CDK7 and MITF repress a transcription program involved in survival and drug tolerance in melanoma.

Melanoma cell phenotype switching between differentiated melanocytic and undifferentiated mesenchymal-like states drives metastasis and drug resistance. CDK7 is the serine/threonine kinase of the basal transcription factor TFIIH. We show that dedifferentiation of melanocytic-type melanoma cells into mesenchymal-like cells and acquisition of tolerance to targeted therapies is achieved through chronic inhibition of CDK7. In addition to emergence of a mesenchymal-type signature, we identify a GATA6-dependent gene expression program comprising genes such as AMIGO2 or ABCG2 involved in melanoma survival or targeted drug tolerance, respectively. Mechanistically, we show that CDK7 drives expression of the melanocyte lineage transcription factor MITF that in turn binds to an intronic region of GATA6 to repress its expression in melanocytic-type cells. We show that GATA6 expression is activated in MITF-low melanoma cells of patient-derived xenografts. Taken together, our data show how the poorly characterized repressive function of MITF in melanoma participates in a molecular cascade regulating activation of a transcriptional program involved in survival and drug resistance in melanoma.

Sisal wool skin disease in Merino sheep in the Argentine Patagonia region: Identification and molecular diagnosis of Corynebacterium bovis from skin lesions.

BACKGROUND: Sisal wool condition is a skin disease affecting Merino sheep in the Argentine Patagonia region. Corynebacterium spp. isolates have previously been isolated from skin swabs from lesions, while specific identification of the bacteria involved has not been reported. HYPOTHESIS/OBJECTIVES: The aim of this work was to characterize the bacterial agent isolated from sisal wool lesions and to develop a diagnostic method for field surveillance. MATERIALS AND METHODS: Molecular identification of a collection of 72 isolates obtained previously was performed using PCR and 16S rRNA and rpoB sequencing. A field survey was carried out on two farms in the Río Negro province of Argentine Patagonia. Swab samples from sheep with and without skin lesions were collected and analysed by PCR and culture. RESULTS: Isolates analysed were confirmed by sequencing as Corynebacterium bovis. Using a PCR test without culture step, all field samples from affected sheep were positive for C. bovis; samples from the healthy skin from the same animals or clinically healthy sheep all were negative. CONCLUSIONS AND CLINICAL RELEVANCE: Sisal wool skin disease was associated with C. bovis infection based on culture and PCR methods; the latter may be useful for helping to pursue a disease control strategy.

Genomic and functional conservation of lncRNAs: lessons from flies.

Over the last decade, the increasing interest in long non-coding RNAs (lncRNAs) has led to the discovery of these transcripts in multiple organisms. LncRNAs tend to be specifically, and often lowly, expressed in certain tissues, cell types and biological contexts. Although lncRNAs participate in the regulation of a wide variety of biological processes, including development and disease, most of their functions and mechanisms of action remain unknown. Poor conservation of the DNA sequences encoding for these transcripts makes the identification of lncRNAs orthologues among different species very challenging, especially between evolutionarily distant species such as flies and humans or mice. However, the functions of lncRNAs are unexpectedly preserved among different species supporting the idea that conservation occurs beyond DNA sequences and reinforcing the potential of characterising lncRNAs in animal models. In this review, we describe the features and roles of lncRNAs in the fruit fly Drosophila melanogaster, focusing on genomic and functional comparisons with human and mouse lncRNAs. We also discuss the current state of advances and limitations in the study of lncRNA conservation and future perspectives.

Principal Metabolites in Extracts of Different Plants Responsible for Antibacterial Effects.

The increase in bacterial resistance and decreased effectiveness of antibacterial agents has forced researchers to look for new antibacterial agents from environmentally friendly sources such as essential oils and oil extracts. The functional group of the metabolites present in the essential oils or plant extract and the synergy effects between them play an important role in the biological activity and can be the principal factor affecting the antibacterial effect. All of these bioactive oils showed the same action mechanism, and the best way to implement them is by extracting them without changing their original properties, whereby the characterization and evaluation of the compounds are important steps. All of these themes are extensively reviewed, analyzed, and discussed in this work.

Alpha-mannosidosis caused by toxic plants in ruminants of Argentina.

It is well known that several of the swainsonine-containing plant species found widespread around the world have a negative economic impact in each country. In Argentina, most of the information on the poisonous plant species that produce α-mannosidosis is published in Spanish and thus not available to most English-speaking researchers interested in toxic plants. Therefore, the aim of this review is to summarize the information about swainsonine-containing plants in Argentina, which are extensively distributed throughout different ecoregions of the country. To date, five species from three genera have been shown to induce α-mannosidosis in livestock in Argentina: Ipomoea carnea subsp. fistulosa, Ipomoea hieronymi subsp. calchaquina (Convolvulaceae), Astragalus garbancillo, Astragalus pehuenches (Fabaceae), and Sida rodrigoi (Malvaceae). These species contain the indolizidine alkaloid swainsonine, which inhibits the lysosomal enzyme α-mannosidase and consequently affects glycoprotein metabolism, resulting in partially metabolized sugars. The prolonged consumption of these poisonous plants produces progressive weight loss and clinical signs related to a nervous disorder, characterized by tremors of head and neck, abnormalities of gait, difficulty in standing, ataxia and wide-based stance. Histological lesions are mainly characterized by vacuolation of different cells, especially neurons of the central nervous system. The main animal model used to study α-mannosidosis is the guinea pig because, when experimentally poisoned, it exhibits many of the characteristics of naturally intoxicated livestock.

Minimal Hepatic Encephalopathy and Mild Cognitive Impairment Worsen Quality of Life in Elderly Patients With Cirrhosis.

BACKGROUND & AIMS: Patients with cirrhosis are growing older. The overlap between minimal hepatic encephalopathy (MHE) and predementia mild cognitive impairment (MCI) could affect quality of life (QOL). We investigated the performance of elderly patients with cirrhosis on tests for MHE and MCI and their effects on QOL. METHODS: We recruited outpatients with cirrhosis (n = 109) and without cirrhosis (controls, n = 100), 65 years or older, at 4 centers (derivation cohort). All study participants were assessed for psychometric hepatic encephalopathy score (PHES), EncephalApp score, and QOL. MCI was tested in patients with cirrhosis using the repeatable battery for assessment of neuropsychological status and assigned to the following groups: unimpaired, MCI only, MHE only, and MCI+MHE. We created adjusted norms to detect MHE using PHES and EncephalApp scores from the controls. Findings were validated using data from a separate cohort of 77 patients with cirrhosis (mean age, 69.49 ± 4.36 y; 72% men) at the same study sites. RESULTS: Controls were older but were more educated, performed better cognitively, and had better QOL. Among patients with cirrhosis, age, education, model for end-stage liver disease score, EncephalApp score, and QOL were similar, but PHES and repeatable battery for assessment of neuropsychological status differed among sites. In the derivation cohort, the presence of MHE, with or without MCI, was associated with poor QOL, which was lowest in the MCI+MHE group. When we adjusted for age, sex, and education, 49% of patients with cirrhosis had MHE based on the EncephalApp and 8% had MHE based on the PHES. A similar pattern (49% MHE based on EncephalApp and 6% MHE based on PHES) was found in a validation cohort. CONCLUSIONS: In a multicenter study of patients with cirrhosis (>65 y) and controls, the presence of MHE, regardless of MCI, was associated with poor cognition and QOL. We created adjusted norms that defined the high sensitivity of EncephalApp for the detection of MHE in older individuals and validated it in a separate cohort.

Validation of the all-comers design: Results of the TARGET-AC substudy.

BACKGROUND: Results of clinical trials are often criticized by low inclusion rate and potential sampling bias in patient recruitment. The aim of this validation registry is to evaluate how far an all-comers design in the context of clinical research can ensure the representation of the true all-comers population. METHODS: This validation registry is a prospective international multicentre registry, conducted at 10 out of the total 21 centers, participating in TARGET-AC (registered under NCT02520180). During a predefined four-week period data were recorded prospectively on all PCIs performed in the participating centers, whether or not patients were enrolled in TARGET-AC. Data were collected on patient demographics, angiographic lesion- and procedural characteristics. For patients who were not enrolled in the study, operators were asked to declare the reason for not enrolling the patient, using a single-choice questionnaire. RESULTS: A total of 131 patients were enrolled in the TARGET-AC study during the investigated period (ER group), standing as 20% (range 4% and 54%) of all eligible cases per protocol. In the ER group more patients presented with stable angina (61% vs. 43%, respectively; P < .001). Whereas ST-elevation infarction was less common (5% vs. 26%, respectively; P < .001), there was no difference in non-ST elevation acute coronary syndrome (32% vs. 27%, respectively; P = .248). Risk factors and comorbidities did not show any difference between the ER and the non-enrolled (NER) groups, except for greater rate of significant valvular disease in the NER group (12% vs 19%, respectively; P = .037). The NER group presented more thrombotic stenoses than the ER group (20% vs 12%, respectively; P = .040). No difference was found in any other investigated angiographic parameters, like target vessels, bifurcation lesion, severe calcification or chronic total occlusions. Admission during regular working hours and availability of study nurse were associated with markedly higher recruitment rate. CONCLUSION: Results suggest that TARGET AC was outbalanced for stable patients over primary PCIs as compared to real world. However in terms of risk factors and comorbidities the trial managed to represent the collective of real world clinical practice. Fairly representative cases were included at an average inclusion-to-eligible rate of 20%.

Modified Anesthesia Protocol for Electroconvulsive Therapy Permits Reduction in Aerosol-Generating Bag-Mask Ventilation during the COVID-19 Pandemic.

INTRODUCTION: Electroconvulsive therapy (ECT) is a critical procedure in psychiatric treatment, but as typically delivered involves the use of bag-mask ventilation (BMV), which during the COVID-19 pandemic exposes patients and treatment staff to potentially infectious aerosols. OBJECTIVE: To demonstrate the utility of a modified anesthesia protocol for ECT utilizing preoxygenation by facemask and withholding the use of BMV for only those patients who desaturate during the apneic period. METHODS: This chart review study analyzes patients who were treated with ECT using both the traditional and modified anesthesia protocols. RESULTS: A total of 106 patients were analyzed, of whom 51 (48.1%) required BMV using the new protocol. Of clinical factors, only patient BMI was significantly associated with the requirement for BMV. Mean seizure duration reduced from 52.0 ± 22.4 to 46.6 ± 17.1 s, but seizure duration was adequate in all cases. No acute physical, respiratory, or psychiatric complications occurred during treatment. CONCLUSIONS: A modified anesthesia protocol reduces the use of BMV by more than 50%, while retaining adequate seizure duration.

Updates in Consultation-Liaison Psychiatry: 2019.

BACKGROUND: The scientific literature in consultation-liaison psychiatry continually expands, and remaining familiar with the most current literature is challenging for practicing clinicians. The Guidelines and Evidence-Based Medicine Subcommittee of the Academy of Consultation-Liaison Psychiatry writes quarterly annotations of articles of interest to help Academy members gain familiarity with the most current evidence-based practices. These annotations are available on the Academy Website. OBJECTIVE: We identify the 10 most important manuscripts for clinical practice in consultation-liaison psychiatry from 2019. METHODS: Sixty-four abstracts were authored in 2019. Manuscripts were rated on clinical relevance to practice and quality of scholarship. The 10 articles with the highest aggregate scores from 19 raters are described. RESULTS: The resulting articles provide practical guidance for consultation psychiatrists on several topic areas including the treatment of substance use disorders. CONCLUSION: We suggest that these clinical findings should be familiar to all consultation-liaison psychiatrists regardless of practice area. Regular article reviews and summaries help busy clinicians deliver cutting-edge care and maintain a high standard of care across the specialty.

[Corynebacterium pseudotuberculosis biovar ovis: Evaluation of antibiotics susceptibility in vitro]. / Corynebacterium pseudotuberculosis biovar ovis: evaluación de la sensibilidad antibiótica in vitro.

The aims of this work were to study the antibiotic susceptibility in Corynebacterium pseudotuberculosis isolated from small ruminants and to determine the presence of integrons that contain resistance genes. Fifteen isolates of different sources were analysed using the diffusion and the dilution methods. When the diffusion method was performed, amoxicillin-clavulanic, ampicillin, cefotaxime, cefoxitin, ciprofloxacin, chloramphenicol, erythromycin, streptomycin, gentamicin, imipenem, kanamycin, norfloxacin, penicillin, rifampicin, tetracycline, trimethoprim-sulfamethoxazole and vancomycin were effective against the 100% of isolates, while amikacin showed variable results. The isolates that were able to grow with amikacin, were studied in relation to the presence of integron class1. The result was negative, suggesting the absence of integron. Using dilution method, the antibiotics belonging to the cephalosporin, glycopeptide, macrolide, quinolone, and tetracycline groups were the most active ones for the C.pseudotuberculosis biovar ovis isolates. Less activity of ß-lactam and aminoglycosides were observed. There was no observation of variability in the antibiotic patterns in the strains coming from different sources.

Variables Influencing the Accuracy of 3D Modeling of Existing Roads Using Consumer Cameras in Aerial Photogrammetry.

Point cloud (PC) generation from photogrammetry⁻remotely piloted aircraft systems (RPAS) at high spatial and temporal resolution and accuracy is of increasing importance for many applications. For several years, photogrammetry⁻RPAS has been used to recover civil engineering works such as digital elevation models (DEMs), triangle irregular networks (TINs), contour levels, orthophotographs, etc. This study analyzes the influence of variables involved in the accuracy of PC generation over asphalt shapes and determines the most influential variable based on the development of an artificial neural network (ANN) with patterns identified in the test flights. The input variables were those involved, and output was the three-dimension root mean square error (3D-RMSE) of the PC in each ground control point (GCP). The result of the study shows that the most influential variable over PC accuracy is the modulation transfer function 50 (MTF50). In addition, the study obtained an average 3D-RMSE of 1 cm. The results can be used by the scientific and civil engineering communities to consider MTF50 variables in obtaining images from RPAS cameras and to predict the accuracy of a PC over asphalt based on the ANN developed. Also, this ANN could be the beginning of a large database containing patterns from several cameras and lenses in the world market.

Uncoupling PIP2-calmodulin regulation of Kv7.2 channels by an assembly destabilizing epileptogenic mutation.

We show that the combination of an intracellular bi-partite calmodulin (CaM)-binding site and a distant assembly region affect how an ion channel is regulated by a membrane lipid. Our data reveal that regulation by phosphatidylinositol(4,5)bisphosphate (PIP2) and stabilization of assembled Kv7.2 subunits by intracellular coiled-coil regions far from the membrane are coupled molecular processes. Live-cell fluorescence energy transfer measurements and direct binding studies indicate that remote coiled-coil formation creates conditions for different CaM interaction modes, each conferring different PIP2 dependency to Kv7.2 channels. Disruption of coiled-coil formation by epilepsy-causing mutation decreases apparent CaM-binding affinity and interrupts CaM influence on PIP2 sensitivity.

Identification and molecular characterization of Orf virus in Argentina.

Orf virus (ORFV) is the etiological agent of contagious ecthyma (CE), a pustular dermatitis of sheep and goats. Outbreaks of ORFV have been observed in all geographical regions of the world, including Argentina. The origin and identity of Argentinian ORFVs are unknown, and no comparative or phylogenetic studies of these viruses have been performed. In this study, we described the sequencing and analysis of five ORFV molecular markers: a partial B2L gene (ORF011), VIR (ORF020), an envelope mature protein (ORF109), vIL10 (ORF127), and GIF (ORF117) from two particular Argentinian outbreaks of CE.

Technical deployment of aggregator business models.

The proliferation of Distributed Energy Resources (DERs) is paving the way for new energy-efficient services that aim to make end-users more active. According to the literature, these services will be managed by a central figure, aggregators. This paper proposes several business models to accommodate them in the electric power industry. Several potential alternatives are identified from the study of different design elements, such as the control strategy, architecture, and signals that need to be exchanged. These alternatives are then tested by analyzing pairwise relationships between all the actors involved (Aggregator-Prosumers, Aggregator-DSO, and Aggregator-TSO). Every business model is first explained individually, including how contracts would operate, in order to determine their advantages and drawbacks. Finally, a comparison of all the alternatives is put forward together with an overview of the main initiatives that have already been implemented.

Preoperative management of medications for psychiatric disorders.

Perioperative medication management is a complex topic. Physicians working in the perioperative space are frequently called upon to make decisions regarding continuing or stopping certain medications. For patients with psychiatric disorders, the overwhelming recommendation is to continue therapy with heightened awareness of anesthesiologists regarding potential side effects or medication interactions.

Annual Meeting Content Analysis: Leveraging Annual Meetings to Promote Diversity, Equity, Inclusion, and Belonging in the Academy of Consultation-Liaison Psychiatry.

BACKGROUND: There is an increasing need to promote diversity, equity, and inclusion (DEI) in all aspects of academic medicine, including through continuing medical education. Although professional medical organizations' annual meetings play an instrumental role in continuing medical education for physicians, there are no studies describing DEI content in the annual meeting programming of professional medical organizations, including the Academy of Consultation-Liaison Psychiatry (ACLP), the primary professional organization for consultation-liaison psychiatrists. OBJECTIVE: To examine the ACLP annual meeting titles using Content Analysis. METHODS: We examined the publicly available ACLP annual meeting content titles on the ACLP website from 2010 to 2021. National DEI leaders from ACLP's DEI subcommittee iteratively generated keywords that covered a broad scope of DEI-related themes. Each annual meeting's content was independently coded by 2 members of the DEI subcommittee with discrepancies adjudicated by 2 additional members. Descriptive statistics were used to characterize the content of the annual meeting. RESULTS: Of the 2615 annual meeting titles from 2010 to 2021 that were analyzed, 2531 were not coded to have DEI themes. Three percent (n = 84) of titles were coded to have a DEI theme as follows: Culture/diversity (n = 20, 24%), bias/disparities (n = 17, 20%), race/racism (n = 17, 20%), social justice (n = 12, 14%), gender/sexism (n = 10, 12%), and LGBTQ+ (n = 8, 10%). The frequency of DEI titles each year ranged from 1% (2010, 2018) to 17% (2021) with an increase in DEI content in 2021 (n = 24, 17%). CONCLUSIONS: Although professional medical organizations like the ACLP are poised to leverage their continuing medical education platforms embedded in annual meeting programming to train consultation-liaison psychiatrists on DEI topics, our findings suggest more work is needed to develop and promote DEI-focused educational programming for their annual meetings.