Miracle-dz/UniFAR-FTUs huggingface dataset:
Assessment of drug‐induced liver injury in clinical practice

Currently, pharmaceutical preparations are serious contributors to liver disease, with hepatotoxicity ranking as the most frequent cause for acute liver failure and post‐marketing regulatory decisions. The diagnostic approach of drug‐induced liver injury (DILI) is still rudimentary and inaccurate because of the lack of reliable markers for use in general clinical practice. To incriminate any given drug in an episode of liver dysfunction is a step‐by‐step process that requires a high degree of suspicion, compatible chronology, awareness of the drug’s hepatotoxic potential, the exclusion of alternative causes of liver damage, and the ability to detect the presence of subtle data that favour a toxic aetiology. Clinical and laboratory data may also be assessed with algorithms or clinical scales, which may add consistency to the clinical judgment by translating the suspicion into a quantitative score. The CIOMS/RUCAM instrument is considered at present the best method for assessing causality in DILI, although it could be improved through the use of large database of bona fide DILI cases for validation criteria.
Preventive strategies and clinical implications for bisphosphonate-related osteonecrosis of the jaw: a review of 282 patients.

OBJECTIVE To describe and evaluate the effectiveness of oral and dental prevention strategies for cancer patients who were about to begin bisphosphonate (BP) intravenous therapy with zoledronate. METHODS Patients were divided into 2 groups according to their history with BPs: group PA (preventive approach) and group OB (observation). Group PA patients had never been previously treated with BPs, and group OB patients had already undergone therapy with BPs. All patients received a complete oral and dental examination and had a panoramic radiograph. If necessary, oral hygiene, and restorative and rehabilitation therapy were offered to patients. All patients participated in regular checkups every 6 months. Group PA patients underwent oral surgical procedures, as needed. RESULTS A total of 282 patients (162 women, 120 men) were included in this analysis (PA: n = 217; OB: n = 65). In group OB, 4.6% of patients presented with osteonecrosis of the jaw (ONJ) at first visit and 10.8% developed new ONJ during the 18-month follow-up period. No patients in group PA had ONJ. Anti-angiogenic therapy was associated with ONJ (p < 0.01) and patients with a higher number of zoledronate infusions were significantly more likely to develop ONJ (p < 0.01). CONCLUSION Although the incidence of BP-related ONJ is fairly low, it remains a painful and difficult complication to treat. An interdisciplinary preventive approach is essential to prevent and manage this condition.
Localised PtdIns(3,4,5)P3 or PtdIns(3,4)P2 at the phagocytic cup is required for both phagosome closure and Ca2+ signalling in HL60 neutrophils

Several events accompany integrin-mediated phagocytosis by myeloid cells. These include local pseudopod and phagocytic cup formation followed by Ca2+ signalling. However, there is also a role for localised phosphatidylinositol (3,4,5) trisphosphate [PtdIns(3,4,5)P3] production. Here we report that in neutrophilic HL-60 cells expressing PH-Akt-GFP, binding of iC3b-coated zymosan particles (2 μm in diameter) via β2 integrin induces an incomplete phagocytic cup to form before either PtdIns(3,4,5)P3 or phosphatidylinositol (3,4) bisphosphate [PtdIns(3,4)P2] production or Ca2+ signalling. These phosphoinositides then accumulated locally at the site of the phagocytic cup and Ca2+ signalling and phagosome closure follows immediately. Although photobleaching showed that PH-Akt-GFP was freely diffusible in the cytosol and able to dissociate from the phagocytic cup, it was restricted to the plasma membrane of the formed but open phagosome and failed to diffuse into the surrounding plasma membrane or neighbouring phagocytic cups even if connected. Inhibition of phosphoinositide (PI) 3-kinase or depletion of membrane cholesterol inhibited both Ca2+ signalling and phagosome closure, but had no effect on particle binding or phagocytic cup formation. We therefore conclude that PtdIns(3,4,5)P3 or PtdIns(3,4)P2 generation was not required for the events that initiate the formation of the phagocytic cup, but that anchoring of PtdIns(3,4,5)P3 at the phagocytic cup is an essential step for phagosome closure and Ca2+ signalling.
Bone morphogenetic protein-2 inhibits MAPK-dependent Elk-1 transactivation and DNA synthesis induced by EGF in mesangial cells.

Bone morphogenetic protein-2 (BMP-2) is a member of the TGFbeta superfamily of growth and differentiation factors. We investigated the effect of BMP-2 on epidermal growth factor (EGF)-induced mitogenic signaling in kidney glomerular mesangial cells. BMP-2 dose-dependently inhibits EGF-induced DNA synthesis. Maximum effect was obtained at a concentration of 100 ng/ml. BMP-2 had no inhibitory effect on the EGF receptor (EGFR)-associated tyrosine kinase activity indicating that inhibition of DNA synthesis is due to regulation of post-receptor signaling event(s). EGF stimulates MAPK activity in mesangial cells in a time-dependent manner. Inhibition of MAPK by the MEK inhibitor PD098059 blocks EGF-induced DNA synthesis indicating the requirement of this enzyme activity in EGF-mediated mitogenic signaling. Furthermore, we show that exposure of mesangial cells to BMP-2 blocks EGF-induced MAPK activity which leads to phosphorylattion of Elk-1 transcription factor. Using a GAL-4 DNA binding-domain-Elk-1 transactivation domain fusion protein-based reporter assay, we demonstrate that BMP-2 inhibits EGF-induced Elk-1-mediated transcription. These data provide the first evidence that BMP-2 signaling in mesangial cells initiates a negative regulatory cross-talk with MAPK-based transcription to inhibit EGF-induced DNA synthesis.
Design Curve to Characterize Fatigue Strength

Fatigue (S-N) data exhibit relatively large scatter. For design purposes, an S-N curve that characterizes fatigue strength is required. This curve should lie on the lower, or safe, side of the data. A method based on a modification of the Owen tolerance interval is proposed. The method is general and can be applied to nonlinear heteroscedastic data having runouts.
Extreme formal modeling (XFM) for hardware models

In this paper, we show the usefulness of an agile formal method (named XFM) based on extreme programming concepts to construct abstract models from a natural language specification of a complex system. Building formal models for verification purposes is being employed in the industry for two different usage modes: (i) descriptive formal models (DFM) which, are used to capture an implementation into an abstract model to submit to analysis by model checking tools, (ii) prescriptive formal models (PFM) which, are used to capture natural language specifications into a formal model to analyze consistency of the specification and also as a reference model to compare a DFM against it. We propose XFM as a methodology to incrementally build a correct PFM from a natural language specification. In this paper, using XFM, on various examples related to microprocessors, we build the models of DLX pipeline in SPIN, the ISA bus monitor and arbitration phase of the Pentium Pro bus in SMV.
Fine Gradings of Low-Rank Complex Lie Algebras and of Their Real Forms

In this review paper, we treat the topic of fine gradings of Lie algebras. This concept is important not only for investigating the structural properties of the algebras, but, on top of that, the fine gradings are often used as the starting point for studying graded contractions or deformations of the algebras. One basic question tackled in the work is the relation between the terms 'grading' and 'group grading'. Although these terms have originally been claimed to coincide for simple Lie algebras, it was revealed later that the proof of this assertion was incorrect. Therefore, the crucial statements about one-to-one correspondence between fine gradings and MAD-groups had to be revised and re-formulated for fine group gradings instead. However, there is still a hypothesis that the terms 'grading' and 'group grading' coincide for simple complex Lie algebras. We use the MAD-groups as the main tool for finding fine group gradings of the complex Lie algebras $A_3 \cong D_3$, $B_2 \cong C_2$, and $D_2$. Besides, we develop also other methods for finding the fine (group) gradings. They are useful especially for the real forms of the complex algebras, on which they deliver richer results than the MAD-groups. Systematic use is made of the faithful representations of the three Lie algebras by $4\times 4$ matrices: $A_3 = sl(4,\mathbb C)$, $C_2 = sp(4,\mathbb C)$, $D_2 = o(4,\mathbb C)$. The inclusions $sl(4,\mathbb C)\supset sp(4,\mathbb C)$ and $sl(4,\mathbb C) \supset o(4,\mathbb C)$ are important in our presentation, since they allow to employ one of the methods which considerably simplifies the calculations when finding the fine group gradings of the subalgebras $sp(4,\mathbb C)$ and $o(4,\mathbb C)$.
Effect of acute hyperoxia during exercise on quadriceps electrical activity in active COPD patients.

AIMS This study investigated whether acute hyperoxia improves electrical muscle activity in active chronic obstructive pulmonary disease (COPD) patients with mild hypoxemia (rest PaO(2) = 9.1 +/- 0.4 kPa). METHODS Two identical incremental exercise tests were performed by nine patients while breathing either air or 30% oxygen. Pulmonary gas exchanges, venous concentrations of lactate and pyruvate, and the electromyographic signal of the quadriceps muscle (vastus lateralis and vastus medialis) were sampled each minute. RESULTS Peak working capacity increased significantly in hyperoxia (94.4 +/- 5.2W) compared with normoxia (85.4 +/- 5.8W, P < 0.01). During hyperoxic exercise and for a given work load, oxygen uptake was increased (P < 0.001) and ventilation decreased (P < 0.05). Lactate concentration was significantly decreased (P < 0.01) at isowork level and during recovery (respectively - 26% and at least - 15%). In the quadriceps muscle, M-wave amplitude (P < 0.05), root mean square (P < 0.01) and root mean square/oxygen uptake ratio (P < 0.001) were significantly increased during hyperoxic exercise compared with room air. Although median frequency values did not differ between conditions, the median frequency was significantly decreased for higher exercise intensity in hyperoxic condition. These modifications reflected better aerobic metabolism, later emergence of muscle fatigue, and greater muscle excitability and activation for the same level of exercise under hyperoxic condition. CONCLUSION These data suggest that the acute addition of oxygen in active COPD patients improves their muscle electrical activity during dynamic exercise. Hypoxemia-induced skeletal muscle dysfunction most probably acts through mechanisms based on oxygen availability.
Isoflurane Reduces Glutamatergic Transmission in Neurons in the Spinal Cord Superficial Dorsal Horn: Evidence for a Presynaptic Site of an Analgesic Action

The minimum alveolar concentration (MAC) of a volatile anesthetic defines anesthetic potency in terms of a suppressed motor response to a noxious stimulus. Therefore, the MAC of an anesthetic might in part reflect depression of motor neuron excitability. In the present study we evaluated the effect of isoflurane (ISO) on neurons in the substantia gelatinosa driven synaptically by putative nociceptive inputs in an in vitro spinal cord preparation of the rat. Whole-cell patch-clamp recordings were performed in neurons with their soma in the substantia gelatinosa of transverse rat spinal cord slices. We investigated the effect of ISO on excitatory postsynaptic currents (EPSC) evoked by dorsal root stimulation (eEPSC), spontaneous (sEPSC), and miniature (mEPSC) EPSC. ISO reversibly reduced the amplitude of eEPSC to 39% ± 22% versus control. ISO decreased the frequency of sEPSC and mEPSC to 39% ± 26% and 63% ± 7%. Neither the amplitudes nor the kinetics of mEPSC and sEPSC were altered by ISO. We conclude that ISO depresses glutamatergic synaptic transmission of putative nociceptive primary-afferent inputs, presumably by reducing the release of the excitatory transmitter. This effect may contribute to an antinociceptive action of volatile anesthetics at the spinal cord level.
Reduction in mitochondrial potential constitutes an early irreversible step of programmed lymphocyte death in vivo

In a number of experimental systems in which lymphocyte depletion was induced by apoptosis-inducing manipulations, no apoptotic morphology and ladder-type DNA fragmentation were detected among freshly isolated peripheral lymphocytes ex vivo. Here we report that one alteration that can be detected among splenocytes stimulated with lymphocyte-depleting doses of dexamethasone (DEX) in vivo is a reduced uptake of 3,3'dihexyloxacarbocyanine iodide (DiOC6[3]), a fluorochrome which incorporates into cells dependent upon their mitochondrial transmembrane potential (delta psi m). In contrast, ex vivo isolated splenocytes still lacked established signs of programmed cell death (PCD):DNA degradation into high or low molecular weight fragments, ultrastructural changes of chromatin arrangement and endoplasmatic reticulum, loss in viability, or accumulation of intracellular peroxides. Moreover, no changes in cell membrane potential could be detected. A reduced delta psi m has been observed in response to different agents inducing lymphoid cell depletion in vivo (superantigen and glucocorticoids [GC]), in mature T and B lymphocytes, as well as their precursors. DEX treatment in vivo, followed by cytofluorometric purification of viable delta psi mlow splenic T cells ex vivo, revealed that this fraction of cells is irreversibly committed to undergoing DNA fragmentation. Immediately after purification neither delta psi mlow, nor delta psi mhigh cells, exhibit detectable DNA fragmentation. However, after short-term culture (37 degrees C, 1 h) delta psi mlow cells show endonucleolysis, followed by cytolysis several hours later. Incubation of delta psi mlow cells in the presence of excess amount of the GC receptor antagonist RU38486 (which displaces DEX from the GC receptor), cytokines that inhibit DEX-induced cell death, or cycloheximide fails to prevent cytolysis. The antioxidant, N- acetylcysteine, as well as linomide, an agent that effectively inhibits DEX or superantigen-induced lymphocyte depletion in vivo, also stabilize the DiOC6(3) uptake. In contrast, the endonuclease inhibitor, aurintricarboxylic acid acts at later stages of apoptosis and only retards the transition from the viable delta psi mlow to the nonviable fraction. Altogether, these data suggest a sequence of PCD-associated events in which a reduction in delta psi m constitutes an obligate irreversible step of ongoing lymphocyte death, preceding other alterations of cellular physiology, and thus allowing for the ex vivo assessment of PCD.
Improving code efficiency for reconfigurable VLIW processors

High code efficiency (operations per instruction) combined with a high degree of instruction level parallelism can rarely be obtained by hardwired microprocessor designs for a broad application domain. The implementation of reconfigurable execution units is a promising way to enhance code efficiency and microprocessor performance. However, the unit reconfiguration process introduces an additional dimension to the code generation phase, which complicates scheduling and may lead to code deficiencies if resource conflicts occure. This paper discusses code generation issues for a runtime-reconfigurable VLIW processor model, which combines fixed and flexible functional units (FU) in one template. Reconfigurable units (RFU) can be adapted to the application demands exploiting more coarse-grain parallelism than common instruction-level FUs. A case study illustrates the extraction of conditions for reconfigurable instructions proves scheduling possibilities for a set of common DSP benchmark algorithms. The software environment described includes a retargetable, parallelizing C compiler based on the SUIF compiler kit and a simulator, which can be used for identifying application-specific SIMD-instruction candidates and for evaluating the runtime behavior of the created object code.
Paxillin kinase linker (PKL) regulates Vav2 signaling during cell spreading and migration

Rho GTPases play an important role in cell migration. Here the activity of the Rho GTPase GEF Vav2 is shown to be regulated by a phosphorylation-dependent interaction with PKL (GIT2). PKL is required for Vav2 activation, and, in turn, Vav2 regulates the localization of PKL and β-PIX to focal adhesions and to the leading edge of migrating cells.
Coupled Resonances in Multiple Silicon Photonic Crystal Cavities in All-Optical Solid-State Analogy to Electromagnetically Induced Transparency

We present experimental and theoretical studies of coupled resonances in multiple silicon photonic crystal cavities in an all-optical classical analogy to electromagnetically induced transparency. Multiple implementation schemes are demonstrated, such as two (in various configurations), and four cavities. The photonic crystal cavities are embedded in 2-D photonic crystal slabs and designed in the overcoupled regime. Our observations include measured transparency resonance lifetimes more than three times the single-cavity lifetimes, Fano-like lineshapes, and stepwise resonance control through multiple aligned external optical pump beams. All observed schemes are analyzed rigorously through finite-difference time-domain simulations and the coupled-mode formalism. Our experimental and theoretical results are applicable to optical pulse trapping and all-optical dynamical storage of light in the solid state.
Morin hydrate inhibits amyloid formation by islet amyloid polypeptide and disaggregates amyloid fibers

The polypeptide hormone Islet Amyloid Polypeptide (IAPP, amylin) is responsible for islet amyloid formation in type‐2 diabetes and in islet cell transplants, where it may contribute to graft failure. Human IAPP is extremely amyloidogenic and fewer inhibitors of IAPP amyloid formation have been reported than for the Alzheimer's Aβ peptide or for α‐synuclein. The ability of a set of hydroxyflavones to inhibit IAPP amyloid formation was tested. Fluorescence detected thioflavin‐T‐binding assays are the most popular methods for measuring the kinetics of amyloid formation and for screening potential inhibitors; however, we show that they can lead to false positives with hydroxyflavones. Several of the compounds inhibit thioflavin‐T fluorescence, but not amyloid formation; a result which highlights the hazards of relying solely on thioflavin‐T assays to screen potential inhibitors. Transmission electron microscopy (TEM) and right‐angle light scattering show that Morin hydrate (2′,3,4′,5,7‐Pentahydroxyflavone) inhibits amyloid formation by human IAPP and disaggregates preformed IAPP amyloid fibers. In contrast, Myricetin, Kaempferol, and Quercetin, which differ only in hydroxyl groups on the B‐ring, are not effective inhibitors. Morin hydrate represents a new type of IAPP amyloid inhibitor and the results with the other compounds highlight the importance of the substitution pattern on the B‐ring.
Special Morphological Features at the Interface of the Renal Stem/Progenitor Cell Niche Force to Reinvestigate Transport of Morphogens During Nephron Induction

Abstract Formation of a nephron depends on reciprocal signaling of different morphogens between epithelial and mesenchymal cells within the renal stem/progenitor cell niche. Previously, it has been surmised that a close proximity exists between both involved cell types and that morphogens are transported between them by diffusion. However, actual morphological data illustrate that mesenchymal and epithelial stem/progenitor cell bodies are separated by a striking interface. Special fixation of specimens by glutaraldehyde (GA) solution including cupromeronic blue, ruthenium red, or tannic acid for electron microscopy depicts that the interface is not void but filled in extended areas by textured extracellular matrix. Surprisingly, projections of mesenchymal cells cross the interface to contact epithelial cells. At those sites the plasma membranes of a mesenchymal and an epithelial cell are connected via tunneling nanotubes. Regarding detected morphological features in combination with involved morphogens, their transport cannot longer be explained solely by diffusion. Instead, it has to be sorted according to biophysical properties of morphogens and to detected environment. Thus, the new working hypothesis is that morphogens with good solubility such as glial cell line-derived neurotrophic factor (GDNF) or fibroblast growth factors (FGFs) are transported by diffusion. Morphogens with minor solubility such as bone morphogenetic proteins (BMPs) are secreted and stored for delivery on demand in illustrated extracellular matrix. In contrast, morphogens with poor solubility such as Wnts are transported in mesenchymal cell projections along the plasma membrane or via illustrated tunneling nanotubes. However, the presence of an intercellular route between mesenchymal and epithelial stem/progenitor cells by tunneling nanotubes also makes it possible that all morphogens are transported this way.
Total arterial compliance estimated by stroke volume-to-aortic pulse pressure ratio in humans.

On the basis of the windkessel model, the stroke volume-to-aortic pulse pressure ratio (SV/PP) has been proposed as an estimate of total arterial compliance, but recent studies have questioned this approximation. Aortic pressure was obtained at rest in 31 adults undergoing cardiac catheterization (47 ± 14 yr): controls ( n = 7), patients with dilated cardiomyopathy ( n = 10), and patients with other cardiac diseases ( n = 14). We calculated PP, mean aortic pressure (MAoP), heart period ( T), SV (thermodilution cardiac output/heart rate), total peripheral resistance ( R), total arterial compliance estimated by area method ( C area), and the time constant of aortic pressure decay in diastole ( RC area). In the overall population ( n = 31), there was no significant difference between SV/PP and C area. SV/PP was linearly related to C area (SV/PP = 0.99 C area + 0.05; r = 0.98; P < 0.001); the slope and intercept did not differ from unity and zero, respectively. Similar results were obtained in the three subgroups. These results implied that PP/MAoP and T/ RC areawere proportionally related ( T/ RC area= 1.18PP/MAoP - 0.07; r = 0.96; P < 0.001). We conclude that for humans at rest 1) SV/PP gave a reliable estimate of C area, and 2) T normalized by the time constant of aortic pressure decay in diastole was proportionally related to PP/MAoP. This last relationship could be considered an aspect of the coupling between the left ventricle and its load.
Impact of Employee Training and Empowerment on Employee Creativity Through Employee Engagement: Empirical Evidence from the Manufacturing Sector of Pakistan

2 Abstract: Since last two decades, in response to changes in the competitive working world of business and management, organizational researchers have focused their attention towards high performance work practices that enhance the employee creativity through better engagement of employees in their work. In consistent with this stream of research, this study aims to find the impact of two High Performance Work Practices i.e. employee training & empowerment on employee creativity via employee engagement. Data was collected from 400 respondents from 110 organizations representing mainly textile, FMCG, cement, petroleum, fertilizers, pesticides, chemicals, electronics, pharmaceuticals and other sectors. SPSS 17 has been used for Factor analysis, cronbach's alpha, correlation and regression analysis. The findings show that employee engagement partially mediates the relationship between HR practices and employee creativity. Theoretical & managerial implications along with limitations and recommendations for future research have also been discussed in the paper.