Miracle-dz/UniFAR-FTUs huggingface dataset:
Pharmacological Inhibition of Core Regulatory Circuitry Liquid–liquid Phase Separation Suppresses Metastasis and Chemoresistance in Osteosarcoma

Liquid–liquid phase‐separated (LLPS) transcriptional factor assemblies at super‐enhancers (SEs) provide a conceptual framework for underlying transcriptional control in mammal cells. However, the mechanistic understanding of LLPS in aberrant transcription driven by dysregulation of SEs in human malignancies is still elusive. By integrating SE profiling and core regulatory circuitry (CRC) calling algorithm, the CRC of metastatic and chemo‐resistant osteosarcoma is delineated. CRC components, HOXB8 and FOSL1, produce dense and dynamic phase‐separated droplets in vitro and liquid‐like puncta in cell nuclei. Disruption of CRC phase separation decreases the chromatin accessibility in SE regions and inhibits the release of RNA polymerase II from the promoter of SE‐driven genes. Importantly, absence of CRC key component causes a reduction in osteosarcoma tumor growth and metastasis. Moreover, it is shown that CRC condensates can be specifically attenuated by the H3K27 demethylase inhibitor, GSK‐J4. Pharmacological inhibition of the CRC phase separation results in metastasis suppression and re‐sensitivity to chemotherapy drugs in patient‐derived xenograft model. Taken together, this study reveals a previously unknown mechanism that CRC factors formed LLPS condensates, and provides a phase separation‐based pharmacological strategy to target undruggable CRC components for the treatment of metastatic and chemo‐resistant osteosarcoma.
Do Sideline Tests of Vestibular and Oculomotor Function Accurately Diagnose Sports-Related Concussion in Adults? A Systematic Review and Meta-analysis

Background: Sports-related concussion (SRC) assessment tools are primarily based on subjective assessments of somatic, cognitive, and psychosocial/emotional symptoms. SRC symptoms remain underreported, and objective measures of SRC impairments would be valuable to assist diagnosis. Measurable impairments to vestibular and oculomotor processing have been shown to occur after SRC and may provide valid objective assessments. Purpose: Determine the diagnostic accuracy of sideline tests of vestibular and oculomotor dysfunction to identify SRC in adults. Study Design: Systematic review; Level of evidence, 4. Methods: Electronic databases and gray literature were searched from inception until February 12, 2020. Physically active individuals (>16 years of age) who participated in sports were included. The reference standard for SRC was a combination of clinical signs and symptoms (eg, the Sport Concussion Assessment Tool [SCAT]), and index tests included any oculomotor assessment tool. The QUADAS tool was used to assess risk of bias, with the credibility of the evidence being rated according to GRADE. Results: A total of 8 studies were included in this review. All included studies used the King-Devick test, with no other measures being identified. Meta-analysis was performed on 4 studies with a summary sensitivity and specificity of 0.77 and 0.82, respectively. The overall credibility of the evidence was rated as very low. Conclusion: Caution must be taken when interpreting these results given the very low credibility of the evidence, and the true summary sensitivity and specificity may substantially differ from the values calculated within this systematic review. Therefore, we recommend that clinicians using the King-Devick test to diagnose SRC in adults do so in conjunction with other tools such as the SCAT. PROSPERO Registration: CRD42018106632.
TCF19 Impacts a Network of Inflammatory and DNA Damage Response Genes in the Pancreatic β-Cell

Transcription factor 19 (TCF19) is a gene associated with type 1 diabetes (T1DM) and type 2 diabetes (T2DM) in genome-wide association studies. Prior studies have demonstrated that Tcf19 knockdown impairs β-cell proliferation and increases apoptosis. However, little is known about its role in diabetes pathogenesis or the effects of TCF19 gain-of-function. The aim of this study was to examine the impact of TCF19 overexpression in INS-1 β-cells and human islets on proliferation and gene expression. With TCF19 overexpression, there was an increase in nucleotide incorporation without any change in cell cycle gene expression, alluding to an alternate process of nucleotide incorporation. Analysis of RNA-seq of TCF19 overexpressing cells revealed increased expression of several DNA damage response (DDR) genes, as well as a tightly linked set of genes involved in viral responses, immune system processes, and inflammation. This connectivity between DNA damage and inflammatory gene expression has not been well studied in the β-cell and suggests a novel role for TCF19 in regulating these pathways. Future studies determining how TCF19 may modulate these pathways can provide potential targets for improving β-cell survival.
Exploiting differential effects of actomyosin contractility to control cell sorting among breast cancer cells

In order to gain a greater understanding of the factors that drive spatial organization in multicellular aggregates of cancer cells, we investigate the segregation patterns of 6 breast cell lines of varying degree of mesenchymal character during formation of mixed aggregates. Cell sorting is considered in the context of available adhesion proteins and cellular contractility. It is found that the primary compaction mediator (cadherins or integrins) for a given cell type in isolation plays an important role in compaction speed, which in turn is the major factor dictating preference for interior or exterior position within mixed aggregates. In particular, cadherin-deficient, invasion-competent cells tend to position towards the outside of aggregates, facilitating access to extracellular matrix. Reducing actomyosin contractility is found to have a differential effect on spheroid formation depending on compaction mechanism. Inhibition of contractility has a significant stabilizing effect on cell-cell adhesions in integrin-driven aggregation and a mildly destabilizing effect in cadherin-based aggregation. This differential response is exploited to statically control aggregate organization and dynamically rearrange cells in pre-formed aggregates. Sequestration of invasive cells in the interior of spheroids provides a physical barrier that reduces invasion in three-dimensional culture, revealing a potential strategy for containment of invasive cell types.
Conservação de espermatozóides bovinos por liofilização (freeze-drying).

30 Conservação de Espermatozóides Bovinos por Liofilização (freeze-drying) Carlos Frederico Martins Margot Nunes Dode Roberto Guimarães Júnior Sônia Nair Báo José Robson Bezerra Sereno Rodolfo Rumpf
Multi-targeted properties of the probiotic saccharomyces cerevisiae CNCM I-3856 against enterotoxigenic escherichia coli (ETEC) H10407 pathogenesis across human gut models

ABSTRACT Enterotoxigenic Escherichia coli (ETEC) is one of the most common causes of acute traveler’s diarrhea. Adhesins and enterotoxins constitute the major ETEC virulence traits. With the dramatic increase in antibiotic resistance, probiotics are considered a wholesome alternative to prevent or treat ETEC infections. Here, we examined the antimicrobial properties of the probiotic Saccharomyces cerevisiae CNCM I-3856 against ETEC H10407 pathogenesis upon co-administration in the TNO gastrointestinal Model (TIM-1), simulating the physicochemical and enzymatic conditions of the human upper digestive tract and preventive treatment in the Mucosal Simulator of the Human Intestinal Microbial Ecosystem (M-SHIME), integrating microbial populations of the ileum and ascending colon. Interindividual variability was assessed by separate M-SHIME experiments with microbiota from six human individuals. The probiotic did not affect ETEC survival along the digestive tract. However, ETEC pathogenicity was significantly reduced: enterotoxin encoding virulence genes were repressed, especially in the TIM-1 system, and a lower enterotoxin production was noted. M-SHIME experiments revealed that 18-days probiotic treatment stimulate the growth of Bifidobacterium and Lactobacillus in different gut regions (mucosal and luminal, ileum and ascending colon) while a stronger metabolic activity was noted in terms of short-chain fatty acids (acetate, propionate, and butyrate) and ethanol production. Moreover, the probiotic pre-treated microbiota displayed a higher robustness in composition following ETEC challenge compared to the control condition. We thus demonstrated the multi-inhibitory properties of the probiotic S. cerevisiae CNCM I-3856 against ETEC in the overall simulated human digestive tract, regardless of the inherent variability across individuals in the M-SHIME.
Near Equilibrium 13C18O Bonding During Inorganic Calcite Precipitation Under Chemo‐Stat Conditions

We report results of 13C/12C, 18O/16O, and 13C18O “clumped” isotope analyses from a series of calcite precipitation experiments from aqueous solutions under laboratory conditions. Chemo‐stat precipitation experiments were performed to synthetically form calcite from aqueous solution onto 43Ca‐labeled calcite seed crystals. Formation rate was controlled during the experiments to investigate the effect of precipitation rate and temperature on 13C18O bonding in calcite, where rates ranged from 10−6.88 to 10−8.20 mol m−2 s−1 at three temperatures (10, 20, and 30°C). No relation was observed between precipitation rate and 13C18O bonding proportion over the range of precipitation rates used. The relation between Δ47 and temperature produced was comparable to calibration studies which report a relatively high sensitivity of 13C18O bonding to temperature over the range investigated. Comparing solution conditions across multiple experimental data sets indicates an inverse relation between saturation state and 13C18O bonding, where high super‐saturation conditions are likely to be furthest from equilibrium 13C18O partitioning. Carbon fractionation between calcite and HCO3(aq)− was found to be a temperature independent value of +1.6‰. The temperature‐dependent calcite‐water 18O/16O fractionation relation determined in this study is slightly different (larger αcalcite‐H2O value) than those measured in several previous investigations. Significantly, we observe a dependence of the 18O/16O isotope fractionation factor on growth rate. Taken together, these findings suggest carbonate growth in our experiments approached equilibrium more closely than previous experiments of this type, yet did not achieve full O isotope equilibrium.
Intrarenal pelvic bradykinin-induced sympathoexcitatory reno-renal reflex is attenuated in rats exposed to chronic intermittent hypoxia

Supplemental Digital Content is available in the text Objective: In this study, we hypothesized that excitatory reno-renal reflex control of sympathetic outflow is enhanced in rats exposed to chronic intermittent hypoxia (CIH) with established hypertension. Methods: Under anaesthesia, renal sensory nerve endings in the renal pelvic wall were chemically activated using bradykinin (150, 400 and 700 μmol/l) and capsaicin (1.3 μmol/l), and cardiovascular parameters and renal sympathetic nerve activity (RSNA) were measured. Results: CIH-exposed rats were hypertensive with elevated basal heart rate and increased basal urine flow compared with sham. The intrarenal pelvic infusion of bradykinin was associated with contralateral increase in the RSNA and heart rate, without concomitant changes in blood pressure. This was associated with a drop in the glomerular filtration rate, which was significant during a 5 min period after termination of the infusion but without significant changes in urine flow and absolute sodium excretion. In response to intrarenal pelvic infusion of 700 μmol/l bradykinin, the increases in RSNA and heart rate were blunted in CIH-exposed rats compared with sham rats. Conversely, the intrarenal pelvic infusion of capsaicin evoked an equivalent sympathoexcitatory effect in CIH-exposed and sham rats. The blockade of bradykinin type 1 receptors (BK1R) suppressed the bradykinin-induced increase in RSNA by ∼33%, with a greater suppression obtained when bradykinin type 2 receptors (BK2R) and BK1R were contemporaneously blocked (∼66%). Conclusion: Our findings reveal that the bradykinin-dependent excitatory reno-renal reflex does not contribute to CIH-induced sympathetic hyperactivity and hypertension. Rather, there is evidence that the excitatory reno-renal reflex is suppressed in CIH-exposed rats, which might relate to a downregulation of BK2R.
Effect of bariatric surgery on neurocognitive function after 6 months of follow-up: a pilot study.

BACKGROUND reduced cognitive performance has been observed in patients with severe obesity. Bariatric surgery and subsequent adipose tissue loss seem to affect cognitive functioning positively; however, improvement predictors are not well established. AIM to evaluate the cognitive performance and the nutritional status of patients with severe obesity 6-month after bariatric surgery. METHODS we assessed the neuropsychological performance of 22 patients with obesity (body mass index: ~ 42.9 kg/m²). The nutritional evaluation consisted of the routine tests performed in the baseline and postoperative periods. Lastly, we calculated the correlation between neuropsychological assessment results and blood biomarkers. RESULTS the patients did not present cognitive impairment in the preoperative assessment, but performed below the standard range. The patients underwent significant weight loss after 6 months from surgery (~ 22 kg), with a change in obesity class III to I. Also, the patients presented a significant improvement in attention, mental flexibility, inhibitory control, and processing speed. Additionally, we observed a significant improvement in serum folic acid (108 %), gamma-glutamyl transferase (-41 %), uric acid (-32 %), ferritin (-28 %), triglycerides (-19 %), and high-density lipoprotein (9 %). Lastly, we found a moderate positive correlation between processing speed and body weight (r = 0.46), gamma-glutamyl transferase (r = 0.54), and total protein and mental flexibility (r = 0.75). CONCLUSION bariatric surgery promoted significant weight loss and improved attention, mental flexibility, processing speed, and several nutritional biomarkers. Nevertheless, the surgery had limited effects on other cognitive functions such as short- and long-term memory and language.
Microbiome-mediated response to pulse fire disturbance outweighs the effects of fire legacy on plant performance.

Fire plays a major role in structuring plant communities across the globe. Interactions with soil microbes impact plant fitness, scaling up to influence plant populations and distributions. Here we present the first factorial manipulation of both fire and soil microbiome presence to investigate their interactive effects on plant performance across a suite of plant species with varying life history traits. We conducted fully-factorial experiments on each of 11 species from the Florida scrub ecosystem to test plant performance responses to soils with varying fire histories (36 soil sources), the presence/absence of a microbiome, and exposure to an experimental burn. Results revealed interactive 'pulse' effects between fire and the soil microbiome on plant performance. On average, post-fire soil microbiomes strongly reduced plant productivity compared to unburned or sterilized soils. Interestingly, longer-term fire 'legacy' effects had minor impacts on plant performance and were unrelated to soil microbiomes. While pulse fire effects on plant-microbiome interactions are short-term, they could have long-term consequences for plant communities by establishing differential microbiome-mediated priority effects during post-disturbance succession. The prominence of pulse fire effects on plant-microbe interactions has even greater import due to expected increases in fire disturbances resulting from anthropogenic climate change.
Δ 9-Tetrahydrocannabinol During Adolescence Reprograms the Nucleus Accumbens Transcriptome, Affecting Reward Processing, Impulsivity, and Specific Aspects of Cocaine Addiction-Like Behavior in a Sex-Dependent Manner

Abstract Background Cannabis exposure during adolescence is associated with emotional and motivational alterations that may entail an enhanced risk of developing psychiatric disorders. In rodent models, exposure to cannabinoids during adolescence leads to increased self-administration of opiates and cocaine, however, the psychological and neural mechanisms and the sex-specificity of this phenomenon are largely unknown. Methods We exposed male and female adolescent rats to Δ9-tetrahydrocannabinol (THC) and studied at adulthood the effects of such treatment on psychological processes related to reward, such as Pavlovian conditioned approach, Pavlovian to instrumental transfer, habit formation and waiting impulsivity. In the light of these data and given the involvement of the nucleus accumbens in the processes examined, we performed an RNASeq transcriptomic study and assessed cocaine addiction-like behavior. Results THC exposure increased goal-tracking (in males and females) and enhanced Pavlovian to instrumental transfer (especially in males) but did not affect habit formation. THC-exposed rats exhibited subtle, state-dependent changes in premature responding in the 2-CSRTT task. RNASeq data showed gene expression alterations in a marked sex-specific manner. While no effects were found on the acquisition of cocaine self-administration or punished drug-seeking, rats exposed to THC self-administered more cocaine under a progressive ratio schedule (males), had a higher rebound upon returning to continuous access to the drug (females) and showed reduced drug-seeking after 30 days of withdrawal (females). Conclusions Adolescent THC affects specific aspects of reward- (and cocaine-) guided behavior and the function of a key brain region mediating these effects, in a remarkable sex-specific manner.
Batrachochytrium salamandrivorans Threat to the Iberian Urodele Hotspot

The recent introduction of the chytrid fungus Batrachochytrium salamandrivorans into northeastern Spain threatens salamander diversity on the Iberian Peninsula. We assessed the current epidemiological situation with extensive field sampling of urodele populations. We then sought to delineate priority regions and identify conservation units for the Iberian Peninsula by estimating the susceptibility of Iberian urodeles using laboratory experiments, evidence from mortality events in nature and captivity and inference from phylogeny. None of the 1395 field samples, collected between 2015 and 2021 were positive for Bsal and no Bsal-associated mortality events were recorded, in contrast to the confirmed occurrence of Bsal outbreak previously described in 2018. We classified five of eleven Iberian urodele species as highly susceptible, predicting elevated mortality and population declines following potential Bsal emergence in the wild, five species as intermediately susceptible with variable disease outcomes and one species as resistant to disease and mortality. We identified the six conservation units (i.e., species or lineages within species) at highest risk and propose priority areas for active disease surveillance and field biosecurity measures. The magnitude of the disease threat identified here emphasizes the need for region-tailored disease abatement plans that couple active disease surveillance to rapid and drastic actions.
Cost-benefit analysis of hepatic resection, radiofrequency ablation and liver transplantation in small hepatocellular carcinoma

ABSTRACT Objective The aim of the present study was to evaluate the cost-effectiveness ratio of surgical treatment options for small hepatocellular carcinoma (SHC) by using the decision tree model and providing a reference for the clinical therapeutic decisions for SHC. Methods The data of 719 cases with SHC in the BCLC 0-A who were treated in the past were collected. The survival duration and treatment cost of patients in each experimental group after hepatic resection (HR), radiofrequency ablation (RFA), and orthotopic liver transplantation (OLT) were statistically analyzed. Results For SHC with a diameter of less than 3.0 cm, HR, RFA, and OLT had similar cost-effectiveness ratios. OLT could achieve a longer life expectancy, but it was greatly affected by the dropout rate while waiting for the liver donor. RFA was preferred when the willingness to pay (WTP) < 2,5000 RMB/QALY, OLT was preferred when WTP > 75,000 RMB/QALY, and HR was preferred when WTP was between the two. Expert opinion HR in SHC with OLT had the longest life expectancy, but due to the limitations of organ sources, OLT was the preferred treatment option when the WTP was large enough.
The Diplodia Tip Blight Pathogen Sphaeropsis sapinea Is the Most Common Fungus in Scots Pines’ Mycobiome, Irrespective of Health Status—A Case Study from Germany

The opportunistic pathogen Sphaeropsis sapinea (≡Diplodia sapinea) is one of the most severe pathogens in Scots pine, causing the disease Diplodia tip blight on coniferous tree species. Disease symptoms become visible when trees are weakened by stress. Sphaeropsis sapinea has an endophytic mode in its lifecycle, making it difficult to detect before disease outbreaks. This study aims to record how S. sapinea accumulates in trees of different health status and, simultaneously, monitor seasonal and age-related fluctuations in the mycobiome. We compared the mycobiome of healthy and diseased Scots pines. Twigs were sampled in June and September 2018, and filamentous fungi were isolated. The mycobiome was analyzed by high-throughput sequencing (HTS) of the ITS2 region. A PERMANOVA analysis confirmed that the mycobiome community composition significantly differed between growth years (p < 0.001) and sampling time (p < 0.001) but not between healthy and diseased trees. Sphaeropsis sapinea was the most common endophyte isolated and the second most common in the HTS data. The fungus was highly abundant in symptomless (healthy) trees, presenting in its endophytic mode. Our results highlight the ability of S. sapinea to accumulate unnoticed as an endophyte in healthy trees before the disease breaks out, representing a sudden threat to Scots pines in the future, especially with increasing drought conditions experienced by pines.
Epidemiology of Candidemia in Kuwait: A Nationwide, Population-Based Study

The Candida species cause a majority of invasive fungal infections. In this article, we describe the nationwide epidemiology of candidemia in Kuwait in 2018. Yeast bloodstream isolates submitted from all major hospitals and identified by phenotypic MALDI-TOF MS and/or by molecular methods were studied. Susceptibility testing was performed by Etest. Out of 313 bloodstream yeasts, 239 Candida spp. isolates (excluding duplicate isolates) were obtained during 234 candidemic episodes among 223 patients. Mixed-species candidemia and re-infection occurred in 5 and 11 patients, respectively. C. albicans (n = 74), C. parapsilosis (n = 54), C. tropicalis (n = 35), C. auris (n = 33), C. glabrata (n = 32), other Candida spp. (n = 11), and other yeasts (n = 9) caused fungemia. Nearly 50% of patients were in intensive care units. Candida spp. isolates (except C. glabrata) were susceptible to caspofungin and 27% of C. auris were amphotericin B-resistant. Resistance to fluconazole was 100% in C. auris, 17% in C. parapsilosis, 12% in C. glabrata, and 1% in C. albicans. Mortality was 47% for other Candida/yeast infections. Nationwide candidemia incidence in 2018 was 5.29 cases/100,000 inhabitants. Changes in species spectrum, increasing fluconazole resistance in C. parapsilosis, and the emergence of C. auris as a major pathogen in Kuwait are noteworthy findings. The data could be of help in informing decisions regarding planning, in the allocation of resources, and in antimicrobial stewardship.