Miracle-dz/UniFAR-FTUs huggingface dataset:
Bisphosphonates Targeting Ion Channels and Musculoskeletal Effects

Bisphosphonates (BPs) are the most used bone-specific anti-resorptive agents, often chosen as first-line therapy in several bone diseases characterized by an imbalance between osteoblast-mediated bone production and osteoclast-mediated bone resorption. BPs target the farnesyl pyrophosphate synthase (FPPS) in osteoclasts, reducing bone resorption. Lately, there has been an increasing interest in BPs direct pro-survival/pro-mineralizing properties in osteoblasts and their pain-relieving effects. Even so, molecular targets involved in these effects appear now largely elusive. Ion channels are emerging players in bone homeostasis. Nevertheless, the effects of BPs on these proteins have been poorly described. Here we reviewed the actions of BPs on ion channels in musculoskeletal cells. In particular, the TRPV1 channel is essential for osteoblastogenesis. Since it is involved in bone pain sensation, TRPV1 is a possible alternative target of BPs. Ion channels are emerging targets and anti-target for bisphosphonates. Zoledronic acid can be the first selective musculoskeletal and vascular KATP channel blocker targeting with high affinity the inward rectifier channels Kir6.1-SUR2B and Kir6.2-SUR2A. The action of this drug against the overactive mutants of KCNJ9-ABCC9 genes observed in the Cantu’ Syndrome (CS) may improve the appropriate prescription in those CS patients affected by musculoskeletal disorders such as bone fracture and bone frailty.
Green Banana Flour Contributes to Gut Microbiota Recovery and Improves Colonic Barrier Integrity in Mice Following Antibiotic Perturbation

Green banana flour (GBF) is rich in resistant starch that has been used as a prebiotic to exert beneficial effects on gut microbiota. In this study, GBF was evaluated for its capacity to restore gut microbiota and intestinal barrier integrity from antibiotics (Abx) perturbation by comparing it to natural recovery (NR) treatment. C57B/L 6 J mice were exposed to 3 mg ciprofloxacin and 3.5 mg metronidazole once a day for 2 weeks to induce gut microbiota dysbiosis model. Then, GBF intervention at the dose of 400 mg/kg body weight was conducted for 2 weeks. The results showed that mice treated with Abx displayed increased gut permeability and intestinal barrier disruption, which were restored more quickly with GBF than NR treatment by increasing the secretion of mucin. Moreover, GBF treatment enriched beneficial Bacteroidales S24-7, Lachnospiraceae, Bacteroidaceae, and Porphyromonadaceae that accelerated the imbalanced gut microbiota restoration to its original state. This study puts forward novel insights into the application of GBF as a functional food ingredient to repair gut microbiota from Abx perturbation.
Innate Lymphoid Cells Are Required to Induce Airway Hyperreactivity in a Murine Neutrophilic Asthma Model

Rationale Non-allergic asthma is driven by multiple endotypes of which neutrophilic and pauci-granulocytic asthma have been best established. However, it is still puzzling what drives inflammation and airway hyperreactivity (AHR) in these patients and how it can be treated effectively. Recently, a potential role of the innate immune system and especially the innate lymphoid cells (ILC) has been proposed. Objective In this study, we investigated the effects of LPS inhalation on airway inflammation and AHR as a potential model for elucidating the pathogenesis of non-allergic asthma. Methods Wild-type (BALB/c), SCID, IL-17A-/-, and Rag2-/- γC-/- mice were endonasally exposed to lipopolysaccharide (LPS, 2 µg) on four consecutive days. Twenty-four hours after the last exposure, AHR to methacholine was assessed. Cytokine levels and ILC subpopulations were determined in lung tissue. Cellular differential analysis was performed in BAL fluid. Main Results In this study, we developed a murine model for non-allergic neutrophilic asthma. We found that repeated endonasal applications of low-dose LPS in BALB/c mice led to AHR, BAL neutrophilia, and a significant increase in lung ILC3 as well as a significant increase in lung chemokines KC and MIP-2 and cytokines IL-1β, IL-17A, IL-22, and TNF. The adoptive transfer of ILC in Rag2-/- γC-/- mice showed that ILC played a causal role in the induction of AHR in this model. Antagonising IL-1β, but not IL-17A or neutrophils, resulted in a partial reduction in LPS-induced AHR. Conclusion In conclusion, we report here a murine model for neutrophilic asthma where ILC are required to induce airway hyperreactivity.
Comparative Study on the Efficiency of Mercury Removal From Wastewater Using Bacterial Cellulose Membranes and Their Oxidized Analogue

A comparative study was conducted on the efficiency of mercury removal using bacterial nanocellulose (BNC) membranes obtained from the fermentation of the microorganism Komagataeibacter medellinensis, in contrast with its oxidized analog obtained by modifying the bacterial nanocellulose membranes via oxidation with 2,2,6,6-Tetramethylpiperidine-1-oxyl. Both types of membranes (modified and unmodified) were characterized to identify variations in the Physico-chemical parameters after modification. FTIR spectra confirmed the chemical modification of cellulose in all reaction conditions by the presence of a new characteristic band at ∼1730 cm−1, corresponding to the new carboxylic groups produced by the oxidative process, and the decline of the band at ∼1,650 cm−1, corresponding to the hydroxyl groups of the C6 carbon. While the XRD profiles indicated that the percentage of BNC crystallinity decreased and the SEM images showed that the nanoribbon network was interrupted as the amount of oxidizing agent increased. The kinetics of mercury removal from both types of membrane was evaluated by calculating the concentration of mercury at different times and establishing a mathematical model to describe the kinetics of this process. The modified membranes improved significantly the adsorption process of the metal ion and it was found that the modification that results in the greatest adsorption efficiency was BNC-m 7.5 with a value of 92.97%. The results obtained suggest that the modification of the bacterial nanocellulose membranes by oxidation transcendentally improves the mercury removal capacity, outlining the modified membranes as an excellent material for mercury removal in wastewater.
Exploring the Antecedents and Outcomes of Entrepreneurial Well-Being: Empirical Evidence From Iranian Rural Entrepreneurs

Studies regarding rural entrepreneurs in developing countries and, specifically, their well-being have not been sufficiently developed in the literature. The present study was an attempt to fill this gap and to examine important antecedents and outcomes associated with entrepreneurial well-being among a sample of 102 Iranian rural entrepreneurs. This research established a theoretical research model that highlighted the relationships among job fit, entrepreneurial passion, well-being, and persistence. The results of structural equation modeling supported the hypothesized model. In particular, the results indicated that higher job fit was associated with higher levels of entrepreneurial well-being through an entrepreneurial passion mechanism. Moreover, the results supported the hypothesized serial mediating effect. In other words, a high level of job fit enhances entrepreneurial persistence through a high level of entrepreneurial passion and well-being. This study provides significant input to policymakers and practitioners in their efforts to promote the antecedents and outcomes of well-being among rural entrepreneurs.
Interaction of Metallic Nanoparticles With Biomimetic Lipid Liquid Crystalline Cubic Interfaces

In the past decades, events occurring at the nano-bio interface (i.e., where engineered nanoparticles (NPs) meet biological interfaces such as biomembranes) have been intensively investigated, to address the cytotoxicity of nanomaterials and boost their clinical translation. In this field, lamellar synthetic model membranes have been instrumental to disentangle non-specific interactions between NPs and planar biological interfaces. Much less is known on nano-biointeractions occurring at highly curved biological interfaces, such as cubic membranes. These non-lamellar architectures play a crucial -but far from understood-role in several biological processes and occur in cells as a defence mechanism against bacterial and viral pathologies, including coronaviruses infections. Despite its relevance, the interaction of cubic membranes with nano-sized objects (such as viral pathogens, biological macromolecules and synthetic NPs) remains largely unexplored to date. Here, we address the interaction of model lipid cubic phase membranes with two prototypical classes of NPs for Nanomedicine, i.e., gold (AuNPs) and silver NPs (AgNPs). To this purpose, we challenged lipid cubic phase membranes, either in the form of dispersed nanoparticles (i.e., cubosomes) or solid-supported layers of nanometric thickness, with citrate-stabilized AuNPs and AgNPs and monitored the interaction combining bulk techniques (UV-visible spectroscopy, Light and Synchrotron Small-Angle X-ray Scattering) with surface methods (Quartz Crystal Microbalance and Confocal Laser Scanning Microscopy). We show that the composition of the metal core of NPs (i.e., Au vs Ag) modulates their adsorption and self-assembly at cubic interfaces, leading to an extensive membrane-induced clustering of AuNPs, while only to a mild adsorption of isolated AgNPs. Such differences mirror opposite effects at the membrane level, where AuNPs induce lipid extraction followed by a fast disruption of the cubic assembly, while AgNPs do not affect the membrane morphology. Finally, we propose an interaction mechanism accounting for the different behaviour of AuNPs and AgNPs at the cubic interface, highlighting a prominent role of NPs’ composition and surface chemistry in the overall interaction mechanism.
The Small GTPase RHOA Links SLP65 Activation to PTEN Function in Pre B Cells and Is Essential for the Generation and Survival of Normal and Malignant B Cells

The generation, differentiation, survival and activation of B cells are coordinated by signals emerging from the B cell antigen receptor (BCR) or its precursor, the pre-BCR. The adaptor protein SLP65 (also known as BLNK) is an important signaling factor that controls pre-B cell differentiation by down-regulation of PI3K signaling. Here, we investigated the mechanism by which SLP65 interferes with PI3K signaling. We found that SLP65 induces the activity of the small GTPase RHOA, which activates PTEN, a negative regulator of PI3K signaling, by enabling its translocation to the plasma membrane. The essential role of RHOA is confirmed by the complete block in early B cell development in conditional RhoA-deficient mice. The RhoA-deficient progenitor B cells showed defects in activation of immunoglobulin gene rearrangement and fail to survive both in vitro and in vivo. Reconstituting the RhoA-deficient cells with RhoA or Foxo1, a transcription factor repressed by PI3K signaling and activated by PTEN, completely restores the survival defect. However, the defect in differentiation can only be restored by RhoA suggesting a unique role for RHOA in B cell generation and selection. In full agreement, conditional RhoA-deficient mice develop increased amounts of autoreactive antibodies with age. RHOA function is also required at later stage, as inactivation of RhoA in peripheral B cells or in a transformed mature B cell line resulted in cell loss. Together, these data show that RHOA is the key signaling factor for B cell development and function by providing a crucial SLP65-activated link between BCR signaling and activation of PTEN. Moreover, the identified essential role of RHOA for the survival of transformed B cells offers the opportunity for targeting B cell malignancies by blocking RHOA function.
Prognostic Pathways Guide Drug Indications in Pan-Cancers

Pathway-level analysis is a powerful approach enabling the interpretation of post-genomic data at a higher level than that of individual molecules. Molecular-targeted therapy focusing on cascade signaling pathways has become a new paradigm in anticancer therapy, instead of a single protein. However, the approaches to narrowing down the long list of biological pathways are limited. Here, we proposed a strategy for in silico Drug Prescription on biological pathways across pan-Cancers (CDP), by connecting drugs to candidate pathways. Applying on a list of 120 traditional Chinese medicines (TCM), we especially identified the “TCM–pathways–cancers” triplet and constructed it into a heterogeneous network across pan-cancers. Applying them into TCMs, the computational prescribing methods deepened the understanding of the efficacy of TCM at the molecular level. Further applying them into Western medicines, CDP could promote drug reposition avoiding time-consuming developments of new drugs.
Generation of Transfer-DNA-Free Base-Edited Citrus Plants

To recover transgenic citrus plants in the most efficient manner, the use of selection marker genes is essential. In this work, it was shown that the mutated forms of the acetolactate synthase (ALS) gene in combination with the herbicide selection agent imazapyr (IMZ) added to the selection medium may be used to achieve this goal. This approach enables the development of cisgenic regenerants, namely, plants without the incorporation of those bacterial genes currently employed for transgenic selection, and additionally it allows the generation of edited, non-transgenic plants with altered endogenous ALS genes leading to IMZ resistance. In this work, the citrus mutants, in which ALS has been converted into IMZ-resistant forms using a base editor system, were recovered after cocultivation of the explants with Agrobacterium tumefaciens carrying a cytidine deaminase fused to nSpCas9 in the T-DNA and selecting regenerants in the culture medium supplemented with IMZ. Analysis of transgene-free plants indicated that the transient expression of the T-DNA genes was sufficient to induce ALS mutations and thus generate IMZ-resistant shoots at 11.7% frequency. To our knowledge, this is the first report of T-DNA-free edited citrus plants. Although further optimization is required to increase edition efficiency, this methodology will allow generating new citrus varieties with improved organoleptic/agronomic features without the need to use foreign genes.
WiSE CRT Is Beneficial for Heart Failure Patients as a Rescue Therapy: Evidence From a Meta-Analysis

Background Leadless endocardial left ventricular (LV) pacing resynchronization therapy is a novel solution for patients with heart failure (HF) in whom conventional cardiac resynchronization therapy (CRT) failed. Methods PubMed and the Cochrane Library were searched for relevant cohort studies. Clinical outcomes of interest such as ejection fraction (EF), QRS duration (QRSd), and left ventricular end-systolic volume (LVESV) were extracted and analyzed. Results Five studies involving 175 HF patients for WiSE CRT were included, and patients were followed-up for 6 months. The implanted success rate ranged from 76.5 to 100%. WiSE CRT resulted in significantly narrower QRSd [mean difference (MD): −38.21 ms, 95% confidence interval (CI): −44.36 to −32.07, p < 0.001], improved left ventricular ejection fraction (MD: 6.07%, 95% CI: 4.43 to 7.71, I2 = 0%, p < 0.001), reduced left ventricular end-systolic volume (MD: −23.47 ml, 95% CI: −37.18 to −9.13, p < 0.001), and reduced left ventricular end-diastolic volume (MD: −24.02 ml, 95% CI: −37.01 to −11.03, p = 0.02). Conclusion Evidence from current studies suggests that leadless endocardial LV pacing resynchronization is effective for HF patients who failed conventional CRT or needed a device upgrade, and it may be an interesting rescue therapy.
Whole-Genome Resequencing to Evaluate Life History Variation in Anadromous Migration of Oncorhynchus mykiss

Anadromous fish experience physiological modifications necessary to migrate between vastly different freshwater and marine environments, but some species such as Oncorhynchus mykiss demonstrate variation in life history strategies with some individuals remaining exclusively resident in freshwater, whereas others undergo anadromous migration. Because there is limited understanding of genes involved in this life history variation across populations of this species, we evaluated the genomic difference between known anadromous (n = 39) and resident (n = 78) Oncorhynchus mykiss collected from the Klickitat River, WA, USA, with whole-genome resequencing methods. Sequencing of these collections yielded 5.64 million single-nucleotide polymorphisms that were tested for significant differences between resident and anadromous groups along with previously identified candidate gene regions. Although a few regions of the genome were marginally significant, there was one region on chromosome Omy12 that provided the most consistent signal of association with anadromy near two annotated genes in the reference assembly: COP9 signalosome complex subunit 6 (CSN6) and NACHT, LRR, and PYD domain–containing protein 3 (NLRP3). Previously identified candidate genes for anadromy within the inversion region of chromosome Omy05 in coastal steelhead and rainbow trout were not informative for this population as shown in previous studies. Results indicate that the significant region on chromosome Omy12 may represent a minor effect gene for male anadromy and suggests that this life history variation in Oncorhynchus mykiss is more strongly driven by other mechanisms related to environmental rearing such as epigenetic modification, gene expression, and phenotypic plasticity. Further studies into regulatory mechanisms of this trait are needed to understand drivers of anadromy in populations of this protected species.
Investigate the Effects of Industrial Agglomeration on Nitrogen Dioxide Pollution Using Spatial Panel Durbin and Panel Threshold Models

The degree of industrial agglomeration in China has contributed to the reduction of nitrogen dioxide pollution because of financial support, the allocation of environmental governance efficiency, and technological advantages. However, the intensity and scope of the spatial effect of this contribution needs to be studied in depth. Based on the influence mechanism and intermediate mechanism of the spatial pattern, this paper uses the panel data of 282 prefecture-level and above cities in China from 2015 to 2018, draws on the STIRPAT model, and uses the Spatial Panel Durbin and Panel Threshold models to investigate the effects of industrial agglomeration on nitrogen dioxide. The study finds that 1) industrial agglomeration has a significant spatial spillover effect on the reduction of nitrogen dioxide pollution, and the increase in the level of local industrial agglomeration can greatly reduce the concentration of nitrogen dioxide in the surrounding area. 2) This kind of spatial overflow has a threshold boundary. Within 100 km, it is a dense area of overflow and reaches the threshold boundary beyond 150 km. 3) Under the influence of the three intermediate mechanisms of industrial agglomeration, the increase in car ownership, and the level of economic development, the impact of industrial agglomeration on the reduction of nitrogen dioxide pollution has gradually increased. The above conclusion is still valid after various robustness tests.
The Antecedents and Consequences of Workaholism: Findings From the Modern Japanese Labor Market

The present study examined the direct and indirect (via workaholism) relationships between competitive work environments and subjective unhealthiness. It also examined the effects of adjusting for cognitive distortions in the relationship between a competitive work environment and subjective unhealthiness and between a competitive work environment and workaholism. Data were collected from 9,716 workers in various industries, occupations, and positions. The results show that competitive work environments were positively related to subjective unhealthiness, both directly and through workaholism. Furthermore, cognitive distortions moderated the positive effect between a competitive work environment and workaholism, and the positive relationship was stronger when cognitive distortions were high (as compared to low). This study has important and practical implications for companies that are increasingly concerned about the health of their employees.
The Tomato Transcription Factor SlNAC063 Is Required for Aluminum Tolerance by Regulating SlAAE3-1 Expression

Aluminum (Al) toxicity constitutes one of the major limiting factors of plant growth and development on acid soils, which comprises approximately 50% of potentially arable lands worldwide. When suffering Al toxicity, plants reprogram the transcription of genes, which activates physiological and metabolic pathways to deal with the toxicity. Here, we report the role of a NAM, ATAF1, 2 and CUC2 (NAC) transcription factor (TF) in tomato Al tolerance. Among 53 NAC TFs in tomatoes, SlNAC063 was most abundantly expressed in root apex and significantly induced by Al stress. Furthermore, the expression of SlNAC063 was not induced by other metals. Meanwhile, the SlNAC063 protein was localized at the nucleus and has transcriptional activation potentials in yeast. By constructing CRISPR/Cas9 knockout mutants, we found that slnac063 mutants displayed increased sensitivity to Al compared to wild-type plants. However, the mutants accumulated even less Al than wild-type (WT) plants, suggesting that internal tolerance mechanisms but not external exclusion mechanisms are implicated in SlNAC063-mediated Al tolerance in tomatoes. Further comparative RNA-sequencing analysis revealed that only 45 Al-responsive genes were positively regulated by SlNAC063, although the expression of thousands of genes (1,557 upregulated and 636 downregulated) was found to be affected in slnac063 mutants in the absence of Al stress. The kyoto encyclopedia of genes and genomes (KEGG) pathway analysis revealed that SlNAC063-mediated Al-responsive genes were enriched in “phenylpropanoid metabolism,” “fatty acid metabolism,” and “dicarboxylate metabolism,” indicating that SlNAC063 regulates metabolisms in response to Al stress. Quantitative real-time (RT)-PCR analysis showed that the expression of SlAAE3-1 was repressed by SlNAC063 in the absence of Al. However, the expression of SlAAE3-1 was dependent on SlNAC063 in the presence of Al stress. Taken together, our results demonstrate that a NAC TF SlNAC063 is involved in tomato Al tolerance by regulating the expression of genes involved in metabolism, and SlNAC063 is required for Al-induced expression of SlAAE3-1.