Miracle-dz/UniFAR-FTUs huggingface dataset:
RECAP reveals the true statistical significance of ChIP-seq peak calls

Motivation ChlP-seq is used extensively to identify sites of transcription factor binding or regions of epigenetic modifications to the genome. A key step in ChIP-seq analysis is peak calling, where genomic regions enriched for ChIP versus control reads are identified. Many programs have been designed to solve this task, but nearly all fall into the statistical trap of using the data twice—once to determine candidate enriched regions, and again to assess enrichment by classical statistical hypothesis testing. This double use of the data invalidates the statistical significance assigned to enriched regions, and as a consequence, invalidates false discovery rate estimates. Thus, the true significance or reliability of peak calls remains unknown. Results Using simulated and real ChIP-seq data sets, we show that three well-known peak callers, MACS, SICER and diffReps, output optimistically biased p-values, and therefore optimistic false discovery rate estimates—in some cases, many orders of magnitude too optimistic. We propose a wrapper algorithm, RECAP, that uses resampling of ChIP-seq and control data to estimate and correct for biases built into peak calling algorithms. P-values recalibrated by RECAP are approximately uniformly distributed when applied to null hypothesis data, in which ChIP-seq and control come from the same genomic distributions. When applied to non-null data, RECAP p-values give a better estimate of the true statistical significance of candidate peaks and better false discovery rate estimates, which correlate better with empirical reproducibility. RECAP is a powerful new tool for assessing the true statistical significance of ChIP-seq peak calls. Availability The RECAP software is available on github at https://github.com/theodorejperkins/RECAP. Contact tperkins@ohri.ca
Comparison of dual-time point 18F-FDG PET/CT tumor-to-background ratio, intraoperative 5-aminolevulinic acid fluorescence scale, and Ki-67 index in high-grade glioma

Abstract The aim of this study was to compare preoperative dual-time point 18F-fluorodeoxyglucose (FDG) uptake pattern with intraoperative 5-aminolevulinic acid (5-ALA) fluorescence in high-grade gliomas. In addition, we assessed for possible associations with a pathologic parameter (Ki-67 index). Thirty-one patients with high-grade glioma (M:F = 19:12, mean age = 60.6 ± 11.2 years) who underwent dual-time point 18F-FDG positron emission tomography (PET)/computed tomography (CT) scan before surgery were retrospectively enrolled; 5-ALA was applied to the surgical field of all these patients and its fluorescence intensity was evaluated during surgery. Measured 18F-FDG PET/CT parameters were maximum and peak tumor-to-background ratio (maxTBR and peakTBR) at base (-base) and delayed (-delay) scan. The intensity of 5-ALA fluorescence was graded on a scale of three (grade I as no or mild intensity, grade II as moderate intensity, and grade III as strong intensity). Seven of the patients had WHO grade III brain tumors and 24 had WHO grade IV tumors (mean tumor size = 4.8 ± 1.8 cm). MaxTBR-delay and peakTBR-delay showed significantly higher values than maxTBR-base and peakTBR-base, respectively (all P < .001). Among the 18F-FDG PET/CT parameters, only maxTBR-delay demonstrated significance according to grade of 5-ALA (P = .030), and maxTBR-delay gradually decreased as the fluorescence intensity increased. Also, maxTBR-delay and peakTBR-delay showed significant positive correlation with Ki-67 index (P = .011 and .009, respectively). Delayed 18F-FDG uptake on PET/CT images could reflect proliferation in high-grade glioma, and it has a complementary role with 5-ALA fluorescence.
Current Understanding of the Molecular Basis of Venezuelan Equine Encephalitis Virus Pathogenesis and Vaccine Development

Dedication This review is dedicated in the memory of Dr Radha K. Maheshwari, a great mentor and colleague, whose passion for research and student training has left a lasting effect on this manuscript and many other works. Abstract Venezuelan equine encephalitis virus (VEEV) is an alphavirus in the family Togaviridae. VEEV is highly infectious in aerosol form and a known bio-warfare agent that can cause severe encephalitis in humans. Periodic outbreaks of VEEV occur predominantly in Central and South America. Increased interest in VEEV has resulted in a more thorough understanding of the pathogenesis of this disease. Inflammation plays a paradoxical role of antiviral response as well as development of lethal encephalitis through an interplay between the host and viral factors that dictate virus replication. VEEV has efficient replication machinery that adapts to overcome deleterious mutations in the viral genome or improve interactions with host factors. In the last few decades there has been ongoing development of various VEEV vaccine candidates addressing the shortcomings of the current investigational new drugs or approved vaccines. We review the current understanding of the molecular basis of VEEV pathogenesis and discuss various types of vaccine candidates.
Chemical Diversity of Codium bursa (Olivi) C. Agardh Headspace Compounds, Volatiles, Fatty Acids and Insight into Its Antifungal Activity

The focus of present study is on Codium bursa collected from the Adriatic Sea. C. bursa volatiles were identified by gas chromatography and mass spectrometry (GC-FID; GC-MS) after headspace solid-phase microextraction (HS-SPME), hydrodistillation (HD), and supercritical CO2 extraction (SC-CO2). The headspace composition of dried (HS-D) and fresh (HS-F) C. bursa was remarkably different. Dimethyl sulfide, the major HS-F compound was present in HS-D only as a minor constituent and heptadecane percentage was raised in HS-D. The distillate of fresh C. bursa contained heptadecane and docosane among the major compounds. After air-drying, a significantly different composition of the volatile oil was obtained with (E)-phytol as the predominant compound. It was also found in SC-CO2 extract of freeze-dried C. bursa (FD-CB) as the major constituent. Loliolide (3.51%) was only identified in SC-CO2 extract. Fatty acids were determined from FD-CB after derivatisation as methyl esters by GC-FID. The most dominant acids were palmitic (25.4%), oleic (36.5%), linoleic (11.6%), and stearic (9.0%). FD-CB H2O extract exhibited better antifungal effects against Fusarium spp. , while dimethyl sulfoxide (DMSO) extract was better for the inhibition of Penicillium expansum, Aspergillus flavus, and Rhizophus spp. The extracts showed relatively good antifungal activity, especially against P. expansum (for DMSO extract MIC50 was at 50 µg/mL).
Functional Mesoporous Silica Nanocomposites: Biomedical Applications and Biosafety

The rise and development of nanotechnology has enabled the creation of a wide number of systems with new and advantageous features to treat cancer. However, in many cases, the lone application of these new nanotherapeutics has proven not to be enough to achieve acceptable therapeutic efficacies. Hence, to avoid these limitations, the scientific community has embarked on the development of single formulations capable of combining functionalities. Among all possible components, silica—either solid or mesoporous—has become of importance as connecting and coating material for these new-generation therapeutic nanodevices. In the present review, the most recent examples of fully inorganic silica-based functional composites are visited, paying particular attention to those with potential biomedical applicability. Additionally, some highlights will be given with respect to their possible biosafety issues based on their chemical composition.
Finger-Actuated Microfluidic Concentration Gradient Generator Compatible with a Microplate

The generation of concentration gradients is an essential part of a wide range of laboratory settings. However, the task usually requires tedious and repetitive steps and it is difficult to generate concentration gradients at once. Here, we present a microfluidic device that easily generates a concentration gradient by means of push-button actuated pumping units. The device is designed to generate six concentrations with a linear gradient between two different sample solutions. The microfluidic concentration gradient generator we report here does not require external pumps because changes in the pressure of the fluidic channel induced by finger actuation generate a constant volume of fluid, and the design of the generator is compatible with the commonly used 96-well microplate. Generation of a concentration gradient by the finger-actuated microfluidic device was consistent with that of the manual pipetting method. In addition, the amount of fluid dispensed from each outlet was constant when the button was pressed, and the volume of fluid increased linearly with respect to the number of pushing times. Coefficient of variation (CV) was between 0.796% and 13.539%, and the error was between 0.111% and 19.147%. The design of the microfluidic network, as well as the amount of fluid dispensed from each outlet at a single finger actuation, can be adjusted to the user’s demand. To prove the applicability of the concentration gradient generator, an enzyme assay was performed using alkaline phosphatase (ALP) and para-nitrophenyl phosphate (pNPP). We generated a linear concentration gradient of the pNPP substrate, and the enzyme kinetics of ALP was studied by examining the initial reaction rate between ALP and pNPP. Then, a Hanes–Woolf plot of the various concentration of ALP was drawn and the Vmax and Km value were calculated.
Preparation and Characterization of Erythrocyte Membrane-Camouflaged Berberine Hydrochloride-Loaded Gelatin Nanoparticles

The discovery of a new pharmacological application of berberine hydrochloride (BH) made it more clinically valuable. However, the further development of BH was hampered by its short half-life and side effects after intravenous injection. To overcome these problems, a novel BH delivery system was developed using natural red blood cell membrane-camouflaged BH-loaded gelatin nanoparticles (RBGPs) to reduce the toxicity associated with injections and achieve sustained release. The size of the RBGPs was 260.3 ± 4.1 nm, with an obvious core–shell structure, and the membrane proteins of the RBGPs were mostly retained. The RBGP system showed significant immune-evading capabilities and little cytotoxicity to human embryonic kidney (HEK) 293T cells and LO2 cells. Finally, RBGPs improved the sustained releasing effect of BH significantly. When the cumulative release time reached 120 h, the cumulative release rate of RBGPs was 78.42%. In brief, RBGPs hold the potential to achieve long circulation and sustained-release of BH, avoid side effects caused by high plasma concentration in common injection formulations, and broaden the clinical applications of BH.
Recent clinical trials of hypertension management.

The scene for clinical trials of hypertension management is in transition. The era of mega trials may not be over but is certainly in decline, and in the past 2 years there have been no studies reporting primary outcome data the scale of the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT), The ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial (ONTARGET), Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT), and other major studies that marked clinical trial activity and informed guideline committees during the past 2 to 3 decades. This reflects in part the view that the present benchmark pharmacological agents for treating hypertension are difficult to improve, some systemic issues affecting the pharmaceutical industry influencing the ability to make the large investment required to perform mega trials and the quality of the antihypertensive drug pipeline. Together these considerations have tended to drive interest toward equivalence rather than efficacy studies (ie, trials designed to show an investigational agent is as good as, not better than, existing treatment), surrogate end points, including new blood pressure (BP) variables, and studies of combinations and algorithms rather than single interventions. Population studies around the world, however, continue to show that large numbers of people have hypertension that is not treated satisfactorily and are not achieving the goals set by the major national guidelines. These guidelines themselves are under continual scrutiny on the basis of recent data casting doubt on the validity of present BP goals. Guideline committees also face the issue that evidence based on expensive large-scale clinical trials is more often funded by the pharmaceutical or device industries than by government, leaving large evidence gaps in areas of public importance but no direct interest to industry funders. The purpose of the present article is to briefly review clinical trials of …
Seminal vesicle invasion in prostate cancer: evaluation by using multiparametric endorectal MR imaging.

PURPOSE To retrospectively evaluate the diagnostic performance of multiparametric endorectal magnetic resonance (MR) imaging, including T2-weighted, diffusion-weighted (DW), and dynamic contrast material-enhanced (DCE) MR techniques, for the diagnosis of seminal vesicle invasion (SVI) and to determine the incremental value of DW MR and DCE MR images. MATERIALS AND METHODS This retrospective HIPAA-compliant study was approved by the institutional review board, with a waiver of informed consent. The study included 131 patients (mean age, 68 years; range, 43-75 years) who underwent endorectal MR imaging before radical prostatectomy between January 2007 and April 2010. Two radiologists (A: experienced, B: less experienced) estimated the likelihood of SVI by using a five-point ordinal scale in three image-viewing settings: T2-weighted images alone; T2-weighted and DW MR images; and T2-weighted, DW MR, and DCE MR images. Sensitivity, specificity, positive predictive value, negative predictive value, and area under the receiver operating characteristic curve (AUC) were calculated. Confidence intervals estimated with bootstrapping and the McNemar test or Fisher exact test were used to compare sensitivity, specificity, positive predictive value, and negative predictive value. RESULTS Of the 131 patients, 23 (17.6%) had SVI identified after surgery. Review of T2-weighted MR images alone resulted in high specificity (93.1% and 93.6%, for radiologists A and B, respectively) and high negative predictive value (94.8% and 94.0%) but moderate sensitivity (59% and 52%) and positive predictive value (52% and 50%). Review of T2-weighted and DW MR images significantly improved specificity (96.6% [P = .02] and 98.3% [P = .003]) and positive predictive value (70% [P < .05] and 79% [P < .05]) without significantly improving AUC. Additional review of DCE MR images did not yield further incremental improvement. CONCLUSION Additional review of DW MR images improves specificity and positive predictive value in SVI detection compared with reviewing T2-weighted images alone. Addition of DCE MR images to this combination, however, does not provide incremental value for diagnosis of SVI.
Preparation and cytological study of collagen/nano-hydroxyapatite/graphene oxide composites.

PURPOSE Biomimetic mineralized composite scaffolds are widely used as natural bone substitute materials in tissue engineering by inducing and assembling bonelike apatite. In this study, the single lamellar structure of graphene oxide (GO) powder was prepared via an improved Hummers' method. METHODS To better mimic natural bone, the collagen (COL)/Nano-hydroxyapatite (nHA)/graphene oxide (GO) composite material was prepared by simulated body fluid (SBF) method using COL/GO as a matrix template. Hydroxyapatite (HA) with calcium ion deficiency was achieved via biomimetic mineralization, and it had properties closer to those of natural bone than pure HA has. RESULTS The mineralized COL/nHA/GO composites exhibited loose porous structures, and the connectivity of the holes was good and thus beneficial to the exchange of nutrients and excreted metabolites. Conculsions: Antibacterial and MTT experiment confirmed that the COL/nHA/GO composite material had excellent antibacterial property and biocompatibility. Hence, these results strongly suggested the mineralized COL/nHA/GO composite is a good candidate biomaterial to be applied in bone tissue engineering.
Eigenvector-Free Solutions to the Matrix Equation AXBH=E with Two Special Constraints

The matrix equation with or constraint is considered, where S, R are Hermitian idempotent, P, Q are Hermitian involutory, and . By the eigenvalue decompositions of S, R, the equation with constraint is equivalently transformed to an unconstrained problem whose coefficient matrices contain the corresponding eigenvectors, with which the constrained solutions are constructed. The involved eigenvectors are released by Moore-Penrose generalized inverses, and the eigenvector-free formulas of the general solutions are presented. By choosing suitable matrices S, R, we also present the eigenvector-free formulas of the general solutions to the matrix equation with constraint.
Starch Combined with Sucrose Provokes Greater Root Dentine Demineralization than Sucrose Alone

Since there is no consensus about whether starch increases the cariogenic potential of sucrose, we used a validated 3-species biofilm model to evaluate if starch combined with sucrose provokes higher root dentine demineralization than sucrose alone. Biofilms (n = 18) composed by Streptococcus mutans (the most cariogenic bacteria), Actinomces naeslundii (which has amylolytic activity), and Streptococcus gordonii (which binds salivary amylase) were formed on root dentine slabs under exposure 8 ×/day to one of the following treatments: 0.9% NaCl, 1% starch, 10% sucrose, or a combination of 1% starch and 10% sucrose. Before each treatment, biofilms were pretreated with human whole saliva for 1 min. The pH of the culture medium was measured daily as an indicator of biofilm acidogenicity. After 96 h of growth, the biofilms were collected, and the biomass, bacteria viability, and polysaccharides were analyzed. Dentine demineralization was assessed by surface hardness loss (% SHL). Biofilm bioarchitecture was analyzed using confocal laser scanning microscopy. Treatment with a starch and sucrose combination provoked higher (p = 0.01) dentine demineralization than sucrose alone (% SHL = 53.2 ± 7.0 vs. 43.2 ± 8.7). This was supported by lower pH values (p = 0.007) of the culture medium after daily exposure to the starch and sucrose combination compared with sucrose (4.89 ± 0.29 vs. 5.19 ± 0.32). Microbiological and biochemical findings did not differ between biofilms treated with the combination of starch and sucrose and sucrose alone (p > 0.05). Our findings give support to the hypothesis that a starch and sucrose combination is more cariogenic for root dentine than sucrose alone.
Dynamic Diffractive Patterns in Helix-Inverting Cholesteric Liquid Crystals

The future of adaptive materials will rely on transduction of molecular motion across increasing length scales, up to the macroscopic and functional level. In this context, liquid crystals have emerged as a promising amplification medium, in view of their long-range order and high sensitivity to external stimuli, and in particular, chiral liquid crystals have demonstrated widely tunable optical properties and invertible handedness. Here, we demonstrate that by applying weak electric fields, regular, periodic and light-tunable patterns can be formed spontaneously in cholesteric liquid crystals. These patterns can be used as light-tunable diffraction gratings for which the period, the diffraction efficiency, and the in-plane orientation of grating vector can be controlled precisely, reversibly, and independently. Such a photoregulation allows generating a variety of one- and two-dimensional complex diffractive patterns in a single material. Our data are also supported by modeling and theoretical calculations. Overall, the fine tunability of cholesteric materials doped with artificial molecular switches makes them attractive for optics and photonics.
Assessment of non-small cell lung cancer perfusion: pathologic-CT correlation in 15 patients.

PURPOSE To assess tumor perfusion with multi-detector row computed tomography (CT) in patients with non-small cell lung carcinoma and to correlate CT findings with pathologic results. MATERIALS AND METHODS This study was approved by the local Ethics Committee, and all patients provided written informed consent, which included information on the radiation exposure at the CT examinations. Fifteen consecutive patients (mean age, 60.5 years ± 7.7 [standard deviation]), including 14 men (mean age, 59.9 years ± 7.5) and one woman (age, 70 years) with histologically proved non-small cell lung carcinoma were prospectively enrolled. Overall, pathologic-CT correlations were examined in 31 focal tumoral zones. Comparative analysis was performed by using the χ(2) or the Fisher exact test for categoric data. For numeric data, group comparisons were performed by using the Mann-Whitney test. RESULTS Whole-tumor coverage (mean height, 4.3 cm ± 2.1) was possible in all patients with generation of colored parametric maps of volume transfer constant (K(trans)) and blood volume (BV) by using Patlak analysis. Of the 12 areas that showed high BV, 10 (83%) had a high K(trans); in all 12 cases, the vascular score was high, confirming the presence of numerous tumoral vessels. Nineteen areas showed low BV; when observed concurrently with a high K(trans) (seven of 19), the mean vessel number per area was significantly higher than that seen in areas with low BV and low K(trans) (12 of 19) (P = .038), suggestive of tumoral vessels associated with high interstitial pressure. CONCLUSION Whole-tumor perfusion analysis is technically feasible with 64-detector row CT, with two patterns suggestive of high tumoral vascularity. SUPPLEMENTAL MATERIAL http://radiology.rsna. org/lookup/suppl/doi:10.1148/radiol.10100181/-/DC1.