Miracle-dz/UniFAR-FTUs huggingface dataset:
p53 Protein Expression in Chronic Myelomonocytic Leukemia-1 Correlates with Progression to Leukemia and a Poor Prognosis

CMML-1 is controversial. Herein, we performed a retrospective study of the clinical features of patients with CMML-1 in a single institution. In our institution, 20 patients with CMML-1 reclassified retrospectively based on the WHO (2008) criteria and diagnosed as having CMML based on the FAB or WHO (2001) classification were included in this study. Rearrangement of PDGFRA or PDGFRB was excluded in case of eosinophilia. Our series excluded cases of secondary CMML associated with therapy-related MDS/AML. Patients were followed up from 1996 to 2008. Mutational analysis was performed on DNA from BM cells from the study participants. All samples were obtained with informed consent, and the protocols were approved by our institution’s ethics committee. The clinical characteristics and laboratory data were determined by a review of medical records. Laboratory and physical examination data of all patients were obtained at diagnosis. BM aspiration and biopsy samples were taken and analyzed at diagnosis and at the time of transformation to AML. Chromosomal analyses of BM cells were performed by G-banding techniques. Hydroxyurea was used as a cytoreductive drug in some of the CMML patients. After the Chronic myelomonocytic leukemia (CMML) is characterized by persistent monocytosis and by features of a myeloproliferative neoplasm and a myelodysplastic syndrome (MDS). CMML is subdivided into CMML-1, with
Magnetic Structure of Sunspots

In this review we give an overview about the current state-of-knowledge of the magnetic field in sunspots from an observational point of view. We start by offering a brief description of tools that are most commonly employed to infer the magnetic field in the solar atmosphere with emphasis in the photosphere of sunspots. We then address separately the global and local magnetic structure of sunspots, focusing on the implications of the current observations for the different sunspots models, energy transport mechanisms, extrapolations of the magnetic field towards the corona, and other issues.
Cardiac function in an endothermic fish: cellular mechanisms for overcoming acute thermal challenges during diving

Understanding the physiology of vertebrate thermal tolerance is critical for predicting how animals respond to climate change. Pacific bluefin tuna experience a wide range of ambient sea temperatures and occupy the largest geographical niche of all tunas. Their capacity to endure thermal challenge is due in part to enhanced expression and activity of key proteins involved in cardiac excitation–contraction coupling, which improve cardiomyocyte function and whole animal performance during temperature change. To define the cellular mechanisms that enable bluefin tuna hearts to function during acute temperature change, we investigated the performance of freshly isolated ventricular myocytes using confocal microscopy and electrophysiology. We demonstrate that acute cooling and warming (between 8 and 28°C) modulates the excitability of the cardiomyocyte by altering the action potential (AP) duration and the amplitude and kinetics of the cellular Ca2+ transient. We then explored the interactions between temperature, adrenergic stimulation and contraction frequency, and show that when these stressors are combined in a physiologically relevant way, they alter AP characteristics to stabilize excitation–contraction coupling across an acute 20°C temperature range. This allows the tuna heart to maintain consistent contraction and relaxation cycles during acute thermal challenges. We hypothesize that this cardiac capacity plays a key role in the bluefin tunas' niche expansion across a broad thermal and geographical range.
What can vasculitic leg ulcers implicate?

Dear Editors, A 76-year-old woman presented with multiple irregular necrotic leg ulcers surrounded by palpable purpurae on the right leg, persisting for 2 years (Figure 1). Three years before, her left leg was amputated because of ulceration and concomitant septicemia. The patient had pallor, xerostomy, xerophthalmia, distal limb numbness without parotido-, lymphadenoor hepatomegaly. Haematoxylin–eosin-stained sections of the ulcer showed leucocytoclastic vasculitis with erythrocyte extravasation; direct immunofluorescence showed granular IgG and complement factor 3 depositions. Laboratory tests showed marked hypoproteinaemia, hypoalbuminaemia, elevated erythrocyte sedimentation rate, mild pancytopenia, high carbamide, creatinine, uric acid and C-reactive protein levels. Proteinuria, microscopic haematuria, granular, hyalin and cell cylinders suggested glomerular involvement. Autoimmune serology found positive anti-nuclear antibody, a robust elevation of anti-SS-A and rheumatoid factor and a moderate increase in anti-SS-B levels. Cryoprecipitation showed massive cryoglobulinaemia. Immunofixation electrophoresis detected non-quantifiable IgMκ biclonal and IgMλ monoclonal bands, and serum-free light chain assay showed very high κ level and abnormal κ:λ ratio (Table 1). Review of CT images revealed splenomegaly, but no lytic bone lesions related to multiple myeloma. Ultrasound and CT examinations showed bilateral parenchymal atrophy of the kidneys. Bone marrow trephine biopsy revealed discrete interstitial B-cell population suggestive of indolent B-cell lymphoproliferation, but no evidences of B-cell monoclonality was detected by PCR-based immunoglobulin heavy chain gene rearrangement analysis.
DNA Methylation: Insights into Human Evolution

A fundamental initiative for evolutionary biologists is to understand the molecular basis underlying phenotypic diversity. A long-standing hypothesis states that species-specific traits may be explained by differences in gene regulation rather than differences at the protein level. Over the past few years, evolutionary studies have shifted from mere sequence comparisons to integrative analyses in which gene regulation is key to understanding species evolution. DNA methylation is an important epigenetic modification involved in the regulation of numerous biological processes. Nevertheless, the evolution of the human methylome and the processes driving such changes are poorly understood. Here, we review the close interplay between Cytosine-phosphate-Guanine (CpG) methylation and the underlying genome sequence, as well as its evolutionary impact. We also summarize the latest advances in the field, revisiting the main literature on human and nonhuman primates. We hope to encourage the scientific community to address the many challenges posed by the field of comparative epigenomics.
Study of Natural Fiber Breakage during Composite Processing

Biofiber-thermoplastic composites have gained considerable importance in the last century. To provide mechanical reinforcement to the polymer, fibers must be larger than a critical aspect ratio (length-to-width ratio). However, biofibers undergo breakage in length or width during processing, affecting their final aspect ratio in the composites. In this study, influence on biofiber breakage by factors related to processing conditions, fiber morphology and the flow type was investigated through: a) experiments using an internal mixer, a twin-screw extruder (TSE) or a capillary rheometer; and b) a Monte Carlo computer simulation. Composites of thermomechanical fibers of aspen or wheat straw mixed with polypropylene were studied. Internal mixer experiments analyzed wheat straw and two batches of aspen fibers, named AL and AS. AL fibers had longer average length. Processing variables included the temperature, rotors speed and fiber concentration. TSE experiments studied AL and AS fiber composites under various screws speeds, temperatures and feeding rates of the polymer and fibers. Capillary rheometers experiments determined AL fiber breakage in shear and elongational flows for composites processed at different
Different Populations of Blacklegged Tick Nymphs Exhibit Differences in Questing Behavior That Have Implications for Human Lyme Disease Risk

Animal behavior can have profound effects on pathogen transmission and disease incidence. We studied the questing (= host-seeking) behavior of blacklegged tick (Ixodes scapularis) nymphs, which are the primary vectors of Lyme disease in the eastern United States. Lyme disease is common in northern but not in southern regions, and prior ecological studies have found that standard methods used to collect host-seeking nymphs in northern regions are unsuccessful in the south. This led us to hypothesize that there are behavior differences between northern and southern nymphs that alter how readily they are collected, and how likely they are to transmit the etiological agent of Lyme disease to humans. To examine this question, we compared the questing behavior of I. scapularis nymphs originating from one northern (Lyme disease endemic) and two southern (non-endemic) US regions at field sites in Wisconsin, Rhode Island, Tennessee, and Florida. Laboratory-raised uninfected nymphs were monitored in circular 0.2 m2 arenas containing wooden dowels (mimicking stems of understory vegetation) for 10 (2011) and 19 (2012) weeks. The probability of observing nymphs questing on these stems (2011), and on stems, on top of leaf litter, and on arena walls (2012) was much greater for northern than for southern origin ticks in both years and at all field sites (19.5 times greater in 2011; 3.6–11.6 times greater in 2012). Our findings suggest that southern origin I. scapularis nymphs rarely emerge from the leaf litter, and consequently are unlikely to contact passing humans. We propose that this difference in questing behavior accounts for observed geographic differences in the efficacy of the standard sampling techniques used to collect questing nymphs. These findings also support our hypothesis that very low Lyme disease incidence in southern states is, in part, a consequence of the type of host-seeking behavior exhibited by southern populations of the key Lyme disease vector.
Lipoprotein(a) in Familial Hypercholesterolemia With Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) Gain-of-Function Mutations.

BACKGROUND It has been shown that serum lipoprotein(a) [Lp(a)] is elevated in familial hypercholesterolemia (FH) with mutation(s) of the LDL receptor (LDLR) gene. However, few data exist regarding Lp(a) levels in FH with gain-of-function mutations of the PCSK9 gene. METHODSANDRESULTS We evaluated 42 mutation-determined heterozygous FH patients with aPCSK9gain-of-function mutation (FH-PCSK9, mean age 52, mean LDL-C 235 mg/dl), 198 mutation-determined heterozygous FH patients with aLDLRmutation (FH-LDLR, mean age 44, mean LDL-C 217 mg/dl), and 4,015 controls (CONTROL, mean age 56, mean LDL-C 109 mg/dl). We assessed their Lp(a), total cholesterol, triglycerides, HDL-C, LDL-C, use of statins, presence of hypertension, diabetes, chronic kidney disease, smoking, body mass index (BMI) and coronary artery disease (CAD). Multiple regression analysis showed that HDL-C, use of statins, presence of hypertension, smoking, BMI, and Lp(a) were independently associated with the presence of CAD. Under these conditions, the serum levels of Lp(a) in patients with FH were significantly higher than those of the CONTROL group regardless of their causative genes, among the groups propensity score-matched (median Lp(a) 12.6 mg/dl [IQR:9.4-33.9], 21.1 mg/dl [IQR:11.7-34.9], and 5.0 mg/dl [IQR:2.7-8.1] in the FH-LDLR, FH-PCSK9, and CONTROL groups, respectively, P=0.002 for FH-LDLR vs. CONTROL, P=0.002 for FH-PCSK9 vs. CONTROL). CONCLUSIONS These data demonstrate that serum Lp(a) is elevated in patients with FH caused by PCSK9 gain-of-function mutations to the same level as that in FH caused by LDLR mutations.
Robots As Intentional Agents: Using Neuroscientific Methods to Make Robots Appear More Social

Robots are increasingly envisaged as our future cohabitants. However, while considerable progress has been made in recent years in terms of their technological realization, the ability of robots to interact with humans in an intuitive and social way is still quite limited. An important challenge for social robotics is to determine how to design robots that can perceive the user’s needs, feelings, and intentions, and adapt to users over a broad range of cognitive abilities. It is conceivable that if robots were able to adequately demonstrate these skills, humans would eventually accept them as social companions. We argue that the best way to achieve this is using a systematic experimental approach based on behavioral and physiological neuroscience methods such as motion/eye-tracking, electroencephalography, or functional near-infrared spectroscopy embedded in interactive human–robot paradigms. This approach requires understanding how humans interact with each other, how they perform tasks together and how they develop feelings of social connection over time, and using these insights to formulate design principles that make social robots attuned to the workings of the human brain. In this review, we put forward the argument that the likelihood of artificial agents being perceived as social companions can be increased by designing them in a way that they are perceived as intentional agents that activate areas in the human brain involved in social-cognitive processing. We first review literature related to social-cognitive processes and mechanisms involved in human–human interactions, and highlight the importance of perceiving others as intentional agents to activate these social brain areas. We then discuss how attribution of intentionality can positively affect human–robot interaction by (a) fostering feelings of social connection, empathy and prosociality, and by (b) enhancing performance on joint human–robot tasks. Lastly, we describe circumstances under which attribution of intentionality to robot agents might be disadvantageous, and discuss challenges associated with designing social robots that are inspired by neuroscientific principles.
Theta and High-Frequency Activity Mark Spontaneous Recall of Episodic Memories

Humans possess the remarkable ability to search their memory, allowing specific past episodes to be re-experienced spontaneously. Here, we administered a free recall test to 114 neurosurgical patients and used intracranial theta and high-frequency activity (HFA) to identify the spatiotemporal pattern of neural activity underlying spontaneous episodic retrieval. We found that retrieval evolved in three electrophysiological stages composed of: (1) early theta oscillations in the right temporal cortex, (2) increased HFA in the left hemisphere including the medial temporal lobe (MTL), left inferior frontal gyrus, as well as the ventrolateral temporal cortex, and (3) motor/language activation during vocalization of the retrieved item. Of these responses, increased HFA in the left MTL predicted recall performance. These results suggest that spontaneous recall of verbal episodic memories involves a spatiotemporal pattern of spectral changes across the brain; however, high-frequency activity in the left MTL represents a final common pathway of episodic retrieval.
FDA Approval: Ado-Trastuzumab Emtansine for the Treatment of Patients with HER2-Positive Metastatic Breast Cancer

On February 22, 2013, the FDA licensed ado-trastuzumab emtansine (Kadcyla; Genentech, Inc.) for use as a single agent for the treatment of patients with human epidermal growth factor receptor 2 (HER2)–positive metastatic breast cancer (MBC) who previously received trastuzumab and a taxane, separately or in combination. The clinical basis for licensure was a phase III trial in 991 patients with HER2-positive MBC that randomly allocated patients to receive ado-trastuzumab emtansine (n = 495) or lapatinib in combination with capecitabine (n = 496). The coprimary endpoints were progression-free survival (PFS) based on tumor assessments by an independent review committee and overall survival (OS). Statistically significant improvements in PFS and OS were observed in patients receiving ado-trastuzumab emtansine compared with patients receiving lapatinib plus capecitabine [difference in PFS medians of 3.2 months, HR, 0.65 (95% confidence interval, CI, 0.55–0.77), P < 0.0001 and difference in OS medians of 5.8 months, HR, 0.68 (95% CI, 0.55–0.85), P = 0.0006]. The most common adverse reactions in patients receiving ado-trastuzumab emtansine were fatigue, nausea, musculoskeletal pain, thrombocytopenia, headache, increased aminotransferase levels, and constipation. Other significant adverse reactions included hepatobiliary disorders and left ventricular dysfunction. Given the PFS and OS results, the benefit–risk profile was considered favorable. Clin Cancer Res; 20(17); 4436–41. ©2014 AACR.
Analysis of marginal seal of ProRoot MTA, MTA Angelus biodentine, and glass ionomer cement as root-end filling materials: An in vitro study

Background: Search for a root-end filling material fulfilling all the ideal characteristics is an ongoing process. The present study aimed to evaluate the marginal seal of the following materials when used as root-end filling materials, MTA Angelus, White ProRoot MTA, Biodentine and Glass ionomer cement (GIC). Materials and Methods: Sixty single-rooted maxillary central incisors were included in the study. The crowns were resected followed by cleaning and shaping with hand files and protaper rotary files followed by obturation of the roots. The root ends were resected at 3 mm level. Then, root-end cavity preparation of 3 mm depth was done using ultrasonic tips. The samples were randomly divided into four groups of 15 each and cavities restored with, such as (1) Group 1: MTA Angelus, (2) Group 2: ProRoot MTA, (3) Group 3: Biodentine, and (4) Group 4: GIC. The root samples were coated with two coats of nail varnish and immersed in methylene blue dye 2% for 48 h. Longitudinal root resection was done. The depth of dye penetration was evaluated under the stereomicroscope to examine the extent of microleakage. The amount of dye penetration was measured in millimeters. The results were then statistically analyzed using one-way analysis of variance and post-hoc Tukey′s test. Conclusion: Microleakage was present in all the samples. Least amount of apical dye microleakage was seen in biodentine with mean value of 0.16 mm followed by ProRoot MTA 0.68 mm, MTA Angelus 0.74 mm, and GIC 1.53 mm. The best sealing ability was seen in biodentine, and this difference was statistically significant.
Invasive Cyprinid Fish in Europe Originate from the Single Introduction of an Admixed Source Population Followed by a Complex Pattern of Spread

The Asian cyprinid fish, the topmouth gudgeon (Pseudorasbora parva), was introduced into Europe in the 1960s. A highly invasive freshwater fish, it is currently found in at least 32 countries outside its native range. Here we analyse a 700 base pair fragment of the mitochondrial cytochrome b gene to examine different models of colonisation and spread within the invasive range, and to investigate the factors that may have contributed to their invasion success. Haplotype and nucleotide diversity of the introduced populations from continental Europe was higher than that of the native populations, although two recently introduced populations from the British Isles showed low levels of variability. Based on coalescent theory, all introduced and some native populations showed a relative excess of nucleotide diversity compared to haplotype diversity. This suggests that these populations are not in mutation-drift equilibrium, but rather that the relative inflated level of nucleotide diversity is consistent with recent admixture. This study elucidates the colonisation patterns of P. parva in Europe and provides an evolutionary framework of their invasion. It supports the hypothesis that their European colonisation was initiated by their introduction to a single location or small geographic area with subsequent complex pattern of spread including both long distance and stepping-stone dispersal. Furthermore, it was preceded by, or associated with, the admixture of genetically diverse source populations that may have augmented its invasive-potential.
Spinal excitability is increased in the torque-depressed isometric steady state following active muscle shortening

Torque depression (TD) is the reduction in steady-state isometric torque following active muscle shortening when compared with a purely isometric contraction at the same muscle length and level of activation. The purpose of the present study was to assess spinal and supraspinal excitability in the TD state during submaximal contractions of the dorsiflexors. Eleven young (24 ± 2 yrs) males performed 16 contractions at a constant level of electromyographic activity (40% of maximum). Half of the contractions were purely isometric (8 s at an ankle angle of 100°), whereas the other half induced TD (2 s isometric at 140°, a 1 s shortening phase at 40° s−1 and 5 s at 100°). Motor evoked potentials (MEPs), cervicomedullary motor evoked potentials (CMEPs) and compound muscle action potentials (M-waves) were recorded from tibialis anterior during the TD steady-state and purely isometric contractions. When compared with values in the purely isometric condition, following active shortening, there was a 13% decrease in torque (p < 0.05), with a 10% increase in normalized CMEP amplitude (CMEP/Mmax) (p < 0.05) and no change in normalized MEP amplitude (MEP/CMEP) in the TD state (p > 0.05). These findings indicate that during voluntary contractions in the TD state, the history-dependent properties of muscle can increase spinal excitability and influence voluntary control of submaximal torque production.
Estimating Long-Term Survival Temperatures at the Assemblage Level in the Marine Environment: Towards Macrophysiology

Defining ecologically relevant upper temperature limits of species is important in the context of environmental change. The approach used in the present paper estimates the relationship between rates of temperature change and upper temperature limits for survival in order to evaluate the maximum long-term survival temperature (Ts). This new approach integrates both the exposure time and the exposure temperature in the evaluation of temperature limits. Using data previously published for different temperate and Antarctic marine environments, we calculated Ts in each environment, which allowed us to calculate a new index: the Warming Allowance (WA). This index is defined as the maximum environmental temperature increase which an ectotherm in a given environment can tolerate, possibly with a decrease in performance but without endangering survival over seasonal or lifetime time-scales. It is calculated as the difference between maximum long-term survival temperature (Ts) and mean maximum habitat temperature. It provides a measure of how close a species, assemblage or fauna are living to their temperature limits for long-term survival and hence their vulnerability to environmental warming. In contrast to data for terrestrial environments showing that warming tolerance increases with latitude, results here for marine environments show a less clear pattern as the smallest WA value was for the Peru upwelling system. The method applied here, relating upper temperature limits to rate of experimental warming, has potential for wide application in the identification of faunas with little capacity to survive environmental warming.
Controlling molecular transport through nanopores

Nanopores are emerging as powerful tools for the detection and identification of macromolecules in aqueous solution. In this review, we discuss the recent development of active and passive controls over molecular transport through nanopores with emphasis on biosensing applications. We give an overview of the solutions developed to enhance the sensitivity and specificity of the resistive-pulse technique based on biological and solid-state nanopores.