Miracle-dz/UniFAR-FTUs huggingface dataset:
Myeloma bone disease: pathogenesis, current treatments and future targets.

INTRODUCTION Patients with myeloma develop localized and generalized bone loss leading to hypercalcaemia, accelerated osteoporosis, vertebral wedge fractures, other pathological fractures, spinal cord compression and bone pain. Bone loss is mediated by a variety of biological modifiers including osteoclast-activating factors (OAF) and osteoblast (OB) inhibitory factors produced either directly by malignant plasma cells (MPCs) or as a consequence of their interaction with the bone marrow microenvironment (BMM). Raised levels of OAFs such as receptor activator of nuclear factor-kappa B ligand (RANKL), macrophage inflammatory protein 1 alpha, tumour necrosis factor-alpha and interleukin 6 stimulate bone resorption by recruiting additional osteoclasts. Via opposing mechanisms, increases in OB inhibitory factors, such as dickkopf-1 (Dkk-1), soluble frizzled-related protein-3 and hepatocyte growth factor (HGF), suppress bone formation by inhibiting the differentiation and recruitment of OBs. These changes result in an uncoupling of physiological bone remodelling, leading to myeloma bone disease (MBD). Moreover, the altered BMM provides a fertile ground for the growth and survival of MPCs. Current clinical management of MBD is both reactive (to pain and fractures) and preventive, with bisphosphonates (BPs) being the mainstay of pharmacological treatment. However, side effects and uncertainties associated with BPs warrant the search for more targeted treatments for MBD. This review will summarize recent developments in understanding the intimate relationship between MBD and the BMM and the novel ways in which they are being therapeutically targeted. SOURCES OF DATA All data included were sourced and referenced from PubMed. AREAS OF AGREEMENT The clinical utility of BP therapy is well established. However, there is general acknowledgement that BPs are only partially successful in the treatment of MBD. The number of skeletal events attributable to myeloma are reduced by BPs but not totally eliminated. Furthermore, existing damage is not repaired. It is widely recognized that more effective treatments are needed. AREAS OF CONTROVERSY There remains controversy concerning the duration of BP therapy. Whether denosumab is a viable alternative to BP therapy is also contested. Many of the new therapeutic strategies discussed are yet to translate to clinical practice and demonstrate equal efficacy or superiority to BP therapy. It also remains controversial whether reported anti-tumour effects of bone-modulating therapies are clinically significant. GROWING POINTS The potential clinical utility of bone anabolic therapies including agents such as anti-Dkk-1, anti-sclerostin and anti-HGF is becoming increasingly recognized. AREAS TIMELY FOR DEVELOPING RESEARCH Further research effectively targeting the mediators of MBD, targeting both bone resorption and bone formation, is urgently needed. This should translate promptly to clinical trials of combination therapy comprising anti-resorptives and bone anabolic therapies to demonstrate efficacy and improved outcomes over BPs.
The Effect of Short-Term Epidural Local Anesthetic Blockade on Urinary Levels of Substance P in Interstitial Cystitis

We investigated the effect of epidural local anesthetic blockade on urinary substance P levels in five patients suffering from painful flare-ups of interstitial cystitis. Urine was collected in 24-h intervals commencing at the onset of an epidural bolus of 0.25% bupivacaine followed by maintenance epidural infusions of 0.05% bupivacaine. Substance P was measured by radioimmunoassay. After initiation of the epidural infusion, urinary substance P levels increased and then declined in all patients. All patients reported a decrease in pain intensity. We hypothesize that acute release, followed by depletion, of substance P from bladder sensory nerve endings accounts for the transient increase of peptide levels in urine and may contribute to the decrease in pain intensity during a 3-day epidural infusion.
An application of topological multiple recurrence to tiling

We show that given any tiling of Euclidean space, any geometric pattern of points, we can find a patch of tiles (of arbitrarily large size) so that copies of this patch appear in the tiling nearly centered on a scaled and translated version of the pattern. The rather simple proof uses Furstenberg's topological multiple recurrence theorem.
Spatial distribution of regeneration patches in an old-growth Pinus jeffreyi-mixed conifer forest in northwestern Mexico

Abstract Question: What are the shape, abundance, size, and structural characteristics of sapling patches in an old-growth Pinus jeffreyi-mixed conifer forest with a relatively intact disturbance regime? Location: Sierra San Pedro Martir, Baja California, Mexico. Methods: Regeneration was quantified by sampling sapling patches on seven 1200 m permanently marked line transects. For all patches intersected, tree size, species, age, and patch canopy cover were recorded. Patch structural characteristics were statistically compared to data from unbiased forest inventory plots. The minimum regeneration patch was defined as three saplings in a 49-m2 area. Results: We sampled 54 sapling regeneration patches. Patch size varied from 6.6 to 674.8 m2. A small portion of the forest was in patches (patch fraction = 3.8%, patch abundance = 8.5 per ha). The majority of the patches were small; 64.8% were less than the mean patch area of 100.1 m2. Patches were shaped as a rhombus. For all forest characteristics, mean values inside patches were significantly different than those from the unbiased forest inventory plots. Conclusions: These forests have a fine-grained pattern of regeneration patches. Our largest patch size of 674.8 m2 is the smallest reported in Pinus jeffreyi, P. ponderosa, and mixed conifer forests; other studies have probably had more difficulty delineating regeneration patches because of forest ingrowth from fire exclusion. Frequent fire, irregular seed crops, and seed dispersal by small mammals and birds could create this regeneration patch regime. High variation in nutrient availability after fire could also contribute to increased stand patchiness. Nomenclature: Hickman (1993) for vascular plants; Kays & Wilson (2002) for mammals. Abbreviation: Pj-mc = Pinus jeffreyi-mixed conifer; SSPM = Sierra San Pedro Martir.
Somatic Genome Variations in Health and Disease

It is hard to imagine that all the cells of the human organism (about 1014) share identical genome. Moreover, the number of mitoses (about 1016) required for the organism’s development and maturation during ontogeny suggests that at least a proportion of them could be abnormal leading, thereby, to large-scale genomic alterations in somatic cells. Experimental data do demonstrate such genomic variations to exist and to be involved in human development and interindividual genetic variability in health and disease. However, since current genomic technologies are mainly based on methods, which analyze genomes from a large pool of cells, intercellular or somatic genome variations are significantly less appreciated in modern bioscience. Here, a review of somatic genome variations occurring at all levels of genome organization (i.e. DNA sequence, subchromosomal and chromosomal) in health and disease is presented. Looking through the available literature, it was possible to show that the somatic cell genome is extremely variable. Additionally, being mainly associated with chromosome or genome instability (most commonly manifesting as aneuploidy), somatic genome variations are involved in pathogenesis of numerous human diseases. The latter mainly concerns diseases of the brain (i.e. autism, schizophrenia, Alzheimer’s disease) and immune system (autoimmune diseases), chromosomal and some monogenic syndromes, cancers, infertility and prenatal mortality. Taking into account data on somatic genome variations and chromosome instability, it becomes possible to show that related processes can underlie non-malignant pathology such as (neuro)degeneration or other local tissue dysfunctions. Together, we suggest that detection and characterization of somatic genome behavior and variations can provide new opportunities for human genome research and genetics.
Experimental investigation of reinforced concrete slabs with punching shear reinforcement

Over the past century, the use of flat slabs in buildings and especially in parking garages has been growing as it is an economic and efficient solution. Flat slabs are easy to build and have, through their smaller depth, an economical and architectural advantage compared to slabs on girders. Because of their limited depth, flat slabs are especially sensitive to deflections and to punching shear, which are their main design criteria. Furthermore, flat slabs without punching shear reinforcement have a rather brittle failure mode with little deformation capacity. This behavior potentially limits the redistribution of the internal forces in flat slabs in the case of punching of an isolated column and can thus lead to progressive collapse of the entire structure. To increase both the strength and the deformation capacity of flat slabs, punching shear reinforcement can be provided in the vicinity of the columns. Although the influence of punching shear reinforcement on the strength of flat slabs has been intensively investigated, there are still fundamental uncertainties such as the contribution of the shear reinforcement and the strength of the concrete struts close to the column. The paper presents the results of an extensive experimental campaign performed at the Ecole Polytechnique Federale de Lausanne (EPFL). Sixteen full-scale slab specimens (3.0 x 3.0 m in plane) with varying parameters such as the column size, the slab thickness, the shear reinforcement ratio, and the shear reinforcing system have been investigated. The performance of these specimens is analyzed and compared to modern design codes and to the critical shear crack theory.
Effect of a universal anxiety prevention programme (FRIENDS) on children's academic performance: results from a randomised controlled trial

Background Evaluations of school‐based anxiety prevention programmes have reported improvements in psychological functioning although little is known about their effect upon educational outcomes. Methods One thousand three hundred and sixty‐two children from 40 primary schools in England took part in the randomised controlled trial, Preventing Anxiety in Children through Education in Schools. The trial investigated the effectiveness of a universal school‐based cognitive behaviour therapy prevention programme, FRIENDS, delivered by health care staff or school staff compared with usual personal, social, health and education (PSHE) lessons. Self‐report psychological outcomes and educational attainment on national standardised attainment tests in reading, writing and maths were collected 12 months postintervention. Analysis was performed at individual level using multivariable mixed effect models controlling for gender, type of intervention and school effect. Registered trial: ISRCTN: 23563048. Results At 12 months, anxiety reduced in the health‐led FRIENDS group compared to school‐led FRIENDS and PSHE. There were no between‐group differences in academic performance regardless of gender, deprivation, ethnicity and additional educational needs. Conclusions School‐based mental health interventions should assess psychological and educational outcomes. Further research should directly compare the effects of interventions led by health and school staff.
SIZE OF THE VELA PULSAR'S EMISSION REGION AT 18 cm WAVELENGTH

We present measurements of the linear diameter of the emission region of the Vela pulsar at observing wavelength λ = 18 cm. We infer the diameter as a function of pulse phase from the distribution of visibility on the Mopra–Tidbinbilla baseline. As we demonstrate, in the presence of strong scintillation, finite size of the emission region produces a characteristic W-shaped signature in the projection of the visibility distribution onto the real axis. This modification involves heightened probability density near the mean amplitude, decreased probability to either side, and a return to the zero-size distribution beyond. We observe this signature with high statistical significance, as compared with the best-fitting zero-size model, in many regions of pulse phase. We find that the equivalent FWHM of the pulsar's emission region decreases from more than 400 km early in the pulse to near zero at the peak of the pulse and then increases again to approximately 800 km near the trailing edge. We discuss possible systematic effects and compare our work with previous results.
Public Opinion and Executive Compensation

We investigate whether public opinion influences the level and structure of executive compensation. During 1992--2008, the negativity of press coverage of chief executive officer (CEO) pay varied significantly, with stock options being the most criticized pay component. We find that after more negative press coverage of CEO pay, firms reduce option grants and increase less contentious types of pay such as salary, although overall compensation does not change. The reduction in option pay after increased press negativity is more pronounced when firms, CEOs, and boards have stronger reputation concerns. Our within-firm, within-year identification shows the results cannot be explained by annual changes in accounting rules regarding executive compensation, stock market conditions, or pay mean reversion. This paper was accepted by Brad Barber, finance.
K-means with Three different Distance Metrics

power of k-means algorithm is due to its computational efficiency and the nature of ease at which it can be used. Distance metrics are used to find similar data objects that lead to develop robust algorithms for the data mining functionalities such as classification and clustering. In this paper, the results obtained by implementing the k-means algorithm using three different metrics Euclidean, Manhattan and Minkowski distance metrics along with the comparative study of results of basic k-means algorithm which is implemented through Euclidian distance metric for two- dimensional data, are discussed. Results are displayed with the help of histograms.
Intracellular ATP activates inwardly rectifying K+ channels in human and monkey retinal Müller (glial) cells.

1. In the vertebrate retina, the inwardly rectifying K+ (KIR) channels of the Müller (glial) cells are pathways for the redistribution of excess extracellular K+. Due to this role in K+ homeostasis, the activity of Müller cell KIR channels is likely to have significant functional consequences for the retina. In this study we asked whether intracellular ATP regulates the function of KIR channels expressed by Müller cells, the principal glia of the retina. 2. Freshly dissociated Müller cells from the human and monkey (Macaca fascicularis) retina were studied with various configurations of the patch‐clamp technique. 3. Whole‐cell recordings from Müller cells revealed that a run‐down of the inwardly rectifying K+ current (IK(IR)) was prevented if the pipette solution contained Mg‐ATP. Chemical ischaemia induced by inhibitors of glycolysis and oxidative phosphorylation caused a nearly 10‐fold reduction in the IK(IR)) that was fully restored when metabolically inhibited Müller cells were internally perfused with ATP. 4. In recordings from membrane patches of fresh primate Müller cells, we found that inward‐rectifying channels with a conductance of 20 pS in 100 mM Ko+ were the predominant type of KIR channel. In excised patches these 20 pS KIR channels were activated when Mg‐ATP was at the cytoplasmic surface. Experiments with inside‐out patches indicated that the activity of the 20 pS KIR channels can be maintained by ATP synthesized at sites located close to the channel. 5. The inability of the non‐hydrolysable ATP analogue 5'‐adenylylimidodiphosphate (AMP‐PNP) to prevent the run‐down of IK(IR))and the Mg2+ dependence of the ATP effect on KIR channels are consistent with a mechanism of activation requiring the hydrolysis of ATP. 6. These observations suggest that the metabolic state of a Müller cell regulates the activity of its 20 pS KIR channels and thus influences the function of the glial cell in maintaining K+ homeostasis in the retina.
Do they know how hard I work? Investigating how implicit/explicit achievement orientation, reputation, and political skill affect occupational status

ABSTRACT Researchers have yet to precisely test the Socioanalytic proposition that social skill moderates the personality identity–personality reputation relationship. Further, although research has found personality to have both explicit and implicit aspects, scholars have not examined these differences with respect to the Socioanalytic perspective on personality. The present study investigates how explicit and implicit achievement orientation identities relate to one’s reputation for that trait in the workplace and to career success, as measured by occupational status. We propose that explicit and implicit achievement orientation, political skill and their interplay positively relate to reputation of achievement orientation at work, which, in turn, is positively related to occupational status. We found that (1) both explicit and implicit achievement orientation were positively associated with its reputation, as rated by co-workers; (2) reputation mediated both relations between implicit/explicit achievement orientation and occupational status and (3) heightened political skill strengthened the relationship between explicit achievement orientation and its reputation, as well as its indirect effect on occupational status via reputation (first stage moderated mediation). Our research provides a potential explanation for why observer ratings of personality are more strongly associated with outcomes than self-ratings: Observers perceive both implicit and explicit personality behaviours.
A new class of linear feedback shift register generators

An efficient implementation of linear feedback shift register sequences with a given characteristic polynomial is obtained by a novel method. It involves a polynomial linear congruential generator over the finite field with two elements. We obtain maximal equidistribution by constructing a suitable output mapping. Local randomness could be improved by combining the generator's output with that of some other (e.g., nonlinear and efficient) generator.
Task-set Selection in Probabilistic Environments: a Model of Task-set Inference

To act effectively in a complicated, uncertain world, people often rely on task-sets (TSs) that define action policies over a range of stimuli. Effectively selecting amongst TSs requires assessing their individual utility given the current world state. However, the world state is, in general, latent, stochastic, and time-varying, making TS selection a difficult inference for the agent. An open question is how observable environmental factors influence an actor's assessment of the world state and thus the selection of TSs. In this work, we designed a novel task in which probabilistic cues predict one of two TSs on a trial-by-trial basis. With this task, we investigate how people integrate multiple sources of probabilistic information in the service of TS selection. We show that when action feedback is unavailable, TS selection can be modeled as “biased Bayesian inference”, such that individuals participants differentially weight immediate cues over TS priors when inferring the latent world state. Additionally, using the model’s trial-bytrial posteriors over TSs, we calculate a measure of decision confidence and show that it inversely relates to reaction times. This work supports the hierarchical organization of decision-making by demonstrating that probabilistic evidence can be integrated in the service of higher-order decisions over TSs, subsequently simplifying lower-order action selection.
Differential Response Patterns in the Striatum and Orbitofrontal Cortex to Financial Reward in Humans: A Parametric Functional Magnetic Resonance Imaging Study

Responses to monetary reward in humans have been assessed in a number of recent functional imaging studies, and it is clear that the neuronal substrates of financial reinforcement overlap extensively with regions responding to primary reinforcers, such as food. Money has the practical advantage of being an objectively quantifiable reinforcer. In this study, we exploit this advantage using a parametric functional magnetic resonance imaging design to look at the patterns of responding to systematically varying reward values. Twelve healthy volunteers were scanned during performance of a rewarded target detection task, in which the reward value varied between task blocks. We observed three distinct patterns of responding in different regions. Amygdala, striatum, and dopaminergic midbrain responded to the presence of rewards, regardless of value. In contrast, premotor cortex showed a linear increase in response with increasing reward value. Finally, medial and lateral foci of orbitofrontal cortex responded nonlinearly, such that response was enhanced for the lowest and highest reward values relative to the midrange. These results suggest functional distinction in response patterns within a distributed reward system.
Cerebral microcirculation shear stress levels determine Neisseria meningitidis attachment sites along the blood–brain barrier

Neisseria meningitidis is a commensal bacterium of the human nasopharynx. Occasionally, this bacterium reaches the bloodstream and causes meningitis after crossing the blood–brain barrier by an unknown mechanism. An immunohistological study of a meningococcal sepsis case revealed that neisserial adhesion was restricted to capillaries located in low blood flow regions in the infected organs. This study led to the hypothesis that drag forces encountered by the meningococcus in the bloodstream determine its attachment site in vessels. We therefore investigated the ability of N. meningitidis to bind to endothelial cells in the presence of liquid flow mimicking the bloodstream with a laminar flow chamber. Strikingly, average blood flows reported for various organs strongly inhibited initial adhesion. As cerebral microcirculation is known to be highly heterogeneous, cerebral blood velocity was investigated at the level of individual vessels using intravital imaging of rat brain. In agreement with the histological study, shear stress levels compatible with meningococcal adhesion were only observed in capillaries, which exhibited transient reductions in flow. The flow chamber assay revealed that, after initial attachment, bacteria resisted high blood velocities and even multiplied, forming microcolonies resembling those observed in the septicemia case. These results argue that the combined mechanical properties of neisserial adhesion and blood microcirculation target meningococci to transiently underperfused cerebral capillaries and thus determine disease development.