Miracle-dz/UniFAR-FTUs huggingface dataset:
TAS‐120 Cancer Target Binding: Defining Reactivity and Revealing the First Fibroblast Growth Factor Receptor 1 (FGFR1) Irreversible Structure

1‐[(3S)‐3‐[4‐Amino‐3‐[2‐(3,5‐dimethoxyphenyl)ethynyl]‐1H‐pyrazolo[3,4‐d]pyrimidin‐1‐yl]‐1‐pyrrolidinyl]‐2‐propen‐1‐one (TAS‐120) is an irreversible inhibitor of the fibroblast growth factor receptor (FGFR) family, and is currently under phase I/II clinical trials in patients with confirmed advanced metastatic solid tumours harbouring FGFR aberrations. This inhibitor specifically targets the P‐loop of the FGFR tyrosine kinase domain, forming a covalent adduct with a cysteine side chain of the protein. Our mass spectrometry experiments characterise an exceptionally fast chemical reaction in forming the covalent complex. The structural basis of this reactivity is revealed by a sequence of three X‐ray crystal structures: a free ligand structure, a reversible FGFR1 structure, and the first reported irreversible FGFR1 adduct structure. We hypothesise that the most significant reactivity feature of TAS‐120 is its inherent ability to undertake conformational sampling of the FGFR P‐loop. In designing novel covalent FGFR inhibitors, such a phenomenon presents an attractive strategy requiring appropriate positioning of an acrylamide group similarly to that of TAS‐120.
Recruiting on the Spot: A Biodegradable Formulation for Lacewings to Trigger Biological Control of Aphids

Upon herbivory, plants release herbivore-induced plant volatiles (HIPVs), which induce chemical defenses in the plant as well as recruit natural enemies. However, whether synthetic HIPVs can be employed to enhance biological control in a cultivated crop in the field is yet to be explored. Here we show that a biodegradable formulation loaded with induced and food-signaling volatiles can selectively recruit the common green lacewing, Chrysoperla carnea, and reduce pest population under field conditions. In apple orchards, the new formulation attracted lacewing adults over a 4-week period, which correlated well with independent assessments of the longevity of the slow-release matrix measured through chemical analyses. In barley, lacewing eggs and larvae were significantly more abundant in treated plots, whereas a significant reduction of two aphid species was measured (98.9% and 93.6% of population reduction, for Sitobion avenae and Rhopalosiphum padi, respectively). Results show the potential for semiochemical-based targeted recruitment of lacewings to enhance biological control of aphids in a field setting. Further research should enhance selective recruitment by rewarding attracted natural enemies and by optimizing the application technique.
Unified interpretation of liver stiffness measurement by M and XL probes in non-alcoholic fatty liver disease

Objective The latest model of vibration-controlled transient elastography (VCTE) automatically selects M or XL probe according to patients’ body built. We aim to test the application of a unified interpretation of VCTE results with probes appropriate for the body mass index (BMI) and hypothesise that this approach is not affected by hepatic steatosis. Design We prospectively recruited 496 patients with non-alcoholic fatty liver disease who underwent VCTE by both M and XL probes within 1 week before liver biopsy. Results 391 (78.8%) and 433 (87.3%) patients had reliable liver stiffness measurement (LSM) (10 successful acquisitions and IQR:median ratio ≤0.30) by M and XL probes, respectively (p<0.001). The area under the receiver operating characteristic curves was similar between the two probes (0.75–0.88 for F2–4, 0.83–0.91 for F4). When used in the same patient, LSM by XL probe was lower than that by M probe (mean difference 2.3 kPa). In contrast, patients with BMI ≥30 kg/m2 had higher LSM regardless of the probe used. When M and XL probes were used in patients with BMI <30 and ≥30 kg/m2, respectively, they yielded nearly identical median LSM at each fibrosis stage and similar diagnostic performance. Severe steatosis did not increase LSM or the rate of false-positive diagnosis by XL probe. Conclusion High BMI but not severe steatosis increases LSM. The same LSM cut-offs can be used without further adjustment for steatosis when M and XL probes are used according to the appropriate BMI.
Comparison of International Pediatric Sepsis Consensus Conference Versus Sepsis-3 Definitions for Children Presenting With Septic Shock to a Tertiary Care Center in India: A Retrospective Study*

Objectives: To evaluate the proportion of children fulfilling “Sepsis-3” definition and International Pediatric Sepsis Consensus Conference definition among children diagnosed to have septic shock and compare the mortality risk between the two groups. Design: Retrospective chart review. Setting: PICU of a tertiary care teaching hospital from 2014 to 2017. Patients: Children (⩽ 17 yr old) with a diagnosis of septic shock at admission or during PICU stay. Interventions: None. Measurements and Main Results: We applied both International Pediatric Sepsis Consensus Conference and the new “Sepsis-3” definition (sepsis with hypotension requiring vasopressors and a lactate value of ≥ 2 mmol/L) to identify cases of septic shock by these definitions. Key outcomes such as mortality, proportion attaining shock reversal at 24 hours and organ dysfunction were compared between those fulfilling “Sepsis-3” definitions (“Sepsis-3” group) and those fulfilling “International Pediatric Sepsis Consensus Conference” definition (“International Pediatric Sepsis Consensus Conference” group). A total of 216 patients fulfilled International Pediatric Sepsis Consensus Conference definitions of septic shock. Of these, only 104 (48%; 95% CI, 42–55) fulfilled “Sepsis-3” definition. Children fulfilling “Sepsis-3 plus International Pediatric Sepsis Consensus Conference definitions” (“Sepsis-3 and International Pediatric Sepsis Consensus Conference” group) had lower proportion with shock resolution (61% vs 82%; relative risk, 0.73; 95% CI, 0.62–0.88) and higher risk of multiple organ dysfunction (85% vs 68%; 1.24; 1.07–1.45) at 24 hours. The mortality was 48.5% in “Sepsis-3 and International Pediatric Sepsis Consensus Conference” group as compared with 37.5% in the “International Pediatric Sepsis Consensus Conference only” group (relative risk, 1.3; 95% CI, 0.94–1.75). Conclusions: Less than half of children with septic shock identified by International Pediatric Sepsis Consensus Conference definitions were observed to fulfill the criteria for shock as per “Sepsis-3” definitions. Lack of difference in the risk of mortality between children who fulfilled “Sepsis-3” definition and those who did not fulfill the definition raises questions on the appropriateness of using this definition for diagnosis of septic shock in children.
Attentional bias towards angry faces is moderated by the activation of a social processing mode in the general population

ABSTRACT Dot-probe studies usually find an attentional bias towards threatening stimuli only in anxious participants, but not in non-anxious participants. In the present study, we conducted two experiments to investigate whether attentional bias towards angry faces in unselected samples is moderated by the extent to which the current task requires social processing. In Experiment 1, participants performed a dot-probe task involving classification of either socially meaningful targets (schematic faces) or meaningless targets (scrambled schematic faces). Targets were preceded by two photographic face cues, one angry and one neutral. Angry face cues only produced significant cueing scores (i.e. faster target responses if the target replaced the angry face compared to the neutral face) with socially meaningful targets, not with meaningless targets. In Experiment 2, participants classified only meaningful targets, which were either socially meaningful (schematic faces) or not (schematic houses). Again, mean cueing scores were significantly moderated by the social character of the targets. However, cueing scores in this experiment were non-significant in the social target condition and significantly negative in the non-social target condition. These results suggest that attentional bias towards angry faces in the dot-probe task is moderated by the activation of a social processing mode in unselected samples.
Protein Corona Fingerprints of Liposomes: New Opportunities for Targeted Drug Delivery and Early Detection in Pancreatic Cancer

Pancreatic ductal adenocarcinoma (PDAC) is the fourth cause of cancer-related mortality in the Western world and is envisaged to become the second cause by 2030. Although our knowledge about the molecular biology of PDAC is continuously increasing, this progress has not been translated into better patients’ outcome. Liposomes have been used to circumvent concerns associated with the low efficiency of anticancer drugs such as severe side effects and damage of healthy tissues, but they have not resulted in improved efficacy as yet. Recently, the concept is emerging that the limited success of liposomal drugs in clinical practice is due to our poor knowledge of the nano–bio interactions experienced by liposomes in vivo. After systemic administration, lipid vesicles are covered by plasma proteins forming a biomolecular coating, referred to as the protein corona (PC). Recent studies have clarified that just a minor fraction of the hundreds of bound plasma proteins, referred to as “PC fingerprints” (PCFs), enhance liposome association with cancer cells, triggering efficient particle internalization. In this study, we synthesized a library of 10 liposomal formulations with systematic changes in lipid composition and exposed them to human plasma (HP). Size, zeta-potential, and corona composition of the resulting liposome–protein complexes were thoroughly characterized by dynamic light scattering (DLS), micro-electrophoresis, and nano-liquid chromatography tandem mass spectrometry (nano-LC MS/MS). According to the recent literature, enrichment in PCFs was used to predict the targeting ability of synthesized liposomal formulations. Here we show that the predicted targeting capability of liposome–protein complexes clearly correlate with cellular uptake in pancreatic adenocarcinoma (PANC-1) and insulinoma (INS-1) cells as quantified by flow-assisted cell sorting (FACS). Of note, cellular uptake of the liposomal formulation with the highest abundance of PCFs was much larger than that of Onivyde®, an Irinotecan liposomal drug approved by the Food and Drug Administration in 2015 for the treatment of metastatic PDAC. Given the urgent need of efficient nanocarriers for the treatment of PDAC, we envision that our results will pave the way for the development of more efficient PC-based targeted nanomaterials. Here we also show that some BCs are enriched with plasma proteins that are associated with the onset and progression of PDAC (e.g., sex hormone-binding globulin, Ficolin-3, plasma protease C1 inhibitor, etc.). This could open the intriguing possibility to identify novel biomarkers.
Depressive Symptoms and Coping Strategies Among Indian University Students

Depression is now the leading cause of disability worldwide, and globally more than 300 million people of all ages suffer from depression. Depression, despite its major health consequences, frequently goes unnoticed among university students, since their lives are often filled with symptoms normally associated with depression (e.g., loss of sleep, low energy, anxiety, and sadness). Successful adaptation to depression depends on the use of adequate coping strategies. The extent to which university students in India with high and low levels of depressive symptoms use adequate or inadequate coping strategies has not been evaluated. Based on the Center for Epidemiological Scale for Depression score, students were assigned to either the high depressive symptoms or the low depressive symptoms group. We used the Coping Response Inventory-Adult to determine the dominant coping strategies used by the two depressive symptoms groups. The high depressive symptom group resorted to more avoidant coping strategies than the low depressive symptom group, and women were more likely to use avoidant coping strategies than men.
Jak-ing Up the Plaque's Lipid Core…and Even More.

Until recently, many viewed atherosclerosis as a lipid storage disease or a bland accumulation of proliferated smooth muscle cells. How the landscape has changed! Abundant evidence now implicates intertwining pathways of inflammation as crucial to atherogenesis and its clinical consequences. Inflammatory mediators modulate the functions of vascular wall cells that provoke the disease. Multiple cell types beckoned to enter the arterial intima during atherogenesis can produce these inflammatory mediators. Actions of monocyte/macrophages and T lymphocytes implicated both adaptive and innate immunity in atherosclerosis. Indeed, many leukocyte lineages participate in chronic inflammation in the plaque. Recent evidence points to the participation of the acute inflammatory cell, the polymorphonuclear leukocytes, in plaque complication. An ongoing struggle between proinflammatory and anti-inflammatory and proresolving stimuli determine the evolution of the plaque, from its initiation through its thrombotic complications.
Directional asymmetry in the human clavicle

The human right clavicle tends to be shorter than the left. A range of possible explanations can be advanced to account for this asymmetry. In the present work, clavicular morphology was studied in a medieval skeletal assemblage from Wharram Percy, England, with the aim of evaluating these competing explanations. At Wharram Percy, as anticipated, the right clavicle tended to be shorter. Patterns of asymmetry in curvature, robusticity, vascularization, and in the morphology of ligament and muscle attachment sites were also studied. The patterning in these data at Wharram Percy is consistent with inhibition of longitudinal growth of the clavicle on the dominant side due to lateral bias in mechanical loading, particularly in axial compression. Copyright © 1999 John Wiley & Sons, Ltd.
Identification and RNAi-based function analysis of chitinase family genes in diamondback moth, Plutella xylostella.

BACKGROUND Insect chitinases play a vital part in chitin degradation in exoskeletons and gut linings during the molting process, and therefore are considered potential targets for new insecticide designs or RNA interference (RNAi)-based pest management. Systematic functional analysis of chitinase genes has already been conducted in several insect pests, but not Plutella xylostella. RESULTS In this study, 13 full-length chitinase transcripts were obtained in P. xylostella. Developmental and tissue-specific expression pattern analysis revealed that seven chitinase transcripts were periodically expressed during molting stage and mainly expressed in the integument or midgut, including PxCht3, PxCht5, PxCht6-2, PxCht7, PxCht8, PxCht10 and PxCht-h. RNAi-mediated knockdown of these specific expressed genes revealed that PxCht5 and PxCht10 were essential in larval molting, pupation and eclosion, and PxCht7 was indispensable only in eclosion. No significant effects were observed on insect survival or normal development when the rest chitinase transcripts were suppressed by RNAi. CONCLUSION Our results indicated the function of P. xylostella chitinase family genes during the molting process, and may provide potential targets for RNAi-based management of P. xylostella. © 2018 Society of Chemical Industry.
Helmholtz-Zentrum Dresden-Rossendorf (HZDR) Time-of-flight secondary ion mass spectrometry in the helium ion microscope

A helium ion microscope, known for high resolution imaging and modification with helium or neon ions, has been equipped with a time-of-flight spectrometer for compositional analysis. Here we report on its design, implementation and show first results of this powerful add-on. Our design considerations were based on the results of detailed ion collision cascade simulations that focus on the physically achievable resolution for various detection limits. Different secondary ion extraction geometries and spectrometer types are considered and compared with respect to the demands and limitations of the microscope. As a result the development and evaluation of a secondary ion extraction optics and time-of-flight spectrometer that allows the parallel measurement of all secondary ion masses is reported. First experimental results demonstrate an excellent mass resolution as well as high-resolution secondary ion imaging capabilities with sub-8 nm lateral resolution. The combination of high resolution secondary electron images and mass-separated sputtered ion distributions have a high potential to answer open questions in microbiology, cell biology, earth sciences and materials research.
An Interactive Web-Based Educational Tool Improves Detection and Delineation of Barrett's Esophagus-Related Neoplasia.

BACKGROUND & AIMS Endoscopic detection of early Barrett's esophagus-related neoplasia (BORN) is a challenge. We aimed to develop a web-based teaching tool for improving detection and delineation of BORN. METHODS We made high-definition digital videos during endoscopies of patients with BORN and non-dysplastic Barrett's esophagus. Three experts superimposed their delineations of BORN lesions on the videos using special tools. In phase one, 68 general endoscopists from 4 countries assessed 4 batches of 20 videos. After each batch, mandatory feedback compared the assessors' interpretations with those from experts. These data informed the selection of 25 videos for the phase 2 module, which was completed by 121 new assessors from 5 countries. A 5-video test batch was completed before and after scoring of the four 5-video training batches. Mandatory feedback was as in phase 1. Outcome measures were scores for detection, delineation, agreement delineation, and relative delineation of BORN. RESULTS A linear mixed-effect model showed significant sequential improvement for all 4 outcomes over successive training batches in both phases. In phase 2, median detection rates of BORN in the test batch increased by 30% (P < .001) after training. From baseline to the end of the study, there were relative increases in scores of 46% for detection, 129% for delineation, 105% for agreement delineation, and 106% for relative delineation (all, P < .001). Scores improved independent of assessors' country of origin or level of endoscopic experience. CONCLUSIONS We developed a web-based teaching tool for endoscopic recognition of BORN that is easily accessible, efficient, and increases detection and delineation of neoplastic lesions. Widespread use of this tool might improve management of Barrett's esophagus by general endoscopists.
Recurrence of Basal Plate Myofibers, with Further Consideration of Pathogenesis

Abstract Objectives: Basal plate myofibers (BPMF) may indicate morbid adherence. We assessed recurrence and clinical progression of BPMF. Methods: In 5 years, 135 BPMF placentas were reported. Controls were the first 50 placentas in 2009, none of which had reported BPMF. Results: 32% of BPMF patients had other placentas, with a recurrence rate of 100%. Actin stains were needed for diagnosis in 117/179 cases (65%). These cases had clinical features suggestive of morbid adherence in 69/117 (59%). 23/47 (49%) of BPMF recurrences progressed in severity, 5 to hysterectomy (11%). Thinning of the basal plate, perforating vessels, gaps in the basal plate, and villi under the basal plate were observed in BPMF placentas. Conclusions: These findings appear to validate screening for BPMF. The 100% recurrence rate suggests evaluation for a heritable factor, i.e., protease inhibitor deficiency, which may explain pre-delivery basal plate damage.
Birth weight and adolescent blood pressure measured at age 12 years in the Gateshead Millennium Study

Abstract Birth weight and early growth have been associated with later blood pressure. However, not all studies consistently find a significant reduction in blood pressure with an increase in birth weight. In addition, the relative importance of birth weight and of other lifestyle and environmental factors is often overlooked and the association is rarely studied in adolescents. We investigated early life predictors, including birth weight, of adolescent blood pressure in the Gateshead Millennium Study (GMS). The GMS is a cohort of 1029 individuals born in 1999–2000 in Gateshead in Northern England. Throughout infancy and early childhood, detailed information were collected, including birth weight and measures of height and weight. Assessments of 491 returning participants at age 12 years included measures of body mass and blood pressure. Linear regression and path analysis were used to determine predictors and their relative importance on blood pressure. Birth weight was not directly associated with blood pressure at the age of 12. However, after adjustment for contemporaneous body mass index (BMI), an inverse association of standardized birth weight on systolic blood pressure was significant. The relative importance of birth weight on later systolic blood pressure was smaller than other contemporaneous body measures (height and BMI). There was no independent association of birth weight on blood pressure seen in this adolescent population. Contemporaneous body measures have an important role to play. Lifestyle factors that influence body mass or size, such as diet and physical activity, where interventions are directed at early prevention of hypertension should be targeted.
Antileishmanial Activity of Dimeric Flavonoids Isolated from Arrabidaea brachypoda

Leishmaniasis are diseases caused by parasites belonging to Leishmania genus. The treatment with pentavalent antimonials present high toxicity. Secondary line drugs, such as amphotericin B and miltefosine also have a narrow therapeutic index. Therefore, there is an urgent need to develop new drugs to treat leishmaniasis. Here, we present the in vitro anti-leishmanial activity of unusual dimeric flavonoids purified from Arrabidaea brachypoda. Three compounds were tested against Leishmana sp. Compound 2 was the most active against promastigotes. Quantifying the in vitro infected macrophages revealed that compound 2 was also the most active against intracellular amastigotes of L. amazonensis, without displaying host cell toxicity. Drug combinations presented an additive effect, suggesting the absence of interaction between amphotericin B and compound 2. Amastigotes treated with compound 2 demonstrated alterations in the Golgi and accumulation of vesicles inside the flagellar pocket. Compound 2-treated amastigotes presented a high accumulation of cytoplasmic vesicles and a myelin-like structure. When administered in L. amazonensis-infected mice, neither the oral nor the topical treatments were effective against the parasite. Based on the high in vitro activity, dimeric flavonoids can be used as a lead structure for the development of new molecules that could be useful for structure-active studies against Leishmania.