Miracle-dz/UniFAR-FTUs huggingface dataset:
Rapid Throughput Concentration-Response Analysis of Human Taste Discrimination

Human taste threshold measurements often are used to infer tastant receptor functionality. However, taste thresholds can be influenced by receptor-independent variables. Examination of the full range of taste-active concentrations by taste discrimination has been hampered by logistics of testing multiple concentrations in replicate with human subjects. We developed an automated rapid throughput operant methodology for taste discrimination and applied it to concentration-response analysis of human taste. Tastant solutions (200 µl) drawn from a 96-well plate and self-administered to the tongue served as discriminative stimuli for money-reinforced responses on a touch-sensitive display. Robust concentration-response functions for “basic taste” stimuli were established, with particular focus on agonists of the taste 1 receptor member 2–taste 1 receptor member 3 heterodimer receptor (TAS1R2/R3). With a training cue of 100 mM sucrose, EC50 values of 56, 79, and 310 µM and 40 mM were obtained for rebaudioside A, sucralose, acesulfame potassium, and sucrose, respectively. Changing the sucrose training cue to 300 mM had no impact, but changing to 30 mM resulted in slight leftward shifts in potencies. A signal detection method also was used to determine values of d', a probabilistic value for discriminability, which indicated that 5 mM was near the limits of detection for sucrose. With repeated testing, both EC50 values and 5 mM sucrose d' values were established for each individual subject. The results showed little correspondence between threshold sensitivities and EC50 values for sucrose. We conclude that concentration-response analysis of taste discrimination provides a more reliable means of inferring receptor function than measurement of discriminability at the lowest detectable tastant concentrations. SIGNIFICANCE STATEMENT Many inferences about human tastant receptor functionality have been made from taste threshold measurements, which can be influenced by variables unrelated to receptors. We herein report a new methodology that enables rigorous concentration-response analysis of human taste discrimination and its use toward quantitative characterization of tastant agonist activity. Our data suggest that taste discrimination concentration-response functions are a more reliable reflection of underlying receptor activity than threshold measures obtained at the lowest detectable tastant concentrations.
The Interaction of the Senescent and Adjacent Breast Cancer Cells Promotes the Metastasis of Heterogeneous Breast Cancer Cells through Notch Signaling

Chemotherapy is one of the most common strategies for tumor treatment but often associated with post-therapy tumor recurrence. While chemotherapeutic drugs are known to induce tumor cell senescence, the roles and mechanisms of senescence in tumor recurrence remain unclear. In this study, we used doxorubicin to induce senescence in breast cancer cells, followed by culture of breast cancer cells with conditional media of senescent breast cancer cells (indirect co-culture) or directly with senescent breast cancer cells (direct co-culture). We showed that breast cancer cells underwent the epithelial–mesenchymal transition (EMT) to a greater extent and had stronger migration and invasion ability in the direct co-culture compared with that in the indirect co-culture model. Moreover, in the direct co-culture model, non-senescent breast cancer cells facilitated senescent breast cancer cells to escape and re-enter into the cell cycle. Meanwhile, senescent breast cancer cells regained tumor cell characteristics and underwent EMT after direct co-culture. We found that the Notch signaling was activated in both senescent and non-senescent breast cancer cells in the direct co-culture group. Notably, the EMT process of senescent and adjacent breast cancer cells was blocked upon inhibition of Notch signaling with N-[(3,5-difluorophenyl)acetyl]-l-alanyl-2-phenyl]glycine-1,1-dimethylethyl ester (DAPT) in the direct co-cultures. In addition, DAPT inhibited the lung metastasis of the co-cultured breast cancer cells in vivo. Collectively, data arising from this study suggest that both senescent and adjacent non-senescent breast cancer cells developed EMT through activating Notch signaling under conditions of intratumoral heterogeneity caused by chemotherapy, which infer the possibility that Notch inhibitors used in combination with chemotherapeutic agents may become an effective treatment strategy.
SWOTein: A structure-based approach to predict stability Strengths and Weaknesses of prOTEINs

Motivation Although structured proteins adopt their lowest free energy conformation in physiological conditions, the individual residues are generally not in their lowest free energy conformation. Residues that are stability weaknesses are often involved in functional regions, whereas stability strengths ensure local structural stability. The detection of strengths and weaknesses provides key information to guide protein engineering experiments aiming to modulate folding and various functional processes. Results We developed the SWOTein predictor which identifies strong and weak residues in proteins on the basis of three types of statistical energy functions describing local interactions along the chain, hydrophobic forces and tertiary interactions. The large-scale comparison of the different types of strengths and weaknesses showed their complementarity and the enhancement of the information they provide. We applied SWOTein to apocytochrome b562 and found good agreement between predicted strengths and weaknesses and native hydrogen exchange data. Its application to an amino acid-binding protein identified the hinge at the basis of the conformational change. SWOTein is both fast and accurate and can be applied at small and large scale to analyze and modulate folding and molecular recognition processes. Availability The SWOTein webserver provides the list of predicted strengths and weaknesses and a protein structure visualization tool that facilitates the interpretation of the predictions. It is freely available for academic use at http://babylone.ulb. ac.be/SWOTein.
Comparison of New Kairomone-Based Lures for Cydia pomonella (Lepidoptera: Tortricidae) in Italy and USA

Simple Summary Adult codling moth (Cydia pomonella L.) monitoring with lure-baited traps is a prerequisite to effectively manage this key pest in apple and pear crops without over-spraying insecticides. We evaluated new multi-component lures comprised of blends of sex pheromone and volatile organic compounds (pear ester, dimethyl nonatriene and linalool oxide) loaded into different substrates (septa and PVC lures). Acetic acid in a second membrane lure was used as a co-lure with all blends. Lure comparisons were performed during the period 2019/2020 in Italy and Washington State (USA) in orchards treated with or without sex pheromone dispensers for mating disruption. The highest total moth counts occurred with the sex pheromone/pear ester PVC lure in both countries. The new multi-component PVC lure without sex pheromone captured the greatest number of female moths only in the USA. This geographical disparity may limit the effectiveness of using a ‘female removal’ strategy to manage this pest without insecticides across major production areas. Abstract Studies were conducted during the period 2019/2020 to evaluate the effectiveness of four lures for codling moth (Cydia pomonella L.) in pome fruits in Italy and the USA. Multi-component blends of sex pheromone ((E,E)-8,10-dodecadien-1-ol, PH), pear ester ((E,Z)-2,4-ethyl decadienoate, PE), (E)-4,8-dimethyl-1,3,7-nonatriene (DMNT), and pyranoid linalool oxide (6-ethenyl-2,2,6-trimethyloxan-3-ol, LOX) were loaded in either a halobutyl elastomer septum or a PVC matrix and always used in combination with acetic acid (AA) loaded in a closed membrane co-lure. Total moth capture was significantly greater with the PVC than the septum lure loaded with PH/PE + AA in both countries. Female capture in the USA study was significantly greater for 8 weeks in traps baited with the PE/DMNT/LOX blend + AA co-lure than with other lures and adding PH to this blend in a PVC lure significantly reduced female capture. In contrast, female capture in Italy did not differ among lures and counts were similar in both apple and pear crops treated with or without mating disruption. These results suggest that the effectiveness of ‘female removal’ strategies to manage codling moth may be geographically limited and further comparisons are needed in other production regions and in walnut.
PD-L1 Testing and Squamous Cell Carcinoma of the Head and Neck: A Multicenter Study on the Diagnostic Reproducibility of Different Protocols

Simple Summary The introduction of therapies with immune checkpoint inhibitors targeting the programmed cell death protein 1 and its ligand (PD-L1) axis in head and neck squamous cell carcinoma prompted the need of reliable bio-selectors to stratify patients that would benefit from these treatments. The assessment of PD-L1 expression through immunohistochemistry represents the most widely used method to perform this task, being recently approved by regulatory authorities. However, borrowing from previous experiences in lung cancer, the heterogeneity of antibodies and platforms used in the routine clinical practice requires a strict multi-institutional harmonization effort. In this setting, the present study is aimed to assess the performances of different PD-L1 staining protocols and the inter-observer reliability for its interpretation. Abstract Immune checkpoint inhibitors for blocking the programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) axis are now available for squamous cell carcinoma of the head and neck (HNSCC) in relapsing and/or metastatic settings. In this work, we compared the resulting combined positive score (CPS) of PD-L1 using alternative methods adopted in routine clinical practice and determined the level of diagnostic agreement and inter-observer reliability in this setting. The study applied 5 different protocols on 40 tissue microarrays from HNSCC. The error rate of the individual protocols ranged from a minimum of 7% to a maximum of 21%, the sensitivity from 79% to 96%, and the specificity from 50% to 100%. In the intermediate group (1 ≤ CPS < 20), the majority of errors consisted of an underestimation of PD-L1 expression. In strong expressors, 5 out of 14 samples (36%) were correctly evaluated by all the protocols, but no protocol was able to correctly identify all the “strong expressors”. The overall inter-observer agreement in PD-L1 CPS reached 87%. The inter-observer reliability was moderate, with an ICC of 0.774 (95% CI (0.651; 0.871)). In conclusion, our study showed moderate interobserver reliability among different protocols. In order to improve the performances, adequate specific training to evaluate PD-L1 by CPS in the HNSCC setting should be coordinated.
Doing What Spiders Cannot—A Road Map to Supreme Artificial Silk Fibers

Fabricating artificial spider silk fibers in bulk scale has been a major goal in materials science for centuries. Two main routes have emerged for making such fibers. One method uses biomimetics in which the spider silk proteins (spidroins) are produced under nativelike conditions and then spun into fibers in a process that captures the natural, complex molecular mechanisms. However, these fibers do not yet match the mechanical properties of native silk fibers, potentially due to the small size of the designed spidroin used. The second route builds on biotechnological progress that enables production of large spidroins that can be spun into fibers by using organic solvents. With this approach, fibers that equal the native material in terms of mechanical properties can be manufactured, but the yields are too low for economically sustainable production. Hence, the need for new ideas is urgent. Herein, we introduce a structural-biology-based approach for engineering artificial spidroins that circumvents the laws with which spidroins, being secretory proteins, have to comply in order to avoid membrane insertion and provide a road map to the production of biomimetic silk fibers with improved mechanical properties.
Charge Mobility in Discotic Liquid Crystals

Discotic (disk-shaped) molecules or molecular aggregates may form, within a certain temperature range, partially ordered phases, known as discotic liquid crystals, which have been extensively studied in the recent past. On the one hand, this interest was prompted by the fact that they represent models for testing energy and charge transport theories in organic materials. However, their long-range self-assembling properties, potential low cost, ease of processability with a variety of solvents and the relative ease of tailoring their properties via chemical synthesis, drove the attention of researchers also towards the exploitation of their semiconducting properties in organic electronic devices. This review covers recent research on the charge transport properties of discotic mesophases, starting with an introduction to their phase structure, followed by an overview of the models used to describe charge mobility in organic substances in general and in these systems in particular, and by the description of the techniques most commonly used to measure their charge mobility. The reader already familiar or not interested in such details can easily skip these sections and refer to the core section of this work, focusing on the most recent and significant results regarding charge mobility in discotic liquid crystals.
Exposure of Human Skin Models to KrCl Excimer Lamps: The Impact of Optical Filtering †

Far‐UVC radiation is a promising technology that is potentially both effective at killing airborne microbes such as coronaviruses and influenza, and being minimally hazardous to the skin and eyes. Our previous studies on health risks from far‐UVC have employed a krypton‐chloride (KrCl) excimer lamp, emitting principally at 222 nm, supplemented with an optical filter to remove longer wavelength emissions inherent to these lamps. This study explores KrCl lamp health hazards by comparing filtered and unfiltered KrCl lamps using effective spectral irradiance calculations and experimental skin exposures. Analysis of effective irradiances showed a notable increase in allowable exposure when using a filter. Induction of DNA dimers (CPD and 6‐4PP) was measured in human skin models exposed to a range of radiant exposures up to 500 mJ cm−2. Compared to sham‐exposed tissues, the unfiltered KrCl lamps induced a statistically significant increase in the yield of both DNA lesions at all the radiant exposures studied. Conversely, filtered KrCl lamps do not induce increased levels of dimers at the current daily TLV exposure limit for 222 nm (23 mJ cm−2). This work supports the use of filters for far‐UVC KrCl excimer lamps when used to limit disease transmission in occupied locations.
Whole‐body senescent cell clearance alleviates age‐related brain inflammation and cognitive impairment in mice

Cellular senescence is characterized by an irreversible cell cycle arrest and a pro‐inflammatory senescence‐associated secretory phenotype (SASP), which is a major contributor to aging and age‐related diseases. Clearance of senescent cells has been shown to improve brain function in mouse models of neurodegenerative diseases. However, it is still unknown whether senescent cell clearance alleviates cognitive dysfunction during the aging process. To investigate this, we first conducted single‐nuclei and single‐cell RNA‐seq in the hippocampus from young and aged mice. We observed an age‐dependent increase in p16Ink4a senescent cells, which was more pronounced in microglia and oligodendrocyte progenitor cells and characterized by a SASP. We then aged INK‐ATTAC mice, in which p16Ink4a‐positive senescent cells can be genetically eliminated upon treatment with the drug AP20187 and treated them either with AP20187 or with the senolytic cocktail Dasatinib and Quercetin. We observed that both strategies resulted in a decrease in p16Ink4a exclusively in the microglial population, resulting in reduced microglial activation and reduced expression of SASP factors. Importantly, both approaches significantly improved cognitive function in aged mice. Our data provide proof‐of‐concept for senolytic interventions' being a potential therapeutic avenue for alleviating age‐associated cognitive impairment.
Safety of secukinumab for the treatment of active ankylosing spondylitis

ABSTRACT Introduction: Secukinumab is a fully human monoclonal antibody which targets and neutralizes interleukin (IL)-17A, a cytokine that plays an important role in the pathophysiology of ankylosing spondylitis (AS). Secukinumab is the first IL-17A inhibitor approved for the treatment of AS. Areas covered: This paper aimed to evaluate the role of IL-17 in human beings, and the blocking of this cytokine with secukinumab while reviewing its efficacy and safety in the treatment of AS from data of MEASURE clinical trials. Expert opinion: MEASURE clinical trials showed efficacy and safety of secukinumab in patients with AS. Mild infections were the most frequent adverse event observed. Mucocutaneous candidiasis was a relatively common side effect due to the role of IL-17A in mucocutaneous defense against extracellular organisms. Secukinumab remained generally well tolerated over the longer-term. The combination of efficacy and safety makes secukinumab a good option of treatment for patients with AS refractory to non-steroidal anti-inflammatory drugs.
Retinol-binding protein, retinol, and modified-relative-dose response in Ugandan children aged 12–23 months and their non-pregnant caregivers

Retinol-binding protein (RBP), retinol, and modified-relative-dose response (MRDR) are used to assess vitamin A status. We describe vitamin A status in Ugandan children and women using dried blood spot (DBS) RBP, serum RBP, plasma retinol, and MRDR and compare DBS-RBP, serum RBP, and plasma retinol. Blood was collected from 39 children aged 12–23 months and 28 non-pregnant mothers aged 15–49 years as a subsample from a survey in Amuria district, Uganda, in 2016. DBS RBP was assessed using a commercial enzyme immunoassay kit, serum RBP using an in-house sandwich enzyme-linked immunosorbent assay, and plasma retinol/MRDR test using high-performance liquid chromatography. We examined (a) median concentration or value (Q1, Q3); (b) R2 between DBS-RBP, serum RBP, and plasma retinol; and (c) Bland-Altman plots. Median (Q1, Q3) for children and mothers, respectively, were as follows: DBS-RBP 1.15 µmol/L (0.97, 1.42) and 1.73 (1.52, 1.96), serum RBP 0.95 µmol/L (0.78, 1.18) and 1.47 µmol/L (1.30, 1.79), plasma retinol 0.82 µmol/L (0.67, 0.99) and 1.33 µmol/L (1.22, 1.58), and MRDR 0.025 (0.014, 0.042) and 0.014 (0.009, 0.019). DBS RBP-serum RBP R2 was 0.09 for both children and mothers. The mean biases were −0.19 µmol/L (95% limits of agreement [LOA] 0.62, −0.99) for children and −0.01 µmol/L (95% LOA −1.11, −1.31) for mothers. DBS RBP-plasma retinol R2 was 0.11 for children and 0.13 for mothers. Mean biases were 0.33 µmol/L (95% LOA −0.37, 1.03) for children, and 0.29 µmol/L (95% LOA −0.69, 1.27) for mothers. Serum RBP-plasma retinol R2 was 0.75 for children and 0.55 for mothers, with mean biases of 0.13 µmol/L (95% LOA −0.23, 0.49) for children and 0.18 µmol/L (95% LOA −0.61, 0.96) for mothers. Results varied by indicator and matrix. The serum RBP-retinol R2 for children was moderate (0.75), but poor for other comparisons. Understanding the relationships among vitamin A indicators across contexts and population groups is needed.
Infant Emotional Mimicry of Strangers: Associations with Parent Emotional Mimicry, Parent-Infant Mutual Attention, and Parent Dispositional Affective Empathy

Emotional mimicry, the tendency to automatically and spontaneously reproduce others’ facial expressions, characterizes human social interactions from infancy onwards. Yet, little is known about the factors modulating its development in the first year of life. This study investigated infant emotional mimicry and its association with parent emotional mimicry, parent-infant mutual attention, and parent dispositional affective empathy. One hundred and seventeen parent-infant dyads (51 six-month-olds, 66 twelve-month-olds) were observed during video presentation of strangers’ happy, sad, angry, and fearful faces. Infant and parent emotional mimicry (i.e., facial expressions valence-congruent to the video) and their mutual attention (i.e., simultaneous gaze at one another) were systematically coded second-by-second. Parent empathy was assessed via self-report. Path models indicated that infant mimicry of happy stimuli was positively and independently associated with parent mimicry and affective empathy, while infant mimicry of sad stimuli was related to longer parent-infant mutual attention. Findings provide new insights into infants’ and parents’ coordination of mimicry and attention during triadic contexts of interactions, endorsing the social-affiliative function of mimicry already present in infancy: emotional mimicry occurs as an automatic parent-infant shared behavior and early manifestation of empathy only when strangers’ emotional displays are positive, and thus perceived as affiliative.
The Pivotal Role of Viruses in the Pathogeny of Chronic Lymphocytic Leukemia: Monoclonal (Type 1) IgG K Cryoglobulinemia and Chronic Lymphocytic Leukemia Diagnosis in the Course of a Human Metapneumovirus Infection

Background: Type-1 cryoglobulinemia (CG) is a rare disease associated with B-cell lymphoproliferative disorder. Some viral infections, such as Epstein–Barr Virus infections, are known to cause malignant lymphoproliferation, like certain B-cell lymphomas. However, their role in the pathogenesis of chronic lymphocytic leukemia (CLL) is still debatable. Here, we report a unique case of Type-1 CG associated to a CLL transformation diagnosed in the course of a human metapneumovirus (hMPV) infection. Case presentation: A 91-year-old man was initially hospitalized for delirium. In a context of febrile rhinorrhea, the diagnosis of hMPV infection was made by molecular assay (RT-PCR) on nasopharyngeal swab. Owing to hyperlymphocytosis that developed during the course of the infection and unexplained peripheral neuropathy, a type-1 IgG Kappa CG secondary to a CLL was diagnosed. The patient was not treated for the CLL because of Binet A stage classification and his poor physical condition. Conclusions: We report the unique observation in the literature of CLL transformation and hMPV infection. We provide a mini review on the pivotal role of viruses in CLL pathophysiology.