Miracle-dz/UniFAR-FTUs huggingface dataset:
Autocrine CXCL8-dependent invasiveness triggers modulation of actin cytoskeletal network and cell dynamics

Glioblastoma (GB) is the most representative form of primary malignant brain tumour. Several studies indicated a pleiotropic role of CXCL8 in cancer due to its ability to modulate the tumour microenvironment, growth and aggressiveness of tumour cell. Previous studies indicated that CXCL8 by its receptors (CXCR1 and CXCR2) induced activation of the PI3K/p-Akt pathway, a crucial event in the regulation of cytoskeleton rearrangement and cell mobilization. Human GB primary cell culture and U-87MG cell line were used to study the effects of CXCR1 and CXCR2 blockage, by a dual allosteric antagonist, on cell migration and cytoskeletal dynamics. The data obtained point towards a specific effect of autocrine CXCL8 signalling on GB cell invasiveness by the activation of pathways involved in cell migration and cytoskeletal dynamics, such as PI3K/p-Akt/p-FAK, p-cortactin, RhoA, Cdc42, Acetylated α-tubulin and MMP2. All the data obtained support the concept that autocrine CXCL8 signalling plays a key role in the activation of an aggressive phenotype in primary glioblastoma cells and U-87MG cell line. These results provide new insights about the potential of a pharmacological approach targeting CXCR1/CXCR2 pathways to decrease migration and invasion of GB cells in the brain parenchyma, one of the principal mechanisms of recurrence.
Left Atrial Volume, Cardiorespiratory Fitness, and Diastolic Function in Healthy Individuals: The HUNT Study, Norway

Background Left atrial (LA) size and cardiorespiratory fitness (CRF) are predictors of future cardiovascular events in high‐risk populations. LA dilatation is a diagnostic criterion for left ventricular diastolic dysfunction. However, LA is dilated in endurance athletes with high CRF, but little is known about the association between CRF and LA size in healthy, free‐living individuals. We hypothesized that in a healthy population, LA size was associated with CRF and leisure‐time physical activity, but not with echocardiographic indexes of left ventricular diastolic dysfunction. Methods and Results In this cross‐sectional study from HUNT (Nord‐Trøndelag Health Study), 107 men and 138 women, aged 20 to 82 years, without hypertension, cardiovascular, pulmonary, or malignant disease participated. LA volume was assessed by echocardiography and indexed to body surface area LAVI (left atrial volume index). CRF was measured as peak oxygen uptake (VO 2peak) using ergospirometry, and percent of age‐ and‐sex‐predicted VO 2peak was calculated. Indexes of left ventricular diastolic dysfunction were assessed in accordance with latest recommendations. LAVI was >34 mL/m2 in 39% of participants, and LAVI was positively associated with VO 2peak and percentage of age‐ and‐sex‐predicted VO 2peak (β [95% CI], 0.11 [0.06–0.16] and 0.18 [0.09–0.28], respectively) and weighted minutes of physical activity per week (β [95% CI], 0.01 [0.003–0.015]). LAVI was not associated with other indexes of left ventricular diastolic dysfunction. There was an effect modification between age and VO 2peak/percentage of age‐ and‐sex‐predicted VO 2peak showing higher LAVI with advanced age and higher VO 2peak/percentage of age‐ and‐sex‐predicted VO 2peak as presented in prediction diagrams. Conclusions Interpretation of LAVI as a marker of diastolic dysfunction should be done in relation to age‐relative CRF. Studies on the prognostic value of LAVI in fit subpopulations are needed.
A highly efficient uranium grabber derived from acrylic fiber for extracting uranium from seawater.

Acrylic fiber can be chemically converted to an amidoxime and carboxylate containing chelating adsorbent by a two-step synthesis method for extraction of uranium from seawater. A portion of the nitrile groups in the fiber is first converted to amidoxime using hydroxylamine followed by conversion of another portion of the nitrile groups to carboxylate with NaOH. At an optimized ratio of amidoxime/carboxylate (about 1 : 1), the chelating fiber in real seawater shows a higher uranium adsorption capacity and shorter saturation time compared with similar high-surface-area chelating fibers developed recently using a radiation-induced grafting method. The saturation capacity of uranium is estimated to be 7.73 grams per kilogram of the adsorbent at 20 °C and the half-saturation time is about 15.7 days. The fiber shows a vanadium/uranium ratio of about 1 in real seawater tests. The low vanadium adsorption capacity of the fiber is attributed to the branched-chain amidoxime groups formed by the specified amidoximation process. This simple and low-cost synthesis method can be scaled up to mass produce the chelating fiber for recovering metals from various aquatic environments including production of uranium from seawater.
Organelle-specific targeting of polymersomes into the cell nucleus

Significance Synthetic nanomaterials are being sought to shuttle therapeutic payloads directly into the cell nucleus as a major target for chemo- and gene-based therapies. However, it remains uncertain whether and how synthetic entities are able to bypass the nuclear pore complexes (NPCs) that regulate transport into and out of the nucleus. We have constructed biocompatible polymer vesicles that infiltrate NPCs and resolved their nuclear uptake mechanism in vitro and in vivo. Their ability to deliver payloads directly into cell nuclei is further validated by transmission electron microscopy. Organelle-specific nanocarriers (NCs) are highly sought after for delivering therapeutic agents into the cell nucleus. This necessitates nucleocytoplasmic transport (NCT) to bypass nuclear pore complexes (NPCs). However, little is known as to how comparably large NCs infiltrate this vital intracellular barrier to enter the nuclear interior. Here, we developed nuclear localization signal (NLS)-conjugated polymersome nanocarriers (NLS-NCs) and studied the NCT mechanism underlying their selective nuclear uptake. Detailed chemical, biophysical, and cellular analyses show that karyopherin receptors are required to authenticate, bind, and escort NLS-NCs through NPCs while Ran guanosine triphosphate (RanGTP) promotes their release from NPCs into the nuclear interior. Ultrastructural analysis by regressive staining transmission electron microscopy further resolves the NLS-NCs on transit in NPCs and inside the nucleus. By elucidating their ability to utilize NCT, these findings demonstrate the efficacy of polymersomes to deliver encapsulated payloads directly into cell nuclei.
Targeted tPA overexpression in denervated spinal motor neurons promotes stroke recovery in mice

Our previous studies demonstrated that axonal remodeling of the corticospinal tract (CST) contributes to neurological recovery after stroke in rodents. The present study employed a novel non-invasive peripheral approach, to over-express tPA in denervated spinal motor neurons via recombinant adeno-associated virus (AAV) intramuscular injection in transgenic mice subjected to permanent middle cerebral artery occlusion (MCAo), in which the CST axons are specifically and completely labeled with yellow fluorescent protein (YFP). One day after surgery, mice were randomly selected to receive saline, AAV5-RFP, or tPA (1 × 1010 viral particles) injected into the stroke-impaired forelimb muscles (n = 10/group). Functional deficits and recovery were monitored with foot-fault and single pellet reaching tests. At day 28 after MCAo, mice received intramuscular injection of PRV-614-mRFP (1.52 × 107 pfu) as above, and were euthanized four days later. Compared with saline or AAV-RFP-treated mice, AAV-tPA significantly enhanced behavioral recovery (p < 0.01, both tests), as well as increased CST axonal density in the denervated gray matter of the cervical cord (p < 0.001), and RFP-positive pyramidal neurons in both ipsilesional and contralesional cortices (p < 0.001). Behavioral outcomes were significantly correlated to neural remodeling (p < 0.05). Our results provide a fundamental basis for the development of therapeutic approaches aimed at promoting corticospinal innervation for stroke treatment.
Differential effects of N‐TiO2 nanoparticle and its photo‐activated form on autophagy and necroptosis in human melanoma A375 cells

The manipulation of autophagy provides a new opportunity for highly effective anticancer therapies. Recently, we showed that photodynamic therapy (PDT) with nitrogen‐doped titanium dioxide (N‐TiO2) nanoparticles (NPs) could promote the reactive oxygen species (ROS)‐dependent autophagy in leukemia cells. However, the differential autophagic effects of N‐TiO2 NPs in the dark and light conditions and the potential of N‐TiO2‐based PDT for the treatment of melanoma cells remain unknown. Here we show that depending on the visible‐light condition, the autophagic response of human melanoma A375 cells to N‐TiO2 NPs switches between two different statuses (ie., flux or blockade) with the opposite outcomes (ie., survival or death). Mechanistically, low doses of N‐TiO2 NPs (1‐100 µg/ml) stimulate a nontoxic autophagy flux response in A375 cells, whereas their photo‐activation leads to the impairment of the autophagosome‐lysosome fusion, the blockade of autophagy flux and consequently the induction of RIPK1‐mediated necroptosis via ROS production. These results confirm that photo‐controllable autophagic effects of N‐TiO2 NPs can be utilized for the treatment of cancer, particularly melanoma.
Insectivorous bats selectively source moths and eat mostly pest insects on dryland and irrigated cotton farms

Abstract Insectivorous bats are efficient predators of pest arthropods in agroecosystems. This pest control service has been estimated to be worth billions of dollars to agriculture globally. However, few studies have explicitly investigated the composition and abundance of dietary prey items consumed or assessed the ratio of pest and beneficial arthropods, making it difficult to evaluate the quality of the pest control service provided. In this study, we used metabarcoding to identify the prey items eaten by insectivorous bats over the cotton‐growing season in an intensive cropping region in northern New South Wales, Australia. We found that seven species of insectivorous bat (n = 58) consumed 728 prey species, 13 of which represented around 50% of total prey abundance consumed. Importantly, the identified prey items included major arthropod pests, comprising 65% of prey relative abundance and 13% of prey species recorded. Significant cotton pests such as Helicoverpa punctigera (Australian bollworm) and Achyra affinitalis (cotton webspinner) were detected in at least 76% of bat fecal samples, with Teleogryllus oceanicus (field crickets), Helicoverpa armigera (cotton bollworm), and Crocidosema plebejana (cotton tipworm) detected in 55% of bat fecal samples. Our results indicate that insectivorous bats are selective predators that exploit a narrow selection of preferred pest taxa and potentially play an important role in controlling lepidopteran pests on cotton farms. Our study provides crucial information for farmers to determine the service or disservice provided by insectivorous bats in relation to crops, for on‐farm decision making.
Circulating tumor DNA as a potential marker of adjuvant chemotherapy benefit following surgery for localized pancreatic cancer.

BACKGROUND In early-stage pancreatic cancer, there are currently no biomarkers to guide selection of therapeutic options. This prospective biomarker trial evaluated the feasibility and potential clinical utility of circulating tumor DNA (ctDNA) analysis to inform adjuvant therapy decision making. MATERIALS AND METHODS Patients considered by the multidisciplinary team to have resectable pancreatic adenocarcinoma were enrolled. Pre- and post-operative samples for ctDNA analysis were collected. PCR-based-SafeSeqS assays were used to identify mutations at codon 12, 13 and 61 of KRAS in the primary pancreatic tumor and to detect ctDNA. Results of ctDNA analysis were correlated with CA19-9, recurrence-free and overall survival (OS). Patient management was per standard of care, blinded to ctDNA data. RESULTS Of 112 patients consented pre-operatively, 81 (72%) underwent resection. KRAS mutations were identified in 91% (38/42) of available tumor samples. Of available plasma samples (N = 42), KRAS mutated ctDNA was detected in 62% (23/37) pre-operative and 37% (13/35) post-operative cases. At a median follow-up of 38.4 months, ctDNA detection in the pre-operative setting was associated with inferior recurrence-free survival (RFS) [hazard ratio (HR) 4.1; P = 0.002)] and OS (HR 4.1; P = 0.015). Detectable ctDNA following curative intent resection was associated with inferior RFS (HR 5.4; P < 0.0001) and OS (HR 4.0; P = 0.003). Recurrence occurred in 13/13 (100%) patients with detectable ctDNA post-operatively, including in seven that received gemcitabine-based adjuvant chemotherapy. CONCLUSION ctDNA studies in localized pancreatic cancer are challenging, with a substantial number of patients not able to undergo resection, not having sufficient tumor tissue for analysis or not completing per protocol sample collection. ctDNA analysis, pre- and/or post-surgery, is a promising prognostic marker. Studies of ctDNA guided therapy are justified, including of treatment intensification strategies for patients with detectable ctDNA post-operatively who appear at very high risk of recurrence despite gemcitabine-based adjuvant therapy.
Topologically Guided Prioritization of Candidate Gene Transcripts Coexpressed with the 5-HT1A Receptor by Combining In Vivo PET and Allen Human Brain Atlas Data

Abstract The serotonin-1A receptor (5-HT1AR) represents a viable target in the treatment of disorders of the brain. However, development of psychiatric drugs continues to be hindered by the relative inaccessibility of brain tissue. Although the efficacy of drugs selective for the 5-HT1AR has not been proven, research continues to focus on drugs that influence this receptor subtype. To further knowledge on this topic, we investigated the topological coexpression patterns of the 5-HT1AR. We calculated Spearman’s rho for the correlation of positron emission tomography-binding potentials (BPND) of the 5-HT1AR assessed in 30 healthy subjects using the tracer [carbonyl-11C]WAY-100635 and predicted whole-brain mRNA expression of 18 686 genes. After applying a threshold of r > 0.3 in a leave-one-out cross-validation of the prediction of mRNA expression, genes with ρ ≥ 0.7 were considered to be relevant. In cortical regions, 199 genes showed high correlation with the BPND of the 5-HT1AR, in subcortical regions 194 genes. Using our approach, we could consolidate the role of BDNF and implicate new genes (AnxA8, NeuroD2) in serotonergic functioning. Despite its explorative nature, the analysis can be seen as a gene prioritization approach to reduce the number of genes potentially connected to 5-HT1AR functioning and guide future in vitro studies.
Temporal trends in age at menarche and age at menopause: a population study of 312 656 women in Norway

Abstract STUDY QUESTION Have mean age at menarche or mean age at natural menopause changed from the 1939 birth cohort to the 1964 birth cohort? SUMMARY ANSWER We estimated a minor decrease in mean age at menarche and an increase by nearly 3 years in mean age at natural menopause. WHAT IS KNOWN ALREADY In the Western world, age at menarche decreased across birth cohorts from the early 1800s until the 1950s. Whether mean age at menarche has continued to decrease in birth cohorts after the 1950s remains uncertain. It is also uncertain whether mean age at natural menopause has changed across birth cohorts. STUDY DESIGN, SIZE, DURATION We performed a retrospective population study of 312 656 women who were born in Norway during the years 1936–1964. PARTICIPANTS/MATERIALS, SETTING, METHODS The data were obtained by two self-administered questionnaires from women who participated in the Norwegian breast cancer screening program (BreastScreen Norway) during the years 2006–2014. We used flexible parametric survival models with restricted cubic splines to estimate mean age at menarche, mean age at menopause and mean number of years between menarche and menopause according to the women’s year of birth. The women who were still having menstrual periods contributed with follow-up time until the time of data collection, and the women who had reported surgical removal of the uterus and/or both ovaries prior to natural menopause contributed with follow-up time until the time of surgery. MAIN RESULTS AND THE ROLE OF CHANCE The mean age at menarche was 13.42 years (95% CI: 13.40–13.44 years) among women born during 1936–1939, and it was 13.24 years (95% CI: 13.22–13.25 years) among women born during 1960–1964. The mean age at natural menopause increased from 50.31 years (95% CI: 50.25–50.37 years) among women born during 1936–1939 to 52.73 years (95% CI: 52.64–52.82 years) among women born during 1960–1964. The mean number of years between menarche and menopause increased from 36.83 years (95% CI: 36.77–36.89 years) to 40.22 years (95% CI: 40.11–40.34 years). LIMITATIONS, REASONS FOR CAUTION Information about age at menarche and age at menopause was based on self-reports. WIDER IMPLICATIONS OF THE FINDINGS Late menopause is associated with increased risk of breast cancer but also with increased life expectancy. Thus, higher mean age at menopause may partly explain the increase in breast cancer incidence after menopause and the increase in life expectancy in recent time. Also, a longer interval between menarche and menopause could suggest that the number of years of female fecundity has increased. STUDY FUNDING/COMPETING INTEREST(S) This work was funded by the South-Eastern Norway Regional Health Authority [grant number 2016112 to M.S.G. ] and by the Norwegian Cancer Society [grant number 6863294-2015 to E.K. B. ]. The authors declare no conflicts of interest.
The influence of experimentally induced polyploidy on the relationships between endopolyploidy and plant function in Arabidopsis thaliana

Abstract Whole genome duplication, leading to polyploidy and endopolyploidy, occurs in all domains and kingdoms and is especially prevalent in vascular plants. Both polyploidy and endopolyploidy increase cell size, but it is unclear whether both processes have similar effects on plant morphology and function, or whether polyploidy influences the magnitude of endopolyploidy. To address these gaps in knowledge, fifty‐five geographically separated diploid accessions of Arabidopsis thaliana that span a gradient of endopolyploidy were experimentally manipulated to induce polyploidy. Both the diploids and artificially induced tetraploids were grown in a common greenhouse environment and evaluated with respect to nine reproductive and vegetative characteristics. Induced polyploidy decreased leaf endopolyploidy and stem endopolyploidy along with specific leaf area and stem height, but increased days to bolting, leaf size, leaf dry mass, and leaf water content. Phenotypic responses to induced polyploidy varied significantly among accessions but this did not affect the relationship between phenotypic traits and endopolyploidy. Our results provide experimental support for a trade‐off between induced polyploidy and endopolyploidy, which caused induced polyploids to have lower endopolyploidy than diploids. Though polyploidy did not influence the relationship between endopolyploidy and plant traits, phenotypic responses to experimental genome duplication could not be easily predicted because of strong cytotype by accession interactions.
Informing management decisions for ecological networks, using dynamic models calibrated to noisy time-series data.

Well-intentioned environmental management can backfire, causing unforeseen damage. To avoid this, managers and ecologists seek accurate predictions of the ecosystem-wide impacts of interventions, given small and imprecise datasets, which is an incredibly difficult task. We generated and analysed thousands of ecosystem population time series to investigate whether fitted models can aid decision-makers to select interventions. Using these time-series data (sparse and noisy datasets drawn from deterministic Lotka-Volterra systems with two to nine species, of known network structure), dynamic model forecasts of whether a species' future population will be positively or negatively affected by rapid eradication of another species were correct > 70% of the time. Although 70% correct classifications is only slightly better than an uninformative prediction (50%), this classification accuracy can be feasibly improved by increasing monitoring accuracy and frequency. Our findings suggest that models may not need to produce well-constrained predictions before they can inform decisions that improve environmental outcomes.
Nonlinearities in the cellular response to ionizing radiation and the role of p53 therein

Abstract Many aspects of the cellular response to agents such as ionizing radiation that cause genotoxic and/or oxidative stress exhibit a nonlinear relationship to the applied stress level. These include elements of the antioxidant response and of the damage-signaling pathways that determine cell fate decisions. The wild-type p53 protein, which is mutated in many cancers, coordinates these responses and is a key determinant of this nonlinearity. Indeed, p53 has been referred to as a ‘cellular rheostat’ that favors antioxidant/cytoprotective functions at low stress levels while switching to a pro-oxidant/cytotoxic role under high-stress conditions. For solid tumor-derived cell lines, moderate doses of radiation, typical of those used to generate clonogenic survival curves (i.e. ≤10 Gy), predominantly invoke a dose-dependent cytostatic response. For cancer cell lines with wild-type p53, cytostasis is primarily associated with features of senescence, whereas cancer cells with aberrant p53 primarily undergo endopolyploidization and enlargement. In line with a commentary by Meyn et al. [Int J Radiat Biol. 2009, 85:107–115] concluding that apoptosis is not the primary cause of radiation-induced loss of clonogenicity in solid tumor-derived cell lines, significant levels of apoptosis are typically seen only after higher doses (≥5 Gy) and this is almost all of the delayed (rather than primary) type. Nonlinearity of the oxidative/genotoxic stress response is already apparent in the early antioxidant events activated by transcription factors such as p53 and Nrf2 and the Ref1 transcription coactivator. These cytoprotective pathways serve to minimize damage to important cellular targets caused by reactive oxygen species (ROS) and other electrophiles. After high/supra-lethal levels of stress these inducible antioxidant pathways can be deactivated in a manner that would reinforce the establishment of the pro-oxidant state, resulting in elevated ROS levels and to cytostasis or apoptosis. Understanding the complex regulation of these damage-signaling pathways in relation to the stress levels is important for the optimal utilization of radiation therapy for cancer.