Miracle-dz/UniFAR-FTUs huggingface dataset:
Wnt signaling regulates hepatocyte cell division by a transcriptional repressor cascade

Significance As a general model for cell cycle control, repressors keep cells quiescent until growth signals remove the inhibition. For S phase, this is exemplified by the Retinoblastoma (RB) protein and its inactivation. It was unknown whether similar mechanisms operate in the M phase. The Wnt signaling pathway is an important regulator of cell proliferation. Here, we find that Wnt induces expression of the transcription factor Tbx3, which in turn represses mitotic inhibitors E2f7 and E2f8 to permit mitotic progression. Such a cascade of transcriptional repressors may be a general mechanism for cell division control. These findings have implications for tissue homeostasis and disease, as the function for Wnt signaling in mitosis is relevant to its widespread role in stem cells and cancer.
Enhanced Stability of Complex Sound Representations Relative to Simple Sounds in the Auditory Cortex

Abstract Typical everyday sounds, such as those of speech or running water, are spectrotemporally complex. The ability to recognize complex sounds (CxSs) and their associated meaning is presumed to rely on their stable neural representations across time. The auditory cortex is critical for the processing of CxSs, yet little is known of the degree of stability of auditory cortical representations of CxSs across days. Previous studies have shown that the auditory cortex represents CxS identity with a substantial degree of invariance to basic sound attributes such as frequency. We therefore hypothesized that auditory cortical representations of CxSs are more stable across days than those of sounds that lack spectrotemporal structure such as pure tones (PTs). To test this hypothesis, we recorded responses of identified layer 2/3 auditory cortical excitatory neurons to both PTs and CxSs across days using two-photon calcium imaging in awake mice. Auditory cortical neurons showed significant daily changes of responses to both types of sounds, yet responses to CxSs exhibited significantly lower rates of daily change than those of PTs. Furthermore, daily changes in response profiles to PTs tended to be more stimulus-specific, reflecting changes in sound selectivity, compared with changes of CxS responses. Last, the enhanced stability of responses to CxSs was evident across longer time intervals as well. Together, these results suggest that spectrotemporally CxSs are more stably represented in the auditory cortex across time than PTs. These findings support a role of the auditory cortex in representing CxS identity across time.
MITF deficiency and oncogenic GNAQ each promote proliferation programs in zebrafish melanocyte lineage cells

Uveal melanoma (UM) is the most common primary malignancy of the adult eye but lacks any FDA‐approved therapy for the deadly metastatic disease. Thus, there is a great need to dissect the driving mechanisms for UM and develop strategies to evaluate potential therapeutics. Using an autochthonous zebrafish model, we previously identified MITF, the master melanocyte transcription factor, as a tumor suppressor in GNAQQ209L‐driven UM. Here, we show that zebrafish mitfa‐deficient GNAQQ209L‐driven tumors significantly up‐regulate neural crest markers, and that higher expression of a melanoma‐associated neural crest signature correlates with poor UM patient survival. We further determined how the mitfa‐null state, as well as expression of GNAQQ209L, YAPS127A;S381A, or BRAFV600E oncogenes, impacts melanocyte lineage cells before they acquire the transformed state. Specifically, examination 5 days post‐fertilization showed that mitfa‐deficiency is sufficient to up‐regulate pigment progenitor and neural crest markers, while GNAQQ209L expression promotes a proliferative phenotype that is further enhanced by YAPS127A;S381A co‐expression. Finally, we show that this oncogene‐induced proliferative phenotype can be used to screen chemical inhibitors for their efficacy against the UM pathway. Overall, this study establishes that a neural crest signature correlates with poor UM survival, and describes an in vivo assay for preclinical trials of potential UM therapeutics.
Role of circulating long non-coding RNA for the improvement of the predictive ability of the CHA2DS2–VASc score in patients with atrial fibrillation

Abstract Background: The CHA2DS2–VASc score was initially applied to stratify stroke risk in patients with atrial fibrillation (AF) and was found to be effective in predicting all-cause mortality outcomes. To date, it is still unclear whether circulating long non-coding RNAs (lncRNAs) as emerging biomarkers, can improve the predictive power of the CHA2DS2–VASc score in stroke and all-cause mortality. Methods: Candidate lncRNAs were screened by searching the literature and analyzing previous RNA sequencing results. After preliminary verification in 29 patients with AF, the final selected lncRNAs were evaluated by Cox proportional hazards regression in 192 patients to determine whether their relative expression levels were associated with stroke and all-cause mortality. The c-statistic, net reclassification improvement (NRI), and integrated discrimination improvement of the patients were calculated to evaluate the discrimination and reclassification power for stroke and all-cause mortality when adding lncRNA expression levels to the CHA2DS2–VASc score model. Results: Five plasma lncRNAs associated with stroke and all-cause mortality in AF patients were selected in our screening process. Patients with elevated H19 levels were found to have a higher risk of stroke (hazard ratio [HR] 3.264, 95% confidence interval [CI]: 1.364–7.813, P = 0.008). Adding the H19 expression level to the CHA2DS2–VASc score significantly improved the discrimination and reclassification power of the CHA2DS2–VASc score for stroke in AF patients. In addition, the H19 level showed a marginally significant association with all-cause mortality (HR 2.263, 95% CI: 0.889–5.760, P = 0.087), although it appeared to have no significant improvement for the CHA2DS2–VASc model for predicting all-cause mortality. Conclusions: Plasma expression of H19 was associated with stroke risk in AF patients and improved the discriminatory power of the CHA2DS2–VASc score. Therefore, lncRNA H19 served as an emerging non-invasive biomarker for stroke risk prediction in patients with AF.
An Augmented Lagrangian Method for

with slack variables si ≥ 0. We use that (why? ) si = 0 or si = ci − μλi . Theorem Let x∗ be a local solution of the full problem with equality constraints (for simplicity). Suppose LICQ and second-order sufficient conditions are satisfied for λ = λ∗. Then there is a threshhold μ̄ such that for any μ ∈ (0, μ̄], x∗ is a strict local minimizer of LA. Proof Goal is to show ∇xLA = 0, and u∇xxLAu > 0 for u ∈ Rn. Since ci(x) = 0, the first KKT condition is obvious: for any μ
Endorhizal fungal symbiosis in lycophytes and metal(loid)-accumulating ferns growing naturally in mine wastes in Mexico

Abstract Ferns and lycophytes are pioneer plants that can be useful for revegetation. Their natural distribution and interaction with soil fungal endophytes can increase plant fitness but have received little attention. This study aimed to identify these plant species in mine wastes, and determine colonization by arbuscular mycorrhizal fungi (AMF) and dark septate endophytes (DSE). The pseudo-total and diethylenetriamine pentaacetic acid (DTPA)-extractable rhizosphere concentrations of As, Cu, Cd, Pb, and Zn, bioavailability index (BI), and bioconcentration factor (BCF) were analyzed. Six ferns and one lycophyte were identified. Arsenic and metal concentrations were high, which were plant and site-dependent. All species showed hyperaccumulation of As in fronds, especially Argyrochosma formosa (2,883) and Notholaena affinis (2,160) had the highest concentrations (mg kg−1). All plants were colonized by AMF (3%−24%) and DSE (2%−33%). Astrolepis sinuata and Myriopteris notholaenoides had the maximum colonization by AMF and A. formosa by DSE. This study identifies for the first time five ferns and one lycophyte species on mine wastes, their As hyperaccumulation capacity and the simultaneous fungal colonization by AMF and DSE. These are relevant plant traits for phytoremediation. However, fungal identification and the role colonization by AMF and DSE requires full analysis. NOVELTY STATEMENT Arsenic accumulator ferns and a lycophytes species naturally established on three polluted sites were found. Astrolepis integerrima, A. sinuata, Myriopteris notholaenoides, Notholaena affinis, N. sulphurea, and the lycophyte Selaginella lepidophylla are for the first time reported in these sites. This is the first evidence of DSE colonization in these plants growing on mine wastes in interaction with AMF-colonization. These plants may be useful in developing phytoremediation alternatives.
The provision of person‐centred care for care home residents with stroke: An ethnographic study

Abstract Care home residents with stroke have higher levels of disability and poorer access to health services than those living in their own homes. We undertook observations and semi‐structured interviews (n = 28 participants) with managers, staff, residents who had experienced a stroke and their relatives in four homes in London, England, in 2018/2019. Thematic analysis revealed that residents' needs regarding valued activity and stroke‐specific care and rehabilitation were not always being met. This resulted from an interplay of factors: staff's lack of recognition of stroke and its effects; gaps in skills; time pressures; and the prioritisation of residents' safety. To improve residential care provision and residents' quality of life, care commissioners, regulators and providers may need to re‐examine how care homes balance safety and limits on staff time against residents' valued activity, alongside improving access to specialist healthcare treatment and support.
Engineered immunomodulatory accessory cells improve experimental allogeneic islet transplantation without immunosuppression

Islet transplantation has been established as a viable treatment modality for type 1 diabetes. However, the side effects of the systemic immunosuppression required for patients often outweigh its benefits. Here, we engineer programmed death ligand-1 and cytotoxic T lymphocyte antigen 4 immunoglobulin fusion protein–modified mesenchymal stromal cells (MSCs) as accessory cells for islet cotransplantation. The engineered MSCs (eMSCs) improved the outcome of both syngeneic and allogeneic islet transplantation in diabetic mice and resulted in allograft survival for up to 100 days without any systemic immunosuppression. Immunophenotyping revealed reduced infiltration of CD4+ or CD8+ T effector cells and increased infiltration of T regulatory cells within the allografts cotransplanted with eMSCs compared to controls. The results suggest that the eMSCs can induce local immunomodulation and may be applicable in clinical islet transplantation to reduce or minimize the need of systemic immunosuppression and ameliorate its negative impact.
Fructosylation of human insulin causes AGEs formation, structural perturbations and morphological changes: an in silico and multispectroscopic study

Abstract Fructosylation of proteins results in the formation of advanced glycation end-products (AGEs). A diet rich in fructose along with hyperglycemia can cause fructose mediated glycation (fructosylation) of proteins, which results in AGEs formation. Insulin is a peptide hormone that is glycated when exposed to carbohydrates such as glucose. In this study, we have analysed the interaction of insulin with fructose and biophysically characterized fructose modified insulin. In silico studies performed through molecular docking and molecular dynamics simulation revealed that fructose binds to insulin with strong affinity resulting in the formation of insulin-fructose complex. Fructosylation of insulin caused hyperchromicity, loss of intrinsic fluorescence, gain in AGEs specific fluorescence and elevated the carbonyl and fructosamine content. Enhanced thioflavin T fluorescence suggested the presence of fibrillar structures at higher concentrations of fructose. Electron microscopy revealed the formation of characteristic amorphous and amyloid like aggregates at lower and higher concentrations of fructose, respectively. These findings show that fructosylation of insulin causes AGEs production, aggregation and alters its gross structural integrity. These changes may reduce the biological activity of insulin that can aggravate conditions like type II diabetes mellitus. Communicated by Ramaswamy H. Sarma
Effect of benzo[a]pyrene on proliferation and metastasis of oral squamous cell carcinoma cells: A transcriptome analysis based on RNA‐seq

Benzo[a]pyrene (BaP), a representative polycyclic aromatic hydrocarbon compound, is a carcinogen that causes head and neck cancers. Despite intensive research, the molecular mechanism of BaP in the development of oral squamous cell carcinoma (OSCC) remains largely unknown. In the present study, the SCC‐9 human OSCC cell line was cultured in vitro, separated into treatment groups, and treated with dimethyl sulfoxide or BaP at various concentrations. The malignant behavior ascribed to the BaP treatment was investigated by cell proliferation, clony formation assay, and Transwell assays. Furthermore, transcriptome sequencing was performed to detect the differentially expressed genes, followed by quantitative real‐time PCR to measure the expression levels of nine of these genes. Moreover, the Gene Ontology (GO) term and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses showed the biological processes and signaling pathways in which the target genes were involved. Significant effects on SCC‐9 cell proliferation, tumorigenicity, cell migration, and invasion were observed after exposure to 8 μM BaP. Additional results revealed that BaP inhibited apoptosis in a dose‐dependent manner. The transcriptome sequencing results showed 137 upregulated genes and 135 downregulated genes induced by BaP, associated with tumor‐related biological processes and signaling pathways, mainly including transcriptional dysregulation in cancer, the tumor necrosis factor signaling pathway, metabolism of xenobiotics by cytochrome P450, mitogen‐activated protein kinase signaling pathway, and so forth. Our study demonstrates that BaP may regulate the expression of certain genes involved in tumor‐associated signaling pathways, thereby promoting the proliferative, tumorigenic, and metastatic behaviors of OSCC cells while suppressing their apoptosis.
Assessing the impact of socio‐economic determinants on access to care, surgical treatment options and outcomes among patients with renal mass: Insight from the universal healthcare system

Abstract Objective To assess whether socio‐economic disparities exist on access to care, treatment options and outcomes among patients with renal mass amenable of surgical treatment within the universal healthcare system. Methods Data of consecutive patients submitted to partial nephrectomy (PN) or radical nephrectomy (RN) at our Institution between 2017 and 2020 were retrospectively evaluated. Patients were grouped according to their income level (low, intermediate, and high) based on the Indicator of Equivalent Economic Situation national criterion. Survival analysis was performed. Cox regression models were employed to analyse the impact of socio‐economic variables on survival outcomes. Results One thousand forty‐two patients were included (841 PN and 201 RN). Patients at the lowest income level were found more likely symptomatic and with a higher pathological tumour stage in the RN cohort (p > 0.05). The guidelines adherence on surgical indication rate as well as the access to minimally invasive surgery did not differ according to patient's income level in both cohorts (p > 0.05). Survival curves were comparable among the groups. Cox regression analysis showed that none of the included socio‐economic variables was associated with survival outcomes in our series. Conclusions Universal healthcare system may increase the possibility to ensure egalitarian treatment modalities for patients with renal cancer.
TSP cuts outside the template paradigm

The early computer implementation of the cutting-plane method for solving the traveling salesman problem, written by Martin, used subtour inequalities as well as cutting planes of Gomory’s type. The practice of looking for and using cuts that match prescribed templates in conjunction with Gomory cuts was continued in computer codes of Miliotis, Land, and Fleischmann. Grötschel, Padberg, and Hong advocated a different policy, where the template paradigm is the only source of cuts; furthermore, they argued for drawing the templates exclusively from the set of linear inequalities that induce facets of the TSP polytope. These policies were adopted in the work of Crowder and Padberg, in the work of Grötschel and Holland, and in the work of Padberg and Rinaldi; their computer codes produced the most impressive computational successes of the nineteen eighties. Eventually, the template paradigm had become the standard frame of reference for cutting planes in the TSP. The purpose of this paper is to describe a technique for finding cuts that disdains all understanding of the TSP polytope and bashes on regardless of all prescribed templates. Combining this technique with the traditional template approach was a crucial step in our solution of a 13,509-city TSP instance.
Decarbonisation of operations management – looking back, moving forward: a review and implications for the production research community

This paper systematically analyses the vital motivations, drivers and barriers to the adoption of low-carbon operations management practices in response to climate change, highlighting the implications for the International Journal of Production Research (IJPR)’s community, which has contributed significantly to discussion of and research into sustainable production. Based on a thorough review of key articles on low-carbon operations management published in a number of prestigious journals, seven propositions for future research are suggested. Additionally, a unique classification of the barriers to and motivations for low-carbon production is put forward. These areas, which deserve further investigation, are (a) economic issues, (b) policy, (c) technology, (d) governance and (e) the market. The research agenda proposed for low-carbon production and operations may prove useful to the production research community in planning future developments and research projects, increasing knowledge and designing teaching modules on the topic. The study concludes by shedding light on the main research opportunities that IJPR’s community will encounter.
Effects of sub-lethal doses of silver nanoparticles on Bacillus subtilis planktonic and 1 sessile cells.

23 Aims: Due to their antimicrobial activity, silver nanoparticles (Ag-NPs) are being 24 increasingly used in a number of industrial products. The accumulation of Ag-NPs in soil 25 might affect plant growth-promoting rhizobacteria and, in turn, plants. We describe the 26 effects of Ag-NPs on the soil bacteria Azotobacter vinelandii and Bacillus subtilis . 27 Methods and Results: In growth inhibition studies, A. vinelandii showed extreme sensitivity 28 to Ag-NPs, compared to B. subtilis . We investigated the effects of Ag-NPs at sub-inhibitory 29 concentrations, both on planktonic and sessile B. subtilis cells. As determined by 2,7- 30 dichlorofluorescein-diacetate assays, Ag-NPs increase the formation of reactive oxygen 31 species in planktonic cells, but not in sessile cells, suggesting the activation of scavenging 32 systems in biofilms. Consistently, proteomic analysis in B. subtilis Ag-NPs-treated biofilms 33 showed increased production of proteins related to quorum sensing and involved in stress 34 responses and redox sensing. Extracellular polysaccharides production and inorganic 35 phosphate solubilization were also increased, possibly as part of a coordinated response to 36 stress. 37 Conclusions: At low concentrations, Ag-NPs killed A. vinelandii and affected cellular 38 processes in planktonic and sessile B. subtilis cells. 39 Significance and Impact of Study: Re-direction of gene expression, linked to selective 40 toxicity, suggests a strong impact of Ag-NPs on soil bacterial communities. 41 , and Our results suggest that we found ,
Formulation and Evaluation of Extended Release Tablets of Darifenacin Hydro bromide

D arifenacin Hydrobromide is a Potent and selective antimuscarinic (M3) agent used in Symptomatic treatment of urge incontinence and/or increased urinary frequency as may occur in adult patients with overactive bladder syndrome. The objective of present study was to develop an effective Extended Release(ER) tablets of Darifenacin Hydrobromide to release the drug over an extended period of time that provide therapeutically effective plasma concentration for the treatment of urinary incontinence in humans with extended duration of action and less number of doses. Darifenacin Hydrobromide ER tablets were prepared by direct compression method using hydrophilic polymers like HPMC (K4M, K15M, K100M, Metalose 60 SR 50) and Xanthan Gum. The ER tablets were evaluated for physicochemical, pre compression, post compression parameters and compared with the marketed product (ENABLEX). The % drug released from the extended release tablets (from F1 to F12) was found to be vary from 9.34% to 104.45% in 24 hours. The optimized formulation F12 showed 97.84% of drug release in 24 hours whereas the marketed extended release tablets (ENABLEX) showed 96.45% in 24 hours. There was no significant difference between the optimized formulation and marketed tablet (ENABLEX) in terms of invitro drug release profile. The extended release tablets prepared were found to be within the official limits with respect to hardness, weight variation, drug content, thickness etc. The optimized formulation (F12) follows first order kinetics and found to be stable for 3 months of period time.
Therapeutic efficacy of the live-attenuated M. tuberculosis 1 vaccine MTBVAC in a preclinical model of bladder cancer

of Bacillus a adverse events in a of is a live attenuated vaccine derived from a clinical and is currently in to replace as a Here, we describe the the potential of MTBVAC as a cancer therapy in vitro and in vivo in a preclinical model. MTBVAC colonized human bladder tumor cells to a much greater extent than BCG via a mechanism mediated by macropinocytosis and induced cell growth inhibition following internalization. testing in an murine model of cancer a higher antitumor effect of MTBVAC in experimental conditions in BCG work. Our data encourage further studies to the
Lateralization of Categorical and Coordinate Stimuli: A Diﬀerential Encoding

diﬃculty, Kosslyn’s holds only when tasks are diﬃcult enough. Our Diﬀerential Encoding (DE) model is a three layer neural network that accounts for lateralization of visual processing via the biologically and developmentally plausible mechanism of diﬀerences in the connection spread of long-range lateral neural connections. We ﬁrst establish certain frequency-encoding properties of the DE model. We then show that our model accounts for Slotnick’s psychological data and show Slotnick’s analysis does not convincingly explain the conﬂicting results. Instead, we propose that Kosslyn’s initial hypothesis was incorrect: categorical and coordinate stimuli are not diﬀerentiated solely by spatial frequencies, which These results therefore cannot