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Abstract Targeting mitochondrial metabolism represents a promising approach for cancer treatment. Here, we investigated the mitotoxic potential of the polybrominated diphenyl ether bromoxib, a natural compound isolated from the marine sponge Dysidea family. We could show that bromoxib comprised strong cytotoxicity in different leukemia and lymphoma cell lines (such as HL60, HPBALL, Jurkat, K562, KOPTK1, MOLT4, SUPB15 and Ramos), but also in solid tumor cell lines (such as glioblastoma cell lines SJ-GBM2 and TP365MG). Bromoxib activated the mitochondrial death pathway as evidenced by the rapid translocation of Bax to the mitochondria and the subsequent mitochondrial release of Smac. Accordingly, bromoxib-induced apoptosis was blocked in caspase 9 deficient Jurkat cells and Jurkat cells overexpressing the antiapoptotic protein Bcl-2. In addition, we could show that bromoxib functioned as an uncoupler of the electron transport chain with similar rapid kinetics as CCCP in terms of dissipation of the mitochondrial membrane potential (ΔΨm), processing of the dynamin-like GTPase OPA1 and subsequent fragmentation of mitochondria. Beyond that, bromoxib strongly abrogated ATP production via glycolysis as well as oxidative phosphorylation (OXPHOS) by targeting electron transport chain complexes II, III, and V (ATP-synthase) in Ramos lymphoma cells. Thus, bromoxib’s potential to act on both cytosolic glycolysis and mitochondrial respiration renders it a promising agent for the treatment of leukemia and lymphoma.

Abstract Background Fabry disease is a rare, progressive X-linked lysosomal storage disorder. It is caused by mutations in the GLA gene resulting in deficiency of α-galactosidase A (α-Gal A), leading to peripheral neuropathy, cardiovascular disease, stroke, end-stage renal disease, gastrointestinal disorders and premature death. Given the long-term nature of disease progression, trials in Fabry disease are often not powered to capture these clinical events. Clinical measures such as estimated glomerular filtration rate (eGFR) and left ventricular mass index (LVMI) are often captured instead. eGFR and LVMI are believed to be associated with long-term Fabry disease clinical events of interest, but the precise relationships are unclear. Objective We aimed to identify published literature exploring the link between eGFR/LVMI and long-term clinical events in Fabry disease. Methods A comprehensive literature search was conducted in Embase® and MEDLINE® (using Embase.com), and a targeted literature review was conducted. Studies reporting a quantitative relationship between eGFR and/or LVMI and clinical events in Fabry disease were extracted, and narrative synthesis was conducted to understand these predictive relationships. Results Eight studies, consisting of seven patient-level retrospective analyses plus one prospective cohort study, met the inclusion criteria. Seven of these studies reported eGFR and six reported LVMI, with five reporting both. All studies presented results for either a composite measure including a range of key Fabry disease clinical events, or a composite outcome that included at least one key Fabry disease clinical event. All studies employed Cox proportional hazards survival modelling. The studies consistently reported that eGFR and LVMI are predictors of key clinical events in Fabry disease, with the findings remaining consistent regardless of the therapy received by patients in the studies. Conclusions The evidence identified suggests that eGFR and LVMI outcomes may be appropriate indicators for long-term clinical events in Fabry disease, and all identified papers implied the same directional relationship. However, additional research is needed to further understand the specific details of these relationships and to quantify them.

Abstract Background The bacterial secondary metabolite prodigiosin has been shown to exert anticancer, antimalarial, antibacterial and immunomodulatory properties. With regard to cancer, it has been reported to affect cancer cells but not non-malignant cells, rendering prodigiosin a promising lead compound for anticancer drug discovery. However, a direct protein target has not yet been experimentally identified. Methods We used mass spectrometry-based thermal proteome profiling in order to identify target proteins of prodigiosin. For target validation, we employed a genetic knockout approach and electron microscopy. Results We identified the Golgi stacking protein GRASP55 as target protein of prodigiosin. We show that prodigiosin treatment severely affects Golgi morphology and functionality, and that prodigiosin-dependent cytotoxicity is partially reduced in GRASP55 knockout cells. We also found that prodigiosin treatment results in decreased cathepsin activity and overall blocks autophagic flux, whereas co-localization of the autophagosomal marker LC3 and the lysosomal marker LAMP1 is clearly promoted. Finally, we observed that autophagosomes accumulate at GRASP55-positive structures, pointing towards an involvement of an altered Golgi function in the autophagy-inhibitory effect of this natural compound. Conclusion Taken together, we propose that prodigiosin affects autophagy and Golgi apparatus integrity in an interlinked mode of action involving the regulation of organelle alkalization and the Golgi stacking protein GRASP55. Video Abstract

Abstract The objective distinction of different types of mental demands as well as their intensity is relevant for research and practical application but poses a challenge for established physiological methods. We investigated whether respiratory gases (oxygen uptake and carbon dioxide output) are suitable to distinguish between emotional stress and cognitive load. To this end, we compared the application of spirometry with an established procedure, namely electrodermal activity (EDA). Our results indicate that electrodermal activity shows a strong responsivity to emotional stress induction, which was highly correlated with its responsivity to cognitive load. Respiratory gases were both sensitive and specific to cognitive load and had the advantage of being predictive for cognitive performance as well as self-reported emotional state. These results support the notion that respiratory gases are a valuable complement to common physiological procedures in the detection and discrimination of different mental demands.

Both anxiety sensitivity (AS) and experiential avoidance (EA) have been linked to social anxiety disorder (SAD). However, previous studies did not consider their joint variance and the heterogeneity of SAD. In this mixed methods cross-sectional survey, we examined 121 online participants (age range: 16-70 years) who self-reported as socially anxious. We compared AS and EA levels in individuals with a primary fear of noticeable anxiety symptoms vs. behaving ineptly. AS and EA were highly prevalent across the sample. Surprisingly, the noticeable symptoms subtype showed slightly lower AS and EA levels than the inept behavior subtype. The noticeable symptoms subtype scored notably lower on social anxiety measures (mean = 69.8) than the inept behavior subtype (mean = 89.3). EA was uniquely associated with social anxiety in both subtypes, while AS was uniquely associated with social anxiety only in the inept behavior subtype. The joint variance explained substantially more of the noticeable symptoms subtype's social anxiety (32.5%) compared to the inept behavior subtype's (9.4%). Qualitative themes aligned with these findings, indicating a self-reinforcing dynamic between high AS, high EA, and social anxiety symptoms. Potential clinical implications are discussed. Future research should examine causality in the AS-EA-SAD dynamic, considering the heterogeneity of SAD.

Once-useful traits that no longer contribute to fitness tend to decay over time. Here, we address whether the expression of mating-related traits that increase the fitness of sexually reproducing individuals but are likely less useful or even costly to asexual counterparts seems to exhibit decay in the latter. Potamopyrgus antipodarum is a New Zealand freshwater snail characterized by repeated transitions from sexual to asexual reproduction. The frequent coexistence of sexual and asexual lineages makes P. antipodarum an excellent model for the study of mating-related trait loss. Under the presumption (inherent in the Biological Species Concept) that failure to discriminate between conspecific and heterospecific mating partners represents a poor mate choice, we used a mating choice assay including sexual and asexual P. antipodarum females and conspecific (presumed better choice) vs. heterospecific (presumed worse choice) males to evaluate the loss of behavioral traits related to sexual reproduction. We found that sexual females engaged in mating behaviors with conspecific mating partners more frequently and for a greater duration than with heterospecific mating partners. By contrast, asexual females mated at similar frequency and duration as sexual females, but did not mate more often or for longer duration with conspecific vs. heterospecific males. While further confirmation will require inclusion of a more diverse array of sexual and asexual lineages, these results are consistent with a scenario where selection acting to maintain effective mate discrimination in asexual P. antipodarum is weak or ineffective relative to sexual females and, thus, where asexual reproduction is associated with the evolutionary decay of mating-related traits in this system.

Abstract The protein kinase TBK1 is a central regulator of innate immune responses and autophagy, and ablation of either function has been linked to neuroinflammatory or degenerative diseases. Autophagy is an intracellular process that recycles old or damaged proteins and organelles. In recent years, the TBK1-dependent regulation of autophagy pathways has been characterized. However, the autophagy-dependent regulation of TBK1 activity awaits further clarification. Here, we observed that TBK1 is recruited to SQSTM1/p62-containing aggregates via the selective autophagy receptor TAX1BP1. In these aggregates, TBK1 phosphorylates SQSTM1/p62 at serine 403 and thus presumably regulates the efficient engulfment and clearance of these structures. We found that TBK1 activation is strongly increased if FIP200, a component of the autophagy-inducing ULK1 complex, is not present or cannot bind to TAX1BP1. Given our collective findings, we hypothesize that FIP200 ensures the inducible activation of TBK1 at SQSTM1/p62 condensates.

ABSTRACT Obstructive sleep apnea is a disorder characterized by complete or incomplete and recurrent upper airway collapse induced by sleep. Several diagnostic methods for obstructive sleep apnea are used, but only sleep endoscopy allows an endoscopic assessment of pharyngeal collapse during sedation. It is essential to carry out sleep endoscopy following a systematic institutional protocol, in preestablished stages, to ensure better reproducibility and reliability of the results found. Sleep endoscopy has few limitations and is a safe test, with a low risk of complications.

Abstract The Met allele of the Val66Met SNP of the BDNF gene (rs6265) is associated with impaired activity-dependent release of brain-derived neurotrophic factor (BDNF), resulting in reduced synaptic plasticity, impaired glutamatergic neurotransmission, and morphological changes. While previous work has demonstrated Val66Met effects on magnetic resonance spectroscopy (MRS) markers of either glutamatergic metabolism (Glx) or neuronal integrity (NAA), no study has investigated Val66Met effects on these related processes simultaneously. As these metabolites share a metabolic pathway, the Glx/NAA ratio may be a more sensitive marker of changes associated with the Val66Met SNP. This ratio is increased in psychiatric disorders linked to decreased functioning in the anterior cingulate cortex (ACC). In this study, we investigated the correlation of the Val66Met polymorphism of the BDNF gene with Glx/NAA in the pregenual anterior cingulate cortex (pgACC) using MRS at 3 Tesla (T) (n = 30, all males) and 7 T (n = 98, 40 females). In both cohorts, Met carriers had lower Glx/NAA compared to Val homozygotes. Follow-up analyses using absolute quantification revealed that the Met carriers do not show decreased pgACC glutamate or glutamine levels, but instead show increased NAA compared to the Val homozygotes. This finding may in part explain conflicting evidence for Val66Met as a risk factor for developing psychiatric illnesses.

BackgroundAge-related diseases such as dementia are playing an increasingly important role in global population development. Thus, prevention, diagnostics, and interventions require more accessibility, which can be realized through digital health apps. With the app on prescription, Germany made history by being the first country worldwide to offer physicians the possibility to prescribe and reimburse digital health apps as of the end of the year 2020. ObjectiveConsidering the lack of knowledge about correlations with the likelihood of use among physicians, this study aimed to address the question of what makes the use of a digital health app by physicians more likely. MethodsWe developed and validated a novel measurement tool—the Digital Health Compliance Questionnaire (DHCQ)—in an interdisciplinary collaboration of experts to assess the role of proposed factors in the likelihood of using a health app. Therefore, a web-based survey was conducted to evaluate the likelihood of using a digital app called DemPredict to screen for Alzheimer dementia. Within this survey, 5 latent dimensions (acceptance, attitude toward technology, technology experience, payment for time of use, and effort of collection), the dependent variable likelihood of use, and answers to exploratory questions were recorded and tested within directed correlations. Following a non–probability-sampling strategy, the study was completed by 331 physicians from Germany in the German language, of whom 301 (90.9%) fulfilled the study criteria (eg, being in regular contact with patients with dementia). These data were analyzed using a range of statistical methods to validate the dimensions of the DHCQ. ResultsThe DHCQ revealed good test theoretical measures—it showed excellent fit indexes (Tucker-Lewis index=0.98; comparative fit index=0.982; standardized root mean square residual=0.073; root mean square error of approximation=0.037), good internal consistency (Cronbach α=.83), and signs of moderate to large correlations between the DHCQ dimensions and the dependent variable. The correlations between the variables acceptance, attitude toward technology, technology experience, and payment for the time of use and the dependent variable likelihood of use ranged from 0.29 to 0.79, and the correlation between effort of the collection and likelihood of use was −0.80. In addition, we found high levels of skepticism regarding data protection, and the age of the participants was found to be negatively related to their technical experience and attitude toward technology. ConclusionsIn the context of the results, increased communication between the medical and technology sectors and significantly more awareness raising are recommended to make the use of digital health apps more attractive to physicians as they can be adjusted to their everyday needs. Further research could explore the connection between areas such as adherence on the patient side and its impact on the likelihood of use by physicians.

Abstract Background Active learning has been shown to improve knowledge retention, facilitate feedback, and motivate learners. Despite this evidence, lecture, a passive mode of instruction, is the most widely utilized instructional method for residency educational conferences. Team-based learning fosters active learning but is infrequently used during residency training. Methods Three team-based learning sessions (one introductory and two content-based) were held during noon conferences in a pediatrics residency program. A pre-post static-group design was used to evaluate learner satisfaction and knowledge gains. Additional data was collected about facilitator preparation, session attendance, and readiness assurance test scores. Descriptive statistics and qualitative content analyses were conducted. Results Forty-seven residents and students participated (81%, 47 of 58). Prior to the introductory session, the majority of participants (55%) were not familiar with team-based learning. After the three sessions, 65% of residents and students reported high levels of satisfaction with team-based learning. When compared to traditional, lecture-based noon conferences, 76% of participants reported more engagement and 48% perceived more learning in team-based learning sessions. Challenges included low completion rates of the assigned reading prior to the session and abridged discussions due to time limitations during sessions. Each session required 10 hours of preparation for curriculum development. Conclusions Team-based learning resulted in greater satisfaction and engagement among learners when compared to lecture-based formats. However, it did not prove to be a feasible instructional method during one-hour residency conferences. Adaptations that promote learner preparation for sessions and overcome time limitations during sessions may improve the feasibility and impact of team-based learning during one-hour conferences. Trial registration Not applicable.

Introduction: Firearm-related deaths and injuries are ongoing public health issues in the United States. We reviewed a series of gun violence- and firearm-related injuries treated at a multi-campus community healthcare system in West Michigan to better understand the demographic and clinical characteristics of these injuries. We also studied hospital charges, and payers responsible, in an effort to identify stakeholders and opportunities for community- and hospital-based prevention. Methods: We performed a retrospective review of firearm injuries treated at Mercy Health Muskegon (MHM) between May 1, 2015 and June 30, 2019. Demographic data, injury type, Injury Severity Score (ISS), anatomic location and organ systems involved, length of stay (LOS), mortality, time of year, and ZIP code in which the injury occurred were reviewed, as were hospital charges and payers responsible. Results: Of those reviewed, 307 firearm-related injuries met inclusion criteria for the study. In 69.4% of cases the injury type was attempted murder or intent to do bodily harm. Accidental and self-inflicted injuries accounted for 25% of cases. There was a statistically significant difference in the mechanism of injury between Black and White patients with a higher proportion of Black men injured due to gun violence (P < 0.001). Median ISS was 8 and the most commonly injured organ system was musculoskeletal. Median LOS was one day. Self-inflicted firearm injuries had the highest rate of mortality (50%) followed by attempted murder (7%) and accidental discharge (3.1%; P < 0.001). Median hospital charge was $8,008. In 68% of cases, Medicaid was the payer. MHM received $4.98 million dollars in reimbursement from Medicaid; however, when direct and indirect costs were taken into account, a loss of $12,648 was observed. Conclusion: Findings from this study reveal that young, Black men are the primary victims of gun violence-related injuries in our West Michigan service area. Hospital care of firearm-related injuries at MHM was predominantly paid for by Medicaid. Multiple stakeholders stand to benefit from funding and supporting community- and hospital-based prevention programs designed to reduce gun violence and firearm-related injuries in our service area.

ABSTRACT Follicular helper T lymphocytes are a subpopulation of CD4+ T lymphocytes initially identified in germinal centers of follicles found in secondary lymphoid organs. The primary function of follicular helper T lymphocytes is to help B lymphocytes’ antibody production. Changing of antibody class and affinity, B cell differentiation and memory generation depend on cooperation between follicular helper T lymphocytes and B cells. In blood, follicular helper T lymphocytes are called circulating follicular helper T lymphocytes. They are considered to have specificities similar to those developed in the secondary lymphoid organs. The phenotype of human follicular helper T lymphocytes is given by simultaneous expression of the markers CXCR5, Bcl-6, CD40L, PD-1, and ICOS. In germinal centers, follicular helper T lymphocytes synthesize interleukin 21 as predominant cytokine. In blood, subpopulations of circulating follicular helper T lymphocytes can be recognized, with different expressions of the classical follicular helper T lymphocytes markers and, in addition, can express other markers such as CXCR3 and CCR6. Presently, there is great interest in follicular helper T lymphocytes and circulating follicular helper T lymphocytes in vaccination studies as indicators of immunization efficacy. In addition, follicular helper T lymphocytes are investigated as possible markers of activity in many diseases and potential therapeutic intervention. This short review describes aspects of immunobiology and quantification of follicular helper T lymphocytes and circulating follicular helper T lymphocytes, and presents a few examples of related findings in systemic lupus erythematosus, rheumatoid arthritis, HIV infection and vaccination.

Background: Homologous recombination deficiencies (HRD) are present in approximately half of epithelial ovarian cancers, for which PARP inhibitors (PARPi) are becoming a preferred treatment option. However, a considerable proportion of these carcinomas acquire resistance or harbour de novo resistance, posing a significant challenge to treatment. Methods: To identify new combinatorial therapeutics to overcome resistance to PARPi, we employed high-throughput conditional RNAi and drug screening of patient-derived ovarian cancer cells. To prioritise clinically relevant drug combinations, we integrated empirical validation with analysis of The Cancer Genome Atlas (TCGA) and Genomics of Drug Sensitivity in Cancer (GDSC) datasets to nominate candidate targets and drugs, reaching three main findings. Findings: Firstly, we found that the PARPi rucaparib enhanced the effect of BET inhibitors (CPI-203 & CPI-0610) irrespective of clinical subtype or HRD status. Additional drug combination screens identified that dasatinib, a non-receptor tyrosine kinase inhibitor, augmented the effects of rucaparib and BET inhibitors, proposing a potential broadly applicable triple-drug combination for high-grade serous and clear cell ovarian carcinomas. Secondly, rucaparib synergised with the BCL2 family inhibitor navitoclax, with preferential activity in ovarian carcinomas that harbour alterations in BRCA1/2, BARD1, or MSH2/6. Thirdly, we identified potentially antagonistic drug combinations between the PARPi rucaparib and vinca alkaloids, anthracyclines, and antimetabolites, cautioning their use in the clinic. Interpretation: These findings propose therapeutic strategies to address PARP inhibitor resistance using agents that are already approved or are in clinical development, with the potential for rapid translation to benefit a broad population of ovarian cancer patients.

Abstract Altered abiotic conditions resulting from human-induced climate change are already driving changes in the spatial and temporal distributions of many organisms. For insects, how species are distributed across elevations is relatively well known, but data on their seasonality at different elevations are lacking. Here we show seasonal variation in beetle abundance and species richness along two spatially-distinct elevational transects (350–1000 m and 100–1000 m asl) in the rainforests of northern Australia. Temperature was the best predictor of temporal abundance and species richness patterns, while rainfall had little influence. Elevation had little effect on seasonal changes in abundance or diversity. Adults of most beetle species exhibited long season-lengths (>6 months of the year) with distinct peaks in abundance during the summer wet-season. We found evidence of phenotypic variation among the more widespread species, with seasonal peaks in abundance often not coinciding across elevations or transects. Due to the wide elevational range of most species, and the lack of consistency in the seasonality of wide-spread individual species, we suggest that many beetles inhabiting the low to mid-elevation mountains in the Wet Tropics, and potentially other tropical rainforests, are not as vulnerable to extinction due to climate change as many other organisms.

In recent years, a number of machine learning models for the prediction of the skin sensitization potential of small organic molecules have been reported and become available. These models generally perform well within their applicability domains but, as a result of the use of molecular fingerprints and other non-intuitive descriptors, the interpretability of the existing models is limited. The aim of this work is to develop a strategy to replace the non-intuitive features by predicted outcomes of bioassays. We show that such replacement is indeed possible and that as few as ten interpretable, predicted bioactivities are sufficient to reach competitive performance. On a holdout data set of 257 compounds, the best model (“Skin Doctor CP:Bio”) obtained an efficiency of 0.82 and an MCC of 0.52 (at the significance level of 0.20). Skin Doctor CP:Bio is available free of charge for academic research. The modeling strategies explored in this work are easily transferable and could be adopted for the development of more interpretable machine learning models for the prediction of the bioactivity and toxicity of small organic compounds.

Membrane nanodomains have been implicated in Ras signaling, but what these domains are and how they interact with Ras remain obscure. Here, using single particle tracking with photoactivated localization microscopy (spt-PALM) and detailed trajectory analysis, we show that distinct membrane domains dictate KRasG12D (an active KRas mutant) diffusion and trafficking in U2OS cells. KRasG12D exhibits an immobile state in ~70 nm domains, each embedded in a larger domain (~200 nm) that confers intermediate mobility, while the rest of the membrane supports fast diffusion. Moreover, KRasG12D is continuously removed from the membrane via the immobile state and replenished to the fast state, reminiscent of Ras internalization and recycling. Importantly, both the diffusion and trafficking properties of KRasG12D remain invariant over a broad range of protein expression levels. Our results reveal how membrane organization dictates membrane diffusion and trafficking of Ras and offer new insight into the spatial regulation of Ras signaling.

Minor prenylated hop compounds have been attracting increasing attention due to their promising anticarcinogenic properties. Even after intensive purification from natural raw extracts, allocating certain activities to single compounds or complex interactions of the main compound with remaining impurities in very low concentration is difficult. In this study, dose-dependent antiproliferative and cytotoxic effects of the promising xanthohumol (XN) analogue xanthohumol C (XNC) were evaluated and compared to XN and a XN-enriched hop extract (XF). It was demonstrated that the cell growth inhibition of human breast cancer cell line (MCF-7) significantly increases after being treated with XNC compared to XN and XF. Based on label-free data-dependent acquisition proteomics, physiological influences on the proteome of MCF-7 cells were analyzed. Different modes of action between XNC and XN treated MCF-7 cells could be postulated. XNC causes ER stress and seems to be involved in cell-cell adhesion, whereas XN influences cell cycles and DNA replication as well as type I interferon signaling pathway. The results demonstrate the utility of using quantitative proteomics for bioactivity screenings of minor hop compounds and underscore the importance of isolating highly pure compounds into their distinct forms to analyze their different and possibly synergistic activities and modes of action.

Monitoring a person’s nutritional consumption is costly and complex. To solve this problem a new technique is proposed to draw conclusions of a person’s food intake. The air pressure signal, recorded in the external acoustic meatus, is used to detect swallow and chew events. A portable device has been developed to record this pressure signal. Due to the constraint of running on a low-power microcontroller, real-time algorithms, used in pattern and speech recognition, were used to develop methods to automatically detect swallow and chew events. A binary classifier was trained by means of manually annotated data sets. Direct comparisons with state of the art technology and tests with several subjects are provided for evaluation purposes.

Clearing of dry forests globally creates edges between remnant forest and open anthropogenic habitats. We used flight intercept traps to evaluate how forest beetle communities are influenced by distance from such edges, together with vertical height, spatial location, and local vegetation structure, in an urbanising region (Brisbane, Australia). Species composition (but not total abundance or richness) differed greatly between ground and canopy. Species composition also varied strongly among sites at both ground and canopy levels, but almost all other significant effects occurred only at ground level, where: species richness declined from edge to interior; composition differed between positions near edges ( 50 m); high local canopy cover was associated with greater total abundance and richness and differing composition; and greater distances to the city centre were associated with increased total abundances and altered composition. Analyses of individual indicator species associated with this variation enabled further biological interpretations. A global literature synthesis showed that most spatially well-replicated studies of edge effects on ground-level beetles within forest fragments have likewise found that positions within tens of metres from edges with open anthropogenic habitats had increased species richness and different compositions from forest interior sites, with fewer effects on abundance. Accordingly, negative edge effects will not prevent relatively small compact fragments (if >10-20 ha) from supporting forest-like beetle communities, although indirect consequences of habitat degradation remain a threat. Retention of multiple spatially scattered forest areas will also be important in conserving forest-dependent beetles, given high levels of between-site diversity.

Bluetooth Low Energy (BLE) has reduced the energy consumption for sensor nodes drastically. One major reason for this improvement is a non-continuous connection between the nodes. But this causes also a nondeterministic data transmission time. Most synchronization protocols are influenced by this characteristic, with the result of less accuracy. In wireless body sensor networks this accuracy is often of vital importance. Therefore this paper evaluates different synchronization principles customized for BLE.

En la Argentina no existen trabajos multicéntricos que eva-lúen el manejo de los pacientes con pancreatitis aguda (PA)a nivel nacional.Objetivos.El objetivo principal de estetrabajo es conocer el manejo de los pacientes con PA en la Argentina. El objetivo secundario es evaluar si los resultadosobtenidos cumplen con los postulados de la Guía Internacio-nal del Colegio Americano de Gastroenterología.Material ymétodos.Participaron 23 centros que ingresaron, en formaprospectiva y consecutiva, a todos los pacientes con diagnós-tico de PA a una base de datos alojada en Internet desdejunio de 2010 a junio de 2013.Resultados.Ingresaron alestudio 854 pacientes (495 mujeres, 58%), edad mediana:47 años (rango: 15-91). La causa más frecuente de PA fue labiliar (88,2%), en el 99% de los pacientes se utilizó un sis-tema pronóstico, el más frecuente fue el de Ranson (74,5%). Fueron clasificados como PA leves 714 pacientes (83,6%) yPA graves 140 (16,4%). Se registraron 43 complicacionessistémicas y 21 locales. A 86 pacientes se les realizó tomogra-fía dinámica y se registraron 73 pacientes con necrosis pan-creática y/o peripancreática. La mortalidad fue de 1,5%. Nohubo diferencia en la mortalidad en relación al volumen,complejidad o afiliación del centro. El cumplimiento de lasprincipales recomendaciones de la guía del Colegio America-no de Gastroenterología fue superior al 80%.Conclusiones.El diagnóstico y el tratamiento de los pacientes con PA en 23centros de salud distribuidos en todo el país fueron óptimos.El manejo cumple con la mayoría de las recomendaciones dela Guía del Colegio Americano de Gastroenterología.

A substantial fraction of the genome is transcribed in a cell-type-specific manner, producing long non-coding RNAs (lncRNAs), rather than protein-coding transcripts. Here, we systematically characterize transcriptional dynamics during hematopoiesis and in hematological malignancies. Our analysis of annotated and de novo assembled lncRNAs showed many are regulated during differentiation and mis-regulated in disease. We assessed lncRNA function via an in vivo RNAi screen in a model of acute myeloid leukemia. This identified several lncRNAs essential for leukemia maintenance, and found that a number act by promoting leukemia stem cell signatures. Leukemia blasts show a myeloid differentiation phenotype when these lncRNAs were depleted, and our data indicates that this effect is mediated via effects on the MYC oncogene. Bone marrow reconstitutions showed that a lncRNA expressed across all progenitors was required for the myeloid lineage, whereas the other leukemia-induced lncRNAs were dispensable in the normal setting.

The hormone estrogen (E2) binds the estrogen receptor to promote transcription of E2-responsive genes in the breast and other tissues. E2 also has links to genomic instability, and elevated E2 levels are tied to breast cancer. Here, we show that E2 stimulation causes a rapid, global increase in the formation of R-loops, co-transcriptional RNA-DNA products, which in some instances have been linked to DNA damage. We show that E2-dependent R-loop formation and breast cancer rearrangements are highly enriched at E2-responsive genomic loci and that E2 induces DNA replication-dependent double-strand breaks (DSBs). Strikingly, many DSBs that accumulate in response to E2 are R-loop dependent. Thus, R-loops resulting from the E2 transcriptional response are a significant source of DNA damage. This work reveals a novel mechanism by which E2 stimulation leads to genomic instability and highlights how transcriptional programs play an important role in shaping the genomic landscape of DNA damage susceptibility.

Steroid-induced sleep disturbance is a common and highly distressing morbidity for children receiving steroid chemotherapy for the treatment of pediatric acute lymphoblastic leukemia (ALL). Sleep disturbance can negatively impact overall quality of life, neurodevelopment, memory consolidation, and wound healing. Hypothalamic orexin neurons are influential wake-promoting neurons, and disturbances in orexin signaling leads to abnormal sleep behavior. A new class of drug, the orexin receptor antagonists, could be an intriguing option for sleep disorders caused by increased orexinergic output. Our aim was to examine the impact of ALL treatment doses of corticosteroids on the orexin system in rodents and in children undergoing treatment for childhood ALL.We administered repeated injections of dexamethasone to rodents and measured responsive orexin neural activity compared to controls. In children with newly diagnosed standard risk B-cell ALL receiving dexamethasone therapy per Children's Oncology Group (COG) induction therapy from 2014-2016, we collected pre- and during-steroids matched CSF samples and measured the impact of steroids on CSF orexin concentration.In both rodents, all markers orexin signaling, including orexin neural output and orexin receptor expression, were preserved in the setting of dexamethasone. Additionally, we did not detect a difference in pre- and during-dexamethasone CSF orexin concentrations in children receiving dexamethasone.Our results demonstrate that rodent and human orexin physiology is largely preserved in the setting of high dose dexamethasone. The data obtained in our experimental model fail to demonstrate a causative role for disruption of the orexin pathway in steroid-induced sleep disturbance.