Miracle-dz/UniFAR-FTUs huggingface dataset:
Prolonged exposure of naïve CD8+ T cells to interleukin‐7 or interleukin‐15 stimulates proliferation without differentiation or loss of telomere length

Interleukin (IL)‐7 and IL‐15 are cytokines implicated in homeostatic control of the peripheral CD8 T‐cell pool. We compared the effects of IL‐7 and IL‐15 on survival and proliferation of purified human CD8+ T‐cell subsets. Low concentrations of either cytokine reduced the spontaneous apoptosis of all subsets, and enhancement of survival corresponded to the extent of Bcl‐2 up‐regulation. Surprisingly, although minimal proliferation of naïve CD8+ T cells was observed during the first week of culture with cytokines, a marked expansion of these cells occurred at later time points, particularly in response to IL‐15. This occurred largely without phenotypic change or acquisition of effector function, indicating a dissociation of differentiation from proliferation. Notably, progression of naïve CD8+ T cells through several cell divisions resulted in up‐regulation of telomerase and the maintenance of telomere length. These data show that IL‐7 and IL‐15 induce cell proliferation and rescue from apoptosis in a concentration, time and subset‐dependent manner, and have implications for the homeostatic expansion of the naïve CD8+ T‐cell pool.
FLT3 inhibitors for the treatment of autoimmune disease

Background: Autoimmune diseases encompass a broad range of illnesses with a variety of underlying causes, some of which are known and some of which remain elusive. Objective: The focus of this review will be on describing the development of a new type of therapy that could potentially treat T cell-mediated autoimmune diseases. Unlike traditional therapies, which have primarily focused on suppressing T cells directly, targeting the step of antigen presentation may allow a less toxic therapy in which autoimmunity is lessened without compromising the entire immune system. This review will outline the science behind the development of the therapy, the roles of dendritic cells in generating autoimmune disease, and the function of the FLT3 receptor in this process.
Regulation and roles of Cdc7 kinase under replication stress

Cdc7 (cell division cycle 7) kinase together with its activation subunit ASK (also known as Dbf4) play pivotal roles in DNA replication and contribute also to other aspects of DNA metabolism such as DNA repair and recombination. While the biological significance of Cdc7 is widely appreciated, the molecular mechanisms through which Cdc7 kinase regulates these various DNA transactions remain largely obscure, including the role of Cdc7-ASK/Dbf4 under replication stress, a condition associated with diverse (patho)physiological scenarios. In this review, we first highlight the recent findings on a novel pathway that regulates the stability of the human Cdc7-ASK/Dbf4 complex under replication stress, its interplay with ATR-Chk1 signaling, and significance in the RAD18-dependent DNA damage bypass pathway. We also consider Cdc7 function in a broader context, considering both physiological conditions and pathologies associated with enhanced replication stress, particularly oncogenic transformation and tumorigenesis. Furthermore, we integrate the emerging evidence and propose a concept of Cdc7-ASK/Dbf4 contributing to genome integrity maintenance, through interplay with RAD18 that can serve as a molecular switch to dictate DNA repair pathway choice. Finally, we discuss the possibility of targeting Cdc7, particularly in the context of the Cdc7/RAD18-dependent translesion synthesis, as a potential innovative strategy for treatment of cancer.
Detection of Lead-Lag Relationships Using Both Time Domain and Time-Frequency Domain; An Application to Wealth-To-Income Ratio

The objective of this paper is the joint application of two different methodological concepts for the detection of lead-lag relationships in economic time-series in order to investigate their consistency and their potential complementarity. The first methodology, a time domain analysis based on vector error correction model, provides evidence about the existence of long-run equilibrium of the time-series and the short-run lead-lag behaviors. The second methodology, a time-frequency concept based on the phase difference of the cross-wavelet coherence, analyzes the lead-lag relationships across various timescales and reveals the altering of leadership over time. The two methods are applied to time-series of wealth-to-income ratio of four developed countries over the period 1970–2010 and analyze the lead-lag relationships of the countries in the long-run and in the short-run. The results show that the two methods are consistent in their major long-run findings, however, they reveal different aspects regarding the short-run dynamics of the lead-lag relationships. Furthermore, the results suggest the complementarity of the two methodologies in the context of a complete framework for the analysis of the lead-lag relationships in non-stationary economic time-series.
Modeling of Solar Flare Plasma and Its Radiation

We present a modular and highly versatile test particle-radiative hydrodynamic code which simultaneously models the particle beam energy transport and deposition, the corresponding explosive response of the flare atmosphere and the NLTE (NLTE, plasma and radiation out of the local thermodynamic equilibrium) radiative transfer for partly ionized hydrogen in the chromosphere and photosphere. The computational domain covers the photosphere, the chromosphere, the transition region, and the corona with the initial hydrostatic preflare atmosphere. To demonstrate the potential of the code, we calculate the time evolution of the Balmer line profiles corresponding to the time variation of the electron beam flux derived from the observed flare hard X-ray emission.
Clinical and therapeutic aspects of diabetic nephropathy.

UNLABELLED The prognosis of renal survival in both type 1 and type 2 diabetes mellitus is not benign. Several factors characterize the increase in the risk of developing renal damage in diabetic patients, distinguished in diabetes-related factors, genetic factors and other factors. DIAGNOSIS Diagnosis requires standard annual urinalysis and dipstick for albumin. In patients with negative urine dipstick, the routine approach is to evaluate the albumin/creatinine ratio (ACR) in the first voided urine. The degree of renal impairment is assessed by an annual evaluation of the glomerular filtration rate (GFR) by the Cockroft/Gault formula in normoalbuminuric patients. In patients with overt nephropathy this evaluation needs to be more frequent. THERAPY A thorough therapeutic approach, in both the early and later stages of diabetic nephropathy, is fundamental because of the increased risk of morbidity and mortality. Renal damage (and the natural history of the disease) is approached on three different levels. Primary prevention, in patients with no clinical and biochemical signs of renal damage, is a strict glycemic control by oral antidiabetic agents or insulin, as required, together with the maintenance of blood pressure (BP) levels < 130/85 mmHg, preferably using ACE-inhibitors. Secondary prevention aims to prevent or slow the progresssion from micro- to macroalbuminuria. BP control is the first-line approach, along with a strict glycemic control. At this stage, it is necessary to use other anti-hypertensive agents besides ACE-inhibitors to achieve optimal BP levels of 130/85 mmHg. Tertiary prevention addresses the reduction in the rate of renal failure progression by optimal BP control, a slightly hypoproteic diet and the control of dyslipidemia, in the presence of a (non-fundamental) euglycemic state. PROMISING NEW TRENDS IN DIABETIC NEPHROPATHY TREATMENT a pharmacological blockade of endothelin and/or sympathetic system, an amelioration of hypoxia by correcting reduced hemoglobin levels, an interference with the formation and accumulation of advanced glycosilation end-products (AGE). Finally, the manipulation of the sex hormone balance, genetic screening for a predisposition to progressive renal dysfunction and, eventually, gene therapy complete the scenario for future approaches to this major complication of diabetic disease.
Melatonin Treatment Entrains the Rest-Activity Circadian Rhythm in Rats With Chronic Inflammation

We assessed the therapeutic effect of exogenous melatonin (MEL), dexamethasone (DEXA), and a combination of both on nociceptive response induced by chronic inflammation and on the rest-activity circadian rhythm in rats. A total of 64 animals were randomly divided into eight groups of eight rats each: one control group and seven groups with complete Freund’s adjuvant–inflamed animals (CFA; injection into the footpad). One of the CFA-inflamed groups did not receive any treatment; the other six were treated with melatonin (MEL), dexamethasone (DEXA), melatonin plus dexamethasone (MELDEXA), and their respective vehicles. Fifteen days after CFA injection, animals were treated with intraperitoneal injection of MEL (50 mg/kg) or its vehicle (8% ethanol in saline), DEXA (0.25 mg/kg) or its vehicle (saline), and MEL plus DEXA or their vehicles, for 8 days. The von Frey test was performed 24 h after the last administration of each treatment regimen. Hind paw thickness was measured using a pachymeter during the treatment days. The degree of swelling and histological findings were analyzed. All treated groups significantly reduced the severity of inflammation when compared with their vehicles (repeated-measures analysis of variance [ANOVA], p < 0.05 for all analyses). Inflamed animals treated with dexamethasone alone or associated with melatonin showed marked inhibition of histological findings. On the other hand, the group treated with melatonin remained with moderate inflammation. The CFA group showed a decrease in the mean rest-activity circadian rhythm, determined by the number of touch-detections per hour during water intake in comparison with the control group; only the group treated with melatonin showed a synchronized rest-activity rhythm. At the end of treatment, a significant increase was observed in hind paw withdrawal threshold on the von Frey test in the treated groups (one-way ANOVA, p < 0.05 for all). Our findings showed that melatonin (50 mg/kg) has strong chronobiotic and antinociceptive effects, but only mild anti-inflammatory effects. This evidence supports the hypothesis that melatonin can induce phase advance and circadian rhythm synchronization in rats with chronic inflammation.
Wideband Interference Mitigation in High-Resolution Airborne Synthetic Aperture Radar Data

Radio frequency interference is a major issue for synthetic aperture radar (SAR) imaging. Especially with the presence of wideband interference (WBI), the signal-to-interference ratio (SIR) of the measurements is greatly degraded, thus making it difficult to produce a high-quality SAR image. Compared with narrow-band interference (NBI), WBI occupies a larger bandwidth and is more complicated to deal with. This paper addresses the detection and mitigation of WBI in high-resolution airborne SAR data. First, a WBI-corrupted echo is characterized in the time-frequency representation by utilizing the short-time Fourier transform. In this way, the original range-spectrum WBI mitigation problem can be simplified into a series of instantaneous-spectrum NBI mitigation problems. For each instantaneous spectrum, the existence of interference signal can be identified according to the negentropy-based statistical test. Furthermore, the interference signal is mitigated by notch filtering or eigensubspace filtering. The experimental results of the simulated data, as well as real measured data sets, show that the proposed scheme is effective in suppressing the interference signal and in obtaining a high-quality image.
Employing volcanic tuff minerals in interior architecture design to reduce microbial contaminants and airborne fungal carcinogens of indoor environments

Indoor volatile organic compounds (VOCs) have posed significant risks to human health since people have both shifted to a life spent, for the most part, indoors. Further, changes in materials used in the construction of buildings, furnishings, and tools either leak or encourage the production of VOCs. Whether these enclosed areas are residences, hospitals or workplaces (specifically composting facilities or closed farm buildings for raising livestock), VOCs can rise to levels that threaten people’s health. VOCs can either originate from phenolic and benzene-like compounds in building materials and office furniture or from molds (fungi) growing inside improperly ventilated or sealed buildings. Regardless of the source, exposure to VOCs could lead to significant health concerns from sick-building syndrome, ‘leukemia houses,’ in-hospital fungemia cases or occupation-associated cancer epidemics due to aflatoxicosis. Innovative 21st-century building materials could offer solutions to these challenges. We propose that volcanic materials, clays and minerals (volcanic tuff, modified clay montmorillonite and mineral clinoptilolite), in their original or chemically modified form, could act like synthetic lungs in building walls, breathing and filtering VOCs, and thus limiting human exposure to disease.
Medication options for treatment-resistant schizophrenia: implications for global mental health financing

Treatment resistance in schizophrenia creates a persistent public health problem and leads to repeated hospitalization. In search for a treatment for such patients, psychiatrists have co-prescribed multiple psychotropic medications simultaneously. Such practice is based mostly on clinical experience, rather than research derived evidence. Such combinations may not be fully “effective” if the cost, adverse effect profile and the potential for noncompliance by patients secondary to regimen complexity are considered. Is it really wise to try these various combinations of costly medicines in the mental health system, which is already struggling with its limited resources and funding worldwide? However, if mental health policy makers restrict reimbursement for such “unproven” combinations, patients might not receive the benefits of some of these combinations, which are showing some promise for the treatment of resistant schizophrenia.
A Dispensable Role for Forespore-Specific Gene Expression in Engulfment of the Forespore during Sporulation ofBacillus subtilis

ABSTRACT During the stage of engulfment in the Bacillus subtilisspore formation pathway, the larger mother cell engulfs the smaller forespore. We have tested the role of forespore-specific gene expression in engulfment using two separate approaches. First, using an assay that unambiguously detects sporangia that have completed engulfment, we found that a mutant lacking the only forespore-expressed engulfment protein identified thus far, SpoIIQ, is able to efficiently complete engulfment under certain sporulation conditions. However, we have found that the mutant is defective, under all conditions, in the expression of the late-forespore-specific transcription factor ςG; thus, SpoIIQ is essential for spore production. Second, to determine if engulfment could proceed in the absence of forespore-specific gene expression, we made use of a strain in which activation of the mother cell-specific sigma factor ςE was uncoupled from forespore-specific gene expression. Remarkably, engulfment occurred in the complete absence of ςF-directed gene expression under the same conditions permissive for engulfment in the absence of SpoIIQ. Our results demonstrate that forespore-specific gene expression is not essential for engulfment, suggesting that the machinery used to move the membranes around the forespore is within the mother cell.
Studying Radiation Therapy Using SEER-Medicare-Linked Data

Background. Numerous studies have used the SEER or Medicare data to assess the use of radiation therapy. However, the completeness of these data has not been evaluated. Methods. Using linked SEER-Medicare data, a cohort was created that included incident cases of breast, endometrial, lung, prostate, or rectal cancer from 1991 to 1996 in persons 65 years and older. For each of these cases, use of radiation therapy as an initial course of treatment reported from the SEER data was compared with use of radiation therapy in the months following diagnosis, as determined from the Medicare claims. Results. Overall, there was a high agreement between SEER and Medicare sources for use of radiation therapy. Agreement was 88% for lung cancer, 93% for prostate cancer, 94% for rectal and breast cancers, and 95% for endometrial cancer. Within the Medicare files, radiation claims were found in MedPAR Physician Supplier Part B and Outpatient files. Conclusions. There is a high level of agreement between SEER and Medicare reporting of radiation treatments after a cancer diagnosis, suggesting that either source can be used to assess radiation-related treatment patterns. However, for the most complete ascertainment of radiation use, both SEER and Medicare sources should be used.
Cell Cycle-dependent Regulation of the Cyclin B1 Promoter (*)

Cyclin B1 mRNA expression varies through the cell cycle with its peak in G/M. In cycling mammalian cells, its lowest level is in G with a steady increase in S until a level 50-fold greater than that in G is reached. In order to characterize the transcriptional component to this variation in expression, we cloned the upstream region 872 base pairs upstream from the start site of the cyclin B1 gene and have demonstrated that it confers cell cycle-dependent regulation onto two reporter genes, both chloramphenicol acetyltransferase and luciferase. Its activity was 25-fold greater in G/M than in G in HeLa cells with intermediate activity in S. This cyclical activity could be seen with sequences encompassing only 90 base pairs upstream from the start site. Protein binding to this region was demonstrated using electrophoretic mobility shift assays, and the binding profiles appeared to vary depending upon the phase of the cycle in which the extracts are made. Thus, transcriptional control plays an important role in determining cyclin B1 mRNA levels, and cell cycle-dependent activity is regulated through interactions with the region 90 bases upstream from the start site.
Increased Protein Stability as a Mechanism That Enhances Nrf2-mediated Transcriptional Activation of the Antioxidant Response Element

Nrf2 (NF-E2-related factor 2) is a central transcription factor involved in the transcriptional activation of many genes encoding phase II drug-metabolizing enzymes via the antioxidant response element. Nrf2 has previously been found to undergo nuclear translocation by a phosphorylation-dependent mechanism mediated by protein kinase C in HepG2 cells treated withtert-butylhydroquinone, β-naphthoflavone, or 12-O-tetradecanoylphorbol-13-acetate. In the present report, we have found that the levels of Nrf2 were increased in cells treated with tert-butylhydroquinone or β-naphthoflavone by a post-transcriptional mechanism. Treatment of HepG2 cells with cycloheximide resulted in the loss of Nrf2 within 30 min. By contrast, treatment with the proteasome inhibitors (lactacystin or MG-132) caused an accumulation of Nrf2 as well as an induction of reporter gene activity in cells transfected with theGSTA2 antioxidant response element-chloramphenicol acetyl transferase construct. Similarly, the protein phosphatase inhibitor okadaic acid also caused an accumulation of Nrf2, whereas the reverse effects were observed with PD 98059 and U 0126, two compounds that block the activation of the MAPK/ERK signaling cascade. These data suggest that Nrf2 is degraded by the ubiquitin-dependent pathway and that phosphorylation of Nrf2 leads to an increase in its stability and subsequent transactivation activity.
Rapid detection of 17p11.2 rearrangements by FISH without cell culture (direct FISH, DFISH): A prospective study of 130 patients with inherited peripheral neuropathies

Charcot‐Marie‐Tooth (CMT) disease and hereditary neuropathy with pressure palsies (HNPP) are two frequent hereditary motor and sensory neuropathies. CMT is characterized by slowly progressive weakness and atrophy, primarily in peroneal and distal leg muscles. The most frequent form, CMT1A, is due, in most cases, to the duplication of a 1.5 Mb region on chromosome 17p11.2 containing the peripheral myelin protein 22 gene (PMP22). The phenotype seems to result from dosage of the PMP22 gene. This hypothesis is reinforced by the existence of HNPP, which is clinically characterized by various recurrent truncular palsies or sensory loss precipitated by minor trauma, which is caused by deletion of the same 1.5 Mb region in 17p11.2. In clinical practice, the detection of the duplication or the deletion in 17p11.2, which permits a positive diagnosis, is still performed by time consuming methods (Southern blot or various combinations of molecular tools). We developed a method for the rapid detection of 17p11.2 rearrangements, using “direct FISH” and PRINS analyses, which does not require cell culture. In a prospective study of 92 patients with CMT and 38 with suspected HNPP, we compared this new technique to classical strategies like Southern blot. The results demonstrate the high sensitivity and specificity of the new FISH technique for the diagnosis of CMT1A and HNPP. Moreover, because of its simplicity and rapidity, this technique provides a useful alternative to the molecular approaches that have been used to diagnose segmental aneusomies, especially in the case of duplications that often go undetected. © 2003 Wiley‐Liss, Inc.
NIH/Ola: a highly productive inbred strain of laboratory mouse

According to historical records the NIH/Ola strain was developed from outbred 'Swiss' mice imported into the USA by Dr C. Lynch in 1926. A comparison of biochemical markers in strain NIH/Ola and other strains such as SJL and SWR derived from the same foundation stock supports the historical records. Data on litter size, length of gestation, bodyweight to 70 days of age, and reproductive performance when housed in polygamous groups of up to 10 females per male were compared with similar data on inbred CBA/CaOla and CS7BL/10ScSnOla mice. NIH/Ola inbred mice had an exceptional reproductive performance, producing about 1·8 young weaned/female/week when housed as monogamous pairs over a period of 20 weeks, compared with less than 1·0 young/female/week with the other 2 strains. NIH/Ola mice were also extremely tolerant to mating in polygamous groups of up to about 8 females per male. Mating ratios of over 2-3 females per male resulted in a marked decline in the total number of litters produced per female in C57BL/10ScSnOla and CBA/CaOla, but this reduction was not nearly so marked in NIH/Ola. It is concluded that the NIH/Ola inbred strain may be particularly useful in studies such as teratology where a high reproductive performance needs to be combined with the advantages of a fully inbred strain.