Miracle-dz/UniFAR-FTUs huggingface dataset:
Use of FOLFIRINOX or Nab-Paclitaxel Plus Gemcitabine for the Treatment of Locally Advanced Pancreatic Adenocarcinoma: A Single Institution Observational Study

Simple Summary We performed a retrospective analysis to evaluate the effect of treatment with FOLFIRINOX (FFN) or Nab-paclitaxel plus gemcitabine (GemNab) in patients with locally advanced (LA) pancreatic adenocarcinoma (PDAC). Forty-eight percent of patients treated with FFN became eligible for radical resection, and twenty-two percent of patients receiving GemNab underwent surgery after neoadjuvant treatment. FFN treatment was associated with a better overall survival, compared with GemNab (mOS 85.1 vs. 54.3 weeks, FFN and GemNab, respectively; HR = 0.54; p = 0.0109). We found different toxicity profiles between the two chemotherapy regimens. Future randomized clinical trials are mandatory to clarify the best treatment in patients with LA PDAC. Abstract Patients with locally advanced (LA) pancreatic ductal adenocarcinoma (PDAC) do not present distant metastases but are not eligible for surgery upfront. Chemotherapy regimens, such as FOLFIRINOX (FFN) or nab-paclitaxel plus gemcitabine (GemNab) in combination with loco-regional treatments are generally used in this setting. However, the best treatment choice is unknown. We retrospectively analyzed the information of 225 patients with stage II–III PDAC treated at our institution between October 2011 and December 2020. A total of 94 patients with LA PDAC who are non-eligible for surgery upfront received neoadjuvant FFN or GemNab. Of the 67 patients receiving FFN, 28 (41.8%) underwent surgery after neoadjuvant therapy. Of the 27 patients treated with GemNab, 6 (22.2%) became eligible for resection. The median overall survival (OS) was 85.1 weeks and 54.3 weeks in the FFN and GemNab groups, respectively (HR = 0.54, p = 0.0109). The median OS was 189.7 weeks and 76.4 weeks in the resected and unresected cohorts, respectively (HR = 0.25, p < 0.0001). Neutropenia (37.3%), anemia (6.0%), and diarrhea (6.0%) in the FFN group and neutropenia (22.2%) and thrombocytopenia (18.5%) in the GemNab groups were the most frequent grade 3–4 side effects. Higher rates of thrombocytosis (p < 0.0001) and peripheral edema (p < 0.0001) were observed in the GemNab group. Our results suggest that the use of FFN is associated with more favorable clinical outcomes than GemNab for patients with LA PDAC. Future randomized and controlled clinical trials are needed to further elucidate the role of these regimens and loco-regional treatments in this setting.
Significance of the Diagnosis of Executive Functions in Patients with Relapsing-Remitting Multiple Sclerosis

Multiple sclerosis (MS) is a progressive chronic disease of the Central Nervous System (CNS). Cognitive decline occurs rather rarely in relapsing–remitting multiple sclerosis (RRMS) compared to other types. The present study aimed to assess executive functions (EF) in relation to clinical and demographic variables in patients with RRMS. The study involved 22 individuals with RRMS (aged 23 to 49 years) and 22 matching controls. All the individuals with RRMS were in the remission phase. The assessments were carried out using MoCA, BDI-II, Halstead Category Test, Porteus Maze Test, verbal fluency tasks and Stroop Colour-Word Interference Test. The findings show that the two groups differed significantly in all the tests. All patients with RRMS in the remission phase presented at least one cognitive deficit, observed in general cognitive functioning, abstract reasoning or other executive functions, i.e., fluency, interference suppression, planning, or ability to modify activity in response to feedback. The deficits in most cases (except for those measured with the MoCA, Category Tests and phonemic fluency), are not related to intensity of depression and duration of the disease. Findings suggest that the diagnostic process in the case of patients with RRMS may include psychological assessment focusing on potentially existing cognitive, mainly executive, deficits and their severity.
Implicit–explicit gradient of nondual awareness or consciousness as such

Abstract Consciousness is multi-dimensional but is most often portrayed with a two-dimensional (2D) map that has global levels or states on one axis and phenomenal contents on the other. On this map, awareness is conflated either with general alertness or with phenomenal content. This contributes to ongoing difficulties in the scientific understanding of consciousness. Previously, I have proposed that consciousness as such or nondual awareness—a basic non-conceptual, non-propositional awareness in itself free of subject-object fragmentation—is a unique kind that cannot be adequately specified by this 2D map of states and contents. Here, I propose an implicit–explicit gradient of nondual awareness to be added as the z-axis to the existing 2D map of consciousness. This gradient informs about the degree to which nondual awareness is manifest in any experience, independent of the specifics of global state or local content. Alternatively, within the multi-dimensional state space model of consciousness, nondual awareness can be specified by several vectors, each representing one of its properties. In the first part, I outline nondual awareness or consciousness as such in terms of its phenomenal description, its function and its neural correlates. In the second part, I explore the implicit–explicit gradient of nondual awareness and how including it as an additional axis clarifies certain features of everyday dualistic experiences and is especially relevant for understanding the unitary and nondual experiences accessed via different contemplative methods, mind-altering substances or spontaneously.
Pursuing High-Resolution Structures of Nicotinic Acetylcholine Receptors: Lessons Learned from Five Decades

Since their discovery, nicotinic acetylcholine receptors (nAChRs) have been extensively studied to understand their function, as well as the consequence of alterations leading to disease states. Importantly, these receptors represent pharmacological targets to treat a number of neurological and neurodegenerative disorders. Nevertheless, their therapeutic value has been limited by the absence of high-resolution structures that allow for the design of more specific and effective drugs. This article offers a comprehensive review of five decades of research pursuing high-resolution structures of nAChRs. We provide a historical perspective, from initial structural studies to the most recent X-ray and cryogenic electron microscopy (Cryo-EM) nAChR structures. We also discuss the most relevant structural features that emerged from these studies, as well as perspectives in the field.
Regulation of O-Linked N-Acetyl Glucosamine Transferase (OGT) through E6 Stimulation of the Ubiquitin Ligase Activity of E6AP

Glycosyltransferase OGT catalyzes the conjugation of O-linked β-D-N-acetylglucosamine (O-GlcNAc) to Ser and Thr residues of the cellular proteins and regulates many key processes in the cell. Here, we report the identification of OGT as a ubiquitination target of HECT-type E3 ubiquitin (UB) ligase E6AP, whose overexpression in HEK293 cells would induce the degradation of OGT. We also found that the expression of E6AP in HeLa cells with the endogenous expression of the E6 protein of the human papillomavirus (HPV) would accelerate OGT degradation by the proteasome and suppress O-GlcNAc modification of OGT substrates in the cell. Overall, our study establishes a new mechanism of OGT regulation by the ubiquitin–proteasome system (UPS) that mediates the crosstalk between protein ubiquitination and O-GlcNAcylation pathways underlying diverse cellular processes.
Effects of the Resilience of Nurses in Long-Term Care Hospitals during on Job Stress COVID-19 Pandemic: Mediating Effects of Nursing Professionalism

Purpose: To investigate nursing professionalism as a mediating factor in the relationship between resilience and job stress levels for nurses working in long-term care hospitals during the COVID-19 pandemic. Methods: A cross-sectional survey was conducted from January to March 2021 in seven long-term care hospitals in the Seoul metropolitan area to measure resilience, nursing professionalism, and job stress among nurses. Simple and multiple regression analyses along with the Sobel test were performed to verify the mediating effect of nursing professionalism. Results: Data from 200 nurses were included in the final analysis. Results showed that individual and occupational characteristics could lead to differences in nurses’ resilience, job stress levels, and nursing professionalism. Nursing professionalism had a significant mediating effect on the relationship between resilience and job stress levels. The effect of resilience on job stress levels was significant (β = −0.16, p = 0.024). After controlling for nursing professionalism, the effect declined and was not statistically significant (β = −0.09, p = 0.251). Conclusion: There is a need to increase individual resilience and nursing professionalism through intervention programs and policy proposals to manage job stress among long-term care hospital nurses during the COVID-19 pandemic.
Surgical Treatment Using Sinus Tarsi Approach with Anterolateral Fragment Open-Door Technique in Sanders Type 3 and 4 Displaced Intraarticular Calcaneal Fracture

Although various outcomes of the sinus tarsi approach have been reported, these are limited to the Sanders type 2 displaced intraarticular calcaneal fractures (DIACF) because of the limited visibility of the posterior facet joint. In this study we aimed to (1) introduce a sinus tarsi approach combined with an anterolateral fragment open-door technique that enables adequate visibility of the innermost and middle portion of the posterior facet joint, and (2) evaluate the radiographic and clinical outcomes of the patients treated with that technique. This is a retrospective case-series study performed on medical records of 25 patients who presented with the Sanders type 3 or 4 DIACF and were treated with the sinus tarsi approach. The radiologic measurements showed significant corrections of the Bohler’s angle, calcaneal width, length, height, and articular step-off in both X-rays and CTs in the last follow-up period. The mean AOFAS score was 90.08 ± 6.44 at the last follow-up. Among all the follow-up patients, two cases (8%) had acute superficial infections, and no other wound complications occurred. Therefore, we suggest that the Sanders type 3 or 4 DIACF could be successfully treated with the proposed technique with low complications and bring out effective clinical and radiologic outcomes.
Flexural Pseudo-Ductility Effect in Hybrid GFRP/CFRP Bars under Static Loading Conditions

The problem with composite rebars in the civil engineering industry is often described as the material’s brittleness while overloaded. To overcome this drawback, researchers pay attention to the pseudo-ductility effect. The paper presents four-point bending tests of pure unidirectional (UD) rods with additional composite layers obtained by filament winding and hand braiding techniques. Two types of core materials, glass FRP (fibre reinforced polymer) and carbon FRP, were used. Regarding the overwrapping material, the filament winding technique utilized carbon and glass roving reinforcement in the epoxy matrix, while in the case of hand braiding, the carbon fibre sleeve was applied with the epoxy matrix. Microstructural analysis using scanning electron microscopy (SEM) and computed tomography (CT) was performed to reveal the structural differences between the two proposed methods. Mechanical test results showed good material behaviour exhibiting the pseudo-ductility effect after the point of maximum force. The two applied overwrapping techniques had different influences on the pseudo-ductility effect. Microstructural investigation revealed differences between the groups of specimens that partially explain their different characters during mechanical testing.
Relationship between Behavioral Infant Speech Perception and Hearing Age for Children with Hearing Loss

(1) Background: Research has demonstrated that early intervention for children who are hard-of-hearing (CHH) facilitates improved language development. Early speech perception abilities may impact CHH outcomes and guide future intervention. The objective of this study was to examine the use of a conditioned head turn (CHT) task as a measure of speech discrimination in CHH using a clinically feasible protocol. (2) Methods: Speech perception was assessed for a consonant and vowel contrast among 57 CHH and 70 children with normal hearing (CNH) aged 5–17 months using a CHT paradigm. (3) Results: Regardless of hearing status, 74% of CHH and 77% of CNH could discriminate /a-i/, and 55% of CHH and 56% of CNH could discriminate /ba-da/. Regression models revealed that both CHH and CNH performed better on /ba-da/ at 70 dBA compared to 50 dBA. Performance by hearing age showed no speech perception differences for CNH and children with mild hearing loss for either contrast. However, children with hearing losses ≥ 41 dB HL performed significantly poorer than CNH for /a-i/. (4) Conclusions: This study demonstrates the clinical feasibility of assessing early speech perception in infants with hearing loss and replicates previous findings of speech perception abilities among CHH and CNH.
Interferons Are Pro-Inflammatory Cytokines in Sheared-Stressed Human Aortic Valve Endothelial Cells

Calcific aortic valve disease (CAVD) is an athero-inflammatory process. Growing evidence supports the inflammation-driven calcification model, mediated by cytokines such as interferons (IFNs) and tumor necrosis factor (TNF)-α. Our goal was investigating IFNs’ effects in human aortic valve endothelial cells (VEC) and the potential differences between aortic (aVEC) and ventricular (vVEC) side cells. The endothelial phenotype was analyzed by Western blot, qPCR, ELISA, monocyte adhesion, and migration assays. In mixed VEC populations, IFNs promoted the activation of signal transducers and activators of transcription-1 and nuclear factor-κB, and the subsequent up-regulation of pro-inflammatory molecules. Side-specific VEC were activated with IFN-γ and TNF-α in an orbital shaker flow system. TNF-α, but not IFN-γ, induced hypoxia-inducible factor (HIF)-1α stabilization or endothelial nitric oxide synthase downregulation. Additionally, IFN-γ inhibited TNF-α–induced migration of aVEC. Also, IFN-γ triggered cytokine secretion and adhesion molecule expression in aVEC and vVEC. Finally, aVEC were more prone to cytokine-mediated monocyte adhesion under multiaxial flow conditions as compared with uniaxial flow. In conclusion, IFNs promote inflammation and reduce TNF-α–mediated migration in human VEC. Moreover, monocyte adhesion was higher in inflamed aVEC sheared under multiaxial flow, which may be relevant to understanding the initial stages of CAVD.
Synthesis, In Vitro, and In Silico Analysis of the Antioxidative Activity of Dapsone Imine Derivatives

Dapsone (DDS) is an antibacterial drug with well-known antioxidant properties. However, the antioxidant behavior of its derivatives has not been well explored. In the present work, the antioxidant activity of 10 dapsone derivatives 4-substituted was determined by an evaluation in two in vitro models (DPPH radical scavenging assay and ferric reducing antioxidant power). These imine derivatives 1–10 were obtained through condensation between DDS and the corresponding aromatic aldehydes 4-substuited. Three derivatives presented better results than DDS in the determination of DPPH (2, 9, and 10). Likewise, we have three compounds with better reducing activity than dapsone (4, 9, and 10). In order to be more insight, the redox process, a conceptual DFT analysis was carried out. Molecular descriptors such as electronic distribution, the total charge accepting/donating capacity (I/A), and the partial charge accepting/donating capacity (ω+/ω−) were calculated to analyze the relative donor-acceptor capacity through employing a donor acceptor map (DAM). The DFT calculation allowed us to establish a relationship between GAPHOMO-LUMO and DAM with the observed antioxidant effects. According to the results, we concluded that compounds 2 and 3 have the lowest Ra values, representing a good antioxidant behavior observed experimentally in DPPH radical capturing. On the other hand, derivatives 4, 9, and 10 display the best reducing capacity activity with the highest ω− and Rd values. Consequently, we propose these compounds as the best antireductants in our DDS imine derivative series.
Upregulated NMDAR-mediated GABAergic transmission underlies autistic-like deficits in Htr3a knockout mice

Mutations in serotonin pathway genes, especially the serotonergic receptor subunit gene HTR3A, are associated with autism. However, the association of HTR3A deficiency with autism and the underlying mechanisms remain unknown. Methods: The Htr3a knockout (KO) mice were generated using transcription activator-like effector nuclease technology. Various behavior tests, including social interaction, social approach task, olfactory habituation/dishabituation, self-grooming, novel object recognition, contextual fear conditioning, elevated plus maze, open field and seizure susceptibility, were performed to assess the phenotypes. Transcriptome sequencing was carried out to search for molecular network and pathways underlying the phenotypes. Electrophysiological recordings, immunoblotting, immunofluorescence staining, immunoprecipitation, and quantitative real-time PCR were performed to verify the potential mechanisms. The N-methyl-D-aspartate receptor (NMDAR) antagonist memantine was used to treat the KO mice for rescuing the phenotypes. Results: The Htr3a KO mouse model showed three phenotypic domains: autistic-like behaviors (including impaired social behavior, cognitive deficits, and increased repetitive self-grooming), impaired memory, and attenuated susceptibility to pentylenetetrazol-induced seizures. We observed enhanced action potential-driven γ-aminobutyric acid-ergic (GABAergic) transmission in pyramidal neurons and decreased excitatory/inhibitory (E/I) ratio using the patch-clamp recording. Transcriptome sequencing on the hippocampus revealed the converged pathways of the dysregulated molecular networks underlying three phenotypic domains with upregulation of NMDAR. We speculated that Htr3a KO promotes an increase in GABA release through NMDAR upregulation. The electrophysiological recordings on hippocampal parvalbumin-positive (PV+) interneuron revealed increased NMDAR current and NMDAR-dependent excitability. The NMDAR antagonist memantine could rescue GABAergic transmission in the hippocampus and ameliorate autistic-like behaviors of the KO mice. Conclusion: Our data indicated that upregulation of the NMDAR in PV+ interneurons may play a critical role in regulating GABAergic input to pyramidal neurons and maybe involve in the pathogenesis of autism associated with HTR3A deficiency. Therefore, we suggest that the NMDAR system could be considered potential therapeutic target for autism.
Diffuse Axonal Injury: Clinical Prognostic Factors, Molecular Experimental Models and the Impact of the Trauma Related Oxidative Stress. An Extensive Review Concerning Milestones and Advances

Traumatic brain injury (TBI) is a condition burdened by an extremely high rate of morbidity and mortality and can result in an overall disability rate as high as 50% in affected individuals. Therefore, the importance of identifying clinical prognostic factors for diffuse axonal injury (DAI) in (TBI) is commonly recognized as critical. The aim of the present review paper is to evaluate the most recent contributions from the relevant literature in order to understand how each single prognostic factor determinates the severity of the clinical syndrome associated with DAI. The main clinical factors with an important impact on prognosis in case of DAI are glycemia, early GCS, the peripheral oxygen saturation, blood pressure, and time to recover consciousness. In addition, the severity of the lesion, classified on the ground of the cerebral anatomical structures involved after the trauma, has a strong correlation with survival after DAI. In conclusion, modern findings concerning the role of reactive oxygen species (ROS) and oxidative stress in DAI suggest that biomarkers such as GFAP, pNF-H, NF-L, microtubule associated protein tau, Aβ42, S-100β, NSE, AQP4, Drp-1, and NCX represent a possible critical target for future pharmaceutical treatments to prevent the damages caused by DAI.
Dynamic Interplay between Lower-Grade Glioma Instability and Brain Metaplasticity: Proposal of an Original Model to Guide the Therapeutic Strategy

Simple Summary The behavior of diffuse lower-grade glioma (LGG) is changing over time, spontaneously, and in reaction to therapies. Due to genomic instability and clonal expansion, although LGG initially progresses slowly, the growth accelerates at the time of malignant transformation. Furthermore, its progression pattern may change by switching from a proliferative towards a more migratory profile. Along with glioma plasticity, the brain itself is constantly adapting to the tumor and treatment(s) thanks to reconfiguration within and between neural networks. The pattern of reallocation can also evolve, especially by shifting from perilesional to contrahemispheric functional reorganization: this reorientation of cerebral reshaping is related to metaplasticity. The interplay between LGG mutations and reactional connectomal rearrangement leads to perpetual modulations in the glioma–neural equilibrium, explaining the possible preservation of quality of life. An original model of these dynamic interactions across LGG plasticity and the brain metanetwork is proposed to guide a tailored step-by-step individualized management over years. Abstract The behavior of lower-grade glioma (LGG) is changing over time, spontaneously, and in reaction to treatments. First, due to genomic instability and clonal expansion, although LGG progresses slowly during the early period of the disease, its growth velocity will accelerate when this tumor will transform to a higher grade of malignancy. Furthermore, its pattern of progression may change following therapy, e.g., by switching from a proliferative towards a more diffuse profile, in particular after surgical resection. In parallel to this plasticity of the neoplasm, the brain itself is constantly adapting to the tumor and possible treatment(s) thanks to reconfiguration within and between neural networks. Furthermore, the pattern of reallocation can also change, especially by switching from a perilesional to a contrahemispheric functional reorganization. Such a reorientation of mechanisms of cerebral reshaping, related to metaplasticity, consists of optimizing the efficiency of neural delocalization in order to allow functional compensation by adapting over time the profile of circuits redistribution to the behavioral modifications of the glioma. This interplay between LGG mutations and reactional connectomal instability leads to perpetual modulations in the glioma–neural equilibrium, both at ultrastructural and macroscopic levels, explaining the possible preservation of quality of life despite tumor progression. Here, an original model of these dynamic interactions across LGG plasticity and the brain metanetwork is proposed to guide a tailored step-by-step individualized therapeutic strategy over years. Integration of these new parameters, not yet considered in the current guidelines, might improve management of LGG patients.