Miracle-dz/UniFAR-FTUs huggingface dataset:
Endless Fluctuations: Temporal Dynamics of the Amplitude of Low Frequency Fluctuations

Intrinsic neural activity ubiquitously persists in all physiological states. However, how intrinsic brain activity (iBA) changes over a short time remains unknown. To uncover the brain dynamics’ theoretic underpinning, electrophysiological relevance, and neuromodulation, we identified iBA dynamics on simulated data, electroencephalogram-functional magnetic resonance imaging (EEG-fMRI) data, and repetitive transcranial magnetic stimulation (rTMS) fMRI data using sliding-window analysis. The temporal variability (dynamics) of iBA were quantified using the variance of the amplitude of low-frequency fluctuations (ALFF) over time. We first used simulated fMRI data to examine the effects of various parameters including window length, and step size on dynamic ALFF. Second, using EEG-fMRI data, we found that the heteromodal association cortex had the most variable dynamics while the limbic regions had the least, consistent with previous findings. In addition, the temporal variability of dynamic ALFF depended on EEG power fluctuations. Moreover, using rTMS fMRI data, we found that the temporal variability of dynamic ALFF could be modulated by rTMS. Taken together, these results provide evidence about the theory, relevance, and adjustability of iBA dynamics.
High-dose rifampicin in tuberculosis: Experiences from a Dutch tuberculosis centre

Background Recent evidence suggests that higher rifampicin doses may improve tuberculosis (TB) treatment outcome. Methods In this observational cohort study we evaluated all TB patients who were treated with high-dose rifampicin (> 10 mg/kg daily) in our reference centre, from January 2008 to May 2018. Indications, achieved plasma rifampicin exposures, safety and tolerability were evaluated. Results Eighty-eight patients were included. The main indications were low plasma concentrations (64.7%) and severe illness (29.5%), including central nervous system TB. Adjusted rifampicin dosages ranged from 900 mg to a maximum of 2400 mg (corresponding to 32 mg/kg) per day. Patients with severe illness received high-dose rifampicin immediately, the others had a higher dosage guided by therapeutic drug monitoring. Four patients developed hepatotoxicity, of which two were proven due to isoniazid. Re-introduction of high-dose rifampicin was successful in all four. Eighty-seven patients tolerated high-dose rifampicin well throughout treatment. Only one patient required a dose reduction due to gastro-intestinal disturbance. Conclusion High-dose rifampicin, used in specific groups of patients in our clinical setting, is safe and well-tolerated for the whole treatment duration. Measurement of drug exposures could be used as a tool/guide to increase rifampicin dosage if a reduced medication absorption or a poor treatment outcome is suspected. We suggest to administer high-dose rifampicin to patients with severe manifestations of TB or low rifampicin exposure to improve treatment outcome.
Novel Fibrinolytic Protease Producing Streptomyces radiopugnans VITSD8 from Marine Sponges

Fibrinolytic enzymes have received more attention due to their medicinal potential for thrombolytic diseases. The aim of this study is to characterize the in vitro fibrinolytic nature of purified protease producing Streptomyces radiopugnans VITSD8 from marine brown tube sponges Agelas conifera. Three varieties of sponge were collected from the Rameshwaram Sea coast, Tamil Nadu, India. The fibrinolytic activity of Streptomyces sp. was screened and determined by casein plasminogen plate and fibrin plate methods respectively. The crude caseinolytic protease was purified using ammonium sulfate fractionation, affinity and ion-exchange chromatography. Based on the morphological, biochemical, and molecular characterization, the isolate VITSD8 was confirmed as Streptomyces radiopugnans. Maltose and peptone were found to be the best carbon and nitrogen sources for the production of fibrinolytic protease. The carbon and nitrogen source peptone showed (781 U/mL) enzyme activity. The optimum pH and temperature for fibrinolytic protease production was found to be 7.0 and 33 °C respectively. The purified enzyme showed a maximum specific activity of 3891 U. The blood clot lysis activity was compared with the standard, and it was concluded that a minimum of 0.18 U (10 µL) of purified protease was required to dissolve the blood clot. This is the first report which exploits the fibrinolytic protease activity of Streptomyces radiopugnans VITSD8 extracted from a marine sponge. Hence the investigation suggests a potential benefit of purified fibrinolytic protease which will serve as an excellent clot buster alternative.
Safety of Inactivated Influenza Vaccine in Cancer Patients Receiving Immune Checkpoint Inhibitors (ICI).

BACKGROUND Cancer patients are at a higher risk for developing influenza (flu) related complications. It is unclear if the flu vaccine exacerbates immune events in patients treated with ICIs. METHODS We conducted an IRB-approved retrospective review of advanced cancer patients on ICIs who received the flu vaccine during three consecutive seasons; 2014-15, 15-16, and 16-17. The primary outcome assessed was any "new onset" immune-related adverse event (IRAE). A subset analysis of vaccinated patients newly treated with anti PD-1 agents (nivolumab or pembrolizumab) was conducted to assess overall IRAE rates for comparison with published clinical trials. RESULTS During the three seasons, 370 patients met criteria for ICI and vaccination within ~ two months (65 days). The most common underlying cancers were lung (46%) and melanoma (19%); 61% of patients received anti PD-1 agent only. In the entire cohort, 20% experienced an IRAE (any grade); incidence of grade 3 or 4 toxicity was 8%. No grade 5 events occurred. In the subset of 170 patients newly treated with anti PD-1 agents, overall IRAE rate was 18%, grade 3/4 events occurred in 7.6%. Influenza was diagnosed in 2 patients. CONCLUSION No increase in incidence or severity of IRAE was detected in patients on ICIs who received the inactivated influenza vaccine within ~ 2 months of ICI. For newly treated patients on anti-PDI agents, IRAE rates were comparable to published clinical trials and did not vary with order of administration. Routine seasonal flu vaccination is encouraged in patients on ICIs.
New drug candidates for bipolar disorder—A nation‐wide population‐based study

Drug repurposing is an increasingly promising idea in many fields of medicine. We systematically used Danish nation‐wide population‐based registers to investigate whether continued use of non‐aspirin non‐steroidal anti‐inflammatory drugs (NSAIDs), low‐dose aspirin, high‐dose aspirin, statins, allopurinol, and angiotensin agents decrease the rate of incident mania/bipolar disorder.
A culturally fair test of processing speed: Construct validity, preliminary normative data, and effects of HIV infection on performance in South African adults.

OBJECTIVES Impaired processing speed (PS) is a feature of cognitive profiles associated with neurological disorders particularly prevalent in low- or middle-income countries (LMICs). However, commonly used PS tests are not validated for use in LMICs. We assessed, using a sample of healthy South African adults, the construct validity of PS tests contained within NeuroScreen (a tablet-based application and test battery designed to be culturally fair), and established preliminary normative data for those tests (Study 1). Moreover, because South Africa has the highest population prevalence of people living with HIV and PS deficits are a core feature of HIV-associated cognitive impairment, we assessed whether NeuroScreen could detect PS impairment in a sample of HIV-infected South African adults (Study 2). METHODS In Study 1 (N = 112 healthy adults) and Study 2 (the Study 1 sample, plus n = 102 HIV-infected adults), we administered Neuroscreen and a standardized paper-and-pencil neuropsychological test battery. RESULTS In Study 1, factor analyses indicated that NeuroScreen PS scores loaded onto one factor and converged with scores on paper-and-pencil PS tests. Regression modeling indicated that age significantly predicted NeuroScreen PS performance (i.e., younger participants performed better). In Study 2, HIV-infected participants performed significantly more poorly on NeuroScreen PS tests than their HIV-uninfected counterparts. Moreover, a significantly larger proportion of HIV-infected participants displayed impaired PS when judged against the regression-based norms. CONCLUSIONS These results suggest that NeuroScreen has cross-cultural utility in assessing adult PS performance, and that it might be useful in tracking trajectories of PS decline within HIV infection. (PsycINFO Database Record (c) 2019 APA, all rights reserved).
Effects of Nigella sativa seeds (black cumin) on insulin secretion and lipid profile: A pilot study in healthy volunteers.

It has been claimed that Nigella sativa seeds (NSS), also known as black cumin, have antidiabetic and lipid-lowering properties. Our pilot study investigated the effects of powdered NSS on insulin secretion and lipid profile in healthy male volunteers. We conducted a double-blind, randomized, placebo-controlled 4-week trial in 30 subjects, receiving NSS powder (1 g/day) or placebo orally (15 subjects/group). Insulin secretion as determined by the hyperglycaemic clamp technique, insulin sensitivity as well as cholesterol and triglycerides serum concentrations, were measured before and after treatment. NSS powder administration was clinically well tolerated. It did not modify fasting glycaemia and insulinaemia, and was ineffective on glucose-induced insulin secretion and insulin sensitivity. No significant changes on serum lipids were observed after treatment in any treatment groups, nor between the two treatment groups. However, in the treated group only, there was a significant correlation between total cholesterol change after treatment and its baseline level (r = -0.71, P = 0.006, n = 13), and between low-density lipoprotein (LDL) cholesterol change after treatment and its baseline level (r = -0.74, P = 0.004, n = 13). No such correlations were found for high-density lipoprotein (HDL) cholesterol, and for triglycerides. These results do not confirm any NSS effect on glucose regulation; however, they suggest that NSS powder may be of interest in lowering lipid concentrations in hyperlipidaemic subjects.
Ethanol sensitizes skeletal muscle to ammonia-induced molecular perturbations

Ethanol causes dysregulated muscle protein homeostasis while simultaneously causing hepatocyte injury. Because hepatocytes are the primary site for physiological disposal of ammonia, a cytotoxic cellular metabolite generated during a number of metabolic processes, we determined whether hyperammonemia aggravates ethanol-induced muscle loss. Differentiated murine C2C12 myotubes, skeletal muscle from pair-fed or ethanol-treated mice, and human patients with alcoholic cirrhosis and healthy controls were used to quantify protein synthesis, mammalian target of rapamycin complex 1 (mTORC1) signaling, and autophagy markers. Alcohol-metabolizing enzyme expression and activity in mouse muscle and myotubes and ureagenesis in hepatocytes were quantified. Expression and regulation of the ammonia transporters, RhBG and RhCG, were quantified by real-time PCR, immunoblots, reporter assays, biotin-tagged promoter pulldown with proteomics, and loss-of-function studies. Alcohol and aldehyde dehydrogenases were expressed and active in myotubes. Ethanol exposure impaired hepatocyte ureagenesis, induced muscle RhBG expression, and elevated muscle ammonia concentrations. Simultaneous ethanol and ammonia treatment impaired protein synthesis and mTORC1 signaling and increased autophagy with a consequent decreased myotube diameter to a greater extent than either treatment alone. Ethanol treatment and withdrawal followed by ammonia exposure resulted in greater impairment in muscle signaling and protein synthesis than ammonia treatment in ethanol-naive myotubes. Of the three transcription factors that were bound to the RhBG promoter in response to ethanol and ammonia, DR1/NC2 indirectly regulated transcription of RhBG during ethanol and ammonia treatment. Direct effects of ethanol were synergistic with increased ammonia uptake in causing dysregulated skeletal muscle proteostasis and signaling perturbations with a more severe sarcopenic phenotype.
Single-cell transcriptome analysis of Physcomitrella leaf cells during reprogramming using microcapillary manipulation

Background Next-generation sequencing technologies have made it possible to carry out transcriptome analysis at the single-cell level. Single-cell RNA-sequencing (scRNA-seq) data provide insights into cellular dynamics, including intercellular heterogeneity as well as inter- and intra-cellular fluctuations in gene expression that cannot be studied using populations of cells. The utilization of scRNA-seq is, however, restricted to specific types of cells that can be isolated from their original tissues, and it can be difficult to obtain precise positional information for these cells in situ. Results Here, we established single cell-digital gene expression (1cell-DGE), a method of scRNA-seq that uses micromanipulation to extract the contents of individual living cells in intact tissue while recording their positional information. Furthermore, we employed a unique molecular identifier to reduce amplification bias in the cDNA libraries. With 1cell-DGE, we could detect differentially expressed genes (DEGs) during the reprogramming of leaf cells into stem cells in excised tissues of the moss Physcomitrella patens, identifying 6,382 DEGs between cells at 0 h and 24 h after excision. We found substantial variations in both the transcript levels of previously reported reprogramming factors and the overall expression profiles between cells, which appeared to be related to their different reprogramming abilities or the estimated states of the cells according to the pseudotime based on the transcript profiles. Conclusions We developed 1cell-DGE with microcapillary manipulation, a technique that can be used to analyze the gene expression of individual cells without detaching them from their tightly associated tissues, enabling us to retain positional information and investigate cell–cell interactions.
A Critical Review of Properties and Analytical/Bioanalytical Methods for Characterization of Cetuximab

Abstract Cetuximab (CTX) is a chimeric monoclonal antibody (mAb) able to selectively bind to the epidermal growth factor receptor (EGFR), resulting in inhibition of EGF linkage and phosphorylation cascade interruption. As a result, it is able to prevent cell proliferation, angiogenesis and metastasis, usually related to cancer malignization. As the EGFR is overexpressed in many human tumors, its use has been approved by FDA since 2006. Clinical use of CTX has been proved to cause skin rash which is related to the better prognosis. Thus, currently strategies also focus on the development of safe and effective drug delivery systems and on quantification methods for CTX in a variety of matrices. Based on the challenges to quantify CTX, immunoassays, spectrophotometric assays, electrophoretic assays and chromatographic assays are under study. Among them, the spectrophotometric/colorimetric techniques, used in near 32% of the papers investigated, followed by chromatographic techniques and immunoassay methods, such as enzyme-linked immunosorbent assay (ELISA), used in 29% and 26%, respectively, and electrophoretic techniques used in near 13%. Herein, we will describe and discuss CTX main aspects and highlight the main quantification methods that are currently used for its quantification in different matrices.
Comparable Genomic Copy Number Aberrations Differ across Astrocytoma Malignancy Grades

Malignancy grades of astrocytomas were analyzed for copy number aberrations by aCGH. Altogether 1438 CNA were found of which losses prevailed. We searched for regions that are more likely to drive cancer pathogenesis with Bioconductor package and Genomic Identification of Significant Targets in Cancer. On our total sample significant deletions affected 14 chromosomal regions, out of which deletions at 17p13.2, 9p21.3, 13q12.11, 22q12.3 remained significant even at 0.05 q-value. When divided to malignancy groups, the regions identified as significantly deleted in high grades were: 9p21.3; 17p13.2; 10q24.2; 14q21.3; 1p36.11 and 13q12.11, while amplified were: 3q28; 12q13.3 and 21q22.3. Low grades comprised significant deletions at 3p14.3; 11p15.4; 15q15.1; 16q22.1; 20q11.22 and 22q12.3 indicating their involvement in early stages of tumorigenesis. Significantly enriched pathways brought by DAVID software were PI3K-Akt, Cytokine-cytokine receptor, NODlike receptor, Jak-STAT, RIG-II-like receptor and Toll-like receptor pathways. HPV and herpex simplex infection and inflammation pathways were also represented. Present study brings new data to astrocytoma research amplifying the wide spectrum of changes which could help us identify the regions critical for tumorigenesis.
Nano-Strategies to Target Breast Cancer-Associated Fibroblasts: Rearranging the Tumor Microenvironment to Achieve Antitumor Efficacy

Cancer-associated fibroblasts (CAF) are the most abundant cells of the tumor stroma and they critically influence cancer growth through control of the surrounding tumor microenvironment (TME). CAF-orchestrated reactive stroma, composed of pro-tumorigenic cytokines and growth factors, matrix components, neovessels, and deregulated immune cells, is associated with poor prognosis in multiple carcinomas, including breast cancer. Therefore, beyond cancer cells killing, researchers are currently focusing on TME as strategy to fight breast cancer. In recent years, nanomedicine has provided a number of smart delivery systems based on active targeting of breast CAF and immune-mediated overcome of chemoresistance. Many efforts have been made both to eradicate breast CAF and to reshape their identity and function. Nano-strategies for CAF targeting profoundly contribute to enhance chemosensitivity of breast tumors, enabling access of cytotoxic T-cells and reducing immunosuppressive signals. TME rearrangement also includes reorganization of the extracellular matrix to enhance permeability to chemotherapeutics, and nano-systems for smart coupling of chemo- and immune-therapy, by increasing immunogenicity and stimulating antitumor immunity. The present paper reviews the current state-of-the-art on nano-strategies to target breast CAF and TME. Finally, we consider and discuss future translational perspectives of proposed nano-strategies for clinical application in breast cancer.
Carcinogenicity of intermediate frequency magnetic field in Tg.rasH2 mice

Although the likelihood of exposure to leaking intermediate frequency magnetic fields (MFs) from electronic devices, such as induction‐heating and wireless power transfer systems, has increased, biological data assessing the health risks associated with human exposure remain insufficient. We examined the carcinogenicity of a 20 kHz MF, a typical frequency produced by induction‐heating cookers, using a transgenic rasH2 mouse model. Twenty‐five male and female CByB6F1‐Tg(HRAS)2Jic mice were exposed to a 0.20 mT, 20 kHz MF (22 h/day) or sham‐exposed for 26 weeks. As a positive control, 10 male and female rasH2 mice from the same batch were administered a single intraperitoneal injection of 75 mg/kg N‐methyl‐N‐nitrosourea. A blinded histopathological evaluation was performed, and the same experiments were conducted twice, independently, to confirm the reproducibility of the results. Histopathological examination revealed that spontaneous neoplastic lesions, such as splenic hemangiosarcomas and gastric squamous cell papillomas, were less (1–3 per group) in the MF‐ and sham‐exposed groups. The frequency of the neoplastic lesions was not significantly different between the groups. Eight to ten mice in each positive‐control group exhibited malignant lymphoma. The outcomes were consistent between duplicated experiments, which indicates lack of carcinogenicity of 20 kHz MF in the rasH2 mouse model. Bioelectromagnetics. © 2019 The Authors. Bioelectromagnetics Published by Wiley Periodicals, Inc.
Stringent response leads to continued cell division and a temporal restart of DNA replication after initial shutdown in Vibrio cholerae

Vibrio cholerae is an aquatic bacterium with the potential to infect humans and cause the cholera disease. While most bacteria have single chromosomes, the V. cholerae genome is encoded on two replicons of different size. This study focuses on the DNA replication and cell division of this bi‐chromosomal bacterium during the stringent response induced by starvation stress. V. cholerae cells were found to initially shut DNA replication initiation down upon stringent response induction by the serine analog serine hydroxamate. Surprisingly, cells temporarily restart their DNA replication before finally reaching a state with fully replicated single chromosome sets. This division‐replication pattern is very different to that of the related single chromosome model bacterium Escherichia coli. Within the replication restart phase, both chromosomes of V. cholerae maintained their known order of replication timing to achieve termination synchrony. Using flow cytometry combined with mathematical modeling, we established that a phase of cellular regrowth be the reason for the observed restart of DNA replication after the initial shutdown. Our study shows that although the stringent response induction itself is widely conserved, bacteria developed different ways of how to react to the sensed nutrient limitation, potentially reflecting their individual lifestyle requirements.
Study of the Chronology of Expression of Ten Extracellular Matrix Molecules during the Myogenesis in Cattle to Better Understand Sensory Properties of Meat

The sensory properties of beef are known to depend on muscle fiber and intramuscular connective tissue composition (IMCT). IMCT is composed of collagens, proteoglycans and glycoproteins. The differentiation of muscle fibers has been extensively studied but there is scarcity in the data concerning IMCT differentiation. In order to be able to control muscle differentiation to improve beef quality, it is essential to understand the ontogenesis of IMCT molecules. Therefore, in this study, we investigated the chronology of appearance of 10 IMCT molecules in bovine Semitendinosus muscle using immunohistology technique at five key stages of myogenesis. Since 60 days post-conception (dpc), the whole molecules were present, but did not have their final location. It seems that they reach it at around 210 dpc. Then, the findings emphasized that since 210 dpc, the stage at which the differentiation of muscle fibers is almost complete, the differentiation of IMCT is almost completed. These data suggested that for the best controlling of the muscular differentiation to improve beef sensory quality, it would be necessary to intervene very early (before the IMCT constituents have acquired their definitive localization and the muscle fibers have finished differentiating), i.e., at the beginning of the first third of gestation.
Real‐world evidence on adherence, persistence, switching and dose escalation with biologics in adult inflammatory bowel disease in the United States: A systematic review

The application of biologics to treat inflammatory bowel disease (IBD), including Crohn's disease and ulcerative colitis, is well established. Our aim was to characterize the most recent five years of data on rates of adherence, persistence, switching and dose escalations with biologics used to treat IBD in the United States.