Miracle-dz/UniFAR-FTUs huggingface dataset:
A Chemically Defined, Xeno- and Blood-Free Culture Medium Sustains Increased Production of Small Extracellular Vesicles From Mesenchymal Stem Cells

Cell therapy is witnessing a notable shift toward cell-free treatments based on paracrine factors, in particular, towards small extracellular vesicles (sEV), that mimic the functional effect of the parental cells. While numerous sEV-based applications are currently in advanced preclinical stages, their promised translation depends on overcoming the manufacturing hurdles posed by the large-scale production of purified sEV. Unquestionably, the culture medium used with the parental cells plays a key role in the sEV’s secretion rate and content. An essential requisite is the use of a serum-, xeno-, and blood-free medium to meet the regulatory entity requirements of clinical-grade sEV’s production. Here, we evaluated OxiumTMEXO, a regulatory complying medium, with respect to production capacity and conservation of the EV’s characteristics and functionality and the parental cell’s phenotype and viability. A comparative study was established with standard DMEM and a commercially available culture medium developed specifically for sEV production. Under similar conditions, OxiumTMEXO displayed a three-fold increase of sEV secretion, with an enrichment of particles ranging between 51 and 200 nm. These results were obtained through direct quantification from the conditioned medium to avoid the isolation method’s interference and variability and were compared to the two culture media under evaluation. The higher yield obtained was consistent with several harvest time points (2, 4, and 6 days) and different cell sources, incluiding umbilical cord-, menstrual blood-derived mesenchymal stromal cells and fibroblasts. Additionally, the stem cell phenotype and viability of the parental cell remained unchanged. Furthermore, OxiumTMEXO-sEV showed a similar expression pattern of the vesicular markers CD63, CD9, and CD81, with respect to sEV derived from the other conditions. The in vitro internalization assays in different target cell types and the pharmacokinetic profile of intraperitoneally administered sEV in vivo indicated that the higher EV production rate did not affect the uptake kinetics or the systemic biodistribution in healthy mice. In conclusion, the OxiumTMEXO medium sustains an efficient and robust production of large quantities of sEV, conserving the classic functional properties of internalization into acceptor target cells and biodistribution in vivo, supplying the amount and quality of EVs for the development of cell-free therapies.
The Ferric Citrate Uptake System Encoded in a Novel blaCTX–M–3- and blaTEM–1-Harboring Conjugative Plasmid Contributes to the Virulence of Escherichia coli

Escherichia coli is one major cause of bacterial infections and can horizontally acquire antimicrobial resistance and virulence genes through conjugation. Because conjugative plasmids can rapidly spread among bacteria of different species, the plasmids carrying both antimicrobial resistance and virulence genes may pose a significant threat to public health. Therefore, the identification and characterization of these plasmids may facilitate a better understanding of E. coli pathogenesis and the development of new strategies against E. coli infections. Because iron uptake ability is a potential virulence trait of bacteria, we screened for E. coli conjugative plasmids able to confer both iron uptake ability and ampicillin resistance. The plasmid pEC41, which was derived from the bacteremia clinical isolate EC41, was identified. EC41, which carried the fimH27 allele, belonged to sequence type (ST) 405 and phylogroup D. According to the sequencing analyses, pEC41 was 86 kb in size, and its backbone structure was almost identical to that of another highly conjugative plasmid, pCTX-M3, in which the extended-spectrum β-lactamase gene blaCTX–M–3 was originally identified. pEC41 carried blaCTX–M–3 and blaTEM–1. The ferric citrate uptake (fec) system was identified in pEC41 and was responsible for conferring iron uptake ability. The fec system contributes to the pathogenesis of EC41 in systemic infections but not in urinary tract infections (UTIs). However, this system promoted competitive fitness of a cystitis-associated clinical isolate to colonize urinary tracts. Additionally, the distribution of the fec system was related to E. coli isolates associated with human bacteremia and UTIs. In summary, the present study identified a novel conjugative plasmid, pEC41, which conferred both antimicrobial resistance and an extra iron uptake ability to E. coli. The iron uptake ability was encoded in the fec system and contributed to E. coli pathogenesis. This study is the first to show that the fec system is a virulence factor in E. coli.
Antitumor and Radiosensitization Effects of a CXCR2 Inhibitor in Nasopharyngeal Carcinoma

CXCR2, a member of the G-protein-coupled cell surface chemokine receptor family, is commonly found on leukocytes, endothelial cells and tumor cells including nasopharyngeal carcinoma cells. However, how the activity of CXCR2 and its ligand CXCL8 affects the development of nasopharyngeal carcinoma (NPC) remains unknown. Here, we found that CXCR2 and CXCL8 were both predicted poor prognosis in NPC patients. Furthermore, we identified that treatment with CXCR2 antagonist SB225002 of nasopharyngeal carcinoma cell lines resulted tumorigenesis inhibition in vitro and in vivo. In addition, we found that SB225002 could enhance NPC cells radiosensitivity through regulating cell circle distribution and interfering with cellular DNA damage repair. SB225002 also exhibited an efficient radiosensitization effect in C666-1 and HONE-1 bearing mice. Functionally, we showed that SB225002 reduced microvessel density and proliferation and induced tumor apoptosis. Furthermore, changes in the tumor microenvironment were also observed in this study. We observed that SB225002 reduced tumor-associated neutrophils (TANs) in the tumors tissue which were recruited especially after irradiation. Taken together, our results suggested that targeting the CXCL8-CXCR2 pathway is a promising therapeutic strategy for comprehensive NPC treatment.
Search Engine Gender Bias

This article discusses possible search engine page rank biases as a consequence of search engine profile information. After describing search engine biases, their causes, and their ethical implications, we present data about the Google search engine (GSE) and DuckDuckGo (DDG) for which only the first uses profile data for the production of page ranks. We analyze 408 search engine screen prints of 102 volunteers (53 male and 49 female) on queries for job search and political participation. For job searches via GSE, we find a bias toward stereotypically “female” jobs for women but also for men, although the bias is significantly stronger for women. For political participation, the bias of GSE is toward more powerful positions. Contrary to our hypothesis, this bias is even stronger for women than for men. Our analysis of DDG does not give statistically significant page rank differences for male and female users. We, therefore, conclude that GSE’s personal profiling is not reinforcing a gender stereotype. Although no gender differences in page ranks was found for DDG, DDG usage in general gave a bias toward “male-dominant” vacancies for both men and women. We, therefore, believe that search engine page ranks are not biased by profile ranking algorithms, but that page rank biases may be caused by many other factors in the search engine’s value chain. We propose ten search engine bias factors with virtue ethical implications for further research.
A2B Adenosine Receptors and Sphingosine 1-Phosphate Signaling Cross-Talk in Oligodendrogliogenesis

Oligodendrocyte-formed myelin sheaths allow fast synaptic transmission in the brain. Impairments in the process of myelination, or demyelinating insults, might cause chronic diseases such as multiple sclerosis (MS). Under physiological conditions, remyelination is an ongoing process throughout adult life consisting in the differentiation of oligodendrocyte progenitor cells (OPCs) into mature oligodendrocytes (OLs). During pathological events, this process fails due to unfavorable environment. Adenosine and sphingosine kinase/sphingosine 1-phosphate signaling axes (SphK/S1P) play important roles in remyelination processes. Remarkably, fingolimod (FTY720), a sphingosine analog recently approved for MS treatment, plays important roles in OPC maturation. We recently demonstrated that the selective stimulation of A2B adenosine receptors (A2BRs) inhibit OPC differentiation in vitro and reduce voltage-dependent outward K+ currents (IK) necessary to OPC maturation, whereas specific SphK1 or SphK2 inhibition exerts the opposite effect. During OPC differentiation A2BR expression increases, this effect being prevented by SphK1/2 blockade. Furthermore, selective silencing of A2BR in OPC cultures prompts maturation and, intriguingly, enhances the expression of S1P lyase, the enzyme responsible for irreversible S1P catabolism. Finally, the existence of an interplay between SphK1/S1P pathway and A2BRs in OPCs was confirmed since acute stimulation of A2BRs activates SphK1 by increasing its phosphorylation. Here the role of A2BR and SphK/S1P signaling during oligodendrogenesis is reviewed in detail, with the purpose to shed new light on the interaction between A2BRs and S1P signaling, as eventual innovative targets for the treatment of demyelinating disorders.
Prognostic Significance of Systemic Immune-Inflammation Index in Patients With Diffuse Large B-Cell Lymphoma

Objective The systemic immune-inflammation index (SII) based on neutrophil, platelet and lymphocyte counts, is a prognostic biomarker in some solid cancers. However, the prognostic value of SII has not yet been validated. This study was to evaluate the role of SII in predicting survival for patients with diffuse large B cell lymphoma (DLBCL). Methods We retrospectively investigated 224 patients with DLBCL between August 2005 and October 2018. Kaplan–Meier analysis and Cox proportional hazard models were used to assess the prognostic value of SII. Results In the ROC curve analysis, SII had the highest AUC and was more accurate as a prognostic factor. Patients with higher SII tended to have higher level of LDH, more advanced stage, poor PS, and high IPI score compared with low SII group. In univariate analyses, SII, PLR and NLR were all prognostic for progression-free survival and overall survival. Moreover, only SII, older age, HBSAg-positive and IPI were the independent prognostic factors for patients in multivariate analysis. The nomogram based on SII, older age, HBSAg status and IPI showed accurate prognostic ability for predicting 3-years and 5-years survival rates (c-index, 0.791) compared to the IPI alone (c-index, 0.716). Conclusion SII was a powerful tool for predicting outcome in patients with DLBCL. It might assist the separation of high-risk patients among patients with the same IPI.
A Dual Peptide Sustained-Release System Based on Nanohydroxyapatite/Polyamide 66 Scaffold for Synergistic-Enhancing Diabetic Rats’ Fracture Healing in Osteogenesis and Angiogenesis

Diabetes mellitus impairs fracture healing and function of stem cells related to bone regeneration; thus, effective bone tissue engineering therapies can intervene with those dysfunctions. Nanohydroxyapatite/polyamide 66 (n-HA/PA66) scaffold has been used in fracture healing, whereas the low bioactivity limits its further application. Herein, we developed a novel bone morphogenetic protein-2- (BMP-2) and vascular endothelial growth factor- (VEGF) derived peptides-decorated n-HA/PA66 (BVHP66) scaffold for diabetic fracture. The n-HA/PA66 scaffold was functionalized by covalent grafting of BMP-2 and VEGF peptides to construct a dual peptide sustained-release system. The structural characteristics and peptide release profiles of BVHP66 scaffold were tested by scanning electron microscopy, Fourier transform infrared spectroscopy, and fluorescence microscope. Under high glucose (HG) condition, the effect of BVHP66 scaffold on rat bone marrow mesenchymal stem cells’ (rBMSCs) adherent, proliferative, and differentiate capacities and human umbilical vein endothelial cells’ (HUVECs) proliferative and tube formation capacities was assessed. Finally, the BVHP66 scaffold was applied to fracture of diabetic rats, and its effect on osteogenesis and angiogenesis was evaluated. In vitro, the peptide loaded on the BVHP66 scaffold was in a sustained-release mode of 14 days. The BVHP66 scaffold significantly promoted rBMSCs’ and HUVECs’ proliferation and improved osteogenic differentiation of rBMSCs and tube formation of HUVECs in HG environment. In vivo, the BVHP66 scaffold enhanced osteogenesis and angiogenesis, rescuing the poor fracture healing in diabetic rats. Comparing with single peptide modification, the dual peptide-modified scaffold had a synergetic effect on bone regeneration in vivo. Overall, this study reported a novel BVHP66 scaffold with excellent biocompatibility and bioactive property and its application in diabetic fracture.
Cryoballoon Ablation of Atrial Fibrillation Without Demonstration of Pulmonary Vein Occlusion—The Simplify Cryo Study

Background: The demonstration of pulmonary vein (PV) occlusion is routinely performed and considered a prerequisite for successful cryoballoon (CB) ablation of atrial fibrillation (AF). The purpose of this study was to assess the feasibility and impact on procedural parameters and outcome of a standardized procedural protocol without demonstrating PV occlusion. Methods and Results: Consecutive patients undergoing CB pulmonary vein isolation (PVI) were studied. After cMRI assessment, patients treated by PVI using a novel no-contrast (NC) protocol without routine contrast injections to demonstrate PV occlusion (NC group) were compared to patients undergoing PVI with contrast injections to demonstrate PV occlusion (standard group). One hundred patients with paroxysmal or persistent AF (age 61 ± 10 years, ejection fraction 59 ± 11%, left atrial volume index 37.2 ± 2.0 mL/m2) were studied. The NC protocol was feasible in 72 of 75 patients (96%). Total procedure time and fluoroscopy time were 64.0 ± 14.1 min and 11.0 ± 4.6 min in the NC group and 92.0 ± 25.3 min and 18.0 ± 6.0 min in the standard group, respectively (all p < 0.001). Dose area product was 368 ± 362 cGy*cm2 in the NC group compared to 1928 ± 1541 cGy*cm2 in the standard group (p < 0.001). Forty-five of 75 patients (60%) in the NC group and 16 of 25 patients (64%) in the standard group remained in stable sinus rhythm after a single PVI and a 1-year follow-up (p = 0.815). Conclusions: Performing CB ablation without using contrast injections to demonstrate PV occlusion was feasible, resulted in reduced radiation exposure, and increased the efficiency of the procedure.
Toward Specialized or Integrated Systems in Northwest Europe: On-Farm Eco-Efficiency of Dairy Farming in Germany

Intensive confinement (IC) systems for dairying have become widespread during the last decades. However, potential advantages of alternative systems such as full-grazing (FG) or integrated dairy/cash-crop (IFG) systems with regards to better provision of ecosystem services are widely discussed. To investigate performance and environmental impacts, we compared four prevailing dairy systems using an on-farm research study. The farm types differed in their share of pasture access and quantity of resource inputs: (i) an IC with a high import of supplements and mineral fertilizers; (ii) a semi-confinement (SC) with daytime pasture access during summer and moderate import of supplementary feeds representing the base-line scenario; (iii) a FG based on grazed seeded grass-clover swards with no purchased N-fertilizers and low quantities of supplementary feeds; and (iv) an IFG comparable to FG but based on grass-clover leys integrated in a cash-crop rotation. Results revealed highest milk productivity (16 t energy-corrected-milk (ECM) ha−1) and farm-N-balance (230 kg N ha−1) in IC; however, the highest product carbon footprint (PCF; 1.2 CO2eq kg ECM−1) and highest N-footprint (13 g N kg ECM−1) were found in the baseline system SC. The FG and IFG revealed on average similar forage dry matter yields (10 – 11 t DM ha−1) at similar crude protein and net-energy-lactation ratios per kg DM-intake compared to the IC and SC. The PCF in FG were comparable to IC (0.9 vs. 1.1 kg CO2eq kg ECM−1) but at a lower N-footprint (9 vs. 12 g N kg ECM−1). However, despite low measured N-losses in the FG system, the farm-N-surplus was exceeded by 90 kg N ha−1. A further reduction was only possible in the IFG (50 kg N ha−1) by accounting for a potential N-carry-over from N-rich plant residues to the cash-crop unit, leading to the lowest PCF (0.6 kg CO2eq kg ECM−1) for the IFG, with still moderate milk yield levels (~10,500 kg ECM ha−1). According to this bottom-up approach based on field data, improved integrated grazing systems could provide an important opportunity to increase the ecosystem services from dairy farming, operating with land use efficiencies similar to IC.
Eco-Evolutionary Perspectives on Mixoplankton

Mixotrophy, i.e., the capability of both phototrophy and phagotrophy within a single organism, is a prominent trophic mode in aquatic ecosystems. Mixotrophic strategies can be highly advantageous when feeding or photosynthesis alone does not sustain metabolic needs. In the current review, we discuss the functional types of mixotrophic marine protists (herein mixoplankton) within the context of evolution. Permanent plastids have been established in large due to gene transfer from prey and/or endosymbionts to the host cell. In some kleptoplastidic mixoplankton, prior gene transfers and active transcription of plastid related genes in the host can help maintain and extend retention of the current kleptoplast. In addition to kleptoplasts, the prey nucleus is also sometimes retained and actively transcribed to help maintain and even replicate the kleptoplasts. Endosymbiotic relations vary considerably in the extent to which hosts affect symbionts. For example, some endosymbionts are heavily modified to increase photosynthetic efficiency, or are controlled in their cell division. It can be proposed that many kleptoplasts and endosymbionts are in fact en route to becoming permanent plastids. Conditions such as increased temperature and limiting nutrients seem to favor phagotrophy in mixoplankton. However, responses of mixoplankton to changing environmental conditions like light irradiance, temperature, nutrient, and prey availability are variable and species-specific. Studying mixotrophs with temporary plastids could elucidate past and future evolutionary mechanisms and dynamics of processes such as phagotrophy and the establishment of (secondary) permanent plastids.
GLI1: A Therapeutic Target for Cancer

GLI1 is a transcriptional effector at the terminal end of the Hedgehog signaling (Hh) pathway and is tightly regulated during embryonic development and tissue patterning/differentiation. GLI1 has low-level expression in differentiated tissues, however, in certain cancers, aberrant activation of GLI1 has been linked to the promotion of numerous hallmarks of cancer, such as proliferation, survival, angiogenesis, metastasis, metabolic rewiring, and chemotherapeutic resistance. All of these are driven, in part, by GLI1’s role in regulating cell cycle, DNA replication and DNA damage repair processes. The consequences of GLI1 oncogenic activity, specifically the activity surrounding DNA damage repair proteins, such as NBS1, and cell cycle proteins, such as CDK1, can be linked to tumorigenesis and chemoresistance. Therefore, understanding the underlying mechanisms driving GLI1 dysregulation can provide prognostic and diagnostic biomarkers to identify a patient population that would derive therapeutic benefit from either direct inhibition of GLI1 or targeted therapy towards proteins downstream of GLI1 regulation.
A Multitubular Kidney-on-Chip to Decipher Pathophysiological Mechanisms in Renal Cystic Diseases

Autosomal Dominant Polycystic Kidney Disease (ADPKD) is a major renal pathology provoked by the deletion of PKD1 or PKD2 genes leading to local renal tubule dilation followed by the formation of numerous cysts, ending up with renal failure in adulthood. In vivo, renal tubules are tightly packed, so that dilating tubules and expanding cysts may have mechanical influence on adjacent tubules. To decipher the role of this coupling between adjacent tubules, we developed a kidney-on-chip reproducing parallel networks of tightly packed tubes. This original microdevice is composed of cylindrical hollow tubes of physiological dimensions, parallel and closely packed with 100–200 μm spacing, embedded in a collagen I matrix. These multitubular systems were properly colonized by different types of renal cells with long-term survival, up to 2 months. While no significant tube dilation over time was observed with Madin-Darby Canine Kidney (MDCK) cells, wild-type mouse proximal tubule (PCT) cells, or with PCT Pkd1+/- cells (with only one functional Pkd1 allele), we observed a typical 1.5-fold increase in tube diameter with isogenic PCT Pkd1-/- cells, an ADPKD cellular model. This tube dilation was associated with an increased cell proliferation, as well as a decrease in F-actin stress fibers density along the tube axis. With this kidney-on-chip model, we also observed that for larger tube spacing, PCT Pkd1-/- tube deformations were not spatially correlated with adjacent tubes whereas for shorter spacing, tube deformations were increased between adjacent tubes. Our device reveals the interplay between tightly packed renal tubes, constituting a pioneering tool well-adapted to further study kidney pathophysiology.
In Chronic Spontaneous Urticaria, Comorbid Depression Linked to Higher Disease Activity, and Substance P Levels

Background: Patients with chronic spontaneous urticaria often exhibit psychiatric comorbidities including depression that contribute to the impairment of their quality of life. How CSU and depression are linked isn't well-understood. Substance P has been shown to be increased in patients with CSU and is held to contribute to the pathogenesis of depression. Methods: We measured disease activity in 30 CSU patients without depression and 30 CSU patients with depression by using the urticaria activity score. The severity of depression was assessed with the Beck Depression Inventory. We measured SP levels in these patients as well as in 30 healthy control subjects. In patients with comorbid depression, we correlated SP levels with CSU disease activity and the severity of depression. Results: In CSU patients, disease activity and the severity of depression were positively linked. UAS7 values were higher in CSU patients with comorbid depression as compared to those without (p < 0.05). SP levels were higher in CSU patients with depression than in those without (p < 0.001), but was similar in all CSU patients compared to healthy controls. SP levels weren't correlated with UAS7 values in CSU patients with depression, whereas they were weakly but significantly correlated with BDI scores (p < 0.05). Conclusion: Our results suggest that, in CSU patients with comorbid depression, CSU disease activity affects the severity of depression. CSU patients with high disease activity should be explored for comorbid depression.