Miracle-dz/UniFAR-FTUs huggingface dataset:
Opioid Pharmacology under the Microscope

The powerful analgesic effects of opioid drugs have captivated the interest of physicians and scientists for millennia, and the ability of opioid drugs to produce serious undesired effects has been recognized for a similar period of time (Kieffer and Evans, 2009). Many of these develop progressively with prolonged or repeated drug use and then persist, motivating particular interest in understanding how opioid drugs initiate adaptive or maladaptive modifications in neural function or regulation. Exciting advances have been made over the past several years in elucidating drug-induced changes at molecular, cellular, and physiologic scales of analysis. The present review will highlight some recent cellular studies that we believe bridge across scales and will focus on optical imaging approaches that put opioid drug action “under the microscope. ” SIGNIFICANCE STATEMENT Opioid receptors are major pharmacological targets, but their signaling at the cellular level results from a complex interplay between pharmacology, regulation, subcellular localization, and membrane trafficking. This minireview discusses recent advances in understanding the cellular biology of opioid receptors, emphasizing particular topics discussed at the 50th anniversary of the International Narcotics Research Conference. Our goal is to highlight distinct signaling and regulatory properties emerging from the cellular biology of opioid receptors and discuss potential relevance to therapeutics.
Intestinal microbiota and its association with colon cancer and red/processed meat consumption

The human colon harbors a high number of microorganisms that were reported to play a crucial role in colorectal carcinogenesis. In the recent decade, molecular detection and metabolomic techniques have expanded our knowledge on the role of specific microbial species in promoting tumorigenesis. In this study, we reviewed the association between microbial dysbiosis and colorectal carcinoma (CRC). Various microbial species and their association with colorectal tumorigenesis and red/processed meat consumption have been reviewed. The literature demonstrated a significant abundance of Fusobacterium nucleatum, Streptococcus bovis/gallolyticus, Escherichia coli, and Bacteroides fragilis in patients with adenoma or adenocarcinoma compared to healthy individuals. The mechanisms in which each organism was postulated to promote colon carcinogenesis were collated and summarized in this review. These include the microorganisms' ability to adhere to colon cells; modulate the inhibition of tumor suppressor genes, the activations of oncogenes, and genotoxicity; and activate downstream targets responsible for angiogenesis. The role of these microorganisms in conjugation with meat components including N‐nitroso compounds, heterocyclic amines, and heme was also evident in multiple studies. The outcome of this review supports the role of red meat consumption in modulating CRC progression and the possibility of gut microbiome influencing the relationship between CRC and diet. The study also demonstrates that microbiota analysis could potentially complement existing screening methods when detecting colonic lesions.
Role of Proton Motive Force in Photoinduction of Cytoplasmic Streaming in Vallisneria Mesophyll Cells

In mesophyll cells of the aquatic monocot Vallisneria, red light induces rotational cytoplasmic streaming, which is regulated by the cytoplasmic concentration of Ca2+. Our previous investigations revealed that red light induces Ca2+ efflux across the plasma membrane (PM), and that both the red light-induced cytoplasmic streaming and the Ca2+ efflux are sensitive to vanadate, an inhibitor of P-type ATPases. In this study, pharmacological experiments suggested the involvement of PM H+-ATPase, one of the P-type ATPases, in the photoinduction of cytoplasmic streaming. We hypothesized that red light would activate PM H+-ATPase to generate a large H+ motive force (PMF) in a photosynthesis-dependent manner. We demonstrated that indeed, photosynthesis increased the PMF and induced phosphorylation of the penultimate residue, threonine, of PM H+-ATPase, which is a major activation mechanism of H+-ATPase. The results suggested that a large PMF generated by PM H+-ATPase energizes the Ca2+ efflux across the PM. As expected, we detected a putative Ca2+/H+ exchange activity in PM vesicles isolated from Vallisneria leaves.
Clinicopathological parameters for circulating tumor DNA shedding in surgically resected non-small cell lung cancer with EGFR or KRAS mutation

Background Circulating tumor DNA (ctDNA) is cell-free DNA that is released into peripheral blood by tumor cells. ctDNA harbors somatic mutations and mutant ctDNA obtained from blood can be used as a biomarker in advanced non-small cell lung cancer (NSCLC). In this study, we investigated the clinicopathological properties of tumors that shed ctDNA in surgically resected NSCLC patients. Methods Consecutive cases of NSCLC with matching surgically resected tissue specimens and peripheral or specimen blood samples were eligible for this study. EGFR and KRAS mutations in plasma ctDNA and formalin-fixed paraffin-embedded tissue were analyzed using peptide nucleic acid clamping-assisted method. The plasma and tissue results were compared according to clinicopathological features. Results Mutation analyses were available for 36 cases. EGFR and KRAS mutations were present in 41.7% (15/36) and 16.7% (6/36) of tissue samples, respectively. Among EGFR and KRAS-mutant tumors, plasma mutation detection sensitivity was 13.3% (2/15) for EGFR and 33.3% (2/6) for KRAS. The presence of ctDNA in plasma was significantly associated with higher pathological tumor stage (p = 0.028), nodal metastasis (p = 0.016), solid adenocarcinoma pattern (p = 0.003), tumor necrosis (p = 0.012), larger primary tumor diameter (p = 0.002) or volume (p = 0.002), and frequent mitosis (p = 0.018) in tissue specimens. All tumors larger than 4 cm in maximal diameter or 25 cm3 in volume shed ctDNA in plasma. In subgroup analysis among EGFR mutated adenocarcinoma, ctDNA was significantly associated with nodal metastasis (p = 0.029), vascular invasion (p = 0.029), solid adenocarcinoma pattern (p = 0.010), and tumor necrosis (p = 0.010), high mitotic rate (p = 0.009), large pathological tumor size (p = 0.027), and large tumor volume on CT (p = 0.027). Conclusion We suggest that primary or total tumor burden, solid adenocarcinoma morphology, tumor necrosis, and frequent mitosis could predict ctDNA shedding in pulmonary adenocarcinoma.
Changes in the Key Aroma Compounds of Raw Shiitake Mushrooms (Lentinula edodes) Induced by Pan-Frying as well as by Rehydration of Dry Mushrooms.

Application of the aroma extract dilution analysis (AEDA) on an extract/distillate from raw shiitake mushrooms revealed 32 odorants among which 3-(methylthio)propanal (cooked potato), 1-octen-3-one and 1-octen-3-ol (both mushroom-like) showed the highest flavor dilution (FD) factors. An isotope enrichment experiment with raw shiitake tissue and either 13C18-linoleic acid or 2H4-1-octen-3-ol confirmed that both, 1-octen-3-ol and 1-octen-3-one are direct degradation products of the fatty acid, but it could be proven for the first time that the ketone is not formed by an oxidation of the alcohol. After pan-frying, 42 odor active compounds appeared among which 3 hydroxy 4,5-dimethylfuran 2(5H) one (savory), 1,2,4,5 tetrathiane (burnt, sulfury), 4 hydroxy-2,5 dimethylfuran 3(2H) one (caramel-like), phenylacetic acid (honey-like), 3 (methylthio)-propanal and trans 4,5 epoxy (E) 2 decenal (metallic) showed the highest FD factors. To get a deeper insight into their aroma contribution, 19 key odorants were quantitated in the raw shiitake and twenty-one in the pan-fried mushrooms by stable isotope dilution assays, and new methods for the quantitation of four sulfur compounds were developed. A calculation of odor activity values (OAV; ratio of concentration to odor threshold) showed that 1-octen-3-one was by far the most important odorant in raw shiitake. During pan-frying, in particular four aroma compounds were significantly increased, i.e., 4 hydroxy-2,5 dimethylfuran 3(2H) one, dimethyl trisulfide, 1,2,4,5 tetrathiane and 1,2,3,5,6-pentathiepane. The overall aroma profile of pan-fried shiitake could very good be mimicked by an aroma recombinate consisting of 15 reference aroma compounds in the concentrations determined in the pan-fried mushrooms. Further results showed that the sulfur compounds were even higher in rehydrated dry shiitake as compared to the pan-fried mushrooms.
Medical-Grade ECG Sensor for Long-Term Monitoring

The recent trend in electrocardiogram (ECG) device development is towards wireless body sensors applied for patient monitoring. The ultimate goal is to develop a multi-functional body sensor that will provide synchronized vital bio-signs of the monitored user. In this paper, we present an ECG sensor for long-term monitoring, which measures the surface potential difference between proximal electrodes near the heart, called differential ECG lead or differential lead, in short. The sensor has been certified as a class IIa medical device and is available on the market under the trademark Savvy ECG. An improvement from the user’s perspective—immediate access to the measured data—is also implemented into the design. With appropriate placement of the device on the chest, a very clear distinction of all electrocardiographic waves can be achieved, allowing for ECG recording of high quality, sufficient for medical analysis. Experimental results that elucidate the measurements from a differential lead regarding sensors’ position, the impact of artifacts, and potential diagnostic value, are shown. We demonstrate the sensors’ potential by presenting results from its various areas of application: medicine, sports, veterinary, and some new fields of investigation, like hearth rate variability biofeedback assessment and biometric authentication.
Endothelin Receptor Antagonists: Status Quo and Future Perspectives for Targeted Therapy

The endothelin axis, recognized for its vasoconstrictive action, plays a central role in the pathology of pulmonary arterial hypertension (PAH). Treatment with approved endothelin receptor antagonists (ERAs), such as bosentan, ambrisentan, or macitentan, slow down PAH progression and relieves symptoms. Several findings have indicated that endothelin is further involved in the pathogenesis of certain other diseases, making ERAs potentially beneficial in the treatment of various conditions. In addition to PAH, this review summarizes the use and perspectives of ERAs in cancer, renal disease, fibrotic disorders, systemic scleroderma, vasospasm, and pain management. Bosentan has proven to be effective in systemic sclerosis PAH and in decreasing the development of vasospasm-related digital ulcers. The selective ERA clazosentan has been shown to be effective in preventing cerebral vasospasm and delaying ischemic neurological deficits and new infarcts. Furthermore, in the SONAR (Study Of Diabetic Nephropathy With Atrasentan) trial, the selective ERA atrasentan reduced the risk of renal events in patients with diabetes and chronic kidney disease. These data suggest atrasentan as a new therapy in the treatment of diabetic nephropathy and possibly other renal diseases. Preclinical studies regarding heart failure, cancer, and fibrotic diseases have demonstrated promising effects, but clinical trials have not yet produced measurable results. Nevertheless, the potential benefits of ERAs may not be fully realized.
Effects of the normal sperm morphology rate on the clinical and neonatal outcomes of conventional IVF cycles

The present study assessed the influences of the normal sperm morphology rate on the clinical and neonatal outcomes of conventional in vitro fertilisation cycles. This retrospective study analysed 427 and 2,728 cycles from the normal sperm morphology rate <4% and ≥4% group respectively. The clinical (total fertilisation failure, clinical pregnancy, implantation and abortion) and neonatal (sex, gestational age, preterm birth, birthweight, low birth weight, live births and birth defects of newborns) outcomes were compared. The rate of total fertilisation failure in the normal sperm morphology rate <4% group was significantly higher compared with that in the normal sperm morphology rate ≥4% group (2.8% versus 1.2%, p = .012). Total fertilisation failure was completely resolved by early rescue intracytoplasmic sperm injection. The clinical pregnancy, implantation and abortion rates were not significantly different between the two groups. Additionally, the sex, preterm birth, low birth weight, live births and birth defect rates, gestational age and birthweight of newborns were not significantly different between the two groups. Thus, normal sperm morphology rate <4% significantly increased the total fertilisation failure rate but did not affect the clinical or neonatal outcomes.
MiR‐20a inhibits the progression of human arthritis fibroblast‐like synoviocytes and inflammatory factor expression by targeting ADAM10

MiR‐20a has been reported as a key regulator to pro‐inflammatory factor release in fibroblast‐like synoviocytes (FLS), which caused rheumatoid arthritis (RA). However, the molecular mechanism of miR‐20a in RA remains to be further elucidated. This study aimed to investigate the roles of miR‐20a in RA pathology. RA (n = 24) and osteoarthritis (OA, n = 20) and normal healthy tissues (n = 16) were collected from operation. TargetScan and dual‐luciferase reporter were performed to predict and confirm the potential binding sites of miR‐20a on ADAM metallopeptidase domain 10 (ADAM10). Pearson's analysis was adopted to evaluate the correlation between miR‐20a and ADAM10 expression. It was found that MiR‐20a was downregulated in RA tissues, and overexpressed miR‐20a inhibited cell viability, migration and invasion, and the expression of inflammatory factors in RA‐FLS MH7A cells. ADAM10 was identified as the target gene of miR‐20a, and upregulation of ADAM10 reversed the inhibitory effects of miR‐20a. In conclusion, miR‐20a inhibits the progression of RA‐FLS as well as the inflammatory factor expression by targeting ADAM10.
Phylogenetic and Demographic Characterization of Directed HIV-1 Transmission Using Deep Sequences from High-Risk and General Population Cohorts/Groups in Uganda

Across sub-Saharan Africa, key populations with elevated HIV-1 incidence and/or prevalence have been identified, but their contribution to disease spread remains unclear. We performed viral deep-sequence phylogenetic analyses to quantify transmission dynamics between the general population (GP), fisherfolk communities (FF), and women at high risk of infection and their clients (WHR) in central and southwestern Uganda. Between August 2014 and August 2017, 6185 HIV-1 positive individuals were enrolled in 3 GP and 10 FF communities, 3 WHR enrollment sites. A total of 2531 antiretroviral therapy (ART) naïve participants with plasma viral load >1000 copies/mL were deep-sequenced. One hundred and twenty-three transmission networks were reconstructed, including 105 phylogenetically highly supported source–recipient pairs. Only one pair involved a WHR and male participant, suggesting that improved population sampling is needed to assess empirically the role of WHR to the transmission dynamics. More transmissions were observed from the GP communities to FF communities than vice versa, with an estimated flow ratio of 1.56 (95% CrI 0.68–3.72), indicating that fishing communities on Lake Victoria are not a net source of transmission flow to neighboring communities further inland. Men contributed disproportionally to HIV-1 transmission flow regardless of age, suggesting that prevention efforts need to better aid men to engage with and stay in care.
Rolling-Element Bearing Fault Diagnosis Using Improved LeNet-5 Network

To address the problems of low recognition accuracy, slow convergence speed and weak generalization ability of traditional LeNet-5 network used in rolling-element bearing fault diagnosis, a rolling-element bearing fault diagnosis method using improved 2D LeNet-5 network is put forward. The following improvements to the traditional LeNet-5 network are made: the convolution and pooling layers are reasonably designed and the size and number of convolution kernels are carefully adjusted to improve fault classification capability; the batch normalization (BN) is adopted after each convolution layer to improve convergence speed; the dropout operation is performed after each full-connection layer except the last layer to enhance generalization ability. To further improve the efficiency and effectiveness of fault diagnosis, on the basis of improved 2D LeNet-5 network, an end-to-end rolling-element bearing fault diagnosis method based on the improved 1D LeNet-5 network is proposed, which can directly perform 1D convolution and pooling operations on raw vibration signals without any preprocessing. The results show that the improved 2D LeNet-5 network and improved 1D LeNet-5 network achieve a significant performance improvement than traditional LeNet-5 network, the improved 1D LeNet-5 network provides a higher fault diagnosis accuracy with a less training time in most cases, and the improved 2D LeNet-5 network performs better than improved 1D LeNet-5 network under small training samples and strong noise environment.
Raman and autofluorescence analysis of human body fluids from patients with malignant tumors

In this study we measured Raman and autofluorescence spectral features of blood and urine from patients with various cancers. A total number of 26 blood samples from patients with lung cancer and 12 blood samples from patients with other cancers, and also 10 urine samples from patients with lung cancer and 9 urine samples from patients with other tumors were tested. The processing of experimental data and definition of informative bands for body fluid spectral analysis were performed on the bases of PLS-DA method. Wherein, there is no significant correlation between the most informative criteria for blood and urine. This fact shows that simultaneous study of blood and urine samples can increase the analysis informativeness. In general, the developed approach of body fluids analysis may become the basis of an inexpensive, quick and reliable method of lung cancer screening.
Bosutinib prevents vascular leakage by reducing focal adhesion turnover and reinforcing junctional integrity

ABSTRACT Endothelial barrier dysfunction leads to edema and vascular leak, causing high morbidity and mortality. Previously, Abl kinase inhibition has been shown to protect against vascular leak. Using the distinct inhibitory profiles of clinically available Abl kinase inhibitors, we aimed to provide a mechanistic basis for novel treatment strategies against vascular leakage syndromes. We found that the inhibitor bosutinib most potently protected against inflammation-induced endothelial barrier disruption. In vivo, bosutinib prevented lipopolysaccharide (LPS)-induced alveolar protein extravasation in an acute lung injury mice model. Mechanistically, mitogen-activated protein 4 kinase 4 (MAP4K4) was identified as important novel mediator of endothelial permeability, which signaled via ezrin, radixin and moesin proteins to increase turnover of integrin-based focal adhesions. The combined inhibition of MAP4K4 and Abl-related gene (Arg, also known as ABL2) by bosutinib preserved adherens junction integrity and reduced turnover of focal adhesions, which synergistically act to stabilize the endothelial barrier during inflammation. We conclude that MAP4K4 is an important regulator of endothelial barrier integrity, increasing focal adhesion turnover and disruption of cell–cell junctions during inflammation. Because it inhibits both Arg and MAP4K4, use of the clinically available drug bosutinib might form a viable strategy against vascular leakage syndromes. Summary: Combined inhibition of Arg and MAP4K4 by bosutinib reduces turnover of integrin-based focal adhesions. This provides robust protection against inflammation-induced vascular leakage.
Associated evolution of fruit size, fruit colour and spines in Neotropical palms

Understanding how ecological interactions have shaped the evolutionary dynamics of species traits remains a challenge in evolutionary ecology. Combining trait evolution models and phylogenies, we analysed the evolution of characters associated with seed dispersal (fruit size and colour) and herbivory (spines) in Neotropical palms to infer the role of these opposing animal–plant interactions in driving evolutionary patterns. We found that the evolution of fruit colour and fruit size was associated in Neotropical palms, supporting the adaptive interpretation of seed‐dispersal syndromes and highlighting the role of frugivores in shaping plant evolution. Furthermore, we revealed a positive association between fruit size and the presence of spines on palm leaves, bracteas and stems. We hypothesize that interactions between palms and large‐bodied frugivores/herbivores may explain the evolutionary relationship between fruit size and spines. Large‐bodied frugivores, such as extinct megafauna, besides consuming the fruits and dispersing large seeds, may also have consumed the leaves or damaged the plants, thus simultaneously favouring the evolution of large fruits and defensive structures. Our findings show how current trait patterns can be understood as the result of the interplay between antagonistic and mutualistic interactions that have happened throughout the evolutionary history of a clade.
MiR-26a inhibits myocardial cell apoptosis in rats with acute myocardial infarction through GSK-3β pathway.

OBJECTIVE To study the influence of micro ribonucleic acid (miR)-26a on myocardial cell apoptosis in rats with acute myocardial infarction (AMI) through the glycogen synthase kinase 3 beta (GSK-3β) pathway. MATERIALS AND METHODS A total of 36 Sprague-Dawley rats were randomly divided into sham group (n=12), model group (n=12), and miR-26a mimics group (n=12). Only the heart was exposed, and normal saline was intraperitoneally injected postoperatively in sham group, and the model of AMI was prepared in model group. Besides, after modeling, miR-26a mimics were injected into the left ventricle in miR-26a mimics group. At 48 h after operation, sampling was performed. Then, the expressions of B-cell lymphoma 2 (Bcl-2) and Bcl-2 associated X protein (Bax), as well as the protein expression of phosphorylated GSK-3β (p-GSK-3β) were detected via immunohistochemistry and Western blotting, respectively. Moreover, the expression level of miR-26a was measured via quantitative polymerase chain reaction (qPCR), and cell apoptosis was evaluated using terminal deoxynucleotidyl transferase (TdT) dUTP nick-end labeling (TUNEL) assay. RESULTS Compared with those in sham group, the expression level of Bax was substantially raised, but that of Bcl-2 was notably lowered in model group and miR-26 mimics group (p<0.05), and miR-26 mimics group had a markedly lower expression level of Bax and a remarkably higher expression level of Bcl-2 than model group (p<0.05). According to Western blotting results, the protein expression level of p-GSK-3β in model and miR-26a mimics groups was considerably higher than that in sham group (p<0.05), and miR-26a mimics group exhibited a notably higher protein expression level of p-GSK-3β than model group (p<0.05). In comparison with that in sham group, the expression level of miR-26a rose markedly in both model group and miR-26a mimics group (p<0.05), and its expression level in miR-26a mimics group was dramatically higher than that in model group (p<0.05). Additionally, the TUNEL-positive cells were considerably increased in both model group and miR-26a mimics group in comparison with that in sham group (p<0.05), and miR-26a mimics group had markedly fewer TUNEL-positive cells than model group (p<0.05). CONCLUSIONS MiR-26a activates the GSK-3β signaling pathway to inhibit myocardial cell apoptosis after AMI.