Miracle-dz/UniFAR-FTUs huggingface dataset:
Development of covalent inhibitors that can overcome resistance to first-generation FGFR kinase inhibitors

Significance Inhibitors of the FGF receptors (FGFRs) are currently under clinical investigation for the treatment of various cancers. All currently approved kinase inhibitors eventually are rendered useless by the emergence of drug-resistant tumors. We used structure-based drug design to develop the first, to our knowledge, selective, next-generation covalent FGFR inhibitors that can overcome the most common form of kinase inhibitor resistance, the mutation of the so-called “gatekeeper” residue located in the ATP-binding pocket. We also describe a novel kinase inhibitor design strategy that uses a single electrophile to target covalently cysteines that are located in different positions within the ATP-binding pocket. These results have important implications for the design of covalent FGFR inhibitors that can overcome clinical resistance. The human FGF receptors (FGFRs) play critical roles in various human cancers, and several FGFR inhibitors are currently under clinical investigation. Resistance usually results from selection for mutant kinases that are impervious to the action of the drug or from up-regulation of compensatory signaling pathways. Preclinical studies have demonstrated that resistance to FGFR inhibitors can be acquired through mutations in the FGFR gatekeeper residue, as clinically observed for FGFR4 in embryonal rhabdomyosarcoma and neuroendocrine breast carcinomas. Here we report on the use of a structure-based drug design to develop two selective, next-generation covalent FGFR inhibitors, the FGFR irreversible inhibitors 2 (FIIN-2) and 3 (FIIN-3). To our knowledge, FIIN-2 and FIIN-3 are the first inhibitors that can potently inhibit the proliferation of cells dependent upon the gatekeeper mutants of FGFR1 or FGFR2, which confer resistance to first-generation clinical FGFR inhibitors such as NVP-BGJ398 and AZD4547. Because of the conformational flexibility of the reactive acrylamide substituent, FIIN-3 has the unprecedented ability to inhibit both the EGF receptor (EGFR) and FGFR covalently by targeting two distinct cysteine residues. We report the cocrystal structure of FGFR4 with FIIN-2, which unexpectedly exhibits a “DFG-out” covalent binding mode. The structural basis for dual FGFR and EGFR targeting by FIIN3 also is illustrated by crystal structures of FIIN-3 bound with FGFR4 V550L and EGFR L858R. These results have important implications for the design of covalent FGFR inhibitors that can overcome clinical resistance and provide the first example, to our knowledge, of a kinase inhibitor that covalently targets cysteines located in different positions within the ATP-binding pocket.
Adaptive Patterns of Mitogenome Evolution Are Associated with the Loss of Shell Scutes in Turtles

Abstract The mitochondrial genome encodes several protein components of the oxidative phosphorylation (OXPHOS) pathway and is critical for aerobic respiration. These proteins have evolved adaptively in many taxa, but linking molecular-level patterns with higher-level attributes (e.g., morphology, physiology) remains a challenge. Turtles are a promising system for exploring mitochondrial genome evolution as different species face distinct respiratory challenges and employ multiple strategies for ensuring efficient respiration. One prominent adaptation to a highly aquatic lifestyle in turtles is the secondary loss of keratenized shell scutes (i.e., soft-shells), which is associated with enhanced swimming ability and, in some species, cutaneous respiration. We used codon models to examine patterns of selection on mitochondrial protein-coding genes along the three turtle lineages that independently evolved soft-shells. We found strong evidence for positive selection along the branches leading to the pig-nosed turtle (Carettochelys insculpta) and the softshells clade (Trionychidae), but only weak evidence for the leatherback (Dermochelys coriacea) branch. Positively selected sites were found to be particularly prevalent in OXPHOS Complex I proteins, especially subunit ND2, along both positively selected lineages, consistent with convergent adaptive evolution. Structural analysis showed that many of the identified sites are within key regions or near residues involved in proton transport, indicating that positive selection may have precipitated substantial changes in mitochondrial function. Overall, our study provides evidence that physiological challenges associated with adaptation to a highly aquatic lifestyle have shaped the evolution of the turtle mitochondrial genome in a lineage-specific manner.
The Influence of “State” Related Factors on Focused Attention Following Whiplash Associated Disorder

The modified Stroop task was presented to 48 patients with a Whiplash Associated Disorder (WAD) and 48 healthy matched controls to investigate possible attentional impairments in relation to state related factors (headache, neck pain, fatigue, tension and state-anxiety). It was expected that performance on the Stroop task is negatively influenced by these state related variables. Confirming the expectations, the results showed that response latencies increase for Subtasks 1 through 4, for both groups. In addition, WAD patients performed significantly worse on all subtasks. There was a significant interaction between the two groups and the four subtasks. The results revealed signs for interference susceptibility or reduced capacity to shift attention on the modified Stroop task. The results concerning the influence of state variables indicated that the intensity of headache was significantly related (demonstrating a worsening) to Stroop task performance in the WAD-group. It was concluded that WAD patients exhibit a general slowing of information processing, especially on tasks that require controlled attention. There are signs for subtle deficits in focused attention. The intensity of headache seems to play an important influence on attentional functioning. Clinical implications are discussed.
A Critique of Software Defect Prediction Models

Many organizations want to predict the number of defects (faults) in software systems, before they are deployed, to gauge the likely delivered quality and maintenance effort. To help in this numerous software metrics and statistical models have been developed, with a correspondingly large literature. We provide a critical review of this literature and the state-of-the-art. Most of the wide range of prediction models use size and complexity metrics to predict defects. Others are based on testing data, the "quality" of the development process, or take a multivariate approach. The authors of the models have often made heroic contributions to a subject otherwise bereft of empirical studies. However, there are a number of serious theoretical and practical problems in many studies. The models are weak because of their inability to cope with the, as yet, unknown relationship between defects and failures. There are fundamental statistical and data quality problems that undermine model validity. More significantly many prediction models tend to model only part of the underlying problem and seriously misspecify it. To illustrate these points the Goldilock's Conjecture, that there is an optimum module size, is used to show the considerable problems inherent in current defect prediction approaches. Careful and considered analysis of past and new results shows that the conjecture lacks support and that some models are misleading. We recommend holistic models for software defect prediction, using Bayesian belief networks, as alternative approaches to the single-issue models used at present. We also argue for research into a theory of "software decomposition" in order to test hypotheses about defect introduction and help construct a better science of software engineering.
Run your research: on the effectiveness of lightweight mechanization

Formal models serve in many roles in the programming language community. In its primary role, a model communicates the idea of a language design; the architecture of a language tool; or the essence of a program analysis. No matter which role it plays, however, a faulty model doesn't serve its purpose. One way to eliminate flaws from a model is to write it down in a mechanized formal language. It is then possible to state theorems about the model, to prove them, and to check the proofs. Over the past nine years, PLT has developed and explored a lightweight version of this approach, dubbed Redex. In a nutshell, Redex is a domain-specific language for semantic models that is embedded in the Racket programming language. The effort of creating a model in Redex is often no more burdensome than typesetting it with LaTeX; the difference is that Redex comes with tools for the semantics engineering life cycle.
Chemokine and chemokine receptors in autoimmunity: the case of primary biliary cholangitis

ABSTRACT Chemokines represent a major mediator of innate immunity and play a key role in the selective recruitment of cells during localized inflammatory responses. Beyond critical extracellular mediators of leukocyte trafficking, chemokines and their cognate receptors are expressed by a variety of resident and infiltrating cells (monocytes, lymphocytes, NK cells, mast cells, and NKT cells). Chemokines represent ideal candidates for mechanistic studies (particularly in murine models) to better understand the pathogenesis of chronic inflammation and possibly become biomarkers of disease. Nonetheless, therapeutic approaches targeting chemokines have led to unsatisfactory results in rheumatoid arthritis, while biologics against pro-inflammatory cytokines are being used worldwide with success. In this comprehensive review we will discuss the evidence supporting the involvement of chemokines and their specific receptors in mediating the effector cell response, utilizing the autoimmune/primary biliary cholangitis setting as a paradigm.
FIFO is Unstable at Arbitrarily Low Rates

In this work, we study the stability of the FIFO (First-In-First-Out) protocol in the context of Adversarial Queueing Theory. As an important intermediate step, we consider dynamic capacities, where each network link capacity may arbitrarily take on values in the two-valued set of integers f1; Cg for C > 1 being the high capacity (a parameter). In this context: (1) We construct a FIFO network of only eight nodes which is already unstable at rate r = 0:41. This is the current record for instability of FIFO over networks of flxed-size (independent of r). (2) For every r > 0 we then construct a FIFO network (whose size increases with 1 ) which is unstable at rate r. Subsequently, we show how to simulate the particular FIFO network in (2) above with dynamic capacities 1, C, in order to produce a FIFO network with all link capacities being equal, while preserving instability thresholds. Hence, we eventually show our main result: FIFO can become unstable in the usual model of unit capacities links, for arbitrarily low packet injection rates. This closes a major open problem (the question of FIFO stability) in the fleld of Adversarial Queueing Theory posed in the pioneering work of Borodin et al. [5].
Single incision laparoscopic liver resection (SILL) – a systematic review

Background: Today, minimally invasive liver resections for both benign and malignant tumors are routinely performed. Recently, some authors have described single incision laparoscopic liver resection (SILL) procedures. Since SILL is a relatively young branch of laparoscopy, we performed a systematic review of the current literature to collect data on feasibility, perioperative results and oncological outcome. Methods: A literature research was performed on Medline for all studies that met the eligibility criteria. Titles and abstracts were screened by two authors independently. A study was included for review if consensus was obtained by discussion between the authors on the basis of predefined inclusion criteria. A thorough quality assessment of all included studies was performed. Data were analyzed and tabulated according to predefined outcome measures. Synthesis of the results was achieved by narrative review. Results: A total of 15 eligible studies were identified among which there was one prospective cohort study and one randomized controlled trial comparing SILL to multi incision laparoscopic liver resection (MILL). The rest were retrospective case series with a maximum of 24 patients. All studies demonstrated convincing results with regards to feasibility, morbidity and mortality. The rate of wound complications and incisional hernia was low. The cosmetic results were good. Conclusions: This is the first systematic review on SILL including prospective trials. The results of the existing studies reporting on SILL are favorable. However, a large body of scientific evidence on the field of SILL is missing, further randomized controlled studies are urgently needed.
Calpain: new perspectives in molecular diversity and physiological‐pathological involvement

Calpain, calcium‐activated neutral protease, stands as a unique receptor for calcium signals in biological systems; its activation leads to irreversible proteolytic processing of substrate proteins, modifying cellular situations in a manner distinct from that of reversible processes including the phosphorylation‐dephosphorylation reactions. Because the enzyme participates not only in normal intracellular signal transduction cascades but also in various pathological states including ischemia, calpain research has attracted tremendous interest in wide areas of life sciences in both basic and clinical terms. This review will address the new perspectives evoked by recent discoveries since 1990. Molecular biological studies have established that calpain in fact constitutes a large family of distinct isozymes differing in structure and distribution, whereas an increasing number of reports describe physiological‐pathological involvement of calpain. Another major accomplishment is the technical breakthrough allowing spatial resolution of calpain action presenting a clearer in vivo picture of how calpain acts in cells and tissues. — ‐Saido, T. C. , Sorimachi, H. , Suzuki, K. Calpain: new perspectives in molecular diversity and physiological‐pathological involvement. FASEB J. 8: 814‐822; 1994.
Breast cancer in Tunisia: clinical and pathological findings.

INTRODUCTION The aim of this study was to survey the clinical and pathological features of breast cancer in the Center of Tunisia. DESIGN Characteristics of all breast cancer cases diagnosed in the Pathology Department, Farhet Hached Hospital, Sousse, Tunisia during a 15-year period (1993-2007) were analyzed. RESULTS A total of 2,404 new cases of breast cancer were recorded, only 48 being diagnosed in men. The age-standardized incidence rate was 0.7 and 29.2 per 100,000 in men and women, respectively, with median ages of 48.0 and 64.5 years. Invasive ductal carcinoma was the most common (2,012 cases). Stage II was the most frequent (47.7%) followed by advanced stages (Stage III and IV, 41%). CONCLUSION Cancer of the breast remains the most common cancer in the absence of specific screening measures among Tunisian women. Our study justifies the need to plan and develop effective programs aiming at the control and prevention of the spread of breast cancer in Tunisia.
A Decision Tree Analysis of Diabetic Foot Amputation Risk in Indian Patients

Aim The aim of this study is to create an evidence-based tool that guides the risk of amputation in diabetic foot patients. Materials and methods Hospital records of 301 diabetic foot patients were examined retrospectively for explanatory variables of foot amputation decisions. The study included all patients with a lower limb ulcer with a known history of diabetes mellitus or those diagnosed post-admission. The dataset was analyzed, and a risk scoring system was constructed using the decision tree algorithm, C5.0. Two classifiers, one simple and another complex, were constructed for predicting amputation outcome. Results and discussion Based on our evaluation, the most influential predictors for a decision to amputate are Doppler flow measurements and the Wagner grading of the ulceration. The simple classifier uses just these two parameters in determining risk. The results obtained show an accuracy of 96.4% in the primary group and an accuracy of 94% in the test group. The second classifier is a more complex computer-derived construct that showed 100% accuracy in the principle group and an accuracy of 96% during testing. Conclusion In the present era of precision medicine, these two classifiers act as an accurate guide to the prognosis of the limb in patients with diabetic foot and can predict the risk of future amputation.
T-Cell-Independent Immunoglobulin G Responses In Vivo Are Elicited by Live-Virus Infection but Not by Immunization with Viral Proteins or Virus-Like Particles

ABSTRACT Immunoglobulin G (IgG) responses to viruses are generally assumed to be T-cell dependent (TD). Recently, however, polyomavirus (PyV) infection of T-cell-deficient (T-cell receptor β chain [TCR-β] −/− or TCR-β×δ −/−) mice was shown to elicit a protective, T-cell-independent (TI) antiviral IgM and IgG response. A repetitive, highly organized antigenic structure common to many TI antigens is postulated to be important in the induction of antibody responses in the absence of helper T cells. To test whether the repetitive structure of viral antigens is essential and/or sufficient for the induction of TI antibodies, we compared the abilities of three forms of PyV antigens to induce IgM and IgG responses in T-cell-deficient mice: soluble capsid antigens (VP1), repetitive virus-like particles (VLPs), and live PyV. Immunization with each of the viral antigens resulted in IgM production. VLPs and PyV elicited 10-fold-higher IgM titers than VP1, indicating that the highly organized, repetitive antigens are more efficient in IgM induction. Antigen-specific TI IgG responses, however, were detected only in mice infected with live PyV, not in VP1- or VLP-immunized mice. These results suggest that the highly organized, repetitive nature of the viral antigens is insufficient to account for their ability to elicit TI IgG response and that signals generated by live-virus infection may be essential for the switch to IgG production in the absence of T cells. Germinal centers were not observed in T-cell-deficient PyV-infected mice, indicating that the germinal center pathway of B-cell differentiation is TD even in the context of a virus infection.
ProNGF, but Not NGF, Switches from Neurotrophic to Apoptotic Activity in Response to Reductions in TrkA Receptor Levels

Nerve growth factor (NGF) promotes the survival and differentiation of neurons. NGF is initially synthesized as a precursor, proNGF, which is the predominant form in the central nervous system. NGF and proNGF bind to TrkA/p75NTR to mediate cell survival and to sortilin/p75NTR to promote apoptosis. The ratio of TrkA to p75NTR affects whether proNGF and mature NGF signal cell survival or apoptosis. The purpose of this study was to determine whether the loss of TrkA influences p75NTR or sortilin expression levels, and to establish whether proNGF and mature NGF have a similar ability to switch between cell survival and cell death. We systematically altered TrkA receptor levels by priming cells with NGF, using small interfering RNA, and using the mutagenized PC12nnr5 cell line. We found that both NGF and proNGF can support cell survival in cells expressing TrkA, even in the presence of p75NTR and sortilin. However, when TrkA is reduced, proNGF signals cell death, while NGF exhibits no activity. In the absence of TrkA, proNGF-induced cell death occurs, even when p75NTR and sortilin levels are reduced. These results show that proNGF can switch between neurotrophic and apoptotic activity in response to changes in TrkA receptor levels, whereas mature NGF cannot. These results also support the model that proNGF is neurotrophic under normal circumstances, but that a loss in TrkA in the presence of p75NTR and sortilin, as occurs in neurodegenerative disease or injury, shifts proNGF, but not NGF, signalling from cell survival to cell death.
Branes and toric geometry

We show that toric geometry can be used rather effectively to translate a brane configuration to geometry. Roughly speaking the skeletons of toric space are identified with the brane configurations. The cases where the local geometry involves hypersurfaces in toric varieties (such as P^2 blown up at more than 3 points) presents a challenge for the brane picture. We also find a simple physical explanation of Batyrev's construction of mirror pairs of Calabi-Yau manifolds using T-duality.
Effect of MK-801 and Clozapine on the Proteome of Cultured Human Oligodendrocytes

Separate lines of evidence have demonstrated the involvement of N-methyl-D-aspartate (NMDA) receptor and oligodendrocyte dysfunctions in schizophrenia. Here, we have carried out shotgun mass spectrometry proteome analysis of oligodendrocytes treated with the NMDA receptor antagonist MK-801 to gain potential insights into these effects at the molecular level. The MK-801 treatment led to alterations in the levels of 68 proteins, which are associated with seven distinct biological processes. Most of these proteins are involved in energy metabolism and many have been found to be dysregulated in previous proteomic studies of post-mortem brain tissues from schizophrenia patients. Finally, addition of the antipsychotic clozapine to MK-801-treated oligodendrocyte cultures resulted in changes in the levels of 45 proteins and treatment with clozapine alone altered 122 proteins and many of these showed opposite changes to the MK-801 effects. Therefore, these proteins and the associated energy metabolism pathways should be explored as potential biomarkers of antipsychotic efficacy. In conclusion, MK-801 treatment of oligodendrocytes may provide a useful model for testing the efficacy of novel treatment approaches.
Age-Related Differences in Neural Activity during Item and Temporal-Order Memory Retrieval: A Positron Emission Tomography Study

Positron emission tomography (PET) was used to investigate the hypothesis that older adults' difficulties with temporal-order memory are related to deficits in frontal function. Young (mean 24.7 years) and old (mean 68.6 years) participants studied a list of words, and were then scanned while retrieving information about what words were in the list (item retrieval) or when they occurred within the list (temporal-order retrieval). There were three main results. First, whereas the younger adults engaged right prefrontal regions more during temporal-order retrieval than during item retrieval, the older adults did not. This result is consistent with the hypothesis that context memory deficits in older adults are due to frontal dysfunction. Second, ventromedial temporal activity during item memory was relatively unaffected by aging. This finding concurs with evidence that item memory is relatively preserved in old adults and with the notion that medial temporal regions are involved in automatic retrieval operations. Finally, replicating the result of a previous study (Cabeza, R., Grady, C. L, Nyberg, L., McIntosh, A. R., Tulving, E., Kapur, S., Jennings, J. M., Houle, S., & Craik, F. I. M., 1997), the old adults showed weaker activations than the young adults in the right prefrontal cortex but stronger activations in the left prefrontal cortex. The age-related increase in left prefrontal activity may be interpreted as compensatory. Taken together, the results suggest that age-related changes in brain activity are rather process- and region-specific, and that they involve increases as well as decreases in neural activity.