Miracle-dz/UniFAR-FTUs huggingface dataset:
Cryo-EM structures reveal distinct mechanisms of inhibition of the human multidrug transporter ABCB1

Significance ABCB1 is a membrane transport protein that protects cells from toxic compounds. At the same time, it limits the uptake of orally administered drugs and contributes to multidrug resistance in cancer cells. Small-molecule inhibitors of ABCB1 could alleviate these negative effects, but their development requires detailed insight into how such compounds interfere with ABCB1-catalyzed drug extrusion. Our study shows how ABCB1 inhibitors bind in pairs and can block the function of the transporter by interacting with structural features that are important for its transport function. Our results therefore provide insight into the mechanism of ABCB1 and will be valuable for the development of more effective inhibitors. ABCB1 detoxifies cells by exporting diverse xenobiotic compounds, thereby limiting drug disposition and contributing to multidrug resistance in cancer cells. Multiple small-molecule inhibitors and inhibitory antibodies have been developed for therapeutic applications, but the structural basis of their activity is insufficiently understood. We determined cryo-EM structures of nanodisc-reconstituted, human ABCB1 in complex with the Fab fragment of the inhibitory, monoclonal antibody MRK16 and bound to a substrate (the antitumor drug vincristine) or to the potent inhibitors elacridar, tariquidar, or zosuquidar. We found that inhibitors bound in pairs, with one molecule lodged in the central drug-binding pocket and a second extending into a phenylalanine-rich cavity that we termed the “access tunnel. ” This finding explains how inhibitors can act as substrates at low concentration, but interfere with the early steps of the peristaltic extrusion mechanism at higher concentration. Our structural data will also help the development of more potent and selective ABCB1 inhibitors.
Resistance to Leaf-Feeding by the Fall Armyworm (Lepidoptera: Noctuidae) in Tissue Culture Derived Sorghums

Sorghum ( Sorghum hieolor (L.) Moench) genotypes regenerated from tissue culture were evaluated under field and laboratory conditions for resistance to leaf-feeding by the fall armyworm, Spodoptera frugiperda (J. E. Smith). Two regenerated lines were identified as having a significantly higher level of resistance to fall armyworm feeding as compared with the non-regenerated and susceptible parent, ‘Hegari. ’ Laboratory studies measuring growth and development of fall armyworm were conducted with meridic diets containing dried sorghum foliage from regenerated or non-regenerated plant material. Significant reductions in larval weights were detected for two R3 lines compared with the non-regenerated parent, suggesting that antibiosis may be involved. Free-choice studies revealed a significant degree of non-preference for the R3 line that had shown the greatest adverse effect on fall armyworm growth in the developmental studies. These results indicate that tissue culture-induced variations can be a viable means of generating new sources of genetic diversity for use in crop improvement.
An Experimental Study of Microchannel and Micro-Pin-Fin Based On-Chip Cooling Systems with Silicon-to-Silicon Direct Bonding

This paper describes an experimental study of the cooling capabilities of microchannel and micro-pin-fin based on-chip cooling systems. The on-chip cooling systems integrated with a micro heat sink, simulated power IC (integrated circuit) and temperature sensors are fabricated by micromachining and silicon-to-silicon direct bonding. Three micro heat sink structures: a microchannel heat sink (MCHS), an inline micro-pin-fin heat sink (I-MPFHS) and a staggered micro-pin-fin heat sink (S-MPFHS) are tested in the Reynolds number range of 79.2 to 882.3. The results show that S-MPFHS is preferred if the water pump can provide enough pressure drop. However, S-MPFHS has the worst performance when the rated pressure drop of the pump is lower than 1.5 kPa because the endwall effect under a low Reynolds number suppresses the disturbance generated by the staggered micro pin fins but S-MPFHS is still preferred when the rated pressure drop of the pump is in the range of 1.5 to 20 kPa. When the rated pressure drop of the pump is higher than 20 kPa, I-MPFHS will be the best choice because of high heat transfer enhancement and low pressure drop price brought by the unsteady vortex street.
Inhibidores de la tirosina cinasa en el tratamiento de la leucemia mieloide crónica, un cambio en el paradigma

Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm with an incidence of 1-2 cases per 100,000 adults and accounts for ~ 15 % of newly diagnosed cases of leukemia in adults. Chronic myeloid leukemia is characterized by a genetic balanced translocation, t (9; 22) (q34 , q11.2), which involves a fusion of the Abelson oncogene (ABL)
Combination therapy of refractory keloid with ultrapulse fractional carbon dioxide (CO2) laser and topical triamcinolone in Asians‐long‐term prevention of keloid recurrence

Keloid often recur after treatment, and recent studies in keloid management favor the combination therapy of laser‐assisted drug delivery over monotherapy. Unfortunately, the previous researches lack long‐term follow‐up. In this prospective study, 41 individuals with refractory keloids underwent eight treatment sessions at 4 weeks intervals consisting of ultrapulse fractional carbon dioxide laser (UFCL), followed by postoperative application topical triamcinolone acetonide (40 mg/ml). Four follow‐up moments were chosen, with follow‐up of 24 months. The effects of combination therapy on scar pliability, thickness, relief, vascularization, surface area, pain, and itchiness were examined by means of the Patient and Observer Scar Assessment Scale (POSAS). 38 patients completed the full 24 months of follow‐up after the whole treatment. The results reveal a fast and abiding improvement of keloid scars after the combination therapy. The mean keloid POSAS scores showed a decreasing trend in subsequent times. All POSAS components improved significantly between baseline and 24 months after start of therapy (P < .05). Long‐term follow‐up results demonstrate that combination keloid therapy using UFCL and tropical triamcinolone has overall significant improvement and low recurrence rate with a long‐term stable results.
Re-using model results to determine materials properties: connector theory approach.

Computational materials design often profits from the fact that some complicated contributions are not calculated for the real material, but replaced by results of models. We turn this approximation into a very general and in principle exact theory by introducing the concept of a connector, which is a prescription of how to use the results of a model system in order to simulate a real system. We set the conditions that must be fulfilled for the existence of an exact connector. We demonstrate that, and why, this approach is a very convenient starting point for approximations. We also show that the connector theory can be used to design new functionals, for example for density functional theory. We illustrate our purposes with simple but realistic examples.
Mortality Resulting from Interactions between Adult Flour Beetles in Laboratory Cultures

THE THE design for this experiment was suggested by the appearance of unbalanced sex ratios in competition cultures when Tribolium confusum was eliminated by T. castaneum (Park, 1957). The new data reveal that adults of these beetles are able to cause mortality among themselves in a way which hitherto was scarcely suspected, but the mechanism underlying the disturbance in sex ratios is still only partially understood.
Review of semi-dry electrodes for EEG recording

Developing reliable and user-friendly electroencephalography (EEG) electrodes remains a challenge for emerging real-world EEG applications. Classic wet electrodes are the gold standard for recording EEG; however, they are difficult to implement and make users uncomfortable, thus severely restricting their widespread application in real-life scenarios. An alternative is dry electrodes, which do not require conductive gels or skin preparation. Despite their quick setup and improved user-friendliness, dry electrodes still have some inherent problems (invasive, relatively poor signal quality, or sensitivity to motion artifacts), which limit their practical utilization. In recent years, semi-dry electrodes, which require only a small amount of electrolyte fluid, have been successfully developed, combining the advantages of both wet and dry electrodes while addressing their respective drawbacks. Semi-dry electrodes can collect reliable EEG signals comparable to wet electrodes. Moreover, their setup is as fast and convenient similar to that of dry electrodes. Hence, semi-dry electrodes have shown tremendous application prospects for real-world EEG acquisition. Herein, we systematically summarize the development, evaluation methods, and practical design considerations of semi-dry electrodes. Some feasible suggestions and new ideas for the development of semi-dry electrodes have been presented. This review provides valuable technical support for the development of semi-dry electrodes toward emerging practical applications.
Feasibility and effectiveness of tools that support communication and decision making in life-prolonging treatments for patients in hospital: a systematic review

Objective Patients with advanced diseases and frail older adults often face decisions regarding life-prolonging treatment. Our aim was to provide an overview of the feasibility and effectiveness of tools that support communication between healthcare professionals and patients regarding decisions on life-prolonging treatments in hospital settings. Design Systematic review: We searched PubMed, CINAHL, PsycINFO, Embase, Cochrane Library and Google Scholar (2009–2019) to identify studies that reported feasibility or effectiveness of tools that support communication about life-prolonging treatments in adult patients with advanced diseases or frail older adults in hospital settings. The Mixed Methods Appraisal Tool was used for quality appraisal of the included studies. Results Seven studies were included, all involving patients with advanced cancer. The overall methodological quality of the included studies was moderate to high. Five studies described question prompt lists (QPLs), either as a stand-alone tool or as part of a multifaceted programme; two studies described decision aids (DAs). All QPLs and one DA were considered feasible by both patients with advanced cancer and healthcare professionals. Two studies reported on the effectiveness of QPL use, revealing a decrease in patient anxiety and an increase in cues for discussing end-of-life care with physicians. The effectiveness of one DA was reported; it led to more understanding of the treatment in patients. Conclusions Use of QPLs or DAs, as a single intervention or part of a programme, may help in communicating about treatment options with patients, which is an important precondition for making informed decisions.
New records of the Polynesian rat Rattus exulans (Mammalia: Rodentia) from Taiwan and the Ryukyus

The Polynesian rat Rattus exulans (Mammalia: Rodentia: Muridae) is newly recorded from Taiwan and the Ryukyus on the basis of 3 specimens from the lowland area of Kuanghua, Hualien County, eastern Taiwan, and 2 from Miyakojima Island, the southern Ryukyus. This rat may have been introduced by ships sailing to Taiwan and the Ryukyus from other islands where the species occurs. The morphological identification of R. exulans from young R. rattus is established on the basis of cranial measurements. In R. exulans, two measurements (breadth across the 1st upper molar and coronal width of the 1st upper molar) are smaller than corresponding values in R. rattus. The alveolar length of the maxillary toothrow is smaller in R. exulans from Taiwan and the Ryukyus than in available conspecific samples from Southeast Asia and other Pacific islands. Thus, this character may be useful in detecting the origin of the northernmost populations of R. exulans represented by the present specimens. The karyotype obtained from one of the Taiwanese specimens does not differ from that previously reported for R. exulans.
Differences of DNA methylation patterns in the placenta of large for gestational age infant

Supplemental Digital Content is available in the text Abstract To investigate the molecular mechanisms of later metabolic health changes in large for gestational age (LGA) newborns by analyzing deoxyribonucleic acid (DNA) methylation patterns in the placenta of LGA and appropriate for gestational age (AGA) newborns. A total of 6 placentas of LGA and 6 placentas of AGA newborns were enrolled as LGA group and AGA group. DNA methylation was analyzed using the Illumina Infinium Human MethylationEPIC BeadChip microarrays and verified via pyrosequencing and reverse transcription-quantitative real-time polymerase chain reaction. Functional enrichment analysis were constructed by gene ontology and Kyoto Encyclopedia of Genes and Genomes pathway analysis based on the differentially methylated regions between LGA and AGA groups. Clinical investigation showed that LGA newborns had significantly lower hemoglobin and blood glucose compared to AGA newborns. Birth weight was negatively correlated to hemoglobin and blood glucose. Genome-wide DNA methylation analysis identified 17 244 methylation variable positions achieving genome-wide significance (adjusted P < .05). 34% methylation variable positions were located in the gene promoter region. A total of 117 differentially methylated regions were revealed by bump hunting analysis, which mapped to 107 genes. Function analysis showed 13 genes enriched in “adhesion and infection process, endocrine and other factor-regulated calcium reabsorption, calcium signaling pathway and transmembrane transport”. Four genes linked to type II diabetes mellitus. Among the 13 genes, we selected GNAS and calcium voltage-gated channel subunit alpha1 G for independent verification of pyrosequencing, and the messenger ribonucleic acid levels of guanine nucleotide binding protein, calcium voltage-gated channel subunit alpha1 G, DECR1, and FK506 binding protein 11 were verified by reverse transcription-quantitative real-time polymerase chain reaction. DNA methylation variation and gene expression differences in placental samples were associated with LGA newborns, which linking the effect of intrauterine environment to regulation of the offspring's gene expression. Furthermore, pathway analysis suggested that intrauterine environment affecting fetal growth might had a functional impact on multiple signaling pathways involved in fetal growth, metabolism, and inflammation. Further studies were required to understand the differences of methylation patterns.
Herbivory causes increases in leaf spinescence and fluctuating asymmetry as a mechanism of delayed induced resistance in a tropical savanna tree

Background and aims – Leaf spinescence is thought to be a defense against herbivory and may increase in years following high herbivory pressure (DIR – delayed induced resistance). Besides DIR, herbivory also causes plant stress, which can be assessed using fluctuating asymmetry analysis (FA – random departures from leaf bilateral symmetry). In this two-year field study we first investigated the relationships between herbivory, FA and spinescence in Solanum lycocarpum trees during an outbreak of moth caterpillars in 2010; then in 2011 we examined whether plants with intense herbivory the previous year presented changes in FA (herbivory induced stress) and spinescence. Key results – In 2010, leaves damaged by moths were significantly more asymmetrical than undamaged leaves. In addition, moths preferentially fed on leaves with fewer and shorter spines. In 2011, plants severely attacked by moths the year before showed significant increases in FA (28%), spine abundance (21%) and spine length (84%), compared to less damaged plants. Conclusions – Our data suggest a delayed response of S. lycocarpum to herbivory, in that plants subjected to high leaf damage the previous year maximized their display of anti-herbivore mechanisms, in this case, leaf spinescence. This is one of the few studies to show that FA increased as a response to herbivore attack. We conclude that FA can be used as an indicator of plant stress following leaf damage.
Revisiting Traumatic Brain Injury: From Molecular Mechanisms to Therapeutic Interventions

Studying the complex molecular mechanisms involved in traumatic brain injury (TBI) is crucial for developing new therapies for TBI. Current treatments for TBI are primarily focused on patient stabilization and symptom mitigation. However, the field lacks defined therapies to prevent cell death, oxidative stress, and inflammatory cascades which lead to chronic pathology. Little can be done to treat the mechanical damage that occurs during the primary insult of a TBI; however, secondary injury mechanisms, such as inflammation, blood-brain barrier (BBB) breakdown, edema formation, excitotoxicity, oxidative stress, and cell death, can be targeted by therapeutic interventions. Elucidating the many mechanisms underlying secondary injury and studying targets of neuroprotective therapeutic agents is critical for developing new treatments. Therefore, we present a review on the molecular events following TBI from inflammation to programmed cell death and discuss current research and the latest therapeutic strategies to help understand TBI-mediated secondary injury.
Tubular gastric adenocarcinoma: Machine learning-based CT texture analysis for predicting lymphovascular and perineural invasion.

PURPOSE Lymphovascular invasion (LVI) and perineural invasion (PNI) are associated with poor prognosis in gastric cancers. In this work, we aimed to investigate the potential role of computed tomography (CT) texture analysis in predicting LVI and PNI in patients with tubular gastric adenocarcinoma (GAC) using a machine learning (ML) approach. METHODS Sixty-eight patients who underwent total gastrectomy with curative (R0) resection and D2-lymphadenectomy were included in this retrospective study. Texture features were extracted from the portal venous phase CT images. Dimension reduction was first done with a reproducibility analysis by two radiologists. Then, a feature selection algorithm was used to further reduce the high-dimensionality of the radiomic data. Training and test splits were created with 100 random samplings. ML-based classifications were done using adaptive boosting, k-nearest neighbors, Naive Bayes, neural network, random forest, stochastic gradient descent, support vector machine, and decision tree. Predictive performance of the ML algorithms was mainly evaluated using the mean area under the curve (AUC) metric. RESULTS Among 271 texture features, 150 features had excellent reproducibility, which were included in the further feature selection process. Dimension reduction steps yielded five texture features for LVI and five for PNI. Considering all eight ML algorithms, mean AUC and accuracy ranges for predicting LVI were 0.777-0.894 and 76%-81.5%, respectively. For predicting PNI, mean AUC and accuracy ranges were 0.482-0.754 and 54%-68.2%, respectively. The best performances for predicting LVI and PNI were achieved with the random forest and Naive Bayes algorithms, respectively. CONCLUSION ML-based CT texture analysis has a potential for predicting LVI and PNI of the tubular GACs. Overall, the method was more successful in predicting LVI than PNI.
Cardiac Autonomic Modulation Is Different in Terms of Clinical Variant of Multiple Sclerosis

This study evaluates whether the cardiac autonomic response to head-up tilt test (HUTT) differs between patients with relapsing-remitting multiple sclerosis (RRMS) and those with progressive MS (PMS) as compared to healthy controls (HC). Baroreflex sensitivity, cardiac parameters, heart rate (HRV) and blood pressure variability (BPV) were compared between 28 RRMS, 21PMS and 25 HC during HUTT. At rest, PMS patients had higher values of the sympathovagal ratio, a low-frequency band HRV (LFnu-RRI) and lower values of parasympathetic parameters (HFnu-RRI, HF-RRI) compared to RRMS and HC. Resting values of cardiac parameters were significantly lower in RRMS compared to PMS patients. No intergroup differences were observed for post-tilt cardiac and autonomic parameters, except for delta HF-RRI with lower values in the PMS group. The MS variant corrected for age, sex and Expanded Disability Status Scale (EDSS) score was an independent predictor of changes in the sympathovagal ratio as measured by HRV. Furthermore, a higher overall EDDS score was related to a higher sympathovagal ratio, lower parasympathetic parameters at rest, and decrease post-tilt changes of the sympathovagal ratio of sBP BPV. Autonomic imbalance is markedly altered in the MS patient group compared to control changes were most pronounced in the progressive variant of MS disease. The MS variant appeared to have a potential influence on cardiac autonomic imbalance at rest.
How Does Our Brain Process Sugars and Non-Nutritive Sweeteners Differently: A Systematic Review on Functional Magnetic Resonance Imaging Studies

This systematic review aimed to reveal the differential brain processing of sugars and sweeteners in humans. Functional magnetic resonance imaging studies published up to 2019 were retrieved from two databases and were included into the review if they evaluated the effects of both sugars and sweeteners on the subjects’ brain responses, during tasting and right after ingestion. Twenty studies fulfilled the inclusion criteria. The number of participants per study ranged from 5 to 42, with a total number of study participants at 396. Seven studies recruited both males and females, 7 were all-female and 6 were all-male. There was no consistent pattern showing that sugar or sweeteners elicited larger brain responses. Commonly involved brain regions were insula/operculum, cingulate and striatum, brainstem, hypothalamus and the ventral tegmental area. Future studies, therefore, should recruit a larger sample size, adopt a standardized fasting duration (preferably 12 h overnight, which is the most common practice and brain responses are larger in the state of hunger), and reported results with familywise-error rate (FWE)-corrected statistics. Every study should report the differential brain activation between sugar and non-nutritive sweetener conditions regardless of the complexity of their experiment design. These measures would enable a meta-analysis, pooling data across studies in a meaningful manner.
β-Phenylethylamine as a Natural Food Additive Shows Antimicrobial Activity against Listeria monocytogenes on Ready-to-Eat Foods

Listeria monocytogenes is an important foodborne pathogen and a major cause of death associated with bacterial foodborne infections. Control of L. monocytogenes on most ready-to-eat (RTE) foods remains a challenge. The potential use of β-phenylethylamine (PEA) as an organic antimicrobial against L. monocytogenes was evaluated in an effort to develop a new intervention for its control. Using a collection of 62 clinical and food-related isolates we determined the minimum inhibitory concentration (MIC) of PEA against L. monocytogenes in different broth and agar media. Bologna type sausage (lyoner) and smoked salmon were used as food model systems to validate the in vitro findings. PEA had a growth inhibitory and bactericidal effect against L. monocytogenes both in in vitro experiments as well as on lyoner and smoked salmon. The MIC’s ranged from 8 to 12.5 mg/mL. Furthermore, PEA also inhibited L. monocytogenes biofilm formation. Based on good manufacturing practices as a prerequisite, the application of PEA to RTE products might be an additional hurdle to limit L. monocytogenes growth thereby increasing food safety.