Miracle-dz/UniFAR-FTUs huggingface dataset:
Assembly and organization of the N-terminal region of mucin MUC5AC: Indications for structural and functional distinction from MUC5B

Significance Gel-forming mucins, MUC5AC and MUC5B, are the essential components of the protective mucus layer of the lungs. MUC5B is crucial for lung innate defense, and MUC5AC is generally secreted disproportionately in response to cigarette smoke and allergens. MUC5AC’s role in airway defense and chronic airway disease pathogenesis and how this emerges from its macromolecular assembly/gel-making properties are not known. We demonstrate MUC5AC binds significantly more to hydrophobic surfaces and forms stiffer and more viscoelastic layers compared to MUC5B. Also, MUC5AC forms higher-order oligomers in addition to dimers. These observations may generate insight into why/how MUC5AC forms a stagnant, “tethered” mucus layer in muco-obstructive lung diseases and could guide the development of strategies to intervene with more effective therapeutic agents. Elevated levels of MUC5AC, one of the major gel-forming mucins in the lungs, are closely associated with chronic obstructive lung diseases such as chronic bronchitis and asthma. It is not known, however, how the structure and/or gel-making properties of MUC5AC contribute to innate lung defense in health and drive the formation of stagnant mucus in disease. To understand this, here we studied the biophysical properties and macromolecular assembly of MUC5AC compared to MUC5B. To study each native mucin, we used Calu3 monomucin cultures that produced MUC5AC or MUC5B. To understand the macromolecular assembly of MUC5AC through N-terminal oligomerization, we expressed a recombinant whole N-terminal domain (5ACNT). Scanning electron microscopy and atomic force microscopy imaging indicated that the two mucins formed distinct networks on epithelial and experimental surfaces; MUC5B formed linear, infrequently branched multimers, whereas MUC5AC formed tightly organized networks with a high degree of branching. Quartz crystal microbalance-dissipation monitoring experiments indicated that MUC5AC bound significantly more to hydrophobic surfaces and was stiffer and more viscoelastic as compared to MUC5B. Light scattering analysis determined that 5ACNT primarily forms disulfide-linked covalent dimers and higher-order oligomers (i.e., trimers and tetramers). Selective proteolytic digestion of the central glycosylated region of the full-length molecule confirmed that MUC5AC forms dimers and higher-order oligomers through its N terminus. Collectively, the distinct N-terminal organization of MUC5AC may explain the more adhesive and unique viscoelastic properties of branched, highly networked MUC5AC gels. These properties may generate insight into why/how MUC5AC forms a static, “tethered” mucus layer in chronic muco-obstructive lung diseases.
IGG4-SPECIFIC RESPONSES IN PATIENTS WITH STAPHYLOCOCCUS AUREUS BONE INFECTIONS ARE NOT PREDICTIVE OF POSTOPERATIVE COMPLICATIONS

The most prevalent pathogen in bone infections is Staphylococcus aureus; its incidence and severity are partially determined by host factors. Prior studies showed that anti-glucosaminidase (Gmd) antibodies are protective in animals, and 93.3 % of patients with culture-confirmed S. aureus osteomyelitis do not have anti-Gmd levels > 10 ng/mL in serum. Infection in patients with high anti-Gmd remains unexplained. Are anti-Gmd antibodies in osteomyelitis patients of the non-opsonising, non-complement-fixing IgG4 isotype? The relative amounts of IgG4 and total IgG against Gmd and 7 other S. aureus antigens: iron-surface determinants (Isd) IsdA, IsdB, and IsdH, amidase (Amd), α-haemolysin (Hla), chemotaxis inhibitory protein from S. aureus (CHIPS), and staphylococcal-complement inhibitor (SCIN) were determined in sera from healthy controls (Ctrl, n = 92), osteomyelitis patients whose surgical treatment resulted in infection control (IC, n = 95) or an adverse outcome (AD, n = 40), and post-mortem (PM, n = 7) blood samples from S. aureus septic-death patients. Anti-Gmd IgG4 levels were generally lower in infected patients compared to controls; however, levels among the infected were higher in AD than IC patients. Anti-IsdA, IsdB and IsdH IgG4 levels were increased in infected patients versus controls, and Jonckheere-Terpstra tests of levels revealed an increasing order of infection (Ctrl < IC < AD < PM) for anti-Isd IgG4 antibodies and a decreasing order of infection (Ctrl > IC > AD > PM) for anti-autolysin (Atl) IgG4 antibodies. Collectively, this does not support an immunosuppressive role of IgG4 in S. aureus osteomyelitis but is consistent with a paradigm of high anti-Isd and low anti-Atl responses in these patients.
Verbal and General IQ Associate with Supragranular Layer Thickness and Cell Properties of the Left Temporal Cortex

Abstract The left temporal lobe is an integral part of the language system and its cortical structure and function associate with general intelligence. However, whether cortical laminar architecture and cellular properties of this brain area relate to verbal intelligence is unknown. Here, we addressed this using histological analysis and cellular recordings of neurosurgically resected temporal cortex in combination with presurgical IQ scores. We find that subjects with higher general and verbal IQ scores have thicker left (but not right) temporal cortex (Brodmann area 21, BA21). The increased thickness is due to the selective increase in layers 2 and 3 thickness, accompanied by lower neuron densities, and larger dendrites and cell body size of pyramidal neurons in these layers. Furthermore, these neurons sustain faster action potential kinetics, which improves information processing. Our results indicate that verbal mental ability associates with selective adaptations of supragranular layers and their cellular micro-architecture and function in left, but not right temporal cortex.
What characteristics make self-generated memory cues effective over time?

ABSTRACT From writing to-do lists to creating mnemonic devices in school, people frequently generate cues to help them remember information. Creating memory cues is a vital aspect of metacognition and allows learners to somewhat control their retrieval circumstances. Across three experiments, we tested the extent to which self-generated memory cues fail at long retention intervals because they are based in fleeting mental states. Participants studied target words and generated mnemonic cues for themselves or for others. Cues intended for others showed greater cue-to-target associative strength, were less distinctive, and were less idiosyncratic (more common) than cues intended for oneself. However, the effectiveness of the cues in supporting recall did not differ by intended recipient at medium (∼3 days) or long (∼1 year) retention intervals. In the third experiment, we directly tested the stability of self-generated cues for oneself (compared to cues for others, descriptions of the target, and focused descriptions) by asking participants to generate cues twice for the same targets across a delay of 3 weeks. Cues intended for others were more stable than all other cues, but the stability of the cues did not affect long term retention. Implications for effective cue generation are discussed.
Debulking followed by intralesional 5‐fluorouracil for the treatment of cutaneous squamous cell carcinoma and keratoacanthoma: A retrospective analysis

Debulking followed by intralesional 5‐fluorouracil (deb‐IL5FU) is a nonsurgical modality which has been used to treat skin cancer anecdotally for many years. There are few in depth studies examining this technique and success rate of intralesional 5‐fluorouracil (IL5FU) for the treatment of cutaneous squamous cell carcinoma (cSCC). To evaluate the response rate of deb‐IL5FU for the treatment of cSCC and to determine which patient factors were associated with tumor clearance or treatment failure. A retrospective chart analysis of patients with the diagnosis of cSCC or keratoacanthoma (KA) and subsequent deb‐IL5FU treatment. Sixty‐one patients with a total of 315 tumors (cSCC and KA), were treated using deb‐IL5FU. The overall tumor clearance rate was 89%. This was highest for well‐differentiated SCC, SCC, KA‐type SCC, and KA. Tumors on the trunk and extremities showed high clearance rates while tumors on the scalp/face/neck/ears showed lower clearance rates. Immunocompetent patients cleared more tumors compared to immunocompromised patients. Limitations included the retrospective nature of this analysis as well as a small sample size. Treatment of cSCC and KA with deb‐IL5FU demonstrated high tumor clearance rates. Lower rates of clearance were seen in males, immunosuppressed patients, tumors located on the scalp and face/neck/ears.
Inflammatory blood parameters as prognostic factors for surgical site infection after primary hip or knee arthroplasty: a systematic review protocol

Introduction Surgical site infection (SSI) is a potential complication of surgical procedure. SSI after implant surgery is a disaster both for patients and surgeons. Although predictive tools for SSI are available, none of them estimate early infection based on inflammatory blood parameters. The inflammatory process can be measured using several parameters including interleukin-6, C reactive protein, neutrophil to lymphocyte ratio, white cell count, erythrocyte sedimentation rate or procalcitonin. This systematic review aims to determine whether inflammatory blood parameters could be used as significant predictive factors for SSI after primary hip or knee arthroplasty. Methods and analysis A systematic review of randomised controlled trials, cross-sectional studies, case–control studies and cohort studies, published in English, will be searched in the following electronic bibliographic databases: MEDLINE, Embase, PubMed, Cochrane Central Register of Controlled Trials and Web of Science. Studies performed in adult patients of all ages who underwent knee or hip arthroplasty, studies containing data on the risk/prognostic factors for preknee or postknee or hip arthroplasty SSI and studies with a minimum follow-up of 30 days after surgery will be included. A standardised form will be used to extract data from the included studies comprising study characteristics, participant characteristics, details of the intervention, study methodology and outcomes. Quality Assessment of Diagnostic Accuracy tool, second version, and Standards for Reporting of Diagnostic Accuracy Studies checklist will be used to assess risk of bias. Heterogeneity will be assessed using Cochran χ² statistic and I2 statistics where applicable. Grading of Recommendations Assessment, Development and Evaluation and Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidance will be used to report findings. Ethics and dissemination No ethics approval is required. The findings will be disseminated at national and international scientific sessions, also to be published in a peer-reviewed journal. PROSPERO registration number CRD42020147925.
Endovascular Treatment of Acute Ischemic Stroke With the Penumbra System in Routine Practice

Supplemental Digital Content is available in the text. Background and Purpose: The purpose of the COMPLETE (International Acute Ischemic Stroke Registry With the Penumbra System Aspiration Including the 3D Revascularization Device) registry was to evaluate the generalizability of the safety and efficacy of the Penumbra System (Penumbra, Inc, Alameda) in a real-world setting. Methods: COMPLETE was a global, prospective, postmarket, multicenter registry. Patients with large vessel occlusion–acute ischemic stroke who underwent mechanical thrombectomy using the Penumbra System with or without the 3D Revascularization Device as frontline approach were enrolled at 42 centers (29 United States, 13 Europe) from July 2018 to October 2019. Primary efficacy end points were successful postprocedure angiographic revascularization (modified Thrombolysis in Cerebral Infarction ≥2b) and 90-day functional outcome (modified Rankin Scale score 0–2). The primary safety end point was 90-day all-cause mortality. An imaging core lab determined modified Thrombolysis in Cerebral Infarction scores, Alberta Stroke Program Early CT Scores, clot location, and occurrence of intracranial hemorrhage at 24 hours. Independent medical reviewers adjudicated safety end points. Results: Six hundred fifty patients were enrolled (median age 70 years, 54.0% female, 49.2% given intravenous recombinant tissue-type plasminogen activator before thrombectomy). Rate of modified Thrombolysis in Cerebral Infarction 2b to 3 postprocedure was 87.8% (95% CI, 85.3%–90.4%). First pass and postprocedure rates of modified Thrombolysis in Cerebral Infarction 2c to 3 were 41.5% and 66.2%, respectively. At 90 days, 55.8% (95% CI, 51.9%–59.7%) had modified Rankin Scale score 0 to 2, and all-cause mortality was 15.5% (95% CI, 12.8%–18.3%). Conclusions: Using Penumbra System for frontline mechanical thrombectomy treatment of patients with large vessel occlusion–acute ischemic stroke in a real-world setting was associated with angiographic, clinical, and safety outcomes that were comparable to prior randomized clinical trials with stringent site and operator selection criteria. Registration: URL: https://www.clinicaltrials. gov; Unique identifier: NCT03464565.
Hierarchy and Reliability of the Preschool Language Scales-Fifth Edition: Mokken Scale Analysis.

Purpose This study examined the psychometric properties of the Preschool Language Scales-Fifth Edition (PLS-5 English) among preschool children from low-socioeconomic status (SES) families. Method The PLS-5 was administered individually to 169 3- to 4-year-old children enrolled in Head Start programs. We carried out a Mokken scale analysis (MSA), which is a nonparametric item response theory analysis, to examine the hierarchy among items and the reliability of test scores of the PLS-5 Auditory Comprehension (AC) and Expressive Communication (EC) scales. Results The PLS-5 EC items retained a moderate Mokken scale with the inclusion of all the items. On the other hand, the PLS-5 AC items formed a moderate Mokken scale only with the exclusion of five unscalable items. The latent class reliability coefficients for the AC and the EC scale scores were both above . 90. Several items that violated the invariant item ordering assumption were found for both scales. Conclusions MSA can be used to examine the relationship between the latent language ability and the probability of passing an item with ordinal responses. Results indicate that for preschool children from low-SES families, it is appropriate to use the PLS-5 EC scale scores for comparing individuals' expressive language abilities; however, researchers and speech-language pathologists should be cautious when using the PLS-5 AC scale scores to evaluate individuals' receptive language abilities. Other implications of the MSA results are further discussed.
Reproductive factors and gall-bladder cancer, and the effect of common genetic variants on these associations: a case–control study in India

Abstract Background In India, as elsewhere, the incidence of gall-bladder cancer (GBC) is substantially higher in women than in men. Yet, the relevance of reproductive factors to GBC remains poorly understood. Methods We used logistic regression adjusted for age, education and area to examine associations between reproductive factors and GBC risk, using 790 cases of histologically confirmed GBC and group-matched 1726 visitor controls. We tested the interaction of these associations by genetic variants known to increase the risk of GBC. Results Parity was strongly positively associated with GBC risk: each additional pregnancy was associated with an ∼25% higher risk {odds ratio [OR] 1.26 [95% confidence interval (95% CI) 1.17–1.37]}. After controlling for parity, GBC risk was weakly positively associated with later age of menarche [postmenopausal women, OR 1.11 (95% CI 1.00–1.22) per year], earlier menopause [OR 1.03 (95% CI 1.00–1.06) per year] and shorter reproductive lifespan [OR 1.04 (95% CI 1.01–1.07) per year], but there was little evidence of an association with breastfeeding duration or years since last pregnancy. Risk alleles of single-nucleotide polymorphisms in the ABCB4 and ABCB1 genetic regions had a multiplicative effect on the association with parity, but did not interact with other reproductive factors. Conclusions We observed higher GBC risk with higher parity and shorter reproductive lifespan, suggesting an important role for reproductive and hormonal factors.
Physical activity influences the mobile phone addiction among Chinese undergraduates: The moderating effect of exercise type

Abstract Background and aims Mobile phone addiction (MPA) has recently aroused much attention due to its high incidence and considerable health hazards. Although some existing studies have documented that physical activity is negatively associated with MPA, it is little known about the potential effects underlying this relation. The aim of this study was to investigate the relationship between physical activity and MPA among undergraduates in China, and to further examine the moderating effect of exercise type in the relation between them. Methods By the quota sampling, a total of 650 participants engaged in this survey and completed relevant measurements including physical activity rating scale-3 (PARS-3) and mobile phone addiction tendency scale (MPATS). Results Gender (β = 0.271, P < 0.05) and major (β = −0.169, P < 0.05) could significantly predict MPA, respectively, and physical activity was an imperative protective factor to decrease MPA (β = −0.266, P < 0.001). While the physical activity level enhanced from none exercise to medium exercise, an optimum dose-response relationship would emerge between physical activity and MPA (F (3,604) = 4.799, P < 0.01). Most important, the relation between physical activity and MPA can be moderated by exercise type. Especially in terms of aerobic endurance exercise, the higher level of physical activity the undergraduates performed, the lower degree of MPA would be suffered by them (β = −0.266, P < 0.001). Discussion These findings could be conducive to better understand the positive and potential effects of physical activity on the intervention in MPA, and served as a persuasive evidence that as for university students, actively engaging in aerobic endurance exercise with the medium activity level would be a practicable exercise strategy to deal with MPA in daily lifestyle behavior.
Disentangling early versus late audiovisual integration in adult ADHD: a combined behavioural and resting-state connectivity study

Background: Studies investigating sensory processing in attention-deficit/hyperactivity disorder (ADHD) have shown altered visual and auditory processing. However, evidence is lacking for audiovisual interplay — namely, multisensory integration. As well, neuronal dysregulation at rest (e.g., aberrant within- or between-network functional connectivity) may account for difficulties with integration across the senses in ADHD. We investigated whether sensory processing was altered at the multimodal level in adult ADHD and included resting-state functional connectivity to illustrate a possible overlap between deficient network connectivity and the ability to integrate stimuli. Methods: We tested 25 patients with ADHD and 24 healthy controls using 2 illusionary paradigms: the sound-induced flash illusion and the McGurk illusion. We applied the Mann–Whitney U test to assess statistical differences between groups. We acquired resting-state functional MRIs on a 3.0 T Siemens magnetic resonance scanner, using a highly accelerated 3-dimensional echo planar imaging sequence. Results: For the sound-induced flash illusion, susceptibility and reaction time were not different between the 2 groups. For the McGurk illusion, susceptibility was significantly lower for patients with ADHD, and reaction times were significantly longer. At a neuronal level, resting-state functional connectivity in the ADHD group was more highly regulated in polymodal regions that play a role in binding unimodal sensory inputs from different modalities and enabling sensory-to-cognition integration. Limitations: We did not explicitly screen for autism spectrum disorder, which has high rates of comorbidity with ADHD and also involves impairments in multisensory integration. Although the patients were carefully screened by our outpatient department, we could not rule out the possibility of autism spectrum disorder in some participants. Conclusion: Unimodal hypersensitivity seems to have no influence on the integration of basal stimuli, but it might have negative consequences for the multisensory integration of complex stimuli. This finding was supported by observations of higher resting-state functional connectivity between unimodal sensory areas and polymodal multisensory integration convergence zones for complex stimuli.
The 100,000 most influential scientists rank: the underrepresentation of Brazilian women in academia

Despite the progress observed in recent years, women are still underrepresented in science worldwide, especially at top positions. Many factors contribute to women progressively leaving academia at different stages of their career, including motherhood, harassment and conscious and unconscious discrimination. Implicit bias plays a major negative role in recognition, promotions and career advancement of female scientists. Recently, a rank on the most influential scientists in the world was created based on several metrics, including the number of published papers and citations. Here, we analyzed the representation of Brazilian scientists in this rank, focusing on gender. Female Brazilian scientists are greatly underrepresented in the rank (11% in the Top 100,000; 18% in the Top 2%). Male scientists have more self-citation than female scientists and positions in the rank varied when self-citations were included, suggesting that self-citation by male scientists increases their visibility. Moreover, male scientists had more papers never cited than female scientists. Possible reasons for this observed scenario are related to the metrics used to rank scientists, since these metrics reproduce and amplify the well-known implicit bias in peer-review and citations. Discussions on the repercussions of such ranks are pivotal to avoid deepening the gender gap in science.
A BRCA1 Coiled-Coil Domain Variant Disrupting PALB2 Interaction Promotes the Development of Mammary Tumors and Confers a Targetable Defect in Homologous Recombination Repair

These findings reveal the importance of a patient-derived BRCA1 coiled-coil domain sequence variant in embryonic development, mammary tumor suppression, and therapy response. The BRCA1 tumor suppressor gene encodes a multidomain protein for which several functions have been described. These include a key role in homologous recombination repair (HRR) of DNA double-strand breaks, which is shared with two other high-risk hereditary breast cancer suppressors, BRCA2 and PALB2. Although both BRCA1 and BRCA2 interact with PALB2, BRCA1 missense variants affecting its PALB2-interacting coiled-coil domain are considered variants of uncertain clinical significance (VUS). Using genetically engineered mice, we show here that a BRCA1 coiled-coil domain VUS, Brca1 p.L1363P, disrupts the interaction with PALB2 and leads to embryonic lethality. Brca1 p.L1363P led to a similar acceleration in the development of Trp53-deficient mammary tumors as Brca1 loss, but the tumors showed distinct histopathologic features, with more stable DNA copy number profiles in Brca1 p.L1363P tumors. Nevertheless, Brca1 p.L1363P mammary tumors were HRR incompetent and responsive to cisplatin and PARP inhibition. Overall, these results provide the first direct evidence that a BRCA1 missense variant outside of the RING and BRCT domains increases the risk of breast cancer. Significance: These findings reveal the importance of a patient-derived BRCA1 coiled-coil domain sequence variant in embryonic development, mammary tumor suppression, and therapy response. See related commentary by Mishra et al., p. 6080 Graphical Abstract