Miracle-dz/UniFAR-FTUs huggingface dataset:
Indirectly Activated Treg Allow Dominant Tolerance to Murine Skin-grafts Across an MHC Class I Mismatch After a Single Donor-specific Transfusion

Background. Tolerance induced in stringent animal transplant models using donor-specific transfusions (DST) has previously required additional immunological manipulation. Here, we demonstrate a dominant skin-allograft tolerance model induced by a single DST across an major histocompatibility class I mismatch in an unmanipulated B6 host. Methods. C57BL/6 (H-2b) (B6) mice were injected intravenously with splenocytes from B6.C. H-2bm1 (H-2kbm1) (bm1) or F1 (B6 × bm1) mice before skin transplantation. Mice were transplanted 7 days postinjection with donor (bm1 or F1) and third-party B10.BR (H-2k) skin grafts. Results. B6 hosts acutely rejected skin grafts from B6.C. H-2bm1 (bm1) and F1 (B6 × bm1) mice. A single transfusion of F1 splenocytes into B6 mice without any additional immune modulation led to permanent acceptance of F1 skin grafts. This graft acceptance was associated with persistence of donor cells long-term in vivo. The more rapid removal of DST bm1 cells than F1 cells was reduced by natural killer-cell depletion. Tolerant grafts survived an in vivo challenge with naive splenocytes. Both CD4+CD25+ and CD4+CD25− T cells from F1 DST treated B6 mice suppressed alloproliferation in vitro. Tolerance was associated with expansion of peripheral Foxp3+CD4+CD25+ regulatory T cells (Treg) and increased forkhead box P3 (Foxp3) expression in tolerant grafts. In tolerant mice, Foxp3+ Treg arises from the proliferation of indirectly activated natural Foxp3+ Treg (nTreg) and depletion of Foxp3+ Treg abrogates skin-graft tolerance. Conclusions. This study demonstrates that the persistence of transfused semiallogeneic donor cells mismatched at major histocompatibility class I can enhance tolerance to subsequent skin allografts through indirectly expanded nTreg leading to dominant tolerance without additional immunological manipulation.
Exploration of databases and methods supporting drug repurposing: a comprehensive survey

Abstract Drug development involves a deep understanding of the mechanisms of action and possible side effects of each drug, and sometimes results in the identification of new and unexpected uses for drugs, termed as drug repurposing. Both in case of serendipitous observations and systematic mechanistic explorations, confirmation of new indications for a drug requires hypothesis building around relevant drug-related data, such as molecular targets involved, and patient and cellular responses. These datasets are available in public repositories, but apart from sifting through the sheer amount of data imposing computational bottleneck, a major challenge is the difficulty in selecting which databases to use from an increasingly large number of available databases. The database selection is made harder by the lack of an overview of the types of data offered in each database. In order to alleviate these problems and to guide the end user through the drug repurposing efforts, we provide here a survey of 102 of the most promising and drug-relevant databases reported to date. We summarize the target coverage and types of data available in each database and provide several examples of how multi-database exploration can facilitate drug repurposing.
Analysis of Network Structure and Doctor Behaviors in E-Health Communities from a Social-Capital Perspective

In tandem with internet development and widespread social media use, e-health communities have begun to emerge in recent years. These communities allow doctors to access forums anywhere, anytime, seek or exchange medical information online, find literature, and so on. This is convenient and can solve some problems for doctors while also promoting doctor communication. This study collected and collated 102 doctors in the “Lilac Forum” and used social network tools to quantify the overall network density, centrality, core–periphery structure, and structural hole indicators of doctors’ information exchange from a social-capital perspective. The results showed that the frequency of interaction between doctors differed because of differences in the identities and participation of doctors in the e-health community. The density of the doctors’ information dissemination network (0.228) and network cohesion (0.610) were relatively high. Thus, the doctors were more closely connected, and information was easily spread. At the same time, doctors with higher professional titles had obvious location characteristics, familiarity and trust, and high levels of reciprocity. They could obtain redundant information in the network and were more likely to influence the behavior of other doctors. This study’s findings provide support for improving information exchange among doctors in e-health communities and improving the service levels of the platforms.
Matrix Effect in the Isolation of Breast Cancer-Derived Nanovesicles by Immunomagnetic Separation and Electrochemical Immunosensing—A Comparative Study

Exosomes are cell-derived nanovesicles released into biological fluids, which are involved in cell-to-cell communication. The analysis of the content and the surface of the exosomes allow conclusions about the cells they are originating from and the underlying condition, pathology or disease. Therefore, the exosomes are currently considered good candidates as biomarkers to improve the current methods for clinical diagnosis, including cancer. However, due to their low concentration, conventional procedures for exosome detection including biosensing usually require relatively large sample volumes and involve preliminary purification and preconcentration steps by ultracentrifugation. In this paper, the immunomagnetic separation is presented as an alternative method for the specific isolation of exosomes in serum. To achieve that, a rational study of the surface proteins in exosomes, which can be recognized by magnetic particles, is presented. The characterization was performed in exosomes obtained from cell culture supernatants of MCF7, MDA-MB-231 and SKBR3 breast cancer cell lines, including TEM and nanoparticle tracking analysis (NTA). For the specific characterization by flow cytometry and confocal microscopy, different commercial antibodies against selected receptors were used, including the general tetraspanins CD9, CD63 and CD81, and cancer-related receptors (CD24, CD44, CD54, CD326 and CD340). The effect of the serum matrix on the immunomagnetic separation was then carefully evaluated by spiking the exosomes in depleted human serum. Based on this study, the exosomes were preconcentrated by immunomagnetic separation on antiCD81-modified magnetic particles in order to achieve further magnetic actuation on the surface of the electrode for the electrochemical readout. The performance of this approach is discussed and compared with classical characterization methods.
Functional and Structural Connectivity Patterns Associated with Clinical Outcomes in Deep Brain Stimulation of the Globus Pallidus Internus for Generalized Dystonia

BACKGROUND AND PURPOSE: Deep brain stimulation is a well-established treatment for generalized dystonia, but outcomes remain variable. Establishment of an imaging marker to guide device targeting and programming could possibly impact the efficacy of deep brain stimulation in dystonia, particularly in the absence of acute clinical markers to indicate benefit. We hypothesize that the stimulation-based functional and structural connectivity using resting-state fMRI and DTI can predict therapeutic outcomes in patients with generalized dystonia and deep brain stimulation. MATERIALS AND METHODS: We performed a retrospective analysis of 39 patients with inherited or idiopathic-isolated generalized dystonia who underwent bilateral globus pallidus internus deep brain stimulation. After electrode localization, the volumes of tissue activated were modeled and used as seed regions for functional and structural connectivity measures using a normative data base. Resulting connectivity maps were correlated with postoperative improvement in the Unified Dystonia Rating Scale score. RESULTS: Structural connectivity between the volumes of tissue activated and the primary sensorimotor cortex was correlated with Unified Dystonia Rating Scale improvement, while more anterior prefrontal connectivity was inversely correlated with Unified Dystonia Rating Scale improvement. Functional connectivity between the volumes of tissue activated and primary sensorimotor regions, motor thalamus, and cerebellum was most correlated with Unified Dystonia Rating Scale improvement; however, an inverse correlation with Unified Dystonia Rating Scale improvement was seen in the supplemental motor area and premotor cortex. CONCLUSIONS: Functional and structural connectivity with multiple nodes of the motor network is associated with motor improvement in patients with generalized dystonia undergoing deep brain stimulation. Results from this study may serve as a basis for future development of clinical markers to guide deep brain stimulation targeting and programming in dystonia.
Des-gamma-carboxyprothrombin is a favorable biomarker for the early diagnosis of alfa-fetoprotein-negative hepatitis B virus-related hepatocellular carcinoma

Objectives Des-gamma-carboxyprothrombin (DCP) is an important serum biomarker for the clinical screening of hepatocellular carcinoma (HCC). This study aimed to evaluate the value of DCP for the early diagnosis of alpha-fetoprotein (AFP)-negative hepatitis B virus (HBV)-related HCC. Methods We retrospectively enrolled patients with AFP-negative HBV-related HCC and benign liver disease. Serum DCP levels in all participants were measured by chemiluminescent enzyme immunoassay. The value of DCP for the early diagnosis of AFP-negative HBV-related HCC was evaluated by receiver operating characteristic curve (ROC) and area under the curve (AUC) analyses. Results A total of 210 patients, including 87 cases with AFP-negative HBV-related HCC and 123 control cases with chronic HBV infection (CHB) or liver cirrhosis (LC), were included. Serum DCP levels were significantly increased in patients with AFP-negative HBV-related HCC compared with those with CHB or LC. The AUC for DCP for distinguishing between the two groups was 0.731 (95% confidence interval (CI), 0.657 to 0.805) and that for early diagnosis was 0.685 (95%CI, 0.596 to 0.774). Conclusions DCP may be a favorable biomarker to improve the early diagnosis rate of AFP-negative HBV-related HCC.
Fiber Spray Ionization Mass Spectrometry in Forensic Chemistry - A Screening of Drugs of Abuse and Direct Determination of Cocaine in Urine.

RATIONALE Ambient mass spectrometry (AMS) techniques are very required in forensic chemistry to evaluate evidence with less analytical interference, high confidence, and accuracy. However, traditional methodologies, such as paper spray ionization (PSI), have been shown to present low sensitivity in the analysis of illicit drugs from biological matrices. METHODS Fiber spray ionization mass spectrometry (FSI-MS) was developed using a capillary polypropylene (PP) hollow fiber. Seized samples of drugs, i.e., a tablet, blotter paper, hashish, and cocaine powder, were analyzed. Cocaine was quantified from whole urine by dipping the fiber directly into the solution. FSI-MS was tested for the analysis of a sample of urine obtained from a drug abuse suspect. RESULTS The FSI(+) analysis showed the detection of different types of synthetic drugs in tablet and blotter paper samples, e.g., amphetamine, cathinones, phenethylamines, and opioids, while pure cocaine and different types of coca alkaloids were identified from cocaine powder with good sensitivity and high mass accuracy. The hashish analysis by FSI(-) revealed signals of cannabinoids, cannabinoids acids, and cannabinoid derivatives detected mainly as [M-H]- ions or chlorine adducts, [M+Cℓ]- . The quantification of cocaine in whole urine showed good sensitivity and precision with LOD and LOQ values of 5.16 and 17.21 ng/mL, respectively, linearity above 0.999, and RSD below 2.71%. The evaluation of seized sample of urine showed the detection of cocaine with relative ion intensity greater than 36%, as well as the metabolites BZE and CE with relative intensity of 1.4% and 6%, respectively. CONCLUSIONS The developed FSI-MS method has the potential to be applied to forensic samples evaluation as well as to determine illicit drugs from biological matrices in toxicological analysis. The use of a capillary PP fiber holds advantages as extractor agent and ionizing substrate, and also the feature of it being dipped directly into the sample, thus preserving the integrity of the sample, which makes this a very promising AMS method and relevant to forensic chemistry.
Erratum

In our recent paper on the taxonomy of Fragilaria (Kahlert et al. 2019), we relied upon a study of the type material of F. subconstricta and F. tenuistriata by Tuji and Williams (2008), whose accuracy we had no reason to doubt. Unfortunately, new studies of this material (by Dr Bart Van de Vijver and colleagues, pers. comm., August 2019; see Heudre et al. 2019, published July 2019) indicate that Tuji and Williams inadvertently exchanged these two species in their paper, their account of F. subconstricta being based, in fact, on the type material of F. tenuistriata and vice versa. Consequently, our paper perpetuates this error and must be corrected on several pages by replacing “F. subconstricta” with “F. tenuistriata” and vice versa in the abstract, discussion, conclusions, figures, tables, the supplementary figure and its legend, as well as in the supplementary material. Please note that “F. tenuistriata” in the results section must not be replaced, as it refers to the clone identification. In detail, “Fragilaria subconstricta” must be replaced by “F. tenuistriata” on pages 948 (Abstract), 952 (Fig. 1), 953 (Table 1), 954 (Table 1), 955 (Table 2), 956 (Table 2), 965 (Fig. 7), 966 (4 occurrences; Discussion), 967 (one out of two occurrences; Discussion), 967 (Conclusion), 970 (figure legend to Fig. S3). One sentence needs to be deleted on page 967 (Discussion) because it compares the wrong species with each other and does not make sense when using the correct species descriptions. In the supplementary material, “Fragilaria subconstricta” must be replaced with “F. tenuistriata” on page 3 (Table S2), in column “D” (Table S3), Figure S1, Figure S3. “Fragilaria tenuistriata” must be replaced with “F. subconstricta” on page 966 (one replacement out of four occurrences; Discussion). In the supplementary material, “Fragilaria tenuistriata” must be replaced with “F. subconstricta” on page 3 (Table S2). The text should have read: “Fragilaria tenuistriata” instead of “F. subconstricta” on pages: 952 (Fig. 1) 953 (Table 1) 954 (Table 1) 955 (Table 2) 956 (Table 2) 965 (Fig. 7) 970 (figure legend to Fig. S3) 3 (Table S2) In column “D” (Table S3) Figure S1 Figure S3
Optimal monetary policy, asset purchases, and credit market frictions1

We examine how borrowing constraints a¤ect monetary transmission and the trade-o¤ of a welfare maximizing central bank. We develop a sticky price model where money serves as the means of payment and exante identical agents borrow/lend among each other. The credit market is distorted as borrowing is constrained by available collateral, while the distortion is ampli ed under higher nominal interest rates. We show that the central bank cannot implement rst best and that optimal monetary policy mainly aims at stabilizing prices. We further demonstrate that central bank purchases of loans can alleviate the borrowing constraint and enhance social welfare. JEL classi cation: E4; E5; E32.
Pharmacodynamic Analysis of BTK Inhibition in Patients with Chronic Lymphocytic Leukemia Treated with Acalabrutinib

Purpose: To determine the pharmacodynamic relationship between target occupancy of Bruton tyrosine kinase (BTK) and inhibition of downstream signaling. Patients and Methods: Patients with chronic lymphocytic leukemia (CLL) enrolled in a phase II clinical trial (NCT02337829) with the covalent, selective BTK inhibitor acalabrutinib donated blood samples for pharmacodynamic analyses. Study design included randomization to acalabrutinib 100 mg twice daily or 200 mg once daily and dose interruptions on day 4 and 5 of the first week. BTK occupancy and readouts of intracellular signaling were assessed sequentially between 4 and 48 hours from last dose. Results: Four hours from last dose, BTK occupancy exceeded 96% and at trough, was higher with twice daily, median 95.3%, than with once daily dosing, median 87.6% (P < 0.0001). By 48 hours from last dose, median free BTK increased to 25.6%. Due to covalent binding of acalabrutinib, free BTK is generated by de novo synthesis. The estimated rate of BTK synthesis varied widely between patients ranging from 3.6% to 31.4% per day. Acalabrutinib reduced phosphorylation of BTK and inhibited downstream B-cell receptor (BCR) and NFκB signaling. During dosing interruptions up to 48 hours, expression of BCR target genes rebounded, while phosphorylation of signaling molecules remained repressed. In vitro cross-linking of IgM on CLL cells obtained 36 to 48 hours from last dose upregulated CD69, with high correlation between cellular free BTK and response (R = 0.7, P ≤ 0.0001). Conclusions: Higher BTK occupancy was achieved with twice daily over once daily dosing, resulting in deeper and more sustained inhibition of BCR signaling.
A review of Panax ginseng as an herbal medicine

Panax ginseng is categorized as parental herb tribe to Asian people, particularly to Korea and China and it is widely used as an alternative remedy in Eastern Asia countries since many years ago. Based on traditional practice and recent research on this ancient herb, all parts of the ginseng contain pharmacologically active elements; however, it has been found that the main ingredient comes from its roots has a numerous compounds and chemicals that can exert the pharmacological properties such as lowering blood glucose, lowering hypertension, anti-inflammatory, antineoplastic agents, anti-stress, improve vitality, sexual dysfunctions, and promote healing process; thus, it is also called as modern tonic traditional complementary medicine. However, some modern research has identified that it can cause severe side effects such as mental disorder, hypertensions, bleeding allergy reactions, and renal toxicity. Therefore, the use of this herb among public is not recommended because there is not definite dose for human.
Comparing the Characteristics and Outcomes of Male and Female Breast Cancer Patients in Korea: Korea Central Cancer Registry

Purpose This study aimed to determine the incidence of male breast cancer (MBC) and its survival outcomes in Korea, and to compare these results to those for female breast cancer (FBC). Materials and Methods We searched the Korea Central Cancer Registry and identified 227,122 breast cancer cases that were diagnosed between 1999 and 2016. Demographic and clinical characteristics and overall survival (OS) rates were estimated according to sex, age, histological type, and cancer stage. Results The 227,122 patients included 1,094 MBC cases and 226,028 FBC cases. Based on the age-standardized rate, the male: female ratio was 0.0055:1. The most common ages at diagnosis were 60-69 years for MBC and 40-49 years for FBC (p < 0.001). Male patients were less likely than female patients to receive adjuvant radiotherapy (7.5% vs. 21.8%, p < 0.001) or adjuvant chemotherapy (40.1% vs. 55.4%, p < 0.001). The 5-year OS rates after diagnosis were 88.8% for all patients, although it was significantly lower for MBC than for FBC (76.2% vs. 88.9%, p < 0.001). In both groups, older age (≥ 60 years) was associated with shorter survival. The 5-year OS rates for the invasive histological types were 75.8% for men and 89.0% for women. The 5-year OS rates in both groups decreased with increasing cancer stage. Conclusion MBC was diagnosed at older ages than FBC, and male patients were less likely to receive radiotherapy and chemotherapy. The survival outcomes were worse for MBC than for FBC, with even poorer outcomes related to older age, the inflammatory histological types, and advanced stage. It is important that clinicians recognize the differences between FBC and MBC when treating these patients.
Effects of Directional Microphone and Noise Reduction on Subcortical and Cortical Auditory-Evoked Potentials in Older Listeners With Hearing Loss

Objectives: Understanding how signal processing influences neural activity in the brain with hearing loss is relevant to the design and evaluation of features intended to alleviate speech-in-noise deficits faced by many hearing aid wearers. Here, we examine whether hearing aid processing schemes that are designed to improve speech-in-noise intelligibility (i.e., directional microphone and noise reduction) also improve electrophysiological indices of speech processing in older listeners with hearing loss. Design: The study followed a double-blind within-subjects design. A sample of 19 older adults (8 females; mean age = 73.6 years, range = 56–86 years; 17 experienced hearing aid users) with a moderate to severe sensorineural hearing impairment participated in the experiment. Auditory-evoked potentials associated with processing in cortex (P1-N1-P2) and subcortex (frequency-following response) were measured over the course of two 2-hour visits. Listeners were presented with sequences of the consonant-vowel syllable /da/ in continuous speech-shaped noise at signal to noise ratios (SNRs) of 0, +5, and +10 dB. Speech and noise stimuli were pre-recorded using a Knowles Electronics Manikin for Acoustic Research (KEMAR) head and torso simulator outfitted with hearing aids programmed for each listener’s loss. The study aid programs were set according to 4 conditions: (1) omnidirectional microphone, (2) omnidirectional microphone with noise reduction, (3) directional microphone, and (4) directional microphone with noise reduction. For each hearing aid condition, speech was presented from a loudspeaker located at 1 m directly in front of KEMAR (i.e., 0° in the azimuth) at 75 dB SPL and noise was presented from a matching loudspeaker located at 1 m directly behind KEMAR (i.e., 180° in the azimuth). Recorded stimulus sequences were normalized for speech level across conditions and presented to listeners over electromagnetically shielded ER-2 ear-insert transducers. Presentation levels were calibrated to match the output of listeners’ study aids. Results: Cortical components from listeners with hearing loss were enhanced with improving SNR and with use of a directional microphone and noise reduction. On the other hand, subcortical components did not show sensitivity to SNR or microphone mode but did show enhanced encoding of temporal fine structure of speech for conditions where noise reduction was enabled. Conclusions: These results suggest that auditory-evoked potentials may be useful in evaluating the benefit of different noise-mitigating hearing aid features.