Development and Validation of a Spontaneous Smile Assay

IMPORTANCE Smiling can be a voluntary or involuntarymovement. Facial reanimation procedures differ in their ability to restore a spontaneous smile, and an assay designed to evoke and evaluate a spontaneous smile is not available. OBJECTIVE To develop and validate an assay to assess the spontaneous smile of patients with facial paralysis. DESIGN, SETTING, AND PARTICIPANTS Thiswas an exploratory cohort study. A series of short video clips were administered to laypersons via an online survey service from January 1, 2014, to March 31, 2014. Respondents rated how funny each video was on a visual analog scale from 0 to 100. The 4 funniest videos were selected to generate a 11/2-minute spontaneous smile assay. The assay was then administered from July 1, 2014, to December 31, 2014, to 2 different study groups: the first was composed of 100 healthy individuals (control group) and the second was composed of 30 patients with facial paralysis.We analyzed the capability of this assay to provoke at least 1 spontaneous smile and calculated smile excursion in both groups. Statistical analysis was performed using analysis of variance. INTERVENTION Spontaneous smile assay administered to both healthy and diseased groups. MAIN OUTCOMES AND MEASURES Ability of the assay to elicit smiles, as defined by an oral commissure excursion greater than 3 mm, as well as difference in commissure excursion. RESULTS Ninety-five (95.0%) participants in the control group and 29 (96.7%) patients with facial paralysis experienced at least 1 oral commissure excursion that appeared to be a spontaneous smile while viewing the assay. Mean oral commissure excursion with spontaneous smile was 9.08mm(95%CI, 2.77-15.39) in controls, 6.72mm(95%CI, 3.13-10.31) on the healthy side in patients with flaccid facial paralysis (P=.004 vs controls), and 9.64mm(95%CI, 3.52-15.76) on the healthy side in patients with nonflaccid facial paralysis (P=.74). Among patients with flaccid facial paralysis, a statistically significant difference was found between smile excursion of the affected and the unaffected sides (P = .03). There was no statistically significant difference in the measurement between sides for the control group (P = .67). CONCLUSIONS AND RELEVANCE Although humor is a challenging construct to universalize, our assay was able to elicit a smile in almost all individuals in the group with facial paralysis and the control group. The spontaneous smile assay will facilitate future research on the ability of facial reanimation procedures and other interventions to restore a spontaneous smile

PSR J1641+3627F: a low-mass He white dwarf orbiting a possible high-mass neutron star in the globular cluster M13

We report on the discovery of the companion star to the millisecond pulsar J1631+3627F in the globular cluster M13. By means of a combination of optical and near-UV high-resolution observations obtained with the Hubble Space Telescope, we identified the counterpart at the radio source position. Its location in the color-magnitude diagrams reveals that the companion star is a faint (V \sim 24.3) He-core white dwarf. We compared the observed companion magnitudes with those predicted by state-of-the-art binary evolution models and found out that it has a mass of 0.23 \pm 0.03 Msun, a radius of 0.033^+0.004_-0.005 Rsun and a surface temperature of 11500^+1900_-1300 K. Combining the companion mass with the pulsar mass function is not enough to determine the orbital inclination and the neutron star mass; however, the last two quantities become correlated: we found that either the system is observed at a low inclination angle, or the neutron star is massive. In fact, assuming that binaries are randomly aligned with respect to the observer line of sight, there is a \sim 70% of probability that this system hosts a neutron star more massive than 1.6 Msun. In fact, the maximum and median mass of the neutron star, corresponding to orbital inclination angles of 90 deg and 60 deg, are M_NS,max = 3.1 \pm 0.6 Msun and M_NS,med = 2.4 \pm 0.5 Msun, respectively. On the other hand, assuming also an empirical neutron star mass probability distribution, we found that this system could host a neutron star with a mass of 1.5 \pm 0.1 Msun if orbiting with a low-inclination angle around 40 deg.Comment: Accepted for publication by Ap

Rational Design and Real Time, In-Cell Detection of the Proapoptotic Activity of a Novel Compound Targeting Bcl-XL

AbstractAntiapoptotic Bcl-2-family proteins Bcl-2 and Bcl-XL have been recently validated as drug discovery targets for cancer. Here, by using a combination of molecular modeling, NMR-based structural analysis, fluorescence polarization assays, and cell-based assays, we have designed and characterized a novel proapoptotic compound targeting these proteins. Our compound, Apogossypol, is capable of binding and inhibiting Bcl-2 and Bcl-XL with high affinity and induces apoptosis of tumor cell lines. Mechanistic studies on the action of our compound were also performed via confocal microscopy that provided real-time detection of the interaction with Bcl-XL in intact cells. Finally, preliminary data on cells freshly isolated from patients affected by chronic lymphocytic leukemia strongly suggest potential applications of Bcl-2 antagonists as chemosensitizers in cancer therapy

JWST uncovers helium and water abundance variations in the bulge globular cluster NGC 6440

We used ultra-deep observations obtained with the NIRCam aboard the James Webb Space Telescope to explore the stellar population of NGC 6440: a typical massive, obscured and contaminated globular cluster formed and orbiting within the Galactic bulge. Leveraging the exceptional capabilities of this camera, we sampled the cluster down to ~5 magnitudes below the main-sequence turn-off in the (mF115W , mF115W - mF200W ) colour-magnitude diagram. After carefully accounting for differential extinction and contamination by field interlopers, we find that the main sequence splits into two branches both above and below the characteristic knee. By comparing the morphology of the colour-magnitude diagram with a suitable set of isochrones, we argue that the upper main-sequence bi-modality is likely due to the presence of a He-enriched stellar population with a helium spread of DeltaY = 0.04. The lower main-sequence bi-modality can be attributed to variations in the abundance of water (i.e., oxygen) with Delta[O/Fe] ~ -0.4. This is the first evidence of both helium and oxygen abundance variations in a globular cluster purely based on JWST observations. These results open the window for future in-depth investigations of the multiple population phenomenon in clusters located in the Galactic bulge, which were previously unfeasible with near-UV observations, due to prohibitive reddening and crowding conditions.Comment: Accepted for publication in A&

A wireless sensor network-based approach to large-scale dimensional metrology

In many branches of industry, dimensional measurements have become an important part of the production cycle, in order to check product compliance with specifications. This task is not trivial especially when dealing with largescale dimensional measurements: the bigger the measurement dimensions are, the harder is to achieve high accuracies. Nowadays, the problem can be handled using many metrological systems, based on different technologies (e.g. optical, mechanical, electromagnetic). Each of these systems is more or less adequate, depending upon measuring conditions, user's experience and skill, or other factors such as time, cost, accuracy and portability. This article focuses on a new possible approach to large-scale dimensional metrology based on wireless sensor networks. Advantages and drawbacks of such approach are analysed and deeply discussed. Then, the article briefly presents a recent prototype system - the Mobile Spatial Coordinate-Measuring System (MScMS-II) - which has been developed at the Industrial Metrology and Quality Laboratory of DISPEA - Politecnico di Torino. The system seems to be suitable for performing dimensional measurements of large-size objects (sizes on the order of several meters). Owing to its distributed nature, the system - based on a wireless network of optical devices - is portable, fully scalable with respect to dimensions and shapes and easily adaptable to different working environments. Preliminary results of experimental tests, aimed at evaluating system performance as well as research perspectives for further improvements, are discusse

Efficacy and Safety of Adalimumab in Conjunction With Surgery in Moderate to Severe Hidradenitis Suppurativa:The SHARPS Randomized Clinical Trial

IMPORTANCE: Surgery is a mainstay in the management of hidradenitis suppurativa (HS). Adalimumab is the first drug approved for HS. OBJECTIVE: To investigate the efficacy and safety of adalimumab in combination with wide-excision surgery followed by secondary intention healing. DESIGN, SETTING, AND PARTICIPANTS: The Safety and Efficacy of Adalimumab for Hidradenitis Suppurativa Peri-Surgically (SHARPS) trial was a phase 4, randomized, double-blind, placebo-controlled study of adalimumab in conjunction with surgery. Patients were enrolled in 45 sites across 20 countries from July 18, 2016, to February 2, 2019, with the last patient visit on October 16, 2019. Eligible patients (aged 18-65 years) had moderate to severe HS that required radical surgery in an axillary or inguinal region and had 2 other anatomical regions affected, with 1 or more regions at Hurley stage II or III. Analysis was conducted in November 2019. INTERVENTIONS: Patients were randomized 1:1 to receive continuous adalimumab, 40 mg, or placebo during presurgery (12 weeks), perioperative (2 weeks), and postoperative (10 weeks) periods. MAIN OUTCOMES AND MEASURES: The primary end point was the proportion of patients achieving HS clinical response across all body regions at week 12. RESULTS: Overall, 103 patients were randomized to adalimumab and 103 to matching placebo. Among all patients, 51% (n = 106) were women, 94% (n = 193) were White, and the mean (SD) age was 37.6 (11.3) years. At week 12, significantly more patients receiving adalimumab (49 of 103 [48%]) vs placebo (35 of 103 [34%]; P = .049) achieved HS clinical response across all body regions (treatment difference, 14% [95% CI, 0%-27%]). Treatment-emergent adverse events were reported in 74 of 103 patients (72%) and 69 of 103 patients (67%) in the adalimumab and placebo groups, respectively. No increased risk of postoperative wound infection, complication, or hemorrhage was observed with adalimumab vs placebo. Two deaths occurred in the adalimumab group; neither was considered as having a reasonable possibility of relationship to study drug. CONCLUSIONS AND RELEVANCE: Adalimumab was efficacious in conjunction with wide-excision surgery followed by secondary intention healing, with no need to interrupt treatment prior to surgery. These data support further investigation of adalimumab as an adjuvant therapy to surgery in patients with moderate to severe HS. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT0280897

Functional Characterization of Two Variants at the Intron 6-Exon 7 Boundary of the KCNQ2 Potassium Channel Gene Causing Distinct Epileptic Phenotypes

Pathogenic variants in KCNQ2 encoding for Kv7.2 potassium channel subunits have been found in patients affected by widely diverging epileptic phenotypes, ranging from Self-Limiting Familial Neonatal Epilepsy (SLFNE) to severe Developmental and Epileptic Encephalopathy (DEE). Thus, understanding the pathogenic molecular mechanisms of KCNQ2 variants and their correlation with clinical phenotypes has a relevant impact on the clinical management of these patients. In the present study, the genetic, biochemical, and functional effects prompted by two variants, each found in a non-familial SLNE or a DEE patient but both affecting nucleotides at the KCNQ2 intron 6-exon 7 boundary, have been investigated to test whether and how they affected the splicing process and to clarify whether such mechanism might play a pathogenetic role in these patients. Analysis of KCNQ2 mRNA splicing in patient-derived lymphoblasts revealed that the SLNE-causing intronic variant (c.928-1G > C) impeded the use of the natural splice site, but lead to a 10-aa Kv7.2 in frame deletion (Kv7.2 p.G310Δ10); by contrast, the DEE-causing exonic variant (c.928G > A) only had subtle effects on the splicing process at this site, thus leading to the synthesis of a full-length subunit carrying the G310S missense variant (Kv7.2 p.G310S). Patch-clamp recordings in transiently-transfected CHO cells and primary neurons revealed that both variants fully impeded Kv7.2 channel function, and exerted strong dominant-negative effects when co-expressed with Kv7.2 and/or Kv7.3 subunits. Notably, Kv7.2 p.G310S, but not Kv7.2 p.G310Δ10, currents were recovered upon overexpression of the PIP2-synthesizing enzyme PIP5K, and/or CaM; moreover, currents from heteromeric Kv7.2/Kv7.3 channels incorporating either Kv7.2 mutant subunits were differentially regulated by changes in PIP2 availability, with Kv7.2/Kv7.2 G310S/Kv7.3 currents showing a greater sensitivity to PIP2 depletion when compared to those from Kv7.2/Kv7.2 G310Δ10/Kv7.3 channels. Altogether, these results suggest that the two variants investigated differentially affected the splicing process at the intron 6-exon 7 boundary, and led to the synthesis of Kv7.2 subunits showing a differential sensitivity to PIP2 and CaM regulation; more studies are needed to clarify how such different functional properties contribute to the widely-divergent clinical phenotypes

Expression and regulation of α-transducin in the pig gastrointestinal tract

Taste signalling molecules are found in the gastrointestinal (GI) tract suggesting that they participate to chemosensing. We tested whether fasting and refeeding affect the expression of the taste signalling molecule, a-transducin (Gatran), throughout the pig GI tract and the peptide content of Gatran cells. The highest density of Gatran-immunoreactive (IR) cells was in the pylorus, followed by the cardiac mucosa, duodenum, rectum, descending colon, jejunum, caecum, ascending colon and ileum. Most Gatran-IR cells contained chromogranin A. In the stomach, many Gatran-IR cells contained ghrelin, whereas in the upper small intestine many were gastrin/cholecystokinin-IR and a few somatostatin-IR. Gatran-IR and Gagust-IR colocalized in some cells. Fasting (24 h) resulted in a significant decrease in Gatran-IR cells in the cardiac mucosa (29.3 0.8 versus 64.8 1.3, P < 0.05), pylorus (98.8 1.7 versus 190.8 1.9, P < 0.0 l), caecum (8 0.01 versus 15.5 0.5, P < 0.01), descending colon (17.8 0.3 versus 23 0.6, P < 0.05) and rectum (15.3 0.3 versus 27.5 0.7, P < 0.05). Refeeding restored the control level of Gatran-IR cells in the cardiac mucosa. In contrast, in the duodenum and jejunum, Gatran-IR cells were significantly reduced after refeeding, whereas Gatran-IR cells density in the ileum was not changed by fasting/refeeding. These findings provide further support to the concept that taste receptors contribute to luminal chemosensing in the GI tract and suggest they are involved in modulation of food intake and GI function induced by feeding and fasting