Miracle-dz/UniFAR-FTUs huggingface dataset:
Prodigiosin synthesis with electron rich 2,2'- bipyrroles

The prodigiosins possess a linear tripyrrolic scaffold with the A and B pyrrolic rings connected directly in a bipyrrole unit, and the B and C rings joined in a dipyrrin. These red streptomycete metabolites exhibit among other activities, antitumor, antimicrobial, and immunomodulating properties. A new prodigiosin synthesis has been developed that employs electron rich 2,2′-bipyrroles. In particular, undecylprodigiosin and PNU-156804 were synthesized by condensations of 4-methoxy and 4-benzyloxy 2,2′-bipyrroles, 20a and 20b, respectively, with 5-undecylpyrrole-2-carboxaldehyde in 75% and 83% yields. The 4-alkoxy-2,2′-bipyrroles were synthesized from 4-alkoxypyrrolyl butenyl ketones (15a and 15b), which were made by a novel one-pot process from 2-acyl-N-(PhF)pyrrolidin-4-one (13) [PhF = 9-(9-phenylfluorenyl)] using PhFNa in the presence of alkyl halide. A sequence of alkoxy pyrrole 15a and 15b protection, olefin oxidation, Paal–Knorr condensation, and deprotection gave the requisite 4-alkoxy-2,2′-bipyrrole.
Lipid nanoparticle-mediated codelivery of Cas9 mRNA and single-guide RNA achieves liver-specific in vivo genome editing of Angptl3

Significance Genome editing technologies enable the permanent repair of disease-causing genetic mutations. However, the application of this technology has been limited by the technical challenge of achieving safe, effective, and specific in vivo delivery of the CRISPR-Cas9 genome editing components. Here, we report the development of a newly identified lipid nanoparticle (LNP) for specific delivery of CRISPR-Cas9 mRNA to the liver. While LNPs have been FDA approved for delivery of siRNA to the liver, here we examine their application for genome editing. When compared head-to-head, our delivery platform significantly outperforms the FDA-approved LNP in the efficient delivery of Cas9 mRNA for knockdown of the Angptl3 gene and subsequent regulation of hypercholesterolemia, while matching the safety and specificity of the approved platform. Loss-of-function mutations in Angiopoietin-like 3 (Angptl3) are associated with lowered blood lipid levels, making Angptl3 an attractive therapeutic target for the treatment of human lipoprotein metabolism disorders. In this study, we developed a lipid nanoparticle delivery platform carrying Cas9 messenger RNA (mRNA) and guide RNA for CRISPR-Cas9–based genome editing of Angptl3 in vivo. This system mediated specific and efficient Angptl3 gene knockdown in the liver of wild-type C57BL/6 mice, resulting in profound reductions in serum ANGPTL3 protein, low density lipoprotein cholesterol, and triglyceride levels. Our delivery platform is significantly more efficient than the FDA-approved MC-3 LNP, the current gold standard. No evidence of off-target mutagenesis was detected at any of the nine top-predicted sites, and no evidence of toxicity was detected in the liver. Importantly, the therapeutic effect of genome editing was stable for at least 100 d after a single dose administration. This study highlights the potential of LNP-mediated delivery as a specific, effective, and safe platform for Cas9-based therapeutics.
A STUDY OF ZINC METAL TOXICITY ON THE CELLULOLYTIC BACTERIA IN ANAEROBIC PASSIVE TREATMENT SYSTEMS 1

The effective use of anaerobic passive treatment systems (APTS), such as sulfate-reducing bioreactors, to treat acid mine drainage will help to mitigate water contamination from mines located in remote areas as well as cut current treatment costs. One draw back to these systems has been the inhibition of sulfate reduction with high concentrations of metals. APTS contain a complex microbial ecosystem, and metal toxicity could be indirectly affecting sulfate-reduction by inhibiting other important microbes. If microbes such as the cellulolytic - fermenting bacteria are inhibited from producing viable substrate for the sulfate- reducing bacteria, then the rate of sulfate reduction over time in APTS will ultimately decline. We examined the toxic effect of zinc, a common metal found in acid mine drainage, on a pure culture of Cellulomonas flavigena, a cellulolytic - fermenting bacteria. Serum bottles containing C. flavigena, at two protein concentrations of 250 and 500 mg/L, were exposed to initial zinc concentrations of 0, 20, and 40 mg/L and monitored over a 9 hour period. The extent of inhibition on C. flavigena activity correlated best (r 2 =0.93) with the mass ratio of zinc uptake to cell protein. Final zinc concentrations ranged from 0.9 to 2.2 mg/L. Zinc uptake was operationally defined as the total zinc removed from solution and includes sorption and internalization. Initial and final dissolved zinc concentration did not correlate well with extent of inhibition. In the presence of higher biomass the relative rate of glucose utilization was 20 to 50% higher in the presence of zinc than at lower biomass concentration. The concurrent internalization of metals with sorption and precipitation processes can produce inhibition in the presence of low metal concentration. Thus low effluent metal concentration may not be indicative of the extent of inhibition experienced by the microbes. The inhibitory effect of metals on cellulolytic - fermenting bacteria is an important aspect to consider when establishing the limitations of sulfate reducing biozones.
Social-ecological factors associated with having a regular healthcare provider among lesbian, gay, bisexual and transgender persons in Jamaica

ABSTRACT Lesbian, gay, bisexual, and transgender (LGBT) people experience a multitude of barriers to healthcare access, particularly in highly stigmatising contexts, such as Jamaica. Access to a regular healthcare source can contribute to uptake of health knowledge and services. Yet social-ecological factors associated with access to a regular healthcare provider among LGBT persons in Jamaica are underexplored. We conducted a cross-sectional survey with LGBT persons in Jamaica to examine socio-demographic and social-ecological factors associated with having a regular healthcare provider. Nearly half (43.6%) of 911 participants reported having a regular healthcare provider. In multivariate analyses, socio-demographic factors (higher age; identifying as a cisgender sexual minority man or woman compared to a transgender woman) were associated with higher odds of having a regular healthcare provider. Socio-demographic (living in Ocho Rios or Montego Bay compared to Kingston), stigma/discrimination (a bad past healthcare experience), and structural factors (insufficient money for housing; reporting medication costs as a barrier; no health insurance) were associated with decreased odds of having a regular healthcare provider. Findings support a multi-level approach to understanding and addressing barriers to having a regular healthcare provider among LGBT people in Jamaica.
Immunotherapy in uveal melanoma: novel strategies and opportunities for personalized treatment

ABSTRACT Introduction Uveal melanoma (UM) is the most common intraocular cancer and represents a discrete subtype of melanoma. Metastatic disease, which occurs in half of patients, has a dismal prognosis. Immunotherapy with immune checkpoint inhibitors has produced promising results in cutaneous melanoma but has failed to show analogous efficacy in metastatic UM. This is attributable to UM’s distinct genetics and its complex interaction with the immune system. Hence, more efficacious immunotherapeutic approaches are under investigation. Areas covered We discuss those novel immunotherapeutic strategies in clinical and preclinical studies for advanced disease and which are thought to overcome the hurdles set by UM in terms of immune recognition. We also highlight the need to determine predictive markers in relation to these strategies to improve clinical outcomes. We used a simple narrative analysis to summarize the data. The search methodology is located in the Introduction. Expert opinion Novel immunotherapeutic strategies focus on transforming immune excluded tumor microenvironment in metastatic UM to T cell inflamed. Preliminary results of approaches such as vaccines, adoptive cell transfer and other novel molecules are encouraging. Factors such as HLA compatibility and expression level of targeted antigens should be considered to optimize personalized management.
A Rest Quality Metric Using a Cluster-Based Analysis of Accelerometer Data and Correlation With Digital Medicine Ingestion Data: Algorithm Development

Background Adherence to medication regimens and patient rest are two important factors in the well-being of patients with serious mental illness. Both of these behaviors are traditionally difficult to record objectively in unsupervised populations. Objective A digital medicine system that provides objective time-stamped medication ingestion records was used by patients with serious mental illness. Accelerometer data from the digital medicine system was used to assess rest quality and thus allow for investigation into correlations between rest and medication ingestion. Methods Longest daily rest periods were identified and then evaluated using a k-means clustering algorithm and distance metric to quantify the relative quality of patient rest during these periods. This accelerometer-derived quality-of-rest metric, along with other accepted metrics of rest quality, such as duration and start time of the longest rest periods, was compared to the objective medication ingestion records. Overall medication adherence classification based on rest features was not performed due to a lack of patients with poor adherence in the sample population. Results Explorations of the relationship between these rest metrics and ingestion did seem to indicate that patients with poor adherence experienced relatively low quality of rest; however, patients with better adherence did not necessarily exhibit consistent rest quality. This sample did not contain sufficient patients with poor adherence to draw more robust correlations between rest quality and ingestion behavior. The correlation of temporal outliers in these rest metrics with daily outliers in ingestion time was also explored. Conclusions This result demonstrates the ability of digital medicine systems to quantify patient rest quality, providing a framework for further work to expand the participant population, compare these rest metrics to gold-standard sleep measurements, and correlate these digital medicine biomarkers with objective medication ingestion data.
Statistical evaporation of rotating clusters. II. Angular momentum distribution

The change in the angular momentum of an atomic cluster following evaporation is investigated using rigorous phase space theory (PST) and molecular dynamics simulations, with an aim at the possible rotational cooling and heating effects. Influences of the shape of the interaction potential, anharmonicity of the vibrational density of states (DOS), and the initial distribution of excitation energies are systematically studied in the example of the Lennard-Jones cluster LJ14. For this system, the predictions of PST are in quantitative agreement with the results of the simulations, provided the correct forms for the vibrational density of states and the interaction potential are used. The harmonic approximation to the DOS is used to obtain explicit forms for the angular momentum distribution in larger clusters. These are seen to undergo preferential cooling when thermally excited and preferential heating when subject to a strong vibrational excitation.
Protective effects of curcumin on chromatin quality, sperm parameters, and apoptosis following testicular torsion-detorsion in mice

Objective The chief outcome of testicular torsion in clinical and experimental contexts is testicular ischemia. Curcumin, a compound with anti-inflammatory and antioxidant properties, has fascinated researchers and clinicians for its promise in the treatment of fertility diseases. Methods Thirty-five fully grown male mice were randomly classified into five groups: control, sham, testicular torsion, treatment group 1 (testicular torsion+short-term curcumin), and treatment group 2 (testicular torsion+long-term curcumin). Thirty-five days later, spermatozoa from the right cauda epididymis were analyzed with regard to count and motility. Toluidine blue (TB), aniline blue (AB), and chromomycin A3 (CMA3) staining assays were used to evaluate the sperm chromatin integrity. In addition, the terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling (TUNEL) test was used to assess apoptosis. Results Treatment group 1 exhibited a remarkably elevated sperm count compared to the testicular torsion group. Additionally, notably lower sperm motility was found in the testicular torsion group compared to the control, treatment 1, and treatment 2 groups. Staining (CMA3, AB, and TB) and the TUNEL test indicated significantly greater testicular torsion in the torsion group compared to the control group (p<0.05). The data also revealed notably lower results of all sperm chromatin assays and lower apoptosis in both treatment groups relative to the testicular torsion group (p<0.05). Significantly elevated (p<0.05) AB and TB results were noted in treatment group 1 compared to treatment group 2. Conclusion Curcumin can compensate for the harmful effects of testicular ischemia and improve sperm chromatin quality in mice.
ASCL2 reciprocally controls key trophoblast lineage decisions during hemochorial placenta development

Significance Defective placentation, including impaired uterine spiral artery remodeling, leads to pregnancy disorders such as pregnancy loss, preeclampsia, intrauterine growth restriction, and preterm birth, all of which cause significant morbidity and mortality for the mother and fetus. Trophoblast cells are central to executing placental functions and can differentiate into two conserved specialized lineages: invasive/extravillous trophoblast cells, which guide uterine transformation, and syncytiotrophoblast, which serve a barrier function. We leveraged model systems to identify achaete-scute homolog 2 as a conserved regulator of the invasive/extravillous trophoblast cell lineage and a modulator of the syncytiotrophoblast phenotype. A key upstream regulator of trophoblast-engineered uterine transformation has been identified representing an entry point into the etiology of pregnancy complications resulting from defective placentation. Invasive trophoblast cells are critical to spiral artery remodeling in hemochorial placentation. Insufficient trophoblast cell invasion and vascular remodeling can lead to pregnancy disorders including preeclampsia, preterm birth, and intrauterine growth restriction. Previous studies in mice identified achaete-scute homolog 2 (ASCL2) as essential to extraembryonic development. We hypothesized that ASCL2 is a critical and conserved regulator of invasive trophoblast cell lineage development. In contrast to the mouse, the rat possesses deep intrauterine trophoblast cell invasion and spiral artery remodeling similar to human placentation. In this study, we investigated invasive/extravillous trophoblast (EVT) cell differentiation using human trophoblast stem (TS) cells and a loss-of-function mutant Ascl2 rat model. ASCL2 transcripts are expressed in the EVT column and junctional zone, which represent tissue sources of invasive trophoblast progenitor cells within human and rat placentation sites, respectively. Differentiation of human TS cells into EVT cells resulted in significant up-regulation of ASCL2 and several other transcripts indicative of EVT cell differentiation. Disruption of ASCL2 impaired EVT cell differentiation, as indicated by cell morphology and transcript profiles. RNA sequencing analysis of ASCL2-deficient trophoblast cells identified both down-regulation of EVT cell-associated transcripts and up-regulation of syncytiotrophoblast-associated transcripts, indicative of dual activating and repressing functions. ASCL2 deficiency in the rat impacted placental morphogenesis, resulting in junctional zone dysgenesis and failed intrauterine trophoblast cell invasion. ASCL2 acts as a critical and conserved regulator of invasive trophoblast cell lineage development and a modulator of the syncytiotrophoblast lineage.
Large-Scale Affine Matrix Rank Minimization With a Novel Nonconvex Regularizer

Low-rank minimization aims to recover a matrix of minimum rank subject to linear system constraint. It can be found in various data analysis and machine learning areas, such as recommender systems, video denoising, and signal processing. Nuclear norm minimization is a dominating approach to handle it. However, such a method ignores the difference among singular values of target matrix. To address this issue, nonconvex low-rank regularizers have been widely used. Unfortunately, existing methods suffer from different drawbacks, such as inefficiency and inaccuracy. To alleviate such problems, this article proposes a flexible model with a novel nonconvex regularizer. Such a model not only promotes low rankness but also can be solved much faster and more accurate. With it, the original low-rank problem can be equivalently transformed into the resulting optimization problem under the rank restricted isometry property (rank-RIP) condition. Subsequently, Nesterov’s rule and inexact proximal strategies are adopted to achieve a novel algorithm highly efficient in solving this problem at a convergence rate of $O(1/K)$ , with $K$ being the iterate count. Besides, the asymptotic convergence rate is also analyzed rigorously by adopting the Kurdyka- ojasiewicz (KL) inequality. Furthermore, we apply the proposed optimization model to typical low-rank problems, including matrix completion, robust principal component analysis (RPCA), and tensor completion. Exhaustively empirical studies regarding data analysis tasks, i.e., synthetic data analysis, image recovery, personalized recommendation, and background subtraction, indicate that the proposed model outperforms state-of-the-art models in both accuracy and efficiency.
Identification of mast cells as a candidate significant target of immunotherapy for acute myeloid leukemia

ABSTRACT Objection Immunotherapy based on T cells is a new therapy for Acute myeloid leukemia (AML). However, there has not been considerable improvement compared with traditional chemotherapeutics. This study aimed to identify important immune cells, genes, and drugs associated with the immunotherapy of AML. Methods The gene expression profile and clinical data of patients with AML were downloaded from TCGA database, and the abundance ratio of immune cells was obtained via CIBERSORT. Kaplan–Meier (KM) survival analysis was used to assess the relationship between immune cells and survival time of patients with AML. Differentially expressed genes (DEGs) analysis was conducted to obtained DEGs related to mast cells. Then, protein-protein interaction (PPI) analysis and enrichment analysis were performed to explore the hub genes. Finally, Connectivity Map (CMap) database was utilized to predicts potential drugs that may reverse or induce the mast cell-related gene expression. Results Our study showed that mast cell was correlated with survival time of patients with AML, and 135 genes were screened to be related with mast cells. 6 hub genes were identified via PPI network, and 3 potential small molecule drugs were screened to be related to regulating the mast cell-related gene expression via CMap database. Conclusion The hub genes and drugs have high research value and clinical application in AML therapy. Our study not only provides gene targets and small molecule drugs for AML immunotherapy concerning mast cells but also provides new ideas for researchers to explore immunotherapy targets of other tumors.
Ultrashort Versus Criterion Heart Rate Variability Among International-Level Girls' Field Hockey Players.

PURPOSE To assess heart rate (HR) variability responses to various markers of training load, quantify associations between HR variability and fitness, and compare responses and associations between 1-minute ultrashort and 5-minute criterion measures among a girls' field hockey team. METHODS A total of 11 players (16.8 [1.1] y) recorded the logarithm of the root mean square of successive differences (LnRMSSD) daily throughout a 4-week training camp. The weekly mean (LnRMSSDM) and coefficient of variation (LnRMSSDCV) were analyzed. The internal training load (ITL) and external training load (ETL) were acquired with session HR and accelerometry, respectively. Speed, agility, repeated sprint ability, and intermittent fitness were assessed precamp and postcamp. RESULTS Similar increases in the ultrashort and criterion LnRMSSDM were observed in week 3 versus week 1 (P < .05-.06, effect size [ES] = 0.28 to 0.36). The ultrashort and criterion LnRMSSDCV showed small ES reductions in week 2 (ES = -0.40 to -0.50), moderate reductions in week 3 (ES = -0.61 to -0.72), and small reductions in week 4 (ES = -0.42 to -0.51) versus week 1 (P > .05). Strong agreement was observed between the ultrashort and criterion values (intraclass correlation coefficient = .979). The ITL:ETL ratio peaked in week 1 (P < .05 vs weeks 2-4), displaying a weekly pattern similar to LnRMSSDCV, and inversely similar to LnRMSSDM. Changes in the ultrashort and criterion LnRMSSDCV from week 1 to 4 were associated with ITL (P < .01). The ultrashort and criterion LnRMSSDCV in week 4 were associated (P < .05) with postcamp fitness. CONCLUSIONS The ultrashort HR variability parameters paralleled the criterion responses, and the associations with ITL and fitness were similar in magnitude.
Absolute Quantitation of Water and Metabolites in the Human Brain. II. Metabolite Concentrations

A method for determining absolute metabolite concentrations with in vivo1H magnetic resonance spectroscopy is presented. Using the compartmentation model introduced in the preceding paper of this series (J. Magn. Reson. B102, 1, 1993), it is possible to express NMR results in terms of most commonly used concentration units. The proposed scheme, involving the measurement of an external standard as well as of the localized water signal, is verified on cerebral spectra obtained from 22 subjects. Besides concentrations, longitudinal and transverse relaxation times are determined for parietal white and occipital gray matter. The determination of these quantities crucially depends on the analysis of the T2 signal decay as a function of echo time. The in vivo concentrations of the four metabolites N-acetyl aspartate, creatine plus phosphocreatine, choline, and myo-inositol are in good agreement with biochemical determinations performed in vitro. Two clinical examples emphasize the relevance of absolute quantitation in the investigation of human neuropathology and normal development.
Phase separation of Axin organizes the β-catenin destruction complex

Assembly of the destruction complex is critical for Wnt/β-catenin signaling. Nong et al. find that Axin undergoes liquid–liquid phase separation, which is promoted by APC. Phase-separated Axin provides a scaffold for recruitment of GSK3β, CK1α, and β-catenin and facilitates GSK3β-mediated β-catenin phosphorylation and thus degradation.