Profiling the genome and proteome of metabolic dysfunction-associated steatotic liver disease identifies potential therapeutic targets.

BACKGROUND & AIMS: Metabolic dysfunction-associated steatotic liver disease (MASLD) affects over 25% of the population and currently has no effective treatments. Plasma proteins with causal evidence may represent promising drug targets. We aimed to identify plasma proteins in the causal pathway of MASLD and explore their interaction with obesity. METHODS: We analysed 2,941 plasma proteins in 43,978 European participants from UK Biobank. We performed genome-wide association study (GWAS) for all MASLD-associated proteins and created the largest MASLD GWAS (109,885 cases/1,014,923 controls). We performed Mendelian Randomization (MR) and integrated proteins and their encoding genes in MASLD ranges to identify candidate causal proteins. We then validated them through independent replication, exome sequencing, liver imaging, bulk and single-cell gene expression, liver biopsies, pathway, and phenome-wide data. We explored the role of obesity by MR and multivariable MR across proteins, body mass index, and MASLD. RESULTS: We found 929 proteins associated with MASLD, reported five novel genetic loci associated with MASLD, and identified 17 candidate MASLD protein targets. We identified four novel targets for MASLD (CD33, GRHPR, HMOX2, and SCG3), provided protein evidence supporting roles of AHCY, FCGR2B, ORM1, and RBKS in MASLD, and validated nine previously known targets. We found that CD33, FCGR2B, ORM1, RBKS, and SCG3 mediated the association of obesity and MASLD, and HMOX2, ORM1, and RBKS had effect on MASLD independent of obesity. CONCLUSIONS: This study identified new protein targets in the causal pathway of MASLD, providing new insights into the multi-omics architecture and pathophysiology of MASLD. These findings advise further therapeutic interventions for MASLD.

Lesión autoinfligida y absceso cerebral secundario en un paciente con esquizofrenia / Self-inflicted injury and secondary cerebral abscess in a patient with schizophrenia

RESUMEN La lesión autoinfligida es un acto intencional de hacerse daño sin propósito suicida. El presente caso describe a un paciente esquizofrénico de 37 años de edad, que ha padecido 20 años con la enfermedad, y síntomas recientes de irritabilidad, agresividad, aislamiento, ideas de perjuicio y contaminación («tengo un estafilococo en mi cabeza¼). Durante 10 años utilizaba varios objetos, incluido un bisturí con el que llegó a remover (extirpar) parte de la calota, ocasionando un edema vasogénico en la región córtico-fronto-parietal izquierda que produjo hemiparesia braquiocrural derecha y motivó su admisión. Luego de descartarse un accidente cerebrovascular o tumor cerebral, fue intervenido quirúrgicamente para la extracción de un absceso cerebral. Recibió varios fármacos antipsicóticos con respuesta parcial, y más tarde mejoró con la administración de paliperidona. En casos como este, es necesario un tamizaje, diagnóstico y tratamiento oportunos para evitar evolución y pronóstico tórpidos en pacientes esquizofrénicos con lesiones autoinfligidas y con historia de pobre respuesta y adherencia al tratamiento.

ABSTRACT Self-injury is the intentional act of causing harm to oneself, without suicidal purposes. This case report describes a 37-year-old schizophrenic patient, with a history of 20 years, and recent symptoms of irritability, aggressiveness, isolation, self-harm and contamination ideas ("I have a staphylococcus in my head"). For 10 years, he used a variety of objects to manipulate himself, among them a scalpel with which he extirpated part of the calotte, causing a vasogenic edema in the left cortico-fronto-parietal region that produced a right brachio-crural haemiparesis, the reason for his admission. After ruling out a stroke or a brain tumor, he underwent surgery for the removal of a brain abscess; he received several antipsychotic agents with only a partial response that later improved after being switched to paliperidone. In cases like this, it is necessary to conduct a timely screening, diagnosis and treatment in order to avoid a torpid evolution and prognosis in schizophrenic patients with long-standing self-inflicted injuries and a history of poor adherence and response to treatment.

Combinatorial effects on gene expression at the Lbx1/Fgf8 locus resolve split-hand/foot malformation type 3.

Split-Hand/Foot Malformation type 3 (SHFM3) is a congenital limb malformation associated with tandem duplications at the LBX1/FGF8 locus. Yet, the disease patho-mechanism remains unsolved. Here we investigate the functional consequences of SHFM3-associated rearrangements on chromatin conformation and gene expression in vivo in transgenic mice. We show that the Lbx1/Fgf8 locus consists of two separate, but interacting, regulatory domains. Re-engineering of a SHFM3-associated duplication and a newly reported inversion in mice results in restructuring of the chromatin architecture. This leads to ectopic activation of the Lbx1 and Btrc genes in the apical ectodermal ridge (AER) in an Fgf8-like pattern induced by AER-specific enhancers of Fgf8. We provide evidence that the SHFM3 phenotype is the result of a combinatorial effect on gene misexpression in the developing limb. Our results reveal insights into the molecular mechanism underlying SHFM3 and provide conceptual framework for how genomic rearrangements can cause gene misexpression and disease.

Studying Juvenile Idiopathic Arthritis through a Network Medicine Approach / Estudando a Artrite Idiopática Juvenil mediante uma abordagem de medicina de redes

Juvenile Idiopathic Arthritis (JIA) is a group of inflammatory conditions of unknown etiology whose underlying molecular pathophysiology is still not well characterized. Several studies have attempted to fill this gap by characterizing the gene expression profiles of JIA patients. However, there is a lack of systematic assessment of the reliability of these transcriptome results on the disease classification, prescription, and monitoring. In addition, despite this disease is more common in females, none of these studies have tried to assess the impact of sex on disease pathophysiology. In this project, we performed a comprehensive systematic review and a gene expression meta-analysis to reveal the core molecular JIA pathophysiology taking into consideration the patient sex. We gathered and cataloged more than 60,000 entries of genomic features reported as JIA-related in the functional genomics literature, and found a dramatic disparity among the JIA transcriptome studies. Near 15,000 genes have been reported as perturbed in JIA leukocytes. Less than one percent of these genes were reported in at least a quarter of the reviewed studies. We then removed the study-specific analytical bias by re-analyzing more than 700 unique pediatric transcriptome profiles from nine JIA studies using a common analytical framework. The differential expression results from different studies were combined using a random effect model meta-analysis approach. We implemented this differential gene expression meta-analysis methodology in the MetaVolcanoR R package that we made available in Bioconductor. Using this package, we confirmed several gene expression signatures previously associated with JIA and uncover new genes whose expression was perturbed in JIA patients. The effect sizes of the topmost reported perturbed genes coincide with our meta-analysis results. Through a meta-coexpression approach, we characterized the cell type signatures of circulating leukocytes in the JIA affected children. Additionally, we characterized the JIA sexual dimorphism. We found that systemic JIA female patients over-activate a gene expression signature which comprises early myelocytes and band neutrophil expression markers. This signature is correlated with the disease status and response to IL-1 receptor blockade. This suggests that sJIA pathophysiology is characterized by a sexually dimorphic neutrophilia that impacts disease progression and the response to anti-IL-1 treatments. We further assessed this immature neutrophil and female-biased signature in other contexts. We found that this signature presents a sex-dependent expression over human lifetime, in other inflammatory diseases, and its expression increases during pregnancy

A Artrite Idiopática Juvenil (AIJ) é um grupo de condições inflamatórias de etiologia desconhecida, cuja patofisiologia molecular subjacente ainda não está bem caracterizada. Vários estudos tentaram preencher essa lacuna, caracterizando os perfis de expressão gênica de pacientes com AIJ. No entanto, há uma falta de avaliação sistemática desses resultados transcriptômicos na classificação, prescrição e monitoramento da doença. Além disso, apesar de esta doença ser mais comum em mulheres, nenhum desses estudos tentou avaliar o impacto do sexo na fisiopatologia da doença. Neste projeto, realizamos uma revisão sistemática abrangente e uma metanálise de expressão gênica para revelar a fisiopatologia molecular da AIJ levando em consideração o sexo do paciente. Reunimos e catalogamos mais de 60.000 entradas de características genômicas reportadas como relacionadas à AIJ na literatura. Entre os estudos de transcriptoma, encontramos uma disparidade dramática. Cerca de 15.000 genes foram reportados como perturbados nos leucócitos da AIJ, sendo que menos de um por cento desses genes foram relatados em pelo menos um quarto dos estudos revisados. Em seguida, re-analisamos mais de 700 transcriptomas pediátricos de nove estudos usando uma abordagem analítica comum. Os resultados de expressão diferencial foram combinados usando meta-análise de modelo de efeitos aleatórios. Implementamos esta abordagem de meta-análise de expressão gênica diferencial no pacote MetaVolcanoR R que disponibilizamos no Bioconductor. Usando este pacote, confirmamos várias assinaturas de expressão gênica previamente associadas à AIJ e descobrimos novos genes cuja expressão está perturbada em pacientes com AIJ. Os tamanhos dos efeitos dos genes mais reportados como perturbados coincidem com os resultados da nossa meta-análise. Por meio de uma análise de meta-co-expressão, caracterizamos as assinaturas dos tipos de leucócitos circulantes. Além disso, caracterizamos o dimorfismo sexual da AIJ. Descobrimos que pacientes do sexo feminino com AIJ sistêmica super-ativam genes característicos de mielócitos precoces e neutrófilos bastonetes. Esta assinatura está correlacionada com o estado clínico da doença e à resposta ao tratamento por bloqueio do receptor de IL-1. Isto sugere que a fisiopatologia da AIJs é caracterizada por uma neutrofilia sexualmente dimórfica que afeta a progressão da doença e a resposta aos tratamentos anti-IL-1. Avaliamos ainda esta assinatura neutrofílica em outros contextos. Descobrimos que essa assinatura apresenta uma expressão dependente do sexo ao longo da vida humana, em outras doenças inflamatórias, e sua expressão aumenta durante a gravidez

Pan-transcriptome identifying master genes and regulation network in response to drought and salt stresses in Alfalfa (Medicago sativa L.).

Alfalfa is an important legume forage grown worldwide and its productivity is affected by environmental stresses such as drought and high salinity. In this work, three alfalfa germplasms with contrasting tolerances to drought and high salinity were used for unraveling the transcriptomic responses to drought and salt stresses. Twenty-one different RNA samples from different germplasm, stress conditions or tissue sources (leaf, stem and root) were extracted and sequenced using the PacBio (Iso-Seq) and the Illumina platforms to obtain full-length transcriptomic profiles. A total of 1,124,275 and 91,378 unique isoforms and genes were obtained, respectively. Comparative analysis of transcriptomes identified differentially expressed genes and isoforms as well as transcriptional and post-transcriptional modifications such as alternative splicing events, fusion genes and nonsense-mediated mRNA decay events and non-coding RNA such as circRNA and lncRNA. This is the first time to identify the diversity of circRNA and lncRNA in response to drought and high salinity in alfalfa. The analysis of weighted gene co-expression network allowed to identify master genes and isoforms that may play important roles on drought and salt stress tolerance in alfalfa. This work provides insight for understanding the mechanisms by which drought and salt stresses affect alfalfa growth at the whole genome level.

Genome-Wide Association Studies Identifying Multiple Loci Associated With Alfalfa Forage Quality.

Autotetraploid alfalfa is a major hay crop planted all over the world due to its adaptation in different environments and high quality for animal feed. However, the genetic basis of alfalfa quality is not fully understood. In this study, a diverse panel of 200 alfalfa accessions were planted in field trials using augmented experimental design at three locations in 2018 and 2019. Thirty-four quality traits were evaluated by Near Infrared Reflectance Spectroscopy (NIRS). The plants were genotyped using a genotyping by sequencing (GBS) approach and over 46,000 single nucleotide polymorphisms (SNPs) were obtained after variant calling and filtering. Genome-wide association studies (GWAS) identified 28 SNP markers associated with 16 quality traits. Among them, most of the markers were associated with fiber digestibility and protein content. Phenotypic variations were analyzed from three locations and different sets of markers were identified by GWAS when using phenotypic data from different locations, indicating that alfalfa quality traits were also affected by environmental factors. Among different sets of markers identified by location, two markers were associated with nine traits of fiber digestibility. One marker associated with lignin content was identified consistently in multiple environments. Putative candidate genes underlying fiber-related loci were identified and they are involved in the lignin and cell wall biosynthesis. The DNA markers and associated genes identified in this study will be useful for the genetic improvement of forage quality in alfalfa after the validation of the markers.

Validation of UAV-based alfalfa biomass predictability using photogrammetry with fully automatic plot segmentation.

Alfalfa is the most widely cultivated forage legume, with approximately 30 million hectares planted worldwide. Genetic improvements in alfalfa have been highly successful in developing cultivars with exceptional winter hardiness and disease resistance traits. However, genetic improvements have been limited for complex economically important traits such as biomass. One of the major bottlenecks is the labor-intensive phenotyping burden for biomass selection. In this study, we employed two alfalfa fields to pave a path to overcome the challenge by using UAV images with fully automatic field plot segmentation for high-throughput phenotyping. The first field was used to develop the prediction model and the second field to validate the predictions. The first and second fields had 808 and 1025 plots, respectively. The first field had three harvests with biomass measured in May, July, and September of 2019. The second had one harvest with biomass measured in September of 2019. These two fields were imaged one day before harvesting with a DJI Phantom 4 pro UAV carrying an additional Sentera multispectral camera. Alfalfa plot images were extracted by GRID software to quantify vegetative area based on the Normalized Difference Vegetation Index. The prediction model developed from the first field explained 50-70% (R Square) of biomass variation in the second field by incorporating four features from UAV images: vegetative area, plant height, Normalized Green-Red Difference Index, and Normalized Difference Red Edge Index. This result suggests that UAV-based, high-throughput phenotyping could be used to improve the efficiency of the biomass selection process in alfalfa breeding programs.

Immature neutrophil signature associated with the sexual dimorphism of systemic juvenile idiopathic arthritis.

Juvenile idiopathic arthritis (JIA) is a group of inflammatory conditions of unknown etiology whose incidence is sex dependent. Although several studies have attempted to identify JIA-related gene signatures, none have systematically assessed the impact of sex on the whole blood transcriptomes of JIA patients. By analyzing over 400 unique pediatric gene expression profiles, we characterized the sexual differences in leukocyte composition of systemic JIA patients and identified sex-specific gene signatures that were related to immature neutrophils. Female systemic JIA patients presented higher activation of immature neutrophil-related genes compared to males, and these genes were associated with the response to IL-1 receptor blockade treatment. Also, we found that this immature neutrophil signature is sexually dimorphic across human lifespan and in adults with rheumatoid arthritis and asthma. These results suggest that neutrophil maturation is sexually dimorphic in rheumatic inflammation, and that this may impact disease progression and treatment.

Identification of genetic loci associated with forage quality in response to water deficit in autotetraploid alfalfa (Medicago sativa L.).

BACKGROUND: Alfalfa has been cultivated in many regions around the world as an important forage crop due to its nutritive value to livestock and ability to adapt to various environments. However, the genetic basis by which plasticity of quality-relevant traits influence alfalfa adaption to different water conditions remain largely unknown. RESULTS: In the present study, 198 accessions of alfalfa of the core collection for drought tolerance were evaluated for 26 forage quality traits in a field trial under an imposed deficit irrigation gradient. Regression analysis between quality traits and water stress revealed that values of fiber-related traits were negatively correlated with values of energy-related traits as water deficit increased. More than one hundred significant markers associated with forage quality under different water treatments were identified using genome-wide association studies with genotyping by sequencing. Among them, 131 markers associated with multiple traits in all the water deficit treatments. Most of the associated markers were dependent to the levels of water deficit, suggesting genetic controls for forage quality traits were dependent to the stress treatment. Twenty-four loci associated with forage quality were annotated to functional genes that may play roles in cell development or in response to water stress. CONCLUSIONS: This study addressed the genetic base of phenotypic variation of forage quality traits under water deficit. The SNP markers identified in this study will be useful in marker-assisted selection for the genetic improvement of alfalfa with enhanced drought tolerance while maintaining forage quality.

Genome-Wide Association and Prediction of Traits Related to Salt Tolerance in Autotetraploid Alfalfa (Medicago sativa L.).

Soil salinity is a growing problem in world production agriculture. Continued improvement in crop salt tolerance will require the implementation of innovative breeding strategies such as marker-assisted selection (MAS) and genomic selection (GS). Genetic analyses for yield and vigor traits under salt stress in alfalfa breeding populations with three different phenotypic datasets was assessed. Genotype-by-sequencing (GBS) developed markers with allele dosage and phenotypic data were analyzed by genome-wide association studies (GWAS) and GS using different models. GWAS identified 27 single nucleotide polymorphism (SNP) markers associated with salt tolerance. Mapping SNPs markers against the Medicago truncatula reference genome revealed several putative candidate genes based on their roles in response to salt stress. Additionally, eight GS models were used to estimate breeding values of the training population under salt stress. Highest prediction accuracies and root mean square errors were used to determine the best prediction model. The machine learning methods (support vector machine and random forest) performance best with the prediction accuracy of 0.793 for yield. The marker loci and candidate genes identified, along with optimized GS prediction models, were shown to be useful in improvement of alfalfa with enhanced salt tolerance. DNA markers and the outcome of the GS will be made available to the alfalfa breeding community in efforts to accelerate genetic gains, in the development of biotic stress tolerant and more productive modern-day alfalfa cultivars.

Expression Atlas update: from tissues to single cells.

Expression Atlas is EMBL-EBI's resource for gene and protein expression. It sources and compiles data on the abundance and localisation of RNA and proteins in various biological systems and contexts and provides open access to this data for the research community. With the increased availability of single cell RNA-Seq datasets in the public archives, we have now extended Expression Atlas with a new added-value service to display gene expression in single cells. Single Cell Expression Atlas was launched in 2018 and currently includes 123 single cell RNA-Seq studies from 12 species. The website can be searched by genes within or across species to reveal experiments, tissues and cell types where this gene is expressed or under which conditions it is a marker gene. Within each study, cells can be visualized using a pre-calculated t-SNE plot and can be coloured by different features or by cell clusters based on gene expression. Within each experiment, there are links to downloadable files, such as RNA quantification matrices, clustering results, reports on protocols and associated metadata, such as assigned cell types.

The role of type III effectors from Xanthomonas axonopodis pv. manihotis in virulence and suppression of plant immunity.

Xanthomonas axonopodis pv. manihotis (Xam) causes cassava bacterial blight, the most important bacterial disease of cassava. Xam, like other Xanthomonas species, requires type III effectors (T3Es) for maximal virulence. Xam strain CIO151 possesses 17 predicted T3Es belonging to the Xanthomonas outer protein (Xop) class. This work aimed to characterize nine Xop effectors present in Xam CIO151 for their role in virulence and modulation of plant immunity. Our findings demonstrate the importance of XopZ, XopX, XopAO1 and AvrBs2 for full virulence, as well as a redundant function in virulence between XopN and XopQ in susceptible cassava plants. We tested their role in pathogen-associated molecular pattern (PAMP)-triggered immunity (PTI) and effector-triggered immunity (ETI) using heterologous systems. AvrBs2, XopR and XopAO1 are capable of suppressing PTI. ETI suppression activity was only detected for XopE4 and XopAO1. These results demonstrate the overall importance and diversity in functions of major virulence effectors AvrBs2 and XopAO1 in Xam during cassava infection.

Survival and SOS response induction in ultraviolet B irradiated Escherichia coli cells with defective repair mechanisms.

Purpose In this paper, the contribution of different genes involved in DNA repair for both survival and SOS induction in Escherichia coli mutants exposed to ultraviolet B radiation (UVB, [wavelength range 280-315 nm]) was evaluated. Materials and methods E. coli strains defective in uvrA, oxyR, recO, recN, recJ, exoX, recB, recD or xonA genes were used to determine cell survival. All strains also had the genetic sulA::lacZ fusion, which allowed for the quantification of SOS induction through the SOS Chromotest. Results Five gene products were particularly important for survival, as follows: UvrA > RecB > RecO > RecJ > XonA. Strains defective in uvrA and recJ genes showed elevated SOS induction compared with the wild type, which remained stable for up to 240 min after UVB-irradiation. In addition, E. coli strains carrying the recO or recN mutation showed no SOS induction. Conclusions The nucleotide excision and DNA recombination pathways were equally used to repair UVB-induced DNA damage in E. coli cells. The sulA gene was not turned off in strains defective in UvrA and RecJ. RecO protein was essential for processing DNA damage prior to SOS induction. In this study, the roles of DNA repair proteins and their contributions to the mechanisms that induce SOS genes in E. coli are proposed.

Ruptura espontánea de pseudoquiste pancreático a cavidad abdominal. Revisión de literatura a propósito del caso / Spontaneous rupture of pancreatic pseudocyst cavity. Literature review regarding the situation

RESUMEN.- Presentamos el caso de un paciente varón de 66 años, natural y procedente de Lima, sin antecedentes de importancia con un cuadro de 3 semanas de evolución caracterizado por dolor abdominal en hemiabdomen superior. Fue hospitalizado en el Hospital Nacional Edgardo Rebagliati Martins (Lima), con un cuadro compatible con peritonitis siendo sometido a Laparotomía exploratoria con el diagnostico postoperatorio de pancreatitis aguda. La TAC confirmo este hallazgo como pancreatitis aguda Balthazar D, Indice de Severidad Tomográfica:8. Durante la octava semana de evolución el control topográfico reveló la formación de pseudoquiste pancreático, durante la décima semana demostró ascitis progresiva compatible con ruptura del pseudoquiste a cavidad abdominal lo cual fue corroborado por estudio bioquímico del líquido ascítico. Los hallazgos clínicos, radiológicos y bioquímicos son presentados debido a la inusual presentación y los pocos casos reportados en la literatura acerca de esta complicación.

SUMMARY.- We report the case of 66 years old men, born and resident of lima, out significant past medical history, with a 3 week , history of upper quadrant abdominal pain. He was admitted with the clinical picture of peritonitis. An emergency laparotomy was performed an the diagnosis of Acute pancreatitis was done. An abdominal CT scan confirmed the finding and also described Acute Pancreatitis Balthazar D TSI 08. During the eight week of course the CT scan control showed development of pancreatic pseudocyst. 10 week showed progressive ascites consistent with spontaneus rupture of pancreatic pseudocyst to abdominal cavity, wich was confirm by biochemistry findings. The clinical, radiological and biochemistry findings are presented, due to the uncommon presentation and the few cases reported in the literature about this complication.