Miracle-dz/UniFAR-FTUs huggingface dataset:
Association between ALDH2 and ADH1B Polymorphisms and the Risk for Colorectal Cancer in Koreans

Purpose Excessive alcohol consumption has been linked to an increased risk of colorectal cancer (CRC). We evaluated the association between alcohol-related genetic variants and CRC risk. Materials and Methods The study cohort consisted of 5,435 CRC cases and 3,553 population-based cancer-free controls. Genotype data were generated from germline DNA using the Infinium OncoArray-500K BeadChip in 2,535 cases and 2,287 controls and the Infinium Multi-Ethnic Global BeadChip in 2,900 cases and 1,266 controls. The associations between aldehyde dehydrogenase 2 (ALDH2) rs671 and alcohol dehydrogenase 1B (ADH1B) rs1229984 polymorphisms and CRC risk were assessed using multivariate logistic regression analyses. Results Compared with the major homozygous ALDH2 genotype (GG), heterozygous or minor homozygous ALDH2 genotype (GA or AA, related to a low alcohol consumption) was significantly associated with a reduced risk for CRC in men (odds ratio [OR], 0.78; 95% confidence interval [CI], 0.68 to 0.90), but not in women (OR, 0.70; 95% CI, 0.47 to 1.05). A stronger association was found among regular drinkers (OR, 0.58; 95% CI, 0.47 to 0.71 in men and OR, 0.33; 95% CI, 0.18 to 0.58 in women). No association of CRC risk with ADH1B rs1229984 genotype was found. The association between alcohol-related combined genotypes and risk of CRC was significant (p for linear=0.001). The combined genotype with the highest genetically predicted alcohol consumption (ALDH2 rs671 GG and ADH1B rs1229984 AG/GG) was associated with a high risk for CRC (OR, 1.35; 95% CI, 1.11 to 1.63). Conclusion Our study provides strong evidence for a possible causal association between alcohol consumption and CRC risk.
Temporary mechanical circulatory support prevents the occurrence of a low‐output state in high‐risk coronary artery bypass grafting: A case series

Coronary artery bypass grafting (CABG) is a durable treatment for coronary artery disease. Left ventricular dysfunction (LVD) (a division of cardiothoracic surgery) (ejection fraction < 35%) significantly elevates perioperative risk for patients pursuing surgical revascularization. Periprocedural support with temporary mechanical circulatory support (tMCS) has shown benefit in this patient population.
A pharmacokinetic study of morphine‐6‐O‐sulfate in rat plasma and brain

Morphine‐6‐O‐sulfate (M6S), a polar, zwitterionic sulfate ester of morphine, is a powerful and safe analgesic in several rat models of pain. A sensitive liquid chromatography–tandem mass spectrometry bioanalytical method was developed and validated for the simultaneous determination of M6S and morphine (MOR) in rat plasma and brain after M6S administration. Morphine‐d6 was used as internal standard. Multiple reaction monitoring was used for detection and quantitation of M6S, MOR, and morphine‐d6 in the turbo ion spray positive mode. The chromatographic separation was carried out on an Alltech Altima C18 column. The analytical method was validated for linearity, precision, accuracy, specificity, and stability over a concentration range of 3–8000 ng/ml in rat plasma and 10–10,000 ng/ml in brain samples for both M6S and MOR. The validated method was applied to determine the PK profile of M6S in plasma after i.v. , i.p., and oral dosing in male Sprague–Dawley rats. Rats were administered M6S by i.p. administration (5.6 and 10.0 mg/kg) or orally (10 and 30 mg/kg) and bioavailability compared to an i.v. injection (1 mg/kg) of M6S. The in vivo results indicate that M6S is not a prodrug of morphine, since M6S is not biotransformed into MOR in plasma after either i.p. or oral administration, and MOR was not detected in brain. The bioavailability of M6S was >93% and about 5% after i.p. and oral dosing, respectively. The low oral bioavailability of M6S may be due to poor permeation of the intestinal epithelial membrane. After i.p.‐administration, M6S appears to reach brain tissues in low, but significant, concentrations.
Adipose tissue macrophages as a therapeutic target in obesity‐associated diseases

Obesity is an increasing problem in developed and developing countries. Individuals with obesity have a higher risk of several diseases, such as cardiovascular disease, increased risk of insulin resistance, type 2 diabetes, infertility, degenerative disorders, and also certain types of cancer. Adipose tissue (AT) is considered an extremely active endocrine organ, and the expansion of AT is accompanied by the infiltration of different types of immune cells, which induces a state of low‐grade, chronic inflammation and metabolic dysregulation. Even though the exact mechanism of this low‐grade inflammation is not fully understood, there is clear evidence that AT‐infiltrating macrophages (ATMs) play a significant role in the pro‐inflammatory state and dysregulated metabolism. ATMs represent the most abundant class of leukocytes in AT, constituting 5% of the cells in AT in individuals with normal weight. However, this percentage dramatically increases up to 50% in individuals with obesity, suggesting an important role of ATMs in obesity and its associated complications. In this review, we discuss current knowledge of the function of ATMs during steady‐state and obesity and analyze its contribution to different obesity‐associated diseases, highlighting the potential therapeutic target of ATMs in these pathological conditions.
Structural characterization of the interaction between αMI‐domain of the integrin Mac‐1 (αMβ2) and the cytokine pleiotrophin

Integrin receptors are involved in numerous physiological processes, including inflammation, cell migration, extracellular matrix recognition, survival, and growth. Integrin Mac‐1 (αMβ2) is a monocyte adhesion receptor that can undergo rapid activation yielding conformational changes that subsequently allow increased affinity for its ligands and enable cellular responses such as rolling, adhesion, and transmigration of phagocytes to the inflammatory sites. αMβ2 is also the most promiscuous integrin receptor because it recognizes a large number of distinct ligands that share no homologous recognition motif. In particular, αMI‐domain is known to bind cationic proteins/peptides depleted in acidic residues. This contradicts the canonical ligand‐binding mechanism of αI‐domains, which requires an acidic amino acid in the ligand to coordinate the divalent cation within the metal ion‐dependent adhesion site (MIDAS) of αI‐domains. The lack of acidic amino acids in the αMI‐domain‐binding sequences suggests the existence of an as‐yet uncharacterized interaction mechanism. In the present study, we analyzed interactions of αMI‐domain with a representative Mac‐1 ligand, the cationic cytokine pleiotrophin (PTN). Through nuclear magnetic resonance (NMR) chemical shift perturbations, cross saturation, and nuclear Overhauser effect spectroscopy (NOESY), we found the interaction between αMI‐domain and PTN is divalent cation‐independent and mediated mostly by hydrophobic contacts between the N‐terminal domain of PTN and residues in the α5‐β5 loop of αMI‐domain. The mutation I265 in the α5‐β5 region confirms this area as a binding site of αMI‐domain for PTN. The observation that both increased ionic strength and mutations of acidic residues in the α5‐β5 loop weaken the interaction between the proteins indicates electrostatic interaction may also play a significant role in the binding. Based on results from these experiments, we formulated a model of the interaction between αMI‐domain and PTN. This unique mechanism of interaction between PTN and αMI‐domain should explain ligand recognition specificity of αMβ2.
When the response does not match the threat: The relationship between threat assessment and behavioural response in ambiguous lethal force decision-making

Deciding when to use lethal force inherently depends on assessing threat, a process that itself incorporates numerous perceptual factors. This study assessed this relationship between perception-based threat assessment and behaviour-based threat response. Specifically, participants completed multiple tasks designed to elicit either a threat rating (e.g., perception-informed threat assessment) or a binary behavioural response (e.g., shoot/don’t-shoot). Actor posture and weapon presence significantly affected the threat assessment, which was an extremely powerful omnibus predictor of threat response. However, for ambiguous threat stimuli, perceived threat became a poor predictor for threat response relative to the omnibus test. Participants appeared to adopt additional rules to inform behaviour independent of the threat assessment when faced with an ambiguous situation. These results demonstrate an intriguing disparity between subjective threat assessment and the behavioural response to use force that does not apply well to ambiguous cases or adequately explain errors in lethal force decisions.
The Effect of Passive Exposure to Tobacco Smoke on the Immune Response in Children with Asthma

Abstract Introduction: There are a few publications about the impact of tobacco smoke on the children’s immune system. Material and Methods: The study group consisted of 43 children with asthma. The control group consisted of 37 healthy children. The exposure to tobacco smoke was assessed by the presence of the cotinine in the urine (metabolit of nicotine). Results: The group of children with asthma exposed to tobacco smoke had significantly higher levels of the IL-1 and lower levels IL-4 than children not exposed to the passive smoking. The children from the control group exposed to tobacco smoke had a significantly higher concentration of IL-4 than unexposed children. In the whole analyzed population, there was a significant positive correlation between cotinine-IL1 and cotinine-CRP. Conclusion: In this study we found that the passive exposure to tobacco smoke has the immunomodulatory effects on the immune system.
Efferent unmasking of speech-in-noise encoding?

Abstract Objective The medial olivocochlear (MOC) reflex provides efferent feedback from the brainstem to cochlear outer hair cells. Physiologic studies have demonstrated that the MOC reflex is involved in “unmasking” of signals-in-noise at the level of the auditory nerve; however, its functional importance in human hearing remains unclear. Design This study examined relationships between pre-neural measurements of MOC reflex strength (click-evoked otoacoustic emission inhibition; CEOAE) and neural measurements of speech-in-noise encoding (speech frequency following response; sFFR) in four conditions (Quiet, Contralateral Noise, Ipsilateral Noise, and Ipsilateral + Contralateral Noise). Three measures of CEOAE inhibition (amplitude reduction, effective attenuation, and input-output slope inhibition) were used to quantify pre-neural MOC reflex strength. Correlations between pre-neural MOC reflex strength and sFFR “unmasking” (i.e. response recovery from masking effects with activation of the MOC reflex in time and frequency domains) were assessed. Study sample 18 young adults with normal hearing. Results sFFR unmasking effects were insignificant, and there were no correlations between pre-neural MOC reflex strength and sFFR unmasking in the time or frequency domain. Conclusion Our results do not support the hypothesis that the MOC reflex is involved in speech-in-noise neural encoding, at least for features that are represented in the sFFR at the SNR tested.
Genetic drivers and cells of origin in sarcomagenesis

Sarcoma comprises a group of malignancies that includes over 100 individual disease entities. Type‐specific genetic events initiate each tumor, occurring within a specific cellular context or circumstance. All sarcomas share a relationship with mesenchymal tissues of origin. Conceptual models for each specific route towards sarcomagenesis have developed over the years as clinical, cellular, and increasingly molecular observations have advanced hypotheses to be tested in the forward or reverse direction in experimental systems, often genetically engineered model organisms. This review considers the history of these discoveries in the context of technologies available at the time each was made and provides a comprehensive summary of the current knowledge of sarcoma genetics, including characteristic translocations, oncogene activation and loss of tumor suppressor gene events, and their putative cells of origin. Also considered are the interrelatedness of molecular clinical observations and genetic experiments in model systems to move this field of knowledge forward, as well as their implications for diagnostic and therapeutic paradigms for sarcoma. © 2021 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
Effect of simulated sensorimotor noise on kinematic variability and stability of a biped walking model

Abstract Whether higher variability in older adults’ walking is an indication of increased instability has been challenged recently. We performed a computer simulation to investigate the effect of sensorimotor noise on the kinematic variability and stability in a biped walking model. Stochastic differential equations of the system with additive Gaussian white noise was constructed and solved. Sensorimotor noise mainly resulted in higher kinematic variability but its influence on gait stability is minimal. This implies that kinematic variability evident in walking gaits of older adults could be the result of internal sensorimotor noise and not an indication of instability.
A mechanobiological approach to find the optimal thickness for the locking compression plate: Finite element investigations

This study aimed at finding the acceptable range, and the optimal value for the locking compression plate (LCP) thickness (THK), through simulating the osteogenic pathway of bone healing, and by checking bone-plate construct’s strength and stability. To attain the goals of this research, a multi-objective approach was adopted, which should trade-off between some conflicting objectives. A finite element model of the long bone-plate construct was made first, and validated against an experimental study. The validated model was then employed to determine the initial strength and stability of the bone-plate construct, for the time right after surgery, for various thicknesses of the LCP. Afterward, coupling with a mechano-regulatory algorithm, the iterative process of bone healing was simulated, and follow up was made for each LCP thickness, over the first 16 post-operative weeks. Results of this study regarding the sequence of tissue evolution inside the fracture gap, showed a similar trend with the existing in-vivo data. For the material and structural properties assigned to the bone-plate construct, in this study, an optimal thickness for the LCP was found to be 4.7 mm, which provides an enduring fixation through secondary healing, whereas for an LCP with a smaller or greater thickness, either bone-implant failure, unstable fixation, impaired fracture consolidation, or primary healing may occur. This result is in agreement with a recent study, that has employed a comprehensive optimization approach to find the optimal thickness.
A large genome with chromosome‐scale assembly sheds light on the evolutionary success of a true toad (Bufo gargarizans)

We present a high‐quality genome assembly for the Asiatic toad (Bufo gargarizans) and explore the evolution of several large gene families in amphibians. With a large genome assembly size of 4.55 Gb, the chromosome‐scale assembly includes 747 scaffolds with an N50 of 539.8 Mb and 1.79% gaps. Long terminal repeats (LTRs) constitute a high proportion of the genome and their expansion is a key contributor to the inflated genome size in this species. This is very different from other small amphibian genomes, but similar to that of the enormous axolotl genome. The genome retains a large number of duplicated genes, with tandem (TD) and proximal duplications (PD) the predominant mode of duplication. A total of 122 gene families have undergone significant expansion and were mainly enriched in sensory perception of smell and bitter taste. The CYP2C subfamily, which plays an important role in metabolic detoxification, specifically expanded via TD and PD in the Asiatic toad and the cane toad (true toads). Most of Na+/K+‐ATPase genes experienced accelerated evolution along Bufonid lineages and two amino acid sites involving toad‐toxin resistance were found to experience positive selection. We also revealed a dynamic evolution of olfactory and vomeronasal receptor gene families which was likely driven by the water‐to‐land transition. The high‐quality genome of the Asiatic toad will provide a solid foundation to understand the genetic basis of its many biological processes.
Individual Differences in the Contents and Form of Present-Moment Awareness: The Multidimensional Awareness Scale

Decentering, a detached, observer perspective on one’s mental activity, is an important concept for understanding mental health. Meta-awareness, people’s awareness of their own current mental activity, is thought to facilitate decentering. However, trait measures of these concepts are not available or have validity concerns. We sought to create a theoretically derived measure of meta-awareness and decentering that allowed an exploration of questions in the literature regarding whether there are multiple forms of decentered awareness and whether meta-awareness and external awareness are distinct. Across six samples and 2,480 participants, we developed the 25-item Multidimensional Awareness Scale, with subscales assessing meta-awareness (present moment awareness of mental activity), decentered awareness (meta-awareness from a psychologically distant perspective), and external awareness (present moment awareness of the world outside of oneself). The scales demonstrated acceptable reliability and validity. Results are discussed in terms of the conceptual implications of the scale structure and its potential uses.
The potency of selatogrel, a reversible antagonist of the P2Y12 receptor, is affected by calcium concentration

Abstract Here, we report the in vitro characterization of the P2Y12 receptor antagonist selatogrel (ACT-246475). Binding studies with radiolabeled selatogrel demonstrated that selatogrel is a competitive antagonist of ADP binding to the P2Y12 receptor with a fast onset of action. Consequently, selatogrel was confirmed to be a potent inhibitor of P2Y12-mediated intra-platelet signaling and ADP-induced platelet activation. Characterization of selatogrel in platelet-rich plasma in vitro demonstrated that the mode of anti-coagulation affected the anti-platelet potency. Specifically, in platelet-rich plasma containing physiological calcium concentration (anticoagulated with a direct thrombin inhibitor), selatogrel achieved half-maximal inhibition of ADP-induced platelet aggregation at a 3-fold lower concentration than in conditions with low calcium concentration (anticoagulated with citrate). Furthermore, calcium-dependent reduction in selatogrel potency was observed in whole blood platelet aggregation using the VerifyNow™ system with a 3.7-fold potency loss in low calcium conditions. A comparable potency loss was also observed with the reversible P2Y12 receptor antagonists ticagrelor, cangrelor and elinogrel. Furthermore, receptor-binding experiments using radiolabeled selatogrel confirmed a 3-fold lowering of selatogrel binding affinity to the P2Y12 receptor in low calcium conditions. In conclusion, our data suggest that in low calcium conditions (i.e., citrate-anticoagulated blood), there is a risk of underestimating the potency of reversible P2Y12 receptor antagonists. To avoid overdosing, and a potential increase in bleeding risk, we propose that the ex vivo evaluation of reversible P2Y12 receptor antagonists should be performed with platelet assay systems containing physiological calcium concentration.
Does variation in trait schizotypy and frequency of cannabis use influence the acute subjective, cognitive and psychotomimetic effects of delta-9-tetrahydrocannabinol? A mega-analysis

Background: While the acute effects of cannabis are relatively benign for most users, some individuals experience significant adverse effects. This study aimed to identify whether variation in schizotypal personality traits and frequency of cannabis use influence the acute effects of delta-9-tetrahydrocannabinol (THC). Methods: Individual participant data from four double-blind, randomised, placebo-controlled, acute crossover studies involving 128 cannabis users were combined for a mega-analysis. Using multilevel linear models and moderation analyses, frequency of cannabis use and schizotypal personality traits were investigated as potential moderators of the subjective, cognitive and psychotomimetic effects of acute THC. Results: There was evidence of a moderating effect where increased frequency of cannabis use was associated with reduced intensity of subjective (changes in alertness and feeling stoned) and psychosis-like effects following THC when compared with placebo. Moderating effects of cannabis use frequency on acute memory impairment were weak. Trait schizotypy did not moderate the acute psychosis-like effects of THC compared with placebo. Conclusions: Our results suggest that a pattern of domain-specific tolerance develops to the acute effects of THC. Tolerance to the alertness-reducing effects occurred more readily than tolerance to psychotomimetic effects. Only partial tolerance to feeling stoned was found, and there was weak evidence for tolerance to memory impairment. Trait schizotypy did not moderate THC’s effects on psychotomimetic symptoms.
Discovery of New Fusion Inhibitor Peptides against SARS-CoV-2 by Targeting the Spike S2 Subunit

A novel coronavirus, severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), caused a worldwide pandemic. Our aim in this study is to produce new fusion inhibitors against SARS-CoV-2, which can be the basis for developing new antiviral drugs. The fusion core comprising the heptad repeat domains (HR1 and HR2) of SARS-CoV-2 spike (S) were used to design the peptides. A total of twelve peptides were generated, comprising a short or truncated 24-mer (peptide #1), a long 36-mer peptide (peptide #2), and ten peptide #2 analogs. In contrast to SARS-CoV, SARS-CoV-2 S-mediated cell-cell fusion cannot be inhibited with a minimal length, 24-mer peptide. Peptide #2 demonstrated potent inhibition of SARS-CoV-2 S-mediated cell-cell fusion at 1 µM concentration. Three peptide #2 analogs showed IC50 values in the low micromolar range (4.7-9.8 µM). Peptide #2 inhibited the SARS-CoV-2 pseudovirus assay at IC50=1.49 µM. Given their potent inhibition of viral activity and safety and lack of cytotoxicity, these peptides provide an attractive avenue for the development of new prophylactic and therapeutic agents against SARS-CoV-2.