Miracle-dz/UniFAR-FTUs huggingface dataset:
Phylogenetic estimates of diversification rate are affected by molecular rate variation

Molecular phylogenies are increasingly being used to investigate the patterns and mechanisms of macroevolution. In particular, node heights in a phylogeny can be used to detect changes in rates of diversification over time. Such analyses rest on the assumption that node heights in a phylogeny represent the timing of diversification events, which in turn rests on the assumption that evolutionary time can be accurately predicted from DNA sequence divergence. But there are many influences on the rate of molecular evolution, which might also influence node heights in molecular phylogenies, and thus affect estimates of diversification rate. In particular, a growing number of studies have revealed an association between the net diversification rate estimated from phylogenies and the rate of molecular evolution. Such an association might, by influencing the relative position of node heights, systematically bias estimates of diversification time. We simulated the evolution of DNA sequences under several scenarios where rates of diversification and molecular evolution vary through time, including models where diversification and molecular evolutionary rates are linked. We show that commonly used methods, including metric‐based, likelihood and Bayesian approaches, can have a low power to identify changes in diversification rate when molecular substitution rates vary. Furthermore, the association between the rates of speciation and molecular evolution rate can cause the signature of a slowdown or speedup in speciation rates to be lost or misidentified. These results suggest that the multiple sources of variation in molecular evolutionary rates need to be considered when inferring macroevolutionary processes from phylogenies.
Vascular cognitive impairment neuropathology guidelines (VCING): the contribution of cerebrovascular pathology to cognitive impairment.

There are no generally accepted protocols for post-mortem assessment in cases of suspected vascular cognitive impairment. Neuropathologists from seven UK centres have collaborated in the development of a set of vascular cognitive impairment neuropathology guidelines (VCING), representing a validated consensus approach to the post-mortem assessment and scoring of cerebrovascular disease in relation to vascular cognitive impairment. The development had three stages: (i) agreement on a sampling protocol and scoring criteria, through a series of Delphi method surveys; (ii) determination of inter-rater reliability for each type of pathology in each region sampled (Gwet's AC2 coefficient); and (iii) empirical testing and validation of the criteria, by blinded post-mortem assessment of brain tissue from 113 individuals (55 to 100 years) without significant neurodegenerative disease who had had formal cognitive assessments within 12 months of death. Fourteen different vessel and parenchymal pathologies were assessed in 13 brain regions. Almost perfect agreement (AC2 > 0.8) was found when the agreed criteria were used for assessment of leptomeningeal, cortical and capillary cerebral amyloid angiopathy, large infarcts, lacunar infarcts, microhaemorrhage, larger haemorrhage, fibrinoid necrosis, microaneurysms, perivascular space dilation, perivascular haemosiderin leakage, and myelin loss. There was more variability (but still reasonably good agreement) in assessment of the severity of arteriolosclerosis (0.45-0.91) and microinfarcts (0.52-0.84). Regression analyses were undertaken to identify the best predictors of cognitive impairment. Seven pathologies-leptomeningeal cerebral amyloid angiopathy, large infarcts, lacunar infarcts, microinfarcts, arteriolosclerosis, perivascular space dilation and myelin loss-predicted cognitive impairment. Multivariable logistic regression determined the best predictive models of cognitive impairment. The preferred model included moderate/severe occipital leptomeningeal cerebral amyloid angiopathy, moderate/severe arteriolosclerosis in occipital white matter, and at least one large infarct (area under the receiver operating characteristic curve 77%). The presence of 0, 1, 2 or 3 of these features resulted in predicted probabilities of vascular cognitive impairment of 16%, 43%, 73% or 95%, respectively. We have developed VCING criteria that are reproducible and clinically predictive. Assuming our model can be validated in an independent dataset, we believe that this will be helpful for neuropathologists in reporting a low, intermediate or high likelihood that cerebrovascular disease contributed to cognitive impairment.10. 1093/brain/aww214_video_abstractaww214_video_abstract.
Autoantibodies to Posttranslational Modifications in Rheumatoid Arthritis

Autoantibodies have been associated with human pathologies for a long time, particularly with autoimmune diseases (AIDs). Rheumatoid factor (RF) is known since the late 1930s to be associated with rheumatoid arthritis (RA). The discovery of anticitrullinated protein antibodies in the last century has changed this and other posttranslational modifications (PTM) relevant to RA have since been described. Such PTM introduce neoepitopes in proteins that can generate novel autoantibody specificities. The recent recognition of these novel specificities in RA provides a unique opportunity to understand human B-cell development in vivo. In this paper, we will review the three of the main classes of PTMs already associated with RA: citrullination, carbamylation, and oxidation. With the advancement of research methodologies it should be expected that other autoantibodies against PTM proteins could be discovered in patients with autoimmune diseases. Many of such autoantibodies may provide significant biomarker potential.
Electrotonic architecture of hippocampal CA1 pyramidal neurons based on three-dimensional reconstructions.

1. The spread of electrical signals in pyramidal neurons from the CA1 field of rat hippocampus was investigated through multicompartmental modeling based on three-dimensional morphometric reconstructions of four of these cells. These models were used to dissect the electrotonic architecture of these neurons, and to evaluate the equivalent cylinder approach that this laboratory and others have previously applied to them. Robustness of results was verified by the use of wide ranges of values of specific membrane resistance (Rm) and cytoplasmic resistivity. 2. The anatomy exhibited extreme departures from a key assumption of the equivalent cylinder model, the so-called "3/2 power law. " 3. The compartmental models showed that the frequency distribution of steady-state electrotonic distances between the soma and the dendritic terminations was multimodal, with a large range and a sizeable coefficient of variation. This violated another central assumption of the equivalent cylinder model, namely, that all terminations are electronically equidistant from the soma. This finding, which was observed both for "centrifugal" (away from the soma) and "centripetal" (toward the soma) spread of electrical signals, indicates that the concept of an equivalent electrotonic length for the whole dendritic tree is not appropriate for these neurons. 4. The multiple peaks in the electrotonic distance distributions, whether for centrifugal or centripetal voltage transfer, were clearly related to the laminar organization of synaptic afferents in the CA1 region. 5. The results in the three preceding paragraphs reveal how little of the electrotonic architecture of these neurons is captured by a simple equivalent cylinder model. The multicompartmental model is more appropriate for exploring synaptic signaling and transient events in CA1 pyramidal neurons. 6. There was significant attenuation of synaptic potential, current, and charge as they spread from the dendritic tree to the soma. Charge suffered the least and voltage suffered the most attenuation. Attenuation depended weakly on Rm and strongly on synaptic location. Delay of time to peak was more distorted for voltage than for current and was more affected by Rm. 7. Adequate space clamp is not possible for most of the synapses on these cells. Application of a somatic voltage clamp had no significant effect on voltage transients in the subsynaptic membrane. 8. The possible existence of steep voltage gradients within the dendritic tree is consistent with the idea that there can be some degree of local processing and that different regions of the neuron may function semiautonomously. These spatial gradients are potentially relevant to synaptic plasticity in the hippocampus, and they also suggest caution in interpreting some neurophysiological results.
Impact of aging on pulmonary responses to acute ozone exposure in mice: role of TNFR1

Context: Chamber studies in adult humans indicate reduced responses to acute ozone with increasing age. Age-related changes in TNFα have been observed. TNFα induced inflammation is predominantly mediated through TNFR1. Objective: To examine the impact of aging on inflammatory responses to acute ozone exposure in mice and determine the role of TNFR1 in age-related differences. Materials and methods: Wildtype and TNFR1 deficient (TNFR1−/–) mice aged 7 or 39 weeks were exposed to ozone (2 ppm for 3 h). Four hours after exposure, bronchoalveolar lavage (BAL) was performed and BAL cells, cytokines, chemokines, and protein were examined. Results: Ozone-induced increases in BAL neutrophils and in neutrophil chemotactic factors were lower in 39- versus 7-week-old wildtype, but not (TNFR1−/–) mice. There was no effect of TNFR1 genotype in 7-week-old mice, but in 39-week-old mice, BAL neutrophils and BAL concentrations of MCP-1, KC, MIP-2, IL-6 and IP-10 were significantly greater following ozone exposure in TNFR1−/– versus wildtype mice. BAL concentrations of the soluble form of the TNFR1 receptor (sTNFR1) were substantially increased in 39-week-old versus 7-week-old mice, regardless of exposure. Discussion and conclusion: The data suggest that increased levels of sTNFR1 in the lungs of the 39-week-old mice may neutralize TNFα and protect these older mice against ozone-induced inflammation.
Anchoring of CREB binding protein to the human T-cell leukemia virus type 1 promoter: a molecular mechanism of Tax transactivation

The human T-cell leukemia virus type 1 (HTLV-1)-encoded Tax protein activates viral transcription through interaction with the cellular transcription factor CREB (cyclic AMP response element [CRE] binding protein). Although Tax stabilizes the binding of CREB to the Tax-responsive viral CREs in the HTLV-1 promoter, the precise molecular mechanism by which Tax mediates strong transcriptional activation through CREB remains unclear. In this report, we show that Tax promotes high-affinity binding of the KIX domain of CREB binding protein (CBP) to CREB-viral CRE complexes, increasing the stability of KIX in these nucleoprotein complexes by up to 4.4 kcal/mol. Comparable KIX binding affinities were measured for both phosphorylated and unphosphorylated forms of CREB, and in all cases high-affinity binding was dependent upon both Tax and the viral CRE. Tax also promoted association of KIX to a truncated form of CREB containing only the 73-amino-acid basic leucine zipper (bZIP) domain, indicating that the entire amino-terminal CBP-interacting domain of CREB is nonessential in the presence of Tax. Functional studies upheld the binding studies, as expression of the bZIP domain of CREB was sufficient to support Tax transactivation of HTLV-1 transcription in vivo. Finally, we show that transfection of a KIX expression plasmid, which lacks activation properties, inhibited Tax transactivation in vivo. This suggests that KIX occupies the CBP binding site on Tax, and therefore CBP is likely a cofactor in mediating Tax stimulation of HTLV-1 transcription. Together, these data support a model in which Tax anchors CBP to the HTLV-1 promoter, with strong transcriptional activation resulting from the CBP-associated activities of nucleosome remodeling and recruitment of the general transcription machinery.
Lasers in Manufacturing Conference 2015 Development of an adaptive focus position control system for a new high-performance laser remote welding head

The Institute of Laser and System Technologies (iLAS) of the Hamburg University of Technology (TUHH) investigated an intelligent vision guided laser remote scanner (LRS) system not only for thin sheet or structure applications, but also for thick sheet welding tasks with brilliant high power lasers up to 30 kw optical laser power. Two different wavelength acting; 532 nm for measuring and analyzing processes, 1070 nm for welding and other laser processes. Mechanical, thermal and optical effects mainly influence the manufacturing results after position, shape and machining path measuring processes. Especially the high laser power induced interaction between the laser beam and optical components will change the optical guidance properties in the course of time. Changing the refraction index n is one of the important effects for the thermo-optical reaction; focal shift takes place. The conclusion is now, that the machining position of an infrared high power laser spot does not fit anymore to the measured and analyzed position of the green pointing laser spot. The paper describes a first basic simulation model of the optics from this new LRS system with influencing components and important parameters. Furthermore the thermal influences have been simulated and the first results are presented. These results demonstrate the importance to develop within the next steps a combined practical and fast correction algorithm design supported by real sensor signals and implemented in the laser remote scanner controller unit.
The Emotion-Evoked Collective Corruption Model: The Role of Emotion in the Spread of Corruption Within Organizations

We draw from research on emotions and moral reasoning to develop a process model of collective corruption that centers on the role of moral emotions in the spread of corruption within organizations. Our focus on a well-intentioned and deliberative path to corruption is a departure from previous theory, which has focused on mindless and ill-intentioned paths. In our model, moral emotions play a critical role in both the initial recruitment of a target individual (the direct process), as well as the spread of corruption to a broader group of nontargeted individuals through emotional contagion (the vicarious process). For both processes we explain how self-directed moral emotions (guilt, shame, embarrassment, and pride) facilitate the spread of corruption and how other-directed moral emotions (anger and contempt) do not. We conclude by discussing the implications of our theory and directions for future research.
EGF‐Induced Connexin43 Negatively Regulates Cell Proliferation in Human Ovarian Cancer

Connexin43 (Cx43) has been shown to regulate cell proliferation and its downregulation is correlated with poor prognosis and survival in several types of human cancer. Cx43 expression levels are frequently downregulated in human ovarian cancer, suggesting a potential role for Cx43 in regulating the progression of this disease. Epidermal growth factor (EGF) is a well‐characterized hormone that stimulates ovarian cancer cell proliferation. Although EGF is able to regulate Cx43 expression in other cell types, it is unclear whether EGF can regulate Cx43 expression in ovarian cancer cells. Additionally, it remains unknown whether Cx43 is involved in EGF‐stimulated ovarian cancer cell proliferation. In the present study, we demonstrate that treatment with EGF upregulates Cx43 expression in two ovarian cancer cell lines, SKOV3 and OVCAR4. Although treatment with EGF activates both ERK1/2 and Akt signaling pathways, pharmacological inhibition and siRNA‐mediated knockdown suggest that only the activation of Akt1 is required for EGF‐induced Cx43 upregulation. Functionally, Cx43 knockdown enhanced basal and EGF‐induced cell proliferation, whereas the proliferative effects of EGF were reduced by Cx43 overexpression. Co‐treatment with the gap junction inhibitor carbenoxolone did not alter the suppressive effects of Cx43 overexpression on EGF‐induced cell proliferation, suggesting a gap junction‐independent mechanism. This study reveals an important role for Cx43 as a negative regulator of EGF‐induced human ovarian cancer cell proliferation. J. Cell. Physiol. 230: 111–119, 2016. © 2015 Wiley Periodicals, Inc.
Leukemic Stem Cell Quantification in Newly Diagnosed Patients With Chronic Myeloid Leukemia Predicts Response to Nilotinib Therapy

Purpose: Leukemic stem cells (LSCs) may harbor important resistance to tyrosine kinase inhibitors in chronic myelogenous leukemia (CML). We identified Philadelphia chromosome (Ph)–positive CD34+CD38− bone marrow cells (here denoted LSCs) and addressed their response-predictive value in patients with CML (n = 48) subjected to nilotinib in the ENEST1st trial (NCT01061177). Experimental design: Two flow cytometry–based cell sorting methods were used with multiparameter-directed CD45- (MPFC) and BCR-ABL1 probe-linked (FISH) identification of Ph-positive cells, respectively. Results: We observed a positive correlation between the proportion of LSCs at diagnosis and established prognostic markers (blast count, spleen size, Sokal score, and hemoglobin). Conversely, a high LSC burden predicted for an inferior molecular response at 3 (MPFC and FISH), 6 (MPFC), 9 (FISH), and 15 months (FISH). During nilotinib therapy, the proportion of LSCs decreased rapidly. At 3 months, a median of only 0.3% LSCs remained among CD34+CD38− cells, and in 33% of the patients the LSC clone was not detectable anymore (FISH). The response kinetics was similar in LSC fractions as it was in the progenitor and unseparated bone marrow cell fractions. Conclusions: The proportion of LSCs at diagnosis, as analyzed by two independent methodologies, reflects the biology of the disease and appeared as a prognostic and response-predictive marker in patients with CML subjected to first-line nilotinib therapy. Clin Cancer Res; 22(16); 4030–8. ©2016 AACR.
Infection of human papillomavirus type 18 and p53 codon 72 polymorphism in lung cancer patients from India.

STUDY OBJECTIVES Infection with specific high-risk HPV types 16 and 18 and polymorphism of p53 codon 72 has been strongly associated with the genesis of various neoplasms in humans, but such study in lung cancer is limited and the results are controversial. In India, the role of these two factors has been strongly implicated in cervical and other cancers, but the occurrence of HPV or p53 codon 72 polymorphism has not been examined in lung cancer, which is the most common cause of cancer-related death in India. DESIGN AND PATIENTS A total of 40 tumor biopsy specimens from advanced lung cancer patients and blood samples from 40 matching control subjects were obtained for the analysis of high-risk HPV types 16 and 18 infection and p53 codon 72 polymorphism by polymerase chain reaction. RESULTS Only HPV type 18 was detected in 5% (2 of 40 lung cancer patients), but no other HPV could be detected. A significantly increased frequency of Arg/Arg homozygotes was observed in patients with advanced lung cancer when compared to that of control subjects (p = 0.004; odds ratio, 5.13; 95% confidence interval, 1.59 to 17.26). However, no significant correlation could be made between p53 polymorphism and different clinical stages, except for advanced stage IV patients, who showed a higher proportion of Arg/Pro heterozygous genotype. CONCLUSIONS HPV detected in a small proportion of lung cancer patients in India demonstrated an exclusive prevalence of HPV type 18, and there was a significantly higher frequency of p53 Arg/Arg genotype when compared to that of control subjects. Observation of a shorter duration of symptoms (< or = 4 months) in as many as 78% (seven of nine stage IV patients) with Arg/Pro genotype may be an indication that lung cancer patients with the heterozygous p53 genotype are more susceptible to early progression.
Interstitial cells of the adult neocortical white matter are the remnant of the early generated subplate neuron population

The postnatal fate of the first‐generated neurons of the cat cerebral cortex was examined. These neurons can be identified uniquely by 3H‐thymidine exposure during the week preceding the neurogenesis of cortical layer 6. Previous studies in which 3H‐thymidine birthdating at embryonic day 27 (E27) was combined with immunohistochemistry have shown that these neurons are present in large numbers during fetal and early postnatal life within the subplate (future white matter), that they are immunoreactive for the neuron‐specific protein MAP2 and for the putative neurotransmitters GABA, NPY, SRIF, and CCK. Here, the same techniques were used to follow the postnatal location and disappearance of the early generated subplate neuron population.
Utilization of Textile Mill Sludge in Burnt Clay Bricks

Investigation of the effect of Textile mill sludge addition in burnt clay bricks is done under this study. Chemical composition of sludge and soil samples was analysed by ICP-AES, SEM and XRF facilities. Sludge percentage is varied from zero to thirty-five percent by weight. Firing temperature and firing period are varied to understand the variations in characteristics of burnt bricks. Parameters such as compressive strength, density, water absorption, efflorescence and ringing sound are studied as per BIS (Bureau of Indian Standards) procedures. Density of bricks, compressive strength and ringing sound reduces as sludge content in bricks increases whereas water absorption and efflorescence increases. Higher firing temperature and firing period i.e. 800 0 C and 24 hours give good results in terms of compressive strength with same percentage of sludge as compared to other temperature and firing period combinations. Textile mill sludge up to 15% can be added so as to get compressive strength greater than 3.5 N/mm 2 .
History-sensitive versus future-sensitive approaches to security in distributed systems

We consider the use of aspect-oriented techniques as a flexible way to deal with security policies in distributed systems. Recent work suggests to use aspects for analysing the future behaviour of programs and to make access control decisions based on this; this gives the flavour of dealing with information flow rather than mere access control. We show in this paper that it is beneficial to augment this approach with history-based components as is the traditional approach in reference monitor-based approaches to mandatory access control. Our developments are performed in an aspect-oriented coordination language aiming to describe the Bell-LaPadula policy as elegantly as possible. Furthermore, the resulting language has the capability of combining both history- and future-sensitive policies, providing even more flexibility and power.
Laminin 1 is critical for Schwann cell differentiation, axon myelination, and regeneration in the peripheral nerve

aminins are heterotrimeric extracellular matrix proteins that regulate cell viability and function. Laminin-2, composed of 2, 1, and 1 chains, is a major matrix component of the peripheral nervous system (PNS). To investigate the role of laminin in the PNS, we used the Cre–loxP system to disrupt the laminin 1 gene in Schwann cells. These mice have dramatically reduced expression of laminin 1 in Schwann cells, which results in a similar reduction in laminin 2 and 1 chains. These mice exhibit motor defects which lead to hind leg paralysis L and tremor. During development, Schwann cells that lack laminin 1 were present in peripheral nerves, and proliferated and underwent apoptosis similar to control mice. However, they were unable to differentiate and synthesize myelin proteins, and therefore unable to sort and myelinate axons. In mutant mice, after sciatic nerve crush, the axons showed impaired regeneration. These experiments demonstrate that laminin is an essential component for axon myelination and regeneration in the PNS.