Miracle-dz/UniFAR-FTUs huggingface dataset:
Effects of altitude and recombinant human erythropoietin on iron metabolism: a randomized controlled trial.

Current markers of iron deficiency (ID) such as ferritin and hemoglobin have shortcomings, and hepcidin and erythroferrone (ERFE) could be of clinical relevance in relation to early assessment of ID. Here, we evaluate whether exposure to altitude-induced hypoxia (2,320 m) alone, or in combination with recombinant human erythropoietin (rHuEPO) treatment, affects hepcidin and ERFE levels before alterations in routine ID biomarkers and stress erythropoiesis manifest. Two interventions were completed, each comprising a four-week baseline, a four-week intervention at either sea level or altitude, and a four-week follow-up. Participants (n=39) were randomly assigned to 20 IU·kg bw-1 rHuEPO or placebo injections every second day for three weeks during the two intervention periods. Venous blood was collected weekly. Altitude increased ERFE (P≤0.001) with no changes in hepcidin or routine iron biomarkers, making ERFE of clinical relevance as an early marker of moderate hypoxia. rHuEPO treatment at sea level induced a similar pattern of changes in ERFE (P<0.05) and hepcidin levels (P<0.05), demonstrating the impact of accelerated erythropoiesis and not of other hypoxia-induced mechanisms. Compared to altitude alone, concurrent rHuEPO treatment and altitude exposure induced additive changes in hepcidin (P<0.05) and ERFE (P≤0.001) parallel with increases in hematocrit (P<0.001), demonstrating a relevant range of both hepcidin and ERFE. A poor but significant correlation between hepcidin and ERFE was found (R2=0.13, P<0.001). The findings demonstrate that hepcidin and ERFE are more rapid biomarkers of changes in iron demands than routine iron markers. Finally, ERFE and hepcidin may be sensitive markers in an anti-doping context.
In-silico evaluations of the isolated phytosterols from polygonum hydropiper L against BACE1 and MAO drug targets

Abstract Our previous anti-Alzheimer's studies on crude extracts, essential oils and isolated compounds including β-sitostrol from Polygonum hydropiper L, motivated us for further studies against beta amyloid cleaving enzyme 1 (BACE1) and monoamine oxidases (MAO-A), (MAO-B) enzymes. Before performing detailed studies on the compounds using animal models and immunohistochemistry, molecular docking study was performed against three vital enzymes implicated in several neurological disorders including Alzheimer's disease (AD), Parkinson's disease (PD), depression and anxiety to predict their inhibitory potential against important enzymes. Beta amyloid cleaving enzyme 1 (BACE1) is important enzyme that catalyze pathological amyloidogenic pathway of processing amyloid precursor proteins to form neurotoxic amyloid plaques. Subsequently, BACE1 inhibitors are considered an important tool in the management of AD. MAOs have been categorized in two well-known groups MAO-A and MAO-B, based on their differential affinity for various monoamines substrates. MAO-A has more affinity for norepinephrine and 5-HT, whereas, MAO-B mainly catalyze the breakdown of dopamine and 2-phenylathylamine (PEA) and other monoamines. Subsequently, they have divergent behavioral outcomes and play a significant role in pathophysiology of several neurodegenerative disorders like AD, depression, drug abuse, migraines, schizophrenia, Attention Deficit Disorder (ADD) and Parkinson’s disease (PD). Molecular docking was carried out to predict the binding modes of β-sitosterol and stigmasterol in the binding pockets of BACE1 (beta-sectretase 1) and MAO (monoamine oxidase A, B) enzymes. The 3 D structure of BACE1 (PDB ID: 2QP8), MAO A (PDB ID: 2ZPX) and MAO B (PDB ID: 2XFN) were downloaded from protein databank. The 3 D structures were then subjected to protonation and energy minimization using default parameters of MOE. Three dimensional structures of β-sitosterol and stigmasterol were built by using Molecular Builder Module program implemented in MOE and saved as a (.mdb) file for molecular docking. Subsequently, the energy of both the compounds were minimized up to 0.05 Gradient using MMFF 94 s force field implemented in MOE. Both the compounds were docked into the active site of proteins using the Triangular Matching docking method (default) and 10 different conformations for each compound were generated. To obtain minimum energy structures the ligands were allowed to be flexible during docking. At the end of docking, the predicted ligand-protein complexes were analyzed for molecular interactions. Overall the docking results showed that these compounds showed good interaction with active site residues of BACE1 as compare to MAO-A and MAO-B. Furthermore, β-sitosterol showed good interaction with BACE1 as compare to stigmasterol. Communicated by Ramaswamy H. Sarma
Hairpin-Spherical Nucleic Acids for Diagnosing COVID-19: a Simple Method to Generalize the Conventional PCR for Molecular Assays

The COVID-19 pandemic revealed during the first global wave of this infectious disease that mass diagnostic testing was necessary to more rapidly detect infection in patients and control the pandemic. Therefore, extra research efforts to develop reliable and more accessible techniques for disease diagnosis are of supreme importance. Here, a target-responsive assembly of gold nanoparticle-core hairpin-spherical nucleic acids (AuNP-core H-SNAs) was implemented to modify the conventional polymerase chain reaction (PCR) assay for the “naked-eye” colorimetric detection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA. Two hairpin DNA ligands are designed based on the two highly conserved regions within N and E genes of SARS-CoV-2 RNA by positioning two short palindromic arms (stem) on either side of a recognition sequence (loop). In the presence of a sequence-specific probe (activator), hairpin DNAs anchored to the surface of AuNPs unfold and expose the palindromic ends to the DNA-directed assembly of AuNPs. The sequence of the activator probes was chosen to be identical to the TaqMan probe in a real-time reverse transcription PCR (RT-PCR) assay for specifically targeting the N and E genes of SARS-CoV-2 RNA. They may either be degraded by the 5′-exonuclease activity of DNA polymerase during PCR cycles or stay intact depending on the presence or absence of the target template in the sample, respectively. Post-addition of H-SNA solutions to the final PCR products of some preconfirmed clinical samples for COVID-19 generated naked-eye-observable red and blue colors for positive and negative cases, respectively, with similar sensitivity to that of the real-time RT-PCR method.
Large‐sample‐size assessment of socioeconomic predictors of community‐level resource management occurrence

Community‐level resource management efforts are cornerstones in ensuring sustainable use of natural resources. Yet, understanding how community characteristics influence management practices remains contested. With a sample size of ≥725 communities, we assessed the effects of key community (i.e., socioeconomic) characteristics (human population size and density, market integration, and modernization) on the probability of occurrence of fisheries management practices, including gear, species, and spatial restrictions. The study was based in Solomon Islands, a Pacific Island country with a population that is highly dependent on coastal fisheries. People primarily dwell in small communities adjacent to the coastline dispersed across 6 island provinces and numerous smaller islands. We used nationally collected data in binomial logistic regression models to examine the likelihood of management occurrence, given socioeconomic context of communities. In contrast to prevailing views, we identified a positive and statistically significant association between both human population size and market integration and all 3 management practices. Human population density, however, had a statistically significant negative association and modernization a varied and limited association with occurrence of all management practices. Our method offers a way to remotely predict the occurrence of resource management practices based on key socioeconomic characteristics. It could be used to improve understanding of why some communities conduct natural resource management activities when statistical patterns suggest they are not likely to and thus improve understanding of how some communities of people beat the odds despite limited market access and high population density.
Radiopotentiation Profiling of Multiple Inhibitors of the DNA Damage Response for Early Clinical Development

Radiotherapy is an effective anticancer treatment, but combinations with targeted agents that maximize efficacy while sparing normal tissue are needed. Here, we assess the radiopotentiation profiles of DNA damage response inhibitors (DDRi) olaparib (PARP1/2), ceralasertib (ATR), adavosertib (WEE1), AZD0156 (ATM), and KU-60648 (DNA-PK). We performed a radiotherapy combination screen and assessed how drug concentration and cellular DDR deficiencies influence the radiopotentiation ability of DDRi. We pre-selected six lung cancer cell lines with different genetic/signaling aberrations (including mutations in TP53 and ATM) and assessed multiple concentrations of DDRi in combination with a fixed radiotherapy dose by clonogenic assay. The effective concentration of DDRi in radiotherapy combinations is lower than that required for single-agent efficacy. This has the potential to be exploited further in the context of DDR deficiencies to increase therapeutic index and we demonstrate that low concentrations of AZD0156 preferentially sensitized p53-deficient cells. Moreover, testing multiple concentrations of DDRi in radiotherapy combinations indicated that olaparib, ceralasertib, and adavosertib have a desirable safety profile showing moderate increases in radiotherapy dose enhancement with increasing inhibitor concentration. Small increases in concentration of AZD0156 and particularly KU-60648, however, result in steep increases in dose enhancement. Radiopotentiation profiling can inform on effective drug doses required for radiosensitization in relation to biomarkers, providing an opportunity to increase therapeutic index. Moreover, multiple concentration testing demonstrates a relationship between drug concentration and radiotherapy effect that provides valuable insights that, with future in vivo validation, can guide dose-escalation strategies in clinical trials.
Diagnostic accuracy of point of care faecal immunochemical testing using a portable high‐speed quantitative analyser for diagnosis in 2‐week wait patients

Laboratory‐based faecal immunochemical testing (FIT) is the gold standard for detecting the presence of blood in the stool. The aim was to perform a diagnostic accuracy study to confirm if a point of care (POC) analyser for FIT could be safely used as an adjunct in the triage and management of 2‐week wait (TWW) colorectal patients.
Diffusion MRI tractography for neurosurgery: the basics, current state, technical reliability and challenges

Diffusion magnetic resonance imaging (dMRI) tractography is currently the only imaging technique that allows for non-invasive delineation and visualisation of white matter (WM) tracts in vivo, prompting rapid advances in related fields of brain MRI research in recent years. One of its major clinical applications is for pre-surgical planning and intraoperative image guidance in neurosurgery, where knowledge about the location of WM tracts nearby the surgical target can be helpful to guide surgical resection and optimise post-surgical outcomes. Surgical injuries to these WM tracts can lead to permanent neurological and functional deficits, making the accuracy of tractography reconstructions paramount. The quality of dMRI tractography is influenced by many modifiable factors, ranging from MRI data acquisition through to the post-processing of tractography output, with the potential of error propagation based on decisions made at each and subsequent processing steps. Research over the last 25 years has significantly improved the anatomical accuracy of tractography. An updated review about tractography methodology in the context of neurosurgery is now timely given the thriving research activities in dMRI, to ensure more appropriate applications in the clinical neurosurgical realm. This article aims to review the dMRI physics, and tractography methodologies, highlighting recent advances to provide the key concepts of tractography-informed neurosurgery, with a focus on the general considerations, the current state of practice, technical challenges, potential advances, and future demands to this field.
Evidence of a double anaerobic threshold in healthy subjects.

AIMS The anaerobic threshold (AT) is an important cardiopulmonary exercise test (CPET) parameter both in healthy and in patients. It is normally determined with three approaches: V-slope method, ventilatory equivalent method, and end-tidal method. The finding of different AT values with these methods is only anecdotic. We defined the presence of a double threshold (DT) when a ΔVO2 > 15 mL/min was observed between the V-slope method (met AT) and the other two methods (vent AT). The aim was to identify whether there is a DT in healthy subjects. METHODS AND RESULTS We retrospectively analysed 476 healthy subjects who performed CPET in our laboratory between 2009 and 2018. We identified 51 subjects with a DT (11% of cases). Cardiopulmonary exercise test data at rest and during the exercise were not different in subjects with DT compared to those without. Met AT always preceded vent AT. Compared to subjects without DT, those with DT showed at met AT lower carbon dioxide output (VCO2), end-tidal carbon dioxide tension (PetCO2) and respiratory exchange ratio (RER), and higher ventilatory equivalent for carbon dioxide (VE/VCO2). Compared to met AT, vent AT showed a higher oxygen uptake (VO2), VCO2, ventilation, respiratory rate, RER, work rate, and PetCO2 but a lower VE/VCO2 and end-tidal oxygen tension. Finally, subjects with DT showed a higher VO2 increase during the isocapnic buffering period. CONCLUSION Double threshold was present in healthy subjects. The presence of DT does not influence peak exercise performance, but it is associated with a delayed before acidosis-induced hyperventilation.
The clear cell sarcoma functional genomic landscape.

Clear Cell Sarcoma (CCS) is a deadly malignancy affecting adolescents and young adults. It is characterized by reciprocal translocations resulting in the expression of the chimeric EWSR1-ATF1 or EWSR1-CREB1 fusion proteins, driving sarcomagenesis. Besides these characteristics, CCS has remained genomically uncharacterized. Copy number analysis of human CCSs showed frequent amplifications of the MITF locus and chromosomes 7 and 8. Few alterations were shared with Ewing sarcoma or desmoplastic small round cell tumors, other EWSR1-rearranged tumors. Exome sequencing in mouse tumors generated by expressing EWSR1-ATF1 from the Rosa26 locus demonstrated no other repeated pathogenic variants. Additionally, we generated a new CCS mouse by Cre-loxP-induced chromosomal translocation between Ewsr1 and Atf1, resulting in copy number loss of chromosome 6 and chromosome 15 instability, including amplification of a portion syntenic with human chromosome 8, surrounding Myc. Additional experiments in the Rosa26 conditional model demonstrated that Mitf or Myc can contribute to sarcomagenesis. Copy number observations in human tumors and genetic experiments in mice render, for the first time, a functional landscape of the CCS genome. These data advance efforts to understand the biology of CCS with innovative models, in which we can eventually validate preclinical therapies, necessary to move toward longer and better survival of the young victims of this disease.
Just a leader? Leadership work challenges and identity contradiction experienced by Finnish physician leaders

Purpose This study seeks to improve the understanding of physician leaders' leadership work challenges. Design/methodology/approach The subjects of the empirical study were physician leaders ( n = 23) in the largest central hospital in Finland. Findings A total of five largely identity-related, partially paradoxical dilemmas appeared regarding why working as “just a leader” is challenging for physician leaders. First, the dilemma of identity ambiguity between being a physician and a leader. Second, the dilemma of balancing the expected commitment to clinical patient work by various stakeholders and that of physician leadership work. Third, the dilemma of being able to compensate for leadership skill shortcomings by excelling in clinical skills, encouraging physician leaders to commit to patient work. Fourth, the dilemma of “medic discourse”, that is, downplaying leadership work as “non-patient work”, making it inferior to patient work. Fifth, the dilemma of a perceived ethical obligation to commit to patient work even if the physician leadership work would be a full-time job. The first two issues support the findings of earlier research, while the remaining three emerging from the authors’ analysis are novel. Practical implications The authors list some of the practical implications that follow from this study and which could help solve some of the challenges. Originality/value This study explores physician leaders' leadership work challenges using authentic physician leader data in a context where no prior empirical research has been carried out.
Mitochondrial transcription factor A plays opposite roles in the initiation and progression of colitis‐associated cancer

Mitochondria are key regulators in cell proliferation and apoptosis. Alterations in mitochondrial function are closely associated with inflammation and tumorigenesis. This study aimed to investigate whether mitochondrial transcription factor A (TFAM), a key regulator of mitochondrial DNA transcription and replication, is involved in the initiation and progression of colitis‐associated cancer (CAC).
[11C]PBR28 radiotracer kinetics are not driven by alterations in cerebral blood flow

The positron emission tomography (PET) radiotracer [11C]PBR28 has been increasingly used to image the translocator protein (TSPO) as a marker of neuroinflammation in a variety of brain disorders. Interrelatedly, similar clinical populations can also exhibit altered brain perfusion, as has been shown using arterial spin labelling in magnetic resonance imaging (MRI) studies. Hence, an unsolved debate has revolved around whether changes in perfusion could alter delivery, uptake, or washout of the radiotracer [11C]PBR28, and thereby influence outcome measures that affect interpretation of TSPO upregulation. In this simultaneous PET/MRI study, we demonstrate that [11C]PBR28 signal elevations in chronic low back pain patients are not accompanied, in the same regions, by increases in cerebral blood flow (CBF) compared to healthy controls, and that areas of marginal hypoperfusion are not accompanied by decreases in [11C]PBR28 signal. In non-human primates, we show that hypercapnia-induced increases in CBF during radiotracer delivery or washout do not alter [11C]PBR28 outcome measures. The combined results from two methodologically distinct experiments provide support from human data and direct experimental evidence from non-human primates that changes in CBF do not influence outcome measures reported by [11C]PBR28 PET imaging studies and corresponding interpretations of the biological meaning of TSPO upregulation.
Age‐related changes in metabolites in young donor livers and old recipient sera after liver transplantation from young to old rats

Liver ageing not only damages liver function but also harms systemic metabolism. To better understand the mechanisms underlying liver ageing, we transplanted the livers of young rats to young and old rats and performed untargeted metabolomics to detect changes in the metabolites in the liver tissues and sera. A total of 153 metabolites in the livers and 83 metabolites in the sera were different between the old and young rats that did not undergo liver transplantation; among these metabolites, 7 different metabolites were observed in both the livers and sera. Five weeks after liver transplantation, the levels of 25 metabolites in the young donor livers were similar to those in the old rats, and this result probably occurred due to the effect of the whole‐body environment of the older recipients on the young livers. The 25 altered metabolites included organic acids and derivatives, lipids and lipid‐like molecules, etc. In the sera, the differences in 78 metabolites, which were significant between the young and old rats, were insignificant in the old recipient rats and made the metabolic profile of the old recipients more similar to that of the young recipients. Finally, combining the above metabolomic data with the transcriptomic data from the GEO, we found that the altered metabolites and genes in the liver were enriched in 9 metabolic pathways, including glycerophospholipid, arachidonic acid, histidine and linoleate. Thus, this study revealed important age‐related metabolites and potential pathways as well as the interaction between the liver and the whole‐body environment.
Antitumour necrosis factor therapy is associated with de novo Crohn’s disease after ileal pouch‐anal anastomosis

Tumour necrosis factor inhibitors (TNFi) have revolutionized the management of moderate to severe ulcerative colitis (UC) since their approval for UC in 2005. However, many patients ultimately require surgery with ileal pouch‐anal anastomosis (IPAA). Development of de novo Crohn's disease (CD) following IPAA is an increasingly common and devastating complication, sometimes progressing to pouch failure. The aim of this study was to evaluate the association of preoperative TNFi exposure and the development of de novo CD after IPAA.
Osteomalacia as a result of phosphorus deficiency in beef cattle grazing subtropical native pastures in Uruguay

We investigated 2 outbreaks of osteomalacia as a result of phosphorus (P) deficiency in herds of lactating beef cows grazing subtropical native pastures in Uruguay. Cows exhibited pica, difficulty to stand and walk, rib fractures, and body weight loss even with adequate forage availability. Osteopenia and severe osteomalacia were observed on gross and histologic examination. The concentrations of bicarbonate-extractable P in soil (4.0, 4.1 mg P/kg), total P in pasture (0.9, 1.1 g P/kg), inorganic P in serum (1.0, 0.71 mmol P/L), and P in bone (73 mg P/mL) were all low. Although injectable and mineral salt supplements provided additional P in both outbreaks, these supplementary amounts were insufficient to prevent P deficiency. The P ingested by the cows from the pasture and supplements would have provided 20–55% of their daily P requirements of ~21 g P/d. Osteomalacia occurred in cattle at the 2 ranches as a result of severe P deficiency in the soil and forage, and inadequate P supplementation. Following diagnosis, control of P deficiency in beef cattle requires estimation of the amount of pasture P ingested and provision of sufficient additional supplementary P to meet the animals’ requirements.