Intracellular crotonyl-CoA stimulates transcription through p300-catalyzed histone crotonylation.

Acetylation of histones at DNA regulatory elements plays a critical role in transcriptional activation. Histones are also modified by other acyl moieties, including crotonyl, yet the mechanisms that govern acetylation versus crotonylation and the functional consequences of this "choice" remain unclear. We show that the coactivator p300 has both crotonyltransferase and acetyltransferase activities, and that p300-catalyzed histone crotonylation directly stimulates transcription to a greater degree than histone acetylation. Levels of histone crotonylation are regulated by the cellular concentration of crotonyl-CoA, which can be altered through genetic and environmental perturbations. In a cell-based model of transcriptional activation, increasing or decreasing the cellular concentration of crotonyl-CoA leads to enhanced or diminished gene expression, respectively, which correlates with the levels of histone crotonylation flanking the regulatory elements of activated genes. Our findings support a general principle wherein differential histone acylation (i.e., acetylation versus crotonylation) couples cellular metabolism to the regulation of gene expression.

A Second Look at FAIR in Proteomic Investigations.

Proteomics is, by definition, comprehensive and large-scale, seeking to unravel ome-level protein features with phenotypic information on an entire system, an organ, cells, or organisms. This scope consistently involves and extends beyond single experiments. Multitudinous resources now exist to assist in making the results of proteomics experiments more findable, accessible, interoperable, and reusable (FAIR), yet many tools are awaiting to be adopted by our community. Here we highlight strategies for expanding the impact of proteomics data beyond single studies. We show how linking specific terminologies, identifiers, and text (words) can unify individual data points across a wide spectrum of studies and, more importantly, how this approach may potentially reveal novel relationships. In this effort, we explain how data sets and methods can be rendered more linkable and how this maximizes their value. We also include a discussion on how data linking strategies benefit stakeholders across the proteomics community and beyond.

A Knowledge Graph Approach to Elucidate the Role of Organellar Pathways in Disease via Biomedical Reports.

The rapidly increasing and vast quantities of biomedical reports, each containing numerous entities and rich information, represent a rich resource for biomedical text-mining applications. These tools enable investigators to integrate, conceptualize, and translate these discoveries to uncover new insights into disease pathology and therapeutics. In this protocol, we present CaseOLAP LIFT, a new computational pipeline to investigate cellular components and their disease associations by extracting user-selected information from text datasets (e.g., biomedical literature). The software identifies sub-cellular proteins and their functional partners within disease-relevant documents. Additional disease-relevant documents are identified via the software's label imputation method. To contextualize the resulting protein-disease associations and to integrate information from multiple relevant biomedical resources, a knowledge graph is automatically constructed for further analyses. We present one use case with a corpus of ~34 million text documents downloaded online to provide an example of elucidating the role of mitochondrial proteins in distinct cardiovascular disease phenotypes using this method. Furthermore, a deep learning model was applied to the resulting knowledge graph to predict previously unreported relationships between proteins and disease, resulting in 1,583 associations with predicted probabilities >0.90 and with an area under the receiver operating characteristic curve (AUROC) of 0.91 on the test set. This software features a highly customizable and automated workflow, with a broad scope of raw data available for analysis; therefore, using this method, protein-disease associations can be identified with enhanced reliability within a text corpus.

Cardiovascular informatics: building a bridge to data harmony.

The search for new strategies for better understanding cardiovascular (CV) disease is a constant one, spanning multitudinous types of observations and studies. A comprehensive characterization of each disease state and its biomolecular underpinnings relies upon insights gleaned from extensive information collection of various types of data. Researchers and clinicians in CV biomedicine repeatedly face questions regarding which types of data may best answer their questions, how to integrate information from multiple datasets of various types, and how to adapt emerging advances in machine learning and/or artificial intelligence to their needs in data processing. Frequently lauded as a field with great practical and translational potential, the interface between biomedical informatics and CV medicine is challenged with staggeringly massive datasets. Successful application of computational approaches to decode these complex and gigantic amounts of information becomes an essential step toward realizing the desired benefits. In this review, we examine recent efforts to adapt informatics strategies to CV biomedical research: automated information extraction and unification of multifaceted -omics data. We discuss how and why this interdisciplinary space of CV Informatics is particularly relevant to and supportive of current experimental and clinical research. We describe in detail how open data sources and methods can drive discovery while demanding few initial resources, an advantage afforded by widespread availability of cloud computing-driven platforms. Subsequently, we provide examples of how interoperable computational systems facilitate exploration of data from multiple sources, including both consistently formatted structured data and unstructured data. Taken together, these approaches for achieving data harmony enable molecular phenotyping of CV diseases and unification of CV knowledge.

Untargeted metabolomics profiling and hemoglobin normalization for archived newborn dried blood spots from a refrigerated biorepository.

Archived dried blood spots (DBS) following newborn screening are an attractive resource for interrogating early-life biology using untargeted metabolomics. Therefore, they have the potential to substantially aid etiological studies, particularly for rare and low-frequency childhood diseases and disorders. However, metabolite quantification in DBS is hindered by variation sources not present in serum and plasma samples such as the hematocrit effect and unknown initial blood volumes. Hemoglobin (Hb) is an appropriate correlate for hematocrit in experimentally-generated DBS punches. However, since many biorepositories worldwide archive DBS at 4-5 °C, there is a need to validate the utility of Hb for DBS archived under refrigeration. We evaluated two simple spectroscopic methods for measuring Hb in DBS stored at 4 +/- 2 °C for up to 21 years, obtained from the newborn screening program at the Karolinska University Hospital, Sweden. Spearman correlation analysis and Akaike Information Criterion model selection found that measurement of a Hb sodium lauryl sulfate complex at 540 nm better described nuisance variation than Hb measured at 404 nm, or using age of spot alone. This is the first study to profile metabolites and to propose a normalization factor for metabolite measurements from DBS archived for decades at 4 °C.

TAZ encodes tafazzin, a transacylase essential for cardiolipin formation and central to the etiology of Barth syndrome.

Tafazzin, which is encoded by the TAZ gene, catalyzes transacylation to form mature cardiolipin and shows preference for the transfer of a linoleic acid (LA) group from phosphatidylcholine (PC) to monolysocardiolipin (MLCL) with influence from mitochondrial membrane curvature. The protein contains domains and motifs involved in targeting, anchoring, and an active site for transacylase activity. Tafazzin activity affects many aspects of mitochondrial structure and function, including that of the electron transport chain, fission-fusion, as well as apoptotic signaling. TAZ mutations are implicated in Barth syndrome, an underdiagnosed and devastating disease that primarily affects male pediatric patients with a broad spectrum of disease pathologies that impact the cardiovascular, neuromuscular, metabolic, and hematologic systems.

c-MYC regulates mRNA translation efficiency and start-site selection in lymphoma.

The oncogenic c-MYC (MYC) transcription factor has broad effects on gene expression and cell behavior. We show that MYC alters the efficiency and quality of mRNA translation into functional proteins. Specifically, MYC drives the translation of most protein components of the electron transport chain in lymphoma cells, and many of these effects are independent from proliferation. Specific interactions of MYC-sensitive RNA-binding proteins (e.g., SRSF1/RBM42) with 5'UTR sequence motifs mediate many of these changes. Moreover, we observe a striking shift in translation initiation site usage. For example, in low-MYC conditions, lymphoma cells initiate translation of the CD19 mRNA from a site in exon 5. This results in the truncation of all extracellular CD19 domains and facilitates escape from CD19-directed CAR-T cell therapy. Together, our findings reveal MYC effects on the translation of key metabolic enzymes and immune receptors in lymphoma cells.

SIZ1/SIZ2 control of chromosome transmission fidelity is mediated by the sumoylation of topoisomerase II.

The Smt3 (SUMO) protein is conjugated to substrate proteins through a cascade of E1, E2, and E3 enzymes. In budding yeast, the E3 step in sumoylation is largely controlled by Siz1p and Siz2p. Analysis of Siz- cells shows that SUMO E3 is required for minichromosome segregation and thus has a positive role in maintaining the fidelity of mitotic transmission of genetic information. Sumoylation of the carboxy-terminus of Top2p, a known SUMO target, is mediated by Siz1p and Siz2p both in vivo and in vitro. Sumoylation in vitro reveals that Top2p is an extremely potent substrate for Smt3p conjugation and that chromatin-bound Top2p can still be sumoylated, unlike many other SUMO substrates. By combining mutations in the TOP2 sumoylation sites and the SIZ1 and SIZ2 genes we demonstrate that the minichromosome segregation defect and dicentric minichromosome stabilization, both characteristic for Smt3p-E3-deficient cells, are mediated by the lack of Top2p sumoylation in these cells. A role for Smt3p-modification as a signal for Top2p targeting to pericentromeric regions was suggested by an analysis of Top2p-Smt3p fusion. We propose a model for the positive control of the centromeric pool of Top2p, required for high segregation fidelity, by Smt3p modification.

MYC-dependent oxidative metabolism regulates osteoclastogenesis via nuclear receptor ERRα.

Osteoporosis is a metabolic bone disorder associated with compromised bone strength and an increased risk of fracture. Inhibition of the differentiation of bone-resorbing osteoclasts is an effective strategy for the treatment of osteoporosis. Prior work by our laboratory and others has shown that MYC promotes osteoclastogenesis in vitro, but the underlying mechanisms are not well understood. In addition, the in vivo importance of osteoclast-expressed MYC in physiological and pathological bone loss is not known. Here, we have demonstrated that deletion of Myc in osteoclasts increases bone mass and protects mice from ovariectomy-induced (OVX-induced) osteoporosis. Transcriptomic analysis revealed that MYC drives metabolic reprogramming during osteoclast differentiation and functions as a metabolic switch to an oxidative state. We identified a role for MYC action in the transcriptional induction of estrogen receptor-related receptor α (ERRα), a nuclear receptor that cooperates with the transcription factor nuclear factor of activated T cells, c1 (NFATc1) to drive osteoclastogenesis. Accordingly, pharmacological inhibition of ERRα attenuated OVX-induced bone loss in mice. Our findings highlight a MYC/ERRα pathway that contributes to physiological and pathological bone loss by integrating the MYC/ERRα axis to drive metabolic reprogramming during osteoclast differentiation.

Chikungunya virus infection: first detection of imported and autochthonous cases in Panama.

Chikungunya virus (CHIKV) is a mosquito-borne pathogen that was only endemic in Africa and south Asia until 2005 and 2006, when the virus spread into the Indian Ocean islands, Europe, and Asia. Autochthonous CHIKV transmission in the Caribbean islands was reported in December of 2013. In Panama, two febrile cases were detected in May of 2014: one traveling from Haiti, and the other traveling from the Dominican Republic. After other imported cases were detected, the first autochthonous case was reported in August of the same year. We detected CHIKV viral RNA and isolated the virus from serum samples. The phylogenetic analysis of the two imported isolates and one autochthonous CHIKV isolate indicated that the viruses belong to the Asian lineage in the Caribbean clade and are related to viruses recently identified in Saint Martin island, British Virgin Islands, China, and the Philippines. Although the circulating CHIKV lineages in the Americas have not yet been described, our results suggest that the Asian lineage is circulating in most American countries reporting autochthonous infection.

Inmunoterapia con vacunas Valergen por vía sublingual en asmáticos de Cabaiguán, Sancti Spíritus / Imunoterapia com vacinas de Valerge por via sublingual em asmáticos de Cabaiguán, Sancti Spíritus / Immunotherapy with Valergen sublingual vaccines in asthmatics patients from Cabaiguan to Sancti Spiritus

Introducción: la inmunoterapia sublingual se abre paso en la práctica alergológica, numerosos estudios avalan su eficacia y seguridad. Objetivo: caracterizar los resultados con el uso de las vacunas Valergen vía sublingual, en pacientes asmáticos, del municipio Cabaiguán. Método: se realizó una investigación descriptiva-prospectiva, de enero del 2013 a diciembre del 2016 en pacientes con diagnóstico de asma bronquial intermitente, persistente leve y moderado. El universo quedó constituido por 467 pacientes. La muestra fue de 44 pacientes, de todas las edades y sexos que reunían esas condiciones, fueron atendidos en consulta durante todo el periodo de estudio y evaluado cada paciente al cumplir tres años de tratamiento con inmunoterapia. Los datos fueron obtenidos de las historias clínicas y del registro de vacunación del departamento de alergia. Resultados: predominaron los pacientes del sexo femenino, entre 5-14 años (34,1 por ciento), el Dermatofagoide pteronyssinus fue el ácaro de mayor sensibilidad y utilización (45,4 por ciento), a los 3 años de tratamiento predominaron los pacientes con un mejor control de sus síntomas (72,7 por ciento), no se presentaron eventos adversos (79,5 por ciento) en los pacientes, los presentados fueron clasificados como locales y/o sistémicos leves (20,5 por ciento). Conclusiones: la inmunoterapia sublingual para el asma bronquial demostró ser segura y clínicamente favorable en los pacientes estudiados(AU)

Introduction: sublingual immunotherapy makes its way into allergological practice and numerous studies confirm its effectiveness and safety. Objective: to characterize the results with the use of Valergen sublingual vaccines in asthmatic patients of Cabaiguan municipality. Method: a descriptive-prospective investigation was conducted from January 2013 to December 2016 in patients diagnosed with intermittent bronchial asthma, persistent, slow and moderate. The universe was constituted by 467 patients. The sample was of 44 patients, of all ages and sexes, who met these conditions, were seen in consultation during the studied period and evaluated each patient after three years of treatment with immunotherapy. The data were obtained from the clinical records and the vaccination record of the allergy department. Results: female patients between 5-14 years (34.1 percent), and Dermatophagoide pteronyssinus was the mite with the highest sensitivity and use (45.4 percent), after 3 years of treatment, patients with a better control of their symptoms (72.7 percent), there were no adverse events (79.5 percent) in the patients, those presented were classified as local and mild systemic (20.5 percent). Conclusions: sublingual immunotherapy for bronchial asthma proved to be safe and clinically favorable in the patients(AU)

Introdução: a imunoterapia sublingual faz parte da prática alergológica, e numerosos estudos confirmam sua eficácia e segurança. Objetivo: caracterizar os resultados com o uso de vacinas sublinguais de Valergen, em pacientes asmáticos, do município de Cabaiguán. Método: inquérito descritivo-prospectivo foi realizado no período de janeiro de 2013 a dezembro de 2016 em pacientes com diagnóstico de asma brônquica intermitente, persistente leve e moderada. O universo foi constituído por 467 pacientes. A amostra foi de 44 pacientes, de todas as idades e sexos que preencheram essas condições, foram atendidos em consulta durante todo o período do estudo e avaliaram cada paciente após três anos de tratamento com imunoterapia. Os dados foram obtidos a partir dos registros clínicos e do registro de vacinação do departamento de alergia. Resultados: predominaram pacientes do sexo feminino, entre 5-14 anos (34,1 por cento), Dermatophagoide pteronyssinus foi o ácaro com maior sensibilidade e utilização (45,4 por cento), após 3 anos de tratamento, pacientes com melhor controle de seus sintomas (72,7 por cento), não houve eventos adversos (79,5 por cento) nos pacientes, aqueles apresentados foram classificados como sistêmicos locais e / ou leves (20,5 por cento). Conclusões: a imunoterapia sublingual para asma brônquica mostrou-se segura e clinicamente favorável nos pacientes estudados(AU)

Condensin function at centromere chromatin facilitates proper kinetochore tension and ensures correct mitotic segregation of sister chromatids.

The condensin complex is essential for sister chromatid segregation in eukaryotic mitosis. Nevertheless, in budding yeast, condensin mutations result in massive mis-segregation of chromosomes containing the nucleolar organizer, while other chromosomes, which also contain condensin binding sites, remain genetically stable. To investigate this phenomenon we analyzed the mechanism of the cell-cycle arrest elicited by condensin mutations. Under restrictive conditions, the majority of condensin-deficient cells arrest in metaphase. This metaphase arrest is mediated by the spindle checkpoint, particularly by the spindle-kinetochore tension-controlling pathway. Inactivation of the spindle checkpoint in condensin mutants resulted in frequent chromosome non-disjunction, eliminating the bias in chromosome mis-segregation towards rDNA-containing chromosomes. The spindle tension defect in condensin-impaired cells is likely mediated by structural defects in centromere chromatin reflected by the partial loss of the centromere histone Cse4p. These findings show that, in addition to its essential role in rDNA segregation, condensin mediates segregation of the whole genome by maintaining the centromere structure in Saccharomyces cerevisiae.

Cdc14p/FEAR pathway controls segregation of nucleolus in S. cerevisiae by facilitating condensin targeting to rDNA chromatin in anaphase.

The condensin complex is the chief molecular machine of mitotic chromosome condensation. Nucleolar concentration of condensin in mitosis was previously shown to correlate with proficiency of rDNA condensation and segregation. To uncover the mechanisms facilitating this targeting we conducted a screen for mutants that impair mitotic condensin congression to the nucleolus. Mutants in the cdc14, esp1 and cdc5 genes, which encode FEAR-network components, showed the most prominent defects in mitotic condensin localization. We established that Cdc14p activity released by the FEAR pathway was required for proper condensin-to-rDNA targeting in anaphase. The MEN pathway was dispensable for condensin-to-rDNA targeting, however MEN-mediated release of Cdc14p later in anaphase allowed for proper, albeit delayed, condensin targeting to rDNA and successful segregation of nucleolus in the slk19 FEAR mutant. Although condensin was physically dislodged from rDNA in the cdc14 mutant, it was properly assembled, phosphorylated and chromatin-bound, suggesting that condensin was mis-targeted but active. This study identifies a novel pathway promoting condensin targeting to a specific chromosomal address, the rDNA locus.

Enfermedad luxante de la cadera. Reultados de su tratamiento / Congenital dislocation of hip. Its treatment results

En este trabajo se realiza una revisión de 31 pacientes con enfermedad luxante de la cadera, atendidos y tratados en el Servicio de Ortopedia y Traumatología del Hospital Pediátrico Provincial Docente "José Luis Miranda" de Santa Clara, en el periodo comprendido entre enero de 1989 y junio de 1991. Se realiza un Análisis de variables importantes como edad, sexo, elementos clínicos que propiciaron el diagnóstico, clasificación, tratamiento empleado y periodo de sanidad. Se hace especial énfasis en las ventajas que reportaron el arnés de Pavlik y la órtesis de Ponseti, así como los efectos favorables que nos brindaron su colocación precoz. Se muestran los resultados finales obtenidos al tratar esta patología que continúa siendo un problema difícil que debe enfrentar el cirujano ortopédico. Se recomienda nuestro esquema de tratamiento por considerar que favorece la curación y porque acorta el periodo de rehabilitación.