Miracle-dz/UniFAR-FTUs huggingface dataset:
Identifying the reactive metabolites of tyrosine kinase inhibitors in a comprehensive approach: Implications for drug‐drug interactions and hepatotoxicity

Tyrosine kinase inhibitors (TKI) are small heterocyclic molecules targeting transmembrane and cytoplasmic tyrosine kinases that have met with considerable success in clinical oncology. TKI are associated with toxicities including liver injury that may be serious and even life‐threatening. Many of them require warnings in drug labeling against liver injury, and five of them have Black Box Warning (BBW) labels. Although drug‐induced liver injury is a matter of clinical and industrial concern, little is known about the underlying mechanisms that likely involve reactive metabolites (RM). RM are electrophiles or radicals originating from the metabolic activation of particular functional groups, known as structural alerts or toxicophores. RM are able to covalently bind to proteins and macromolecules, causing cellular damage and even cell death. If the adducted protein is the enzyme involved in RM formation, time‐dependent inhibition of the enzyme—also called mechanism‐based inhibition (MBI) or inactivation—can occur and lead to pharmacokinetic drug‐drug interactions. To mitigate RM liabilities, common practice in drug development includes avoiding structural alerts and assessing RM formation via RM trapping screens with soft and hard nucleophiles (glutathione, potassium cyanide, and methoxylamine) in liver microsomes. RM‐positive derivatives are further optimized to afford drug candidates with blocked or minimized bioactivation potential. However, different structural alerts are still commonly used scaffolds in drug design, including in TKI structures. This review focuses on the current state of knowledge of the relations among TKI structures, bioactivation pathways, RM characterization, and hepatotoxicity and cytochrome P450 MBI in vitro.
Gender and Age Variations in Pharmacists’ Job Satisfaction in the United States

While several studies have attested the presence of systematic gender and age variations in pharmacists’ satisfaction with their jobs, only a few of them have considered both classifications simultaneously. None have done so while systematically examining multiple facets of practitioners’ work. This article estimated U.S. pharmacists’ satisfaction levels with various facets of their work, compared them simultaneously between genders and among age groups, and tested for the presence of gender–age interaction effects. The study was based on self-reported survey data collected from 701 pharmacists (31.0% response rate). Mean and standard deviation values for 18 indices related to pharmacists’ work were calculated. When age groups were controlled, female pharmacists expressed overall higher levels of satisfaction with their job than male pharmacists; they also expressed greater satisfaction with multiple specific facets and with the profession, as well as greater workload and stress than male pharmacists. The findings revealed few significant differences among age groups and a limited gender–age interaction effect for pharmacists’ satisfaction with key facets of their work. These findings should contribute to the development and refinement of rational criteria for increasing sources of satisfaction in pharmacy settings.
Associations of perceived stress and state anger with symptom burden and functional status in patients with heart failure

Abstract Background: Psychosocial stress and anger trigger cardiovascular events, but their relationship to heart failure (HF) exacerbations is unclear. We investigated perceived stress and anger associations with HF functional status and symptoms. Methods and Results: In a prospective cohort study (BETRHEART), 144 patients with HF (77% male; 57.5 ± 11.5 years) were evaluated for perceived stress (Perceived Stress Scale; PSS) and state anger (STAXI) at baseline and every 2 weeks for 3 months. Objective functional status (6-min walk test; 6MWT) and health status (Kansas City Cardiomyopathy Questionnaire; KCCQ) were also measured biweekly. Linear mixed model analyses indicated that average PSS and greater than usual increases in PSS were associated with worsened KCCQ scores. Greater than usual increases in PSS were associated with worsened 6MWT. Average anger levels were associated with worsened KCCQ, and increases in anger were associated with worsened 6MWT. Adjusting for PSS, anger associations were no longer statistically significant. Adjusting for anger, PSS associations with KCCQ and 6MWT remained significant. Conclusion: In patients with HF, both perceived stress and anger are associated with poorer functional and health status, but perceived stress is a stronger predictor. Negative effects of anger on HF functional status and health status may partly operate through psychological stress.
Loss of Prefrontal Cortical Higher Cognition with Uncontrollable Stress: Molecular Mechanisms, Changes with Age, and Relevance to Treatment

The newly evolved prefrontal cortex (PFC) generates goals for “top-down” control of behavior, thought, and emotion. However, these circuits are especially vulnerable to uncontrollable stress, with powerful, intracellular mechanisms that rapidly take the PFC “off-line. ” High levels of norepinephrine and dopamine released during stress engage α1-AR and D1R, which activate feedforward calcium-cAMP signaling pathways that open nearby potassium channels to weaken connectivity and reduce PFC cell firing. Sustained weakening with chronic stress leads to atrophy of dendrites and spines. Understanding these signaling events helps to explain the increased susceptibility of the PFC to stress pathology during adolescence, when dopamine expression is increased in the PFC, and with advanced age, when the molecular “brakes” on stress signaling are diminished by loss of phosphodiesterases. These mechanisms have also led to pharmacological treatments for stress-related disorders, including guanfacine treatment of childhood trauma, and prazosin treatment of veterans and civilians with post-traumatic stress disorder.
When does NIP transfer from fields to henselian expansions

Let $K$ be an NIP field and let $v$ be a henselian valuation on $K$. We ask whether $(K,v)$ is NIP as a valued field. By a result of Shelah, we know that if $v$ is externally definable, then $(K,v)$ is NIP. Using the definability of the canonical $p$-henselian valuation, we show that whenever the residue field of $v$ is not separably closed, then $v$ is externally definable. In the case of separably closed residue field, we show that $(K,v)$ is NIP as a pure valued field.
Cannabidiol for the Reduction of Cue-Induced Craving and Anxiety in Drug-Abstinent Individuals With Heroin Use Disorder: A Double-Blind Randomized Placebo-Controlled Trial.

OBJECTIVE Despite the staggering consequences of the opioid epidemic, limited nonopioid medication options have been developed to treat this medical and public health crisis. This study investigated the potential of cannabidiol (CBD), a nonintoxicating phytocannabinoid, to reduce cue-induced craving and anxiety, two critical features of addiction that often contribute to relapse and continued drug use, in drug-abstinent individuals with heroin use disorder. METHODS This exploratory double-blind randomized placebo-controlled trial assessed the acute (1 hour, 2 hours, and 24 hours), short-term (3 consecutive days), and protracted (7 days after the last of three consecutive daily administrations) effects of CBD administration (400 or 800 mg, once daily for 3 consecutive days) on drug cue-induced craving and anxiety in drug-abstinent individuals with heroin use disorder. Secondary measures assessed participants' positive and negative affect, cognition, and physiological status. RESULTS Acute CBD administration, in contrast to placebo, significantly reduced both craving and anxiety induced by the presentation of salient drug cues compared with neutral cues. CBD also showed significant protracted effects on these measures 7 days after the final short-term (3-day) CBD exposure. In addition, CBD reduced the drug cue-induced physiological measures of heart rate and salivary cortisol levels. There were no significant effects on cognition, and there were no serious adverse effects. CONCLUSIONS CBD's potential to reduce cue-induced craving and anxiety provides a strong basis for further investigation of this phytocannabinoid as a treatment option for opioid use disorder.
Fibroblast-Mediated Immunoregulation of Macrophage Function Is Maintained after Irradiation

The abilities of cancer-associated fibroblasts (CAFs) to regulate immune responses in the context of radiotherapy remain largely unknown. This study was undertaken to determine whether ionizing radiation alters the CAF-mediated immunoregulatory effects on macrophages. CAFs were isolated from freshly-resected non-small cell lung cancer tumors, while monocyte-derived macrophages were prepared from peripheral blood of healthy donors. Experimental settings included both (CAF-macrophage) co-cultures and incubations of M0 and M1-macrophages in the presence of CAF-conditioned medium (CAF-CM). Functional assays to study macrophage polarization/activation included the expression of cell surface markers, production of nitric oxide, secretion of inflammatory cytokines and migratory capacity. We show that CAFs promote changes in M0-macrophages that harmonize with both M1-and M2-phenotypes. Additionally, CAFs inhibit pro-inflammatory features of M1-macrophages by reducing nitric oxide production, pro-inflammatory cytokines, migration, and M1-surface markers expression. Radiation delivered as single-high dose or in fractioned regimens did not modify the immunoregulatory features exerted by CAFs over macrophages in vitro. Protein expression analyses of CAF supernatants showed that irradiated and non-irradiated CAFs produce approximately the same protein levels of immunoregulators. Thus, CAF-derived soluble factors mediate measurable changes on uncommitted macrophages and down-regulate pro-inflammatory features of M1-polarized macrophages. Notably, ionizing radiation does not curtail the CAF-mediated immunosuppressive effects.
Biomechanics of the craniocervical region: The alar and transverse ligaments

In the treatment of spine fractures and fracture‐dislocations, stability of the spine is one of the major objectives. In the craniocervical joint, the alar and transverse ligaments provide much of the stability of the healthy spine. Because the anatomy appears well described, the contribution of each of these structures so far has received little attention. The alar ligament restrains rotation of the upper cervical spine, whereas the transverse ligament restricts flexion as well as anterior displacement of the atlas. A lesion in one or both structures can produce damage to the neural structures and/or cause pain. To investigate the possible role of each of these ligaments, a mechanical and histologic study of the upper cervical spine was made. The bone‐ligament‐bone complex of the alar and transverse ligaments was subjected to unlaxial mechanical testing in seven specimens. The alar ligaments had an in vitro strength of 200 N, and the transverse ligaments had an in vitro strength of 350 N. Histologic analysis revealed a mainly collagenous nature of these ligaments. Clinical evidence (broken odontoid processes) suggests that the transverse ligament is strong enough to withstand physiologic loads. The alar ligament, on the other hand, due to its lower strength and its axial direction of loading, might be prone to injury and therefore require stabilization of the appropriate vertebra more often than normally is assumed.
Parvalbumin-Positive Inhibitory Interneurons Oppose Propagation But Favor Generation of Focal Epileptiform Activity

Parvalbumin (Pv)-positive inhibitory interneurons effectively control network excitability, and their optogenetic activation has been reported to block epileptic seizures. An intense activity in GABAergic interneurons, including Pv interneurons, before seizures has been described in different experimental models of epilepsy, raising the hypothesis that an increased GABAergic inhibitory signal may, under certain conditions, initiate seizures. It is therefore unclear whether the activity of Pv interneurons enhances or opposes epileptiform activities. Here we use a mouse cortical slice model of focal epilepsy in which the epileptogenic focus can be identified and the role of Pv interneurons in the generation and propagation of seizure-like ictal events is accurately analyzed by a combination of optogenetic, electrophysiological, and imaging techniques. We found that a selective activation of Pv interneurons at the focus failed to block ictal generation and induced postinhibitory rebound spiking in pyramidal neurons, enhancing neuronal synchrony and promoting ictal generation. In contrast, a selective activation of Pv interneurons distant from the focus blocked ictal propagation and shortened ictal duration at the focus. We revealed that the reduced ictal duration was a direct consequence of the ictal propagation block, probably by preventing newly generated afterdischarges to travel backwards to the original focus of ictal initiation. Similar results were obtained upon individual Pv interneuron activation by intracellular depolarizing current pulses. The functional dichotomy of Pv interneurons here described opens new perspectives to our understanding of how local inhibitory circuits govern generation and spread of focal epileptiform activities.
Super-Wide Impedance Bandwidth Planar Antenna for Microwave and Millimeter-Wave Applications

A feasibility study of a novel configuration for a super-wide impedance planar antenna is presented based on a 2 × 2 microstrip patch antenna (MPA) using CST Microwave Studio. The antenna comprises a symmetrical arrangement of four-square patches that are interconnected to each other with cross-shaped high impedance microstrip lines. The antenna array is excited through a single feedline connected to one of the patches. The proposed antenna array configuration overcomes the main drawback of conventional MPA with a narrow bandwidth that is typically <5%. The antenna exhibits a super-wide frequency bandwidth from 20 GHz to 120 GHz for S11 < −15 dB, which corresponds to a fractional bandwidth of 142.85%. The antenna’s performance of bandwidth, impedance match, and radiation gain were enhanced by etching slots on the patches. With the inclusion of the slot, the maximum radiation gain and efficiency of the MPA increased to 15.11 dBi and 85.79% at 80 GHz, which showed an improvement of 2.58 dBi and 12.54%, respectively. The dimension of each patch antenna was 4.3 × 5.3 mm2. The results showed that the proposed MPA is useful for various existing and emerging communication systems such as ultra-wideband (UWB) communications, RFID systems, massive multiple-output multiple-input (MIMO) for 5G, and radar systems.
Prevalence of Pseudomonas Aeruginosa and its Antibiotic Sensitivity Pattern.

BACKGROUND Pseudomonas aeruginosa is an opportunistic pathogen which causes most of the chronic infection in humans. This study was undertaken to determine the prevalence rate of Pseudomonas aeruginosa that is isolated from various clinical specimens along with its antibiotic susceptibility pattern. METHODS This descriptive cross sectional study was conducted in Kathmandu Medical College and Teaching Hospital (KMCTH) from February to May 2018. Pseudomonas aeruginosa isolated from various clinical specimens were processed in clinical laboratory, Department of Microbiology, KMCTH. Isolation, identification and sensitivity of Pseudomonas aeruginosa to antibiotics were measured. RESULTS A total of 7527 samples were been processed of which 46 isolates of Pseudomonas aeruginosa were obtained. Pseudomonas aeruginosa was isolated mainly from Pus, Wound swab, Sputum and Tracheal aspirate. Here 63.04% Pseudomonas aeruginosa isolates were resistant to Ceftazidime, 65.21% to Cefixime, 56.52% to Ceftriaxone and Cefotaxime followed by 56.52% to Piperacillin. Furthermore, the current study reveals antibiotics like Imipenem, Meropenem, Piperacillin/Tazobactam, Ciprofloxacin, Gentamicin, Amikacin and Tobramycin were found to be good choice for the treatment of infection caused by this organism. CONCLUSIONS Continuous monitoring of antibiotic susceptibility pattern of Pseudomonas aeruginosa is essential and rational treatment regimens prescription by the clinicians is required to limit the spread of antimicrobial resistance.
Recomputation of the Dense Layers for Performance Improvement of DCNN

Gradient descent optimization of learning has become a paradigm for training deep convolutional neural networks (DCNN). However, utilizing other learning strategies in the training process of the DCNN has rarely been explored by the deep learning (DL) community. This serves as the motivation to introduce a non-iterative learning strategy to retrain neurons at the top dense or fully connected (FC) layers of DCNN, resulting in, higher performance. The proposed method exploits the Moore-Penrose Inverse to pull back the current residual error to each FC layer, generating well-generalized features. Further, the weights of each FC layers are recomputed according to the Moore-Penrose Inverse. We evaluate the proposed approach on six most widely accepted object recognition benchmark datasets: Scene-15, CIFAR-10, CIFAR-100, SUN-397, Places365, and ImageNet. The experimental results show that the proposed method obtains improvements over 30 state-of-the-art methods. Interestingly, it also indicates that any DCNN with the proposed method can provide better performance than the same network with its original Backpropagation (BP)-based training.
Pharmacodynamics of Five Anthraquinones (Aloe-emodin, Emodin, Rhein, Chysophanol, and Physcion) and Reciprocal Pharmacokinetic Interaction in Rats with Cerebral Ischemia

(1) Background: Rhubarb anthraquinones—a class of components with neuroprotective function—can be used to alleviate cerebral ischemia reperfusion injury. (2) Methods: The three pharmacodynamic indicators are neurological function score, brain water content, and cerebral infarction area; UPLC-MS/MS was used in pharmacokinetic studies to detect plasma concentrations at different time points, and DAS software was used to calculate pharmacokinetic parameters in a noncompartmental model. (3) Results: The results showed that the pharmacodynamics and pharmacokinetics of one of the five anthraquinone aglycones could be modified by the other four anthraquinones, and the degree of interaction between different anthraquinones was different. The chrysophanol group showed the greatest reduction in pharmacodynamic indicators comparing with other four groups where the rats were administered one of the five anthraquinones, and there was no significant difference between the nimodipine group. While the Aloe-emodin + Physcion group showed the most obvious anti-ischemic effect among the groups where the subjects were administered two of the five anthraquinones simultaneously. Emodin, rhein, chrysophanol, and physcion all increase plasma exposure levels of aloe-emodin, while aloe-emodin lower their plasma exposure levels. (4) Conclusions: This experiment provides a certain preclinical basis for the study of anthraquinone aglycones against cerebral ischemia and a theoretical basis for the study of the mechanism of interaction between anthraquinones.
Protective Effect of 3-Deazaadenosine in a Rat Model of Lipopolysaccharide-Induced Myocardial Dysfunction

Severe sepsis is accompanied by a profound depression of myocardial contractility. Leukocyte adhesion with subsequent local excess nitric oxide and reactive oxygen species production play major roles for this deleterious effect. We hypothesized that 3-deazaadenosine (c3Ado), an adenosine analogue with anti-inflammatory properties, prevents endotoxin-induced myocardial dysfunction. Wistar rats (8 per group) were treated with Escherichia coli lipopolysaccharide (LPS, 1 mg/kg, i.p., strain 0111:B4) ± c3Ado (10 mg/kg, i.p.) 8 h before their hearts were harvested for isolated perfusion, histochemical analysis, or electrophoretic mobility shift assay. LPS induced a marked depression of left ventricular contractility. Immunohistochemistry revealed an upregulation of the adhesion molecules VCAM-1, ICAM-1, and P-selectin within the postcapillary venules. c3Ado inhibited VCAM-1 and ICAM-1 upregulation, but not P-selectin, and prevented cardiodepression. Electrophoretic mobility shift assay revealed inactivation of the transcription factor nuclear factor-&kgr;B and immunohistochemical staining for gp91phox, ED1, and CD11b demonstrated that c3Ado prevented local recruitment of monocytes and polymorph nuclear neutrophils to the myocardium. Accordingly, significantly fewer leukocytes producing nitric oxide or reactive oxygen species accumulated within the myocardium. Intravital microscopy of intestinal venules confirmed that LPS-induced adhesion of leukocytes was prevented by c3Ado. Additionally, c3Ado prevented LPS-induced elevation of serum tumor necrosis factor-&agr; levels. Our results imply that c3Ado may prove to have clinical relevance for inflammatory disease processes.
High Adherence to the Nordic Diet Is Associated with Lower Levels of Total and Platelet-Derived Circulating Microvesicles in a Norwegian Population

Circulating microvesicles (cMV) are small phospholipid-rich blebs shed from the membrane of activated vascular cells that contribute to vascular disease progression. We aimed to investigate whether the quality of the Nordic diet is associated with the degree of blood and vascular cell activation measured by MV shedding in elderly patients after an acute myocardial infarction (AMI). One-hundred and seventy-four patients aged 70–82 years were included in this cross-sectional study. Fasting blood samples were taken within 2 to 8 weeks after an AMI. Annexin V (AV)+ cMV derived from blood and vascular cells were measured through flow cytometry. A patient’s usual diet was recorded with the SmartDiet® questionnaire. Patients with higher adherence to the Nordic diet (highest diet score) had lower levels of total AV+ and platelet-derived (CD61+/AV+ and CD31+/AV+) cMV. Dietary habits influence cellular activation. A high adherence to the Nordic diet (assessed by the SmartDiet® score) in elderly post-AMI patients was associated with lower levels of platelet activation, which was reflected by a lesser release of MV carrying platelet-derived epitopes, potentially contributing to an explanation of the cardioprotective effects of the Nordic diet.
Identifying Dynamic Interactors of Protein Complexes by Quantitative Mass Spectrometry*S

Dynamically interacting proteins associate and dissociate with their binding partners at high on/off rates. Although their identification is of great significance to proteomics research, lack of an efficient strategy to distinguish stable and dynamic interactors has hampered the efforts toward this goal. In this work, we developed a new method, MAP (mixing after purification)-SILAC (stable isotope labeling of amino acids in cell culture), to quantitatively investigate the interactions of protein complexes by mass spectrometry. In combination with the original SILAC approach, stable and dynamic components were effectively distinguished by the differences in their relative abundance ratio changes. We applied the newly developed strategies to decipher the dynamics of the human 26 S proteasome-interacting proteins. A total of 67 putative human proteasome-interacting proteins were identified by the MAP-SILAC method among which 14 proteins would have been misidentified as background proteins due to low relative abundance ratios in standard SILAC experiments and 57 proteins have not been reported previously. In addition, 35 of the 67 proteins were classified as stable interactors of the proteasome complex, whereas 16 of them were identified as dynamic interactors. The methods reported here provide a valuable expansion of proteomics technologies for identification of important but previously unidentifiable interacting proteins.