Miracle-dz/UniFAR-FTUs huggingface dataset:
PAM50 Intrinsic Subtype Profiles in Primary and Metastatic Breast Cancer Show a Significant Shift toward More Aggressive Subtypes with Prognostic Implications

Simple Summary The majority of breast cancer deaths are caused by the spread of the disease to distant locations. The biological processes and molecular characteristics that eventually transform breast cancer into a life-threatening metastatic disease are not fully understood. The molecular subtyping of breast cancer into four tumor subtypes—namely luminal A, luminal B, human epidermal growth factor receptor 2-enriched, and basal-like subtypes—has been implemented for therapeutic guidance in patients with early breast cancer. It is not settled whether molecular subtypes in metastatic tissue can guide the choice of systemic therapy and how these subtypes may change throughout tumor progression. In this study, breast cancer subtypes at different stages of the disease were investigated, and we found changes to more unfavorable subtypes to be common throughout the progression of the disease. These findings suggests that molecular subtyping in metastatic disease could add important prognostic and predictive information to complement information from the primary tumor. Abstract Background: PAM50 breast cancer intrinsic subtyping adds prognostic information in early breast cancer; however, the role in metastatic disease is unclear. We aimed to identify PAM50 subtypes in primary tumors (PTs) and metastases to outline subtype changes and their prognostic role. Methods: RNA was isolated from PTs, lymph node metastases (LNMs), and distant metastases (DMs) in metastatic breast cancer patients (n = 140) included in a prospective study (NCT01322893). Gene expression analyses were performed using the Breast Cancer 360 (BC360) assay from Nano-String. The subtype shifts were evaluated using McNemar and symmetry tests, and clinical outcomes were evaluated with log-rank tests and Cox regression. Results: The PAM50 subtype changed in 25/59 of paired samples between PTs and LNMs (Psymmetry = 0.002), in 31/61 between PTs and DMs (Psymmetry < 0.001), and in 16/38 between LNMs and DMs (Psymmetry = 0.004). Shifts toward subtypes with worse outcomes were the most common. Patients with shifts from the luminal PT to non-luminal DM subtypes had worse progression-free survival compared to patients with a stable subtype (hazard ratio (HR): 2.3; 95% confidence interval (CI): 1.14–4.68, p = 0.02). Conclusion: Strong evidence of PAM50 subtype shifts toward unfavorable subtypes were seen between PTs and metastatic samples. For patients with a shift in subtype from luminal PT to non-luminal DM, a worse prognosis was noted.
Changes in Physical Activity among United Kingdom University Students Following the Implementation of Coronavirus Lockdown Measures

Coronavirus disease (COVID-19) and resulting restrictions have significantly impacted physical activity levels. However, objectively measured changes in physical activity levels among UK university students during lockdown are understudied. Using data collected via remote measurement technology from a mobile physical activity tracker, this study aimed to describe the longitudinal trajectories of physical activity following the start of lockdown among students at a large UK university, and to investigate whether these trajectories varied according to age, gender, and ethnicity. Continuous physical activity data for steps walked per week (n = 730) and miles run per week (n = 264) were analysed over the first period of lockdown and subsequent restriction easing using negative binomial mixed models for repeated measures. Throughout the observation period, more steps were walked by males compared to females, and by White groups compared to all other ethnic groups combined. However, there was a gradual increase in the number of steps walked per week following the commencement of lockdown, irrespective of sociodemographic characteristics. For females only, there was a decrease in the number of miles run per week following lockdown. The long-term impact of the pandemic on physical health is unknown, but our results highlight changes in physical activity which could have implications for physical health.
Impact of Violent Experiences and Social Support on R-NSSI Behavior among Middle School Students in China

Repetitive nonsuicidal self-injury (R-NSSI) is an extreme manifestation of nonsuicidal self-injury (NSSI) behavior that causes bodily harm and emotional and personality disorders. It is a growing concern, especially among adolescents; therefore, this study aims to provide empirical support for effective interventions on R-NSSI behavior among adolescents in China. We used data of about 1180 students from a survey conducted in seven middle schools in Xi’an, China, and applied multiple logistic regression to analyze NSSI and R-NSSI among male and female students, including their influencing factors. We found no significant difference between male and female students’ R-NSSI; however, regarding influencing factors, male students had more violent experiences and less social support than female students. Parental and familial factors played the most prominent role in social support. Social support was found to be a main-effect mechanism in the effect of violent experiences on R-NSSI among male students, whereas the mechanism had both a main effect and a certain buffer effect among female students. R-NSSI was found to be more prevalent among younger children, children with siblings, and those with romantic relationship experiences. We also found that healthy adolescent development involves the participation of families and schools. Health education should be conducted according to the students’ sex and characteristics.
At the Crossroad of Gene Regulation and Genome Organization: Potential Roles for ATP-Dependent Chromatin Remodelers in the Regulation of CTCF-Mediated 3D Architecture

Simple Summary The way DNA is packaged in the nucleus of a cell is important for when and how genes are expressed. There are many levels of packaging, and new techniques have revealed that long-range interactions are important for both promoting and restricting the transcription of genes. Some long-range interactions are mediated by physical loops in the genome where, like a rubber band, the ring-shaped cohesin complex loops sections of DNA bound by CCCTC-binding factor (CTCF). Both cohesin and CTCF act on DNA, and increasing evidence indicates that their function is inhibited by nucleosomes bound to the DNA. In this review, we summarize the current knowledge of how individual chromatin remodelers, which utilize ATP to move nucleosomes on DNA, facilitate or inhibit cohesin/CTCF-dependent looping interactions. Abstract In higher order organisms, the genome is assembled into a protein-dense structure called chromatin. Chromatin is spatially organized in the nucleus through hierarchical folding, which is tightly regulated both in cycling cells and quiescent cells. Assembly and folding are not one-time events in a cell’s lifetime; rather, they are subject to dynamic shifts to allow changes in transcription, DNA replication, or DNA damage repair. Chromatin is regulated at many levels, and recent tools have permitted the elucidation of specific factors involved in the maintenance and regulation of the three-dimensional (3D) genome organization. In this review/perspective, we aim to cover the potential, but relatively unelucidated, crosstalk between 3D genome architecture and the ATP-dependent chromatin remodelers with a specific focus on how the architectural proteins CTCF and cohesin are regulated by chromatin remodeling.
Association of Self-Reported Physical Fitness with Pregnancy Related Symptoms the GESTAFIT Project

We explored the association of physical fitness (PF) with pregnancy-related symptoms, at the 16th and 34th gestational weeks (g.w.). The International Fitness Scale and the Pregnancy Symptoms Inventory were employed to assess self-reported PF and pregnancy-related symptoms, respectively. At the 16th g.w. greater self-reported overall PF was associated with lower incidence of urinary frequency (p = 0.020); greater overall PF, cardiorespiratory fitness (CRF), muscular strength and speed-agility were associated with lower incidence of tiredness-fatigue (all, p < 0.05); greater overall PF and speed-agility were associated with lower incidence of poor sleep (both, p < 0.05); greater CRF and flexibility were associated with lower limitations by tiredness-fatigue (both, p < 0.05); and greater flexibility was associated with lower limitations by poor sleep (p = 0.021). At the 34th g.w. greater self-reported overall PF, CRF and muscular strength were associated with lower incidence of tiredness-fatigue (all, p < 0.05); greater CRF was associated with lower incidence of poor sleep (p = 0.019); and, greater flexibility was associated with lower incidence of increased vaginal discharge (p = 0.023). Adequate levels of PF, especially CRF, may help women to cope with the most endorsed pregnancy-related symptoms and its limitations, especially tiredness-fatigue and poor sleep.
The Impact of CKD on Uremic Toxins and Gut Microbiota

Numerous studies have indicated that the progression of chronic kidney disease (CKD) to end-stage renal disease (ESRD) is strictly associated with the accumulation of toxic metabolites in blood and other metabolic compartments. This accumulation was suggested to be related to enhanced generation of toxins from the dysbiotic microbiome accompanied by their reduced elimination by impaired kidneys. Intestinal microbiota play a key role in the accumulation of uremic toxins due to the fact that numerous uremic solutes are generated in the process of protein fermentation by colonic microbiota. Some disease states, including CKD, are associated with the presence of dysbiosis, which can be defined as an “imbalanced intestinal microbial community with quantitative and qualitative changes in the composition and metabolic activities of the gut microbiota”. The results of studies have confirmed the altered composition and functions of gut microbial community in chronic kidney disease. In the course of CKD protein-bound uremic toxins, including indoxyl sulfate, p-cresyl glucuronide, p-cresyl sulfate and indole-3-acetic acid are progressively accumulated. The presence of chronic kidney disease may be accompanied by the development of intestinal inflammation and epithelial barrier impairment leading to hastened systemic translocation of bacterial-derived uremic toxins and consequent oxidative stress injury to the kidney, cardiovascular and endocrine systems. These findings offer new therapeutic possibilities for the management of uremia, inflammation and kidney disease progression and the prevention of adverse outcomes in CKD patients. It seems that dietary interventions comprising prebiotics, probiotics, and synbiotics could pose a promising strategy in the management of uremic toxins in CKD.
Progressive and Coordinated Mobilization of the Skeletal Muscle Niche throughout Tissue Repair Revealed by Single-Cell Proteomic Analysis

Background: Skeletal muscle is one of the only mammalian tissues capable of rapid and efficient regeneration after trauma or in pathological conditions. Skeletal muscle regeneration is driven by the muscle satellite cells, the stem cell population in interaction with their niche. Upon injury, muscle fibers undergo necrosis and muscle stem cells activate, proliferate and fuse to form new myofibers. In addition to myogenic cell populations, interaction with other cell types such as inflammatory cells, mesenchymal (fibroadipogenic progenitors—FAPs, pericytes) and vascular (endothelial) lineages are important for efficient muscle repair. While the role of the distinct populations involved in skeletal muscle regeneration is well characterized, the quantitative changes in the muscle stem cell and niche during the regeneration process remain poorly characterized. Methods: We have used mass cytometry to follow the main muscle cell types (muscle stem cells, vascular, mesenchymal and immune cell lineages) during early activation and over the course of muscle regeneration at D0, D2, D5 and D7 compared with uninjured muscles. Results: Early activation induces a number of rapid changes in the proteome of multiple cell types. Following the induction of damage, we observe a drastic loss of myogenic, vascular and mesenchymal cell lineages while immune cells invade the damaged tissue to clear debris and promote muscle repair. Immune cells constitute up to 80% of the mononuclear cells 5 days post-injury. We show that muscle stem cells are quickly activated in order to form new myofibers and reconstitute the quiescent muscle stem cell pool. In addition, our study provides a quantitative analysis of the various myogenic populations during muscle repair. Conclusions: We have developed a mass cytometry panel to investigate the dynamic nature of muscle regeneration at a single-cell level. Using our panel, we have identified early changes in the proteome of stressed satellite and niche cells. We have also quantified changes in the major cell types of skeletal muscle during regeneration and analyzed myogenic transcription factor expression in satellite cells throughout this process. Our results highlight the progressive dynamic shifts in cell populations and the distinct states of muscle stem cells adopted during skeletal muscle regeneration. Our findings give a deeper understanding of the cellular and molecular aspects of muscle regeneration.
Antimicrobial Activity of Pyrazinamide Coordination Frameworks Synthesized by Mechanochemistry

The urge for the development of a more efficient antibiotic crystalline forms led us to the disclosure of new antibiotic coordination frameworks of pyrazinamide, a well-known drug used for the treatment of tuberculosis, with some of the novel compounds unravelling improved antimycobacterial activity. Mechanochemistry was the preferred synthetic technique to yield novel compounds, allowing the reproduction of a 1D zinc framework, the synthesis of a novel hydrogen bonding manganese framework, and three new compounds with silver. The structural characterization of the novel forms is presented along with stability studies. The increased antimicrobial activity of the new silver-based frameworks against Escherichia coli, Staphylococcus aureus, and Mycobacterium smegmatis is particularly relevant.
Nutraceutical, Dietary, and Lifestyle Options for Prevention and Treatment of Ventricular Hypertrophy and Heart Failure

Although well documented drug therapies are available for the management of ventricular hypertrophy (VH) and heart failure (HF), most patients nonetheless experience a downhill course, and further therapeutic measures are needed. Nutraceutical, dietary, and lifestyle measures may have particular merit in this regard, as they are currently available, relatively safe and inexpensive, and can lend themselves to primary prevention as well. A consideration of the pathogenic mechanisms underlying the VH/HF syndrome suggests that measures which control oxidative and endoplasmic reticulum (ER) stress, that support effective nitric oxide and hydrogen sulfide bioactivity, that prevent a reduction in cardiomyocyte pH, and that boost the production of protective hormones, such as fibroblast growth factor 21 (FGF21), while suppressing fibroblast growth factor 23 (FGF23) and marinobufagenin, may have utility for preventing and controlling this syndrome. Agents considered in this essay include phycocyanobilin, N-acetylcysteine, lipoic acid, ferulic acid, zinc, selenium, ubiquinol, astaxanthin, melatonin, tauroursodeoxycholic acid, berberine, citrulline, high-dose folate, cocoa flavanols, hawthorn extract, dietary nitrate, high-dose biotin, soy isoflavones, taurine, carnitine, magnesium orotate, EPA-rich fish oil, glycine, and copper. The potential advantages of whole-food plant-based diets, moderation in salt intake, avoidance of phosphate additives, and regular exercise training and sauna sessions are also discussed. There should be considerable scope for the development of functional foods and supplements which make it more convenient and affordable for patients to consume complementary combinations of the agents discussed here. Research Strategy: Key word searching of PubMed was employed to locate the research papers whose findings are cited in this essay.
Targeting Pin1 for Modulation of Cell Motility and Cancer Therapy

Peptidyl-prolyl cis-trans isomerase NIMA-interacting 1 (Pin1) specifically binds and isomerizes the phosphorylated serine/threonine-proline (pSer/Thr-Pro) motif, which leads to changes in protein conformation and function. Pin1 is widely overexpressed in cancers and plays an important role in tumorigenesis. Mounting evidence has revealed that targeting Pin1 is a potential therapeutic approach for various cancers by inhibiting cell proliferation, reducing metastasis, and maintaining genome stability. In this review, we summarize the underlying mechanisms of Pin1-mediated upregulation of oncogenes and downregulation of tumor suppressors in cancer development. Furthermore, we also discuss the multiple roles of Pin1 in cancer hallmarks and examine Pin1 as a desirable pharmaceutical target for cancer therapy. We also summarize the recent progress of Pin1-targeted small-molecule compounds for anticancer activity.
Metabolic Interventions to Prevent Hypertrophy-Induced Alterations in Contractile Properties In Vitro

(1) Background: The exact mechanism(s) underlying pathological changes in a heart in transition to hypertrophy and failure are not yet fully understood. However, alterations in cardiac energy metabolism seem to be an important contributor. We characterized an in vitro model of adrenergic stimulation-induced cardiac hypertrophy for studying metabolic, structural, and functional changes over time. Accordingly, we investigated whether metabolic interventions prevent cardiac structural and functional changes; (2) Methods: Primary rat cardiomyocytes were treated with phenylephrine (PE) for 16 h, 24 h, or 48 h, whereafter hypertrophic marker expression, protein synthesis rate, glucose uptake, and contractile function were assessed; (3) Results: 24 h PE treatment increased expression of hypertrophic markers, phosphorylation of hypertrophy-related signaling kinases, protein synthesis, and glucose uptake. Importantly, the increased glucose uptake preceded structural and functional changes, suggesting a causal role for metabolism in the onset of PE-induced hypertrophy. Indeed, PE treatment in the presence of a PAN-Akt inhibitor or of a GLUT4 inhibitor dipyridamole prevented PE-induced increases in cellular glucose uptake and ameliorated PE-induced contractile alterations; (4) Conclusions: Pharmacological interventions, forcing substrate metabolism away from glucose utilization, improved contractile properties in PE-treated cardiomyocytes, suggesting that targeting glucose uptake, independent from protein synthesis, forms a promising strategy to prevent hypertrophy and hypertrophy-induced cardiac dysfunction.
Investigating colonization patterns of the infant gut microbiome during the introduction of solid food and weaning from breastmilk: A cohort study protocol

The first exposures to microbes occur during infancy and it is suggested that this initial colonization influences the adult microbiota composition. Despite the important role that the gut microbiome may have in health outcomes later in life, the factors that influence its development during infancy and early childhood have not been characterized fully. Guidelines about the introduction of solid foods and cessation of breastfeeding, which is thought to have a significant role in the transition to a more adult-like microbiota, are not based on microbiome research. There is even less understanding of approaches used to transition to solid food in the preterm population. The purpose of this study is to identify the impact of early life dietary events on gut microbiome community structures and function among infants born at term and pre-term. We plan to prospectively monitor the gut microbiome of infants during two critical timepoints in microbial development: the introduction of solid foods and cessation from breastmilk. A total of 35 participants from three primary observational birth cohorts (two full-term cohorts and one pre-term cohort) will be enrolled in this sub-study. Participants will be asked to collect stool samples and fill out a study diary before, during and after the introduction of solids and again during weaning from breastmilk. We will use frequent fecal sampling analyzed using 16S rRNA gene profiling, metagenomics, metabolomics, and targeted bacterial culturing to identify and characterize the microbial communities, as well as provide insight into the phenotypic characteristics and functional capabilities of the microbes present during these transitional periods of infancy. This study will provide a comprehensive approach to detailing the effects of dietary transition from breastmilk to a more adult-like solid food diet on the microbiome and in doing so will contribute to evidence-based infant nutrition guidance.
Unravelling Differences in Candidate Genes for Drought Tolerance in Potato (Solanum tuberosum L.) by Use of New Functional Microsatellite Markers

Potato is regarded as drought sensitive and most vulnerable to climate changes. Its cultivation in drought prone regions or under conditions of more frequent drought periods, especially in subtropical areas, requires intensive research to improve drought tolerance in order to guarantee high yields under limited water supplies. A candidate gene approach was used to develop functional simple sequence repeat (SSR) markers for association studies in potato with the aim to enhance breeding for drought tolerance. SSR primer combinations, mostly surrounding interrupted complex and compound repeats, were derived from 103 candidate genes for drought tolerance. Validation of the SSRs was performed in an association panel representing 34 mainly starch potato cultivars. Seventy-five out of 154 SSR primer combinations (49%) resulted in polymorphic, highly reproducible banding patterns with polymorphic information content (PIC) values between 0.11 and 0.90. Five SSR markers identified allelic differences between the potato cultivars that showed significant associations with drought sensitivity. In all cases, the group of drought-sensitive cultivars showed predominantly an additional allele, indicating that selection against these alleles by marker-assisted breeding might confer drought tolerance. Further studies of these differences in the candidate genes will elucidate their role for an improved performance of potatoes under water-limited conditions.
Atractylodin Produces Antinociceptive Effect through a Long-Lasting TRPA1 Channel Activation

Atractylodin (ATR) is a bioactive component found in dried rhizomes of Atractylodes lancea (AL) De Candolle. Although AL has accumulated empirical evidence for the treatment of pain, the molecular mechanism underlying the anti-pain effect of ATR remains unclear. In this study, we found that ATR increases transient receptor potential ankyrin-1 (TRPA1) single-channel activity in hTRPA1 expressing HEK293 cells. A bath application of ATR produced a long-lasting calcium response, and the response was completely diminished in the dorsal root ganglion neurons of TRPA1 knockout mice. Intraplantar injection of ATR evoked moderate and prolonged nociceptive behavior compared to the injection of allyl isothiocyanate (AITC). Systemic application of ATR inhibited AITC-induced nociceptive responses in a dose-dependent manner. Co-application of ATR and QX-314 increased the noxious heat threshold compared with AITC in vivo. Collectively, we concluded that ATR is a unique agonist of TRPA1 channels, which produces long-lasting channel activation. Our results indicated ATR-mediated anti-nociceptive effect through the desensitization of TRPA1-expressing nociceptors.