bilirubin (ALBI) grade was also used to assess liver function, when available. Results: Grade ≥3 adverse events were observed in 11.8% of Child-Pugh class A and 26.8% class B patients (p = 0.0001), with an odds ratio (OR) of 0.43 (confidence interval [CI] 0.21-0.90; p = 0.02). Progression-free survival (PFS) at both 6 months (4.90 ± 2.08 vs. 4.75 ± 2.08 months; p = 0.0004) and 12 months (8.83 ± 2.32 vs. 7.26 ± 2.33 months; p = 0.002) was lower in Child-Pugh class B patients. A trend toward a higher objective response rate (ORR) was observed in Child-Pugh class A patients (219/856, 25.6%) as compared to Child-Pugh class B patients (25/138, 18.1%; p = 0.070), while the probability of obtaining an ORR was significantly greater in Child-Pugh A patients (OR 1.79, CI 1.12-2.86; p = 0.02). Median overall survival (OS) was 16.8 ± 2.0 and 6.8 ± 3.2 months in Child-Pugh A and B patients, respectively (mean difference 9.06 months, CI 7.01-11.1, p < 0.0001). Lastly, OS was longer in patients with ALBI grades 1-2 than in those with grade 3 (8.3 ± 11.4 vs. 3.3 ± 5.0 months, p = 0.0008). Conclusions: Oncological efficacy of atezolizumab/bevacizumab is moderate in Child-Pugh class B patients, and the shorter PFS and OS associated with the greater likelihood of experiencing treatment-related adverse events observed in these patients suggest great caution and individualization of treatment, possibly with the support of the ALBI grade.

Digitally-enabled, person-centred care (PCC) in allergen immunotherapy: An ARIA-EAACI Position Paper.

In rhinitis and asthma, several mHealth apps have been developed but only a few have been validated. However, these apps have a high potential for improving person-centred care (PCC), especially in allergen immunotherapy (AIT). They can provide support in AIT initiation by selecting the appropriate patient and allergen shared decision-making. They can also help in (i) the evaluation of (early) efficacy, (ii) early and late stopping rules and (iii) the evaluation of (carried-over) efficacy after cessation of the treatment course. Future perspectives have been formulated in the first report of a joint task force (TF)-Allergic Rhinitis and Its Impact on Asthma (ARIA) and the European Academy of Allergy and Clinical Immunology (EAACI)-on digital biomarkers. The TF on AIT now aims to (i) outline the potential of the clinical applications of mHealth solutions, (ii) express their current limitations, (iii) make proposals regarding further developments for both clinical practice and scientific purpose and (iv) suggest which of the tools might best comply with the purpose of digitally-enabled PCC in AIT.