The present study was conducted to investigate the effects of rhizome extract of Dioscorea batatas (Dioscoreae Rhizoma, Chinese Yam) and its bioactive compound, allantoin, on myoblast differentiation and mitochondrial biogenesis in skeletal muscle cells. Yams were extracted in water and the extract was analyzed by HPLC. The expression of C2C12 myotubes differentiation and mitochondrial biogenesis regulators were determined by reverse transcriptase (RT)-PCR or Western blot. The glucose levels and total ATP contents were determined by glucose consumption, glucose uptake and ATP assays, respectively. Treatment with yam extract (1 mg/mL) and allantoin (0.2 and 0.5 mM) significantly increased of MyHC expression compared with non-treated myotubes. Yam extract and allantoin significantly increased the expression of mitochondrial biogenesis regulating proteins, PGC1?, Sirt-1, NRF-1, and TFAM, as well as the phosphorylation of AMPK and ACC in C2C12 myotubes. Furthermore, yam extract and allantoin significantly increased the glucose uptake levels and the ATP contents. Finally, HPLC analysis revealed that the yam extract contained 1.53% of allantoin. Yam extract and allantoin, stimulated myoblast differentiation into myotubes and increased energy production through upregulation of mitochondrial biogenesis regulators. These findings indicate that yam extract and allantoin can help to prevent the skeletal muscle dysfunction through stimulation of energy metabolism.

Increased gut permeability (leaky gut) with increased translocation of Gram-negative bacteria plays a role in the gut-brain axis through effects on systemic immune-inflammatory processes. Deficit schizophrenia is characterized by an immune-inflammatory response combined with a deficit in natural IgM antibodies to oxidative specific epitopes (OSEs), which are a first line defense against bacterial infections. This study measured plasma IgA/IgM responses to 5 Gram-negative bacteria in association with IgM responses to malondialdehyde (MDA) and azelaic acid in 80 schizophrenia patients (40 with the deficit syndrome and 40 without) and in 38 healthy controls.Deficit schizophrenia was characterized by significantly increased IgA responses to Hafnei alvei, Pseudomonas aeruginosa, Morganella morganii and Klebsiella pneumoniae as compared with non-deficit schizophrenia. The presence of deficit schizophrenia was highly predicted by increased IgA responses to Pseudomonas putida and IgM responses to all 5 Gram-negative bacteria and lowered natural IgM to MDA and azelaic acid with a bootstrap area under the ROC curve of 0.960 (2000 random curves). A large proportion of the variance (41.5%) in the PANSS negative score was explained by the regression on IgA responses to K. pneumoniae and IgM responses to the 5 enterobacteria coupled with lowered IgM antibodies to azelaic acid. There were significant associations between IgA levels to Gram-negative bacteria and Mini Mental State Examination, Boston naming test, Verbal Fluency and Word List Memory test scores.These findings provide further evidence that deficit schizophrenia is a distinct phenotype of schizophrenia, which is characterized by an increased impact of Gram-negative commensal bacteria coupled with a deficit in natural IgM, pointing to aberrations in B1 cells. It is concluded that increased bacterial translocation and deficits in the compensatory immune-regulatory system (CIRS) may drive negative symptoms and neurocognitive impairments, which are hallmarks of deficit schizophrenia.

We have successfully measured amyloid beta (Aβ) (1-40) protein added in human serum by a NiCr strain gauge cantilever biosensor immobilized with liposomes incorporating cholesterol. Importantly, we investigated the effect of incorporation of cholesterol in the liposome in order to suppress the interaction between the liposome and many different proteins included in human serum. It was revealed that incorporating cholesterol suppresses the interaction between the proteins other than Aβ in human serum and the liposome. Finally, we detected Aβ(1-40) in human serum with typical chronological behaviors due to Aβ aggregation and fibrillization. Furthermore, as a digital low-pass filtering procedure could reduce external noises, the cantilever sensor immobilized with liposome incorporating cholesterol can detect low-concentrated Aβ in human serum.

Silicon light funnels are three-dimensional subwavelength structures in the shape of inverted cones with respect to the incoming illumination. Light funnel arrays can serve as an efficient absorbing layers on account of their light trapping capabilities associated with the presence of high density complex Mie modes. Specifically, light funnel arrays exhibit broadband absorption enhancement of the of the solar spectrum. In the current study, we numerically explore the optical coupling between surface light funnel arrays and underlying substrates. We show that the absorption in LF array-substrate complex is higher than the absorption in LF arrays of the same height (~10% increase). This, we suggest, imply that a LF array serves as an efficient surface element that imparts additional momentum components to the impinging illumination, and hence optically excites the substrate by near-field light concentration, excitation of traveling guided modes in the substrate and mode hybridization.

Electrode is a key component in a microbial electrolysis cell (MEC) and it needs significant improvement for practical implementation of MEC. For effective development of electrode technology, accurate and reproducible analytical methods are very important. Linear sweep voltammetry (LSV) is an essential analytical method for evaluating electrode performance; however, it has not been firmly established yet in the MEC field. In this study, biological brush (BB), abiotic brush (AB), Pt wire (PtW), stainless steel wire (SSW) and mesh (SSM)) were tested to explore the most suitable counter electrode in different medium conditions. Coefficient of variation (CV) for Imax of LSV were comparatively analyzed. In BB-anode LSV, SSW (0.48%) and SSM (2.17%) showed higher reproducibility as a counter electrode. In SSM-cathode LSV, BB (1.76%) and PtW (2.01%) produced more reproducible results. In the Ni-AC-SSM-cathode LSV, PtW (3.54%) and BB (8.81%) produced more reproducible result. It shows electrode used in the operation is an appropriate counter electrode in the acetate-added condition. However, in the absence of acetate, PtW (1.24%) and BB (1.71%) produced more reproducible results in SSM cathode and PtW (0.61%) and SSW (1.21%) did in the Ni-AC-SSM-cathode, showing PtW is an appropriate counter electrode. These results also shows that PtW is an appropriate counter electrode in cathode LSV.

Reactive oxygen species (ROS), which were originally classified as exclusively deleterious compounds, have gained increasing interest in the recent years given their action as bona fide signalling molecules. The main target of ROS action is the reversible oxidation of cysteines, leading to the formation of disulfide bonds, which modulate protein conformation and activity. ROS endowed with signalling properties are mainly produced by NADPH oxidases at the plasma membrane, but their action also involves a complex machinery of multiple redox-sensitive protein families that differs in their subcellular localization and their activity. Given that the levels and distribution of ROS are highly dynamic in part due to their limited stability, the development of various fluorescent ROS sensors, some of which are quantitative (ratiometric), represents a clear breakthrough in the field and have been adapted to both ex vivo and in vivo applications. The physiological implication of ROS signalling will be presented mainly in the frame of morphogenetics processes, embryogenesis, regeneration, and stem cell differentiation. Gain and loss of function as well as pharmacological strategies have demonstrated the wide but specific requirement of ROS signalling at multiple stages of these processes and its intricate relationship with other well-known signalling pathways.

Inflammatory bowel disease (IBD) is a CC chemokine receptor 6 (CCR6) - associated immune mediated disorder which has attracted an extensive superfluity of experimental analyses. IBD has come to the fore of varied scrutinizing owing to its complexity by nature for comprising of two synergistic sub phenotypes; Crohn’s disease (CD) and Ulcerative colitis (UC). Both these disease entities cause potent immune dysregulation followed by intense tissue damage within the gut mucosal system, initiating symptoms which are severely debilitating. Multiple causative factors are said to be responsible for IBD but direct immune dysfunction is kindled by overplay of innate and adaptive immune responses produced against a pathogenic microbial attack through the weakened or leaky gut epithelial barrier. Once immune homeostasis is not achieved by tolerating agents, the self-assertive adaptive immunity mobilize its various T and B cell cohorts initializing their allied immune mechanisms by vigorously deploying them towards the site of infection. CCR6 and its unique solitary ligand CC-chemokine ligand 20 (CCL20) are small protein molecules which are abundantly expressed by T and B lymphocytes and act as chemotactic immune-modulatory envoys that help in the deployment of the effector lymphocyte arm of the immune system, producing two directly opposing outcomes in IBD. This dichotomous immunity consists of either immune tolerance or inflammation which then develops into a chronic state, remaining catatonic to inherent immunity or targeted clinical therapy. In this review, we have chronologically identified a plethora of experimental studies radiating into 14 different compartments highlighted in the visual depiction which have employed both mouse models and clinical subjects spanning a period of nearly two decades. In doing so, we expect the research community would further benefit by tracing through the history, thereby understanding the CCR6 –CCL20 axis in IBD and identifying the gaps in literature which can be fortuitously filled in the future.

Although the existing paradigm states that CMV reactivation is under control of cellular immune response, the role of humoral counterpart is underestimated. Anti-CMV positive woman after conditioning with Bu-Flu-ATG underwent stem cell transplantation from fully matched, seronegative sibling donor. In immunodeficient recipient fast and significant decrease of specific immune response was observed but reconstitution of marrow-derived B and NK cells was prior thymic origin T cells. The lowest CMV-IgG(89 U/ml) was observed just before CMV viremia. Noteworthy, the sole and exclusive factor of CMV-specific immune response is a residual recipient antibody class IgG. The CMV-quantiferon increase was observed later, but in the first phase immune reconstitution of the PHA-induced IFNγ release was significantly lower than that CMV-induced. It corresponds with NK cells increase at the top of lymphocyte reconstitution and undetected CMV-specific CD8 cells by pentamer technique. Most of NK cells are CD16+, thus are stimulated by residual IgG. In immunocompetent donor the cellular and humoral immune response increases in parallel manner but symptoms of CMV mononucleosis were observed till the increase of specific IgG. Our observations shed light on a unique host-CMV interaction: indicate that significant decrease of CMV-IgG is a good predictor for CMV reactivation during secondary immunodeficiency.

At present, the world is at the peak of production of traditional fossil fuels. Much of the resources that humanity has been consuming (oil, coal and natural gas) are coming to an end. The human being faces a future that must necessarily go through a paradigm shift, which includes a progressive movement towards increasingly less polluting and energetically viable resources. In this sense, nanotechnology has a transcendental role in this change. For decades, new materials capable of being used in energy processes have been synthesized that undoubtedly will be the cornerstone of the future development of the planet. In this review, we report on the current progress in the synthesis and use of one-dimensional (1D) nanostructured materials (specifically nanowires, nanofibers, nanotubes and nanorods), with compositions based on oxides, nitrides, or metals, for applications related to energy. Due to its extraordinary surface-volume relationship, tunable thermal and transport properties, and its high surface area, these 1D nanostructures have become fundamental elements for the development of energy processes. The most relevant 1D nanomaterials, their different synthesis procedures, and useful methods for assembling 1D nanostructures in functional devices will be presented. Applications in relevant topics such as optoelectronic and photochemical devices, hydrogen production or energy storage, among others, will be discussed. The present review concludes with a forecast on the directions towards which future research could be directed on this class of nanostructured materials.

Duchenne muscular dystrophy (DMD) is a fatal X-linked recessive neuromuscular disease prevalent in 1 in 3500 to 5000 males worldwide. As a result of mutations that interrupt the reading frame of the dystrophin gene (DMD), DMD is characterized by a loss of dystrophin protein which leads to decreased muscle membrane integrity, which increases susceptibility to degeneration. CRISPR/Cas9 technology has garnered interest as an avenue for DMD therapy due to its potential for permanent exon skipping, which can restore the disrupted DMD reading frame in DMD and lead to dystrophin restoration. An RNA-guided DNA endonuclease system, CRISPR/Cas9 allows for the targeted editing of specific sequences in the genome. The efficacy and safety of CRISPR/Cas9 as a therapy for DMD has been evaluated by numerous studies in vitro and in vivo, with varying rates of success. Despite the potential of CRISPR/Cas9-mediated gene editing for the long-term treatment of DMD, its translation into the clinic is currently challenged by issues such as off-targeting, immune response activation, and sub-optimal in vivo delivery. Its nature as being mostly a personalized form of therapy also limits applicability to DMD patients, who exhibit a wide spectrum of mutations. This review summarizes the various CRISPR/Cas9 strategies that have been tested in vitro and in vivo for the treatment of DMD. Perspectives on the approach will be provided, and the challenges faced by CRISPR/Cas9 in its road to the clinic will be briefly discussed.

Background: Osteoclastic bone resorption in the compression zone of periodontal ligament (PDL) plays a role in orthodontic tooth movement, and is regulated by the balance of RANKL and OPG. Compression downregulates OPG, conversely, tension upregulates OPG in PDL cells. However, the regulatory mechanism of OPG expression in PDL cells under different mechanical stresses remains unclear. Methods: To study microRNA (miRNA) expression profiles, compression (2g/cm²) or tension (15%-elongation) was applied to immortalized human PDL (HPL) cells, and miRNA was extracted. The miRNA expression was analyzed using a human miRNA microarray, and the changes of the miRNA expression were confirmed by real-time RT-PCR. In addition, miR-3198-mimic and -inhibitor were transfected into HPL cells to understand the resulting OPG expression and production. Results: Certain miRNAs were expressed differentially under compression and tension. Some miRNAs including miR-3198 were upregulated only by compression. Real-time RT-PCR confirmed that compression induced miR-3198, but tension reduced it, in HPL cells. miR-3198-inhibitor upregulated and miR-3198-mimic reduced OPG in HPL cells. miR-3198-inhibitor rescued the compression-mediated downregulation of OPG. On the other hand, miR-3198-mimic reduced OPG expression under tension. Conclusion: We conclude that miR-3198 is upregulated by compression and is downregulated by tension, suggesting that miR-3198 downregulates OPG in response to mechanical stress.

Following an initial mechanical insult, traumatic spinal cord injury (SCI) induces a secondary wave of injury, resulting in a toxic lesion environment inhibitory to axonal regeneration. This review focuses on the glial cell line-derived neurotrophic factor (GDNF) and its application, also in combination with other factors and cell transplantations, for repairing the injured spinal cord. As recent decades of studies strongly suggest combinational treatment approaches hold the greatest therapeutic potential for the central nervous system (CNS) trauma, future directions of combinational therapies will also be discussed.

The high level of dengue virus (DENV) seroprevalence in areas where Zika virus (ZIKV) is circulating and the cross-reactivity between these two viruses have raised concerns on the risk of increased ZIKV disease severity for patients with a history of previous DENV infection. To determine the role of DENV pre-immunity in ZIKV infection, we analysed the T and B cell responses against ZIKV in donors with or without previous DENV infection. Using PBMCs from donors living in an endemic area in Colombia, we have identified, by interferon (IFN)-γ enzyme-linked immunospot (ELISPOT) assay, most of the immunodominant ZIKV T-cell epitopes in the non-structural proteins NS1, NS3 and NS5. Analyses of the T and B-cell responses in the same donors revealed a stronger T-cell response against peptides conserved between DENV and ZIKV, with a higher level of ZIKV-neutralizing antibodies in DENV-immune donors, in comparison with DENV-naïve donors. Strikingly, the potential for antibody mediated enhancement of ZIKV infection was reduced in donors with sequential DENV and ZIKV infection in comparison with donors with DENV infection only. Altogether, these data suggest that individuals with DENV immunity present improved immune responses against ZIKV.

Inflammatory bowel diseases, which consist of chronic inflammatory conditions of the colon and the small intestine, are considered a global disease of our modern society. Recently, the interest toward the use of herbal therapies for the management of inflammatory bowel diseases has increased because of their effectiveness and favorable safety profile, compared to conventional drugs. Boswellia serrata Roxb. and Curcuma longa L. are amongst the most promising herbal drugs, however, their clinical use in inflammatory bowel diseases is limited and little is known on their mechanism of action. The aim of this work was to investigate the effects of two phytochemically characterized extracts of B. serrata and C. longa in an in vitro model of intestinal inflammation. Their impact on cytokine release and reactive oxygen species production, as well as the maintenance of the intestinal barrier function and on intestinal mucosa immune cells infiltration, has been evaluated. The extracts showed a good protective effect on the intestinal epithelium at 1 µg/ml, with TEER values increasing by approximately 1.5 fold, compared to LPS-stimulated cells. C. longa showed an anti-inflammatory mechanism of action, reducing IL-8, TNF-α and IL-6 production by approximately 30%, 25% and 40%, respectively, compared to the inflammatory stimuli. B. serrata action was linked to its antioxidant effect, with ROS production being reduced by 25%, compared to H₂O₂-stimulated Caco-2 cells. C. longa and B. serrata resulted to be promising agents for the management of inflammatory bowel diseases by modulating in vitro parameters which have been identified in the clinical conditions.

The human degenerative cartilage has low regenerative potential. Chondrocyte transplantation offers a promising strategy for cartilage treatment and regeneration. Currently chondrogenesis using human pluripotent stem cells are accomplished using human recombinant growth factors. Here, we differentiated human induced pluripotent stem cells (hiPSCs) into chondrocytes and cartilage pellet using minicircle vectors. Minicircles are used as a non-viral gene delivery system for gene therapy in various diseases. Non-viral gene delivery can produce growth factors without integrating into the host genome. Minicircle vectors containing bone morphogenetic protein 2 (BMP2) and transforming growth factor, beta 3 (TGFβ3) were successfully generated and delivered to hiPSC-derived outgrowth (OG) cells. Cell pellets generated using minicircle-transfected OG cells successfully differentiated into chondrogenic lineage. Chondrogenic pellets transfected with growth factor-encoding minicircles effectively recovered osteochondral defect in rat models. Taken together, this work shows the potential application of minicircles in cartilage regeneration using hiPSCs.

Inflammation associated endothelial dysfunction represents a pivotal contributor to atherosclerosis. Increasingly evidence has demonstrated that interleukin 1 receptor (IL1-R) / toll-like receptor (TLR) signaling participated in the development of atherosclerosis. Previous studies indicated the therapeutic potential of anti-inflammatory therapy in anti-atherosclerosis. The present study examined the effect of IL-1R-associated kinase 1 and 4 inhibitors (IRAK1/4i) in regulating endothelial dysfunction. IRAK1/4i showed little endothelial toxicity at concentrations from 1 to 10 μM. Inhibition of IRAK1/4 alleviated endothelial activation induced by LPS in vitro evidenced by attenuated monocyte adhesion to the endothelium. Mechanistically, blockade of IRAK1/4 ameliorated the transcriptional activity of NF-κB. Taken together, our findings demonstrated that dual inhibition of IRAK1 and IRAK4 attenuates endothelial dysfunction, suggesting pharmaceutical inhibition of IRAK1/4 might be a potential strategy to combat endothelial dysfunction and atherosclerosis.

Type 1 diabetes affects millions of people globally and requires careful management to avoid serious long-term complications, including heart and kidney disease, stroke, and loss of sight. The present standard-of-care for type 1 diabetes is exogenic insulin substitutional therapy. The most advanced stretegies in this area is the development of hybrid-closed loop system and the producing of long-acting insulins. Progresses in stem cell therapies have started to revolutionize the care of patients with type 1 diabetes; however, significant challenges remain including the limited islets availability, difficulties in maintaining the viability, the heterogeneity within a complex pathology and in patients’ responses to treatment. On the way, a considerable amount of efforts in maximizing the islet transplantation effectiveness by controlling the advantageous of different stem cell approaches. With the availability and the use of big data, the concept of precision medicine is gaining wide attention worldwide and could bring the dream of “presonlaized” therapies as a reality in the near future. Here we review the current range of treatments available as well as recent pre-clinical breakthroughs in the field of personlaized medicine for type 1 diabetes.

Extracellular vesicles (EV) such as exosomes, are newly recognized fundamental, natural and physiologic particles of life that seemingly are involved all biologic processes and clinical diseases. Due to their universal involvements, understanding the nature and the potential therapeutic uses of these nano-vesicles requires innovative experimental approaches, in virtually every field. Of the EV group, exosome nano-vesicles and larger companion extracellular micro vesicles (MV) can mediate completely new phenomena dependent on intercellular transfer of proteins and selected RNAs; particularly miRNAs, between donor and targeted cells to elicit epigenetic alterations inducing functional cellular changes. These recipient acceptor cells are nearby (paracrine transfers) or far away after distribution via the circulation (endocrine transfers). The major properties of such vesicles seem to have been conserved over eons, suggesting that they may have ancient evolutionary origins arising perhaps even before cells in the primordial soup from which life evolved. Their potential ancient evolutionary attributes may be responsible for the ability of some modern day exosomes to withstand unusually harsh conditions; perhaps due to unusual membrane lipid compositions. This is exemplified by maternal milk exosome survival of the neonatal acid/enzyme rich stomach. It is postulated that this also applies to their durable presence in phagolysosomes; suggesting unique intracellular release of contents. A major issue discussed is the generally poorly realized superiority of these naturally evolved nano vesicles to therapies compared human engineered artificial nanoparticles; say for treatment of cancers.

Sea anemones are a remarkable source of active principles due to a decentralized venom system. Blood vessel formation or angiogenesis is a very promising target against cancer, but the few available anti-angiogenic compounds have a limited efficacy. In this study, a protein fraction was purified from tentacles of Anemonia viridis able to limit endothelial cells proliferation and vessel network formation or angiogenesis at low concentration (14 nM). The sequences in this protein fraction were determined with Edman degradation and Mass Spectrometry In Source Decay and revealed homologies with BDS sea anemones. The presence of a two turn alpha helix observed with Circular Dichroism and a trypsin activity inhibition suggested that the active principle could be a Kunitz-type inhibitor, which may interact with an integrin due to a RGD motif well exposed to the solvent as revealed by Molecular Modeling. This active principle could improve antiangiogenic therapy from existing antiangiogenic compounds binding on the VEGF.

Beta adrenoblockers is a large class of drugs mainly used to manage abnormal heart rhythms. Over the last couples of decades, the anticancer effects of these compounds has been extensively studied. There is much evidence about their activity in non-small cell lung, pancreatic, breast, colorectal, prostate and ovarian cancer. However, the mechanism of beta blockers anticancer activity is still not known, and more detailed studies are needed. The aim of our study was to evaluate the anticancer activity of beta adrenoblockers in non-small cell lung cancer cell lines A549 and H1299. In order to find the relationship with their selectivity to beta adrenoreceptors, in our study we used selective (atenolol, betaxolol, esmolol, metoprolol) and non-selective (pindolol, propranolol and timolol) beta blockers. The effect on cell viability was evaluated by MTT assay and the activity on cell ability to form colonies was tested by clonogenic assay. The type of cell death was evaluated by cell double staining with Hoechst 33342 and Propidium iodide. The most active adrenoblockers against both tested cancer cell lines were propranolol and betaxolol. They completely inhibited lung cancer cell colony formation at 90% of EC50 (half maximal effective concentration) value. Most tested compounds induced cell death through apoptosis and necrosis. In A549 cell lines apoptosis was mainly induced while in H1299 cell line compounds induced both apoptosis and necrosis. There was no correlation established between beta adrenoblocker anticancer activity and their selectivity to beta adrenoreceptors.

The molecular study of fat cell development in the human body is essential for our understanding of obesity and related diseases. Mesenchymal stem/stromal cells (MSC) are the ideal source to study fat formation as they are the progenitors of adipocytes. In this work, we used human MSCs, received from surgery waste, and differentiate them into fat adipocytes. The combination of several layers of information coming from lipidomics, metabolomics and proteomics enabled comprehensive analysis of the biochemical pathways in adipogenesis. Simultaneous analysis of metabolites, lipids and proteins in cell culture is challenging due to the compound’s chemical difference so that most studies involve separate analysis with unimolecular strategies. In this study, we employed a multimolecular approach using a two–phase extraction to monitor the crosstalk between lipid metabolism and protein-based signaling in a single sample (~105 cells). We developed an innovative analytical workflow including standardization with in-house produced 13C-isotopically labeled compounds, hyphenated high-end mass spectrometry (high-resolution Orbitrap MS) and chromatography (HILIC, RP) for simultaneous untargeted screening and targeted quantification. Metabolite and lipid concentrations ranged over 3-4 orders of magnitude and were detected down to the low fmol (absolute on column) level. Biological validation and data interpretation of the multiomics workflow was performed based on proteomics network reconstruction, metabolic modelling (MetaboAnalyst 4.0) and pathway analysis (OmicsNet). Comparing MSCs and adipocytes, we observed significant regulation of different metabolites and lipids such as triglycerides, gangliosides and carnitine with 113 fully reprogrammed pathways. The observed changes are in accordance with literature findings dealing with adipogenic differentiation of MSC. These results are a proof of principle for the power of multimolecular extraction combined with orthogonal LC-MS assays and network construction. Considering the analytical and biological validation performed in this study, we conclude that the proposed multiomics workflow is ideally suited for comprehensive follow-up studies on adipogenesis and is fit for purpose for different applications.

Coronavirus disease 2019 (COVID-19) caused by novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has reached a global epidemic across the world after first reported in Wuhan, China’s Hubei province in December 2019. The pandemic is also associated with acute respiratory distress syndrome (ARDS) characterized by excess inflammation, progressive arterial hypoxemia and dyspnea. Mesenchymal stem/ stromal cells (MSCs) have been investigated as treatment for ARDS due to immunomodulatory property. Exosomes derived from MSCs play an important role in paracrine signaling of MSCs, thereby contributed to immunomodulation of the immune microenvironment. Exosomes are emerged as potential alternative to MSC cell therapy with superiority of safety. In this review, we will introduce MSC-derived exosomes and briefly discuss current progress on MSCs and exosomes in ARDS, which may have clinical implications in pathogenesis and treatment of COVID-19.

Ovarian cancer is the most lethal gynecological malignancy. Poor overall survival, particularly for patients with high grade serous (HGS) ovarian cancer, are often attributed to late stage at diagnosis and relapse following chemotherapy. HGS ovarian cancer is a heterogenous disease in that few genes are consistently mutated between patients. Additionally, HGS ovarian cancer is characterized by high genomic instability. For these reasons personalized approaches may be necessary for effective treatment and cure. Understanding the molecular mechanisms that contribute to tumor metastasis and chemoresistance are essential to improve survival rates. One favored model for tumor metastasis and chemoresistance is the cancer stem cell (CSC) model. CSCs are cells with enhanced self-renewal properties that are enriched following chemotherapy. Elimination of this cell population is thought to be a mechanism to increase therapeutic response. Therefore, accurate identification of stem cell populations that are most clinically relevant is necessary. While many CSC identifiers (ALDH, OCT4, CD133, and side population) have been established, it is still not clear which population(s) will be most beneficial to targeted in patients. Therefore, there is a critical need to characterize CSCs with reliable markers and find their weaknesses that will make the CSCs amenable to therapy. Many signaling pathways are implicated for their roles in CSC initiation and maintenance. Therapeutically targeting pathways needed for CSC initiation or maintenance may be an effective way of treating HGS ovarian cancer patients. In conclusion, the prognosis for HGS ovarian cancer may be improved by combining CSC phenotyping with targeted therapies for pathways involved in CSC maintenance.

Formation of new blood (angiogenesis) and lymphatic (lymphangiogenesis) vessels are major events associated with most epithelial malignancies, including breast cancer. Angiogenesis is essential for cancer cell survival. Lymphangiogenesis is critical in maintaining tumoral interstitial fluid balance and importing tumor-facilitatory immune cells. Both vascular routes also serve as conduits for cancer metastasis. Intratumoral hypoxia promotes both events by stimulating multiple angiogenic/lymphangiogenic growth factors. Studies on tumor-associated lymphangiogenesis and its exploitation for therapy have received less attention from the research community than those on angiogenesis. Inflammation is a key mediator of both processes, hijacked by many cancers by aberrant expression of the inflammation-associated enzyme cyclo-oxygenase (COX)-2. In this review, we focus on breast cancer and show that COX-2 is a major promoter of both events, primarily resulting from the activation of Prostaglandin (PG) E receptor EP4 on tumor cells, tumor-infiltrating immune cells, and endothelial cells; and induction of oncogenic microRNAs. COX-2/EP4 pathway also promotes additional events in breast cancer progression, such as cancer cell migration, invasion, and stimulation of stem–like cells. Based on a combination of studies using multiple breast cancer models, we show that EP4 antagonists hold a major promise in breast cancer therapy in combination with other modalities including immune check-point inhibitors

Band-gap alignment engineering has now been extensively studied due to its high potential application. Here we demonstrate a simple route to synthesize two metal oxide layers and align them together according to their bandgaps on surface of crystalline silicon (c-Si) solar cells. The metal oxide layers can not only extend absorption spectrum to generate extra carriers but also serve to separate electron-hole pairs more efficiently. As a consequence, the photovoltaic performance of SnO₂/CdO /Si double-layer solar cell (DLSC) is highly improved compared to CdO/Si and SnO₂/Si single-layer solar cells(SLSCs) and SnO₂/CdO/Si double-layer solar cell (DLSC). By the alignment engineering, the SnO₂/CdO/Si DLSC produces a short circuit photocurrent (J_sc) of 38.20 mA/cm², an open circuit photovoltage (V_oc) of 0.575 V and a fill factor (FF) of 68.7%, corresponding to a light to electric power conversion efficiency (η) of 15.09% under AM1.5 illumination. These results suggest that with the use of metal oxide layers by band-gap alignment engineering, new avenues have been opened for developing high-efficiency and cost-effective c-Si solar cells.

Accumulating evidence suggests that metformin, used as an antidiabetic drug, possesses anticancer properties. Metformin reduced the incidence and growth of experimental tumors in vivo. In a randomized clinical trial among nondiabetic patients, metformin treatment significantly decreased the number of aberrant crypt foci compared to the untreated group with a follow-up of 1 month. In our study, HT29 cells were treated with graded concentrations of metformin, 10 mM/25 mM/50 mM, for 24/48 hours. We performed immunofluorescence experiments by means of confocal microscopy and Western blot analysis to evaluate a panel of factors involved in apoptotic/autophagic processes and oxidative stress response. Moreover, HT29 cells treated with metformin were analyzed by flow cytometry assay to detect the cell apoptosis rate. The results demonstrate that metformin exerts growth inhibitory effects on cultured HT29 cells by increasing both apoptosis and autophagy; moreover, it affects the survival of cultured cells inhibiting the transcriptional activation of nuclear factor E2–related factor 2 (NRF-2) and nuclear factor–kappa B (NF-κB). The effects of metformin on HT29 cells were dose- and time-dependent. These results are very intriguing, since metformin is emerging as a multifaceted drug: it has a good safety profile and is associated with low cost, and it might be a promising candidate for the prevention or treatment of colorectal cancer.

Despite great strides being achieved in improving cancer patients’ outcomes through better therapies and combinatorial treatment, several hurdles still remain due to therapy resistance, cancer recurrence and metastasis. Drug resistance, culminating in relapse and metastatic disease continue to be associated with fatal disease. Cancer stem cells (CSCs) are a subpopulation of cancer cells known to be resistant to therapy and cause metastasis. Whilst the debate on whether CSCs are the origins of the primary tumor rages on, CSCs have been further characterised in many cancers with data illustrating that CSCs display great abilities to self-renew, withstand therapies due to enhanced epithelial to mesenchymal (EMT) properties, enhanced expression of ABC membrane transporters, activation of several survival signaling pathways and increased immune evasion DNA repair mechanisms. CSCs also display great heterogeneity with the consequential lack of specific CSC markers presenting a great challenge to their targeting. In this updated review we re-visit CSCs within the tumor microenvironment (TME) and present novel treatment strategies targeting CSCs. These promising strategies include targeting CSCs-specific properties using small molecule inhibitors, immunotherapy, microRNA mediated inhibitors, epigenetic methods as well as targeting CSC niche-microenvironmental factors and differentiation. Lastly, we present recent clinical trials undertaken to try to turn the tide against cancer by targeting CSC-associated drug resistance and metastasis.

Stroke remains a major cause of death and disability in the United States and around the world. Solid safety and efficacy profiles of novel stroke therapeutics have been generated in the laboratory, but most failed in clinical trials. Investigations into the pathology and treatment of the disease remain a key research endeavor in advancing scientific understanding and clinical applications. In particular, cell-based regenerative medicine, specifically stem cells transplantation, may hold promise as stroke therapy because grafted cells and their components may recapitulate the growth and function of the neurovascular unit, which arguably represents the alpha and omega of stroke brain pathology and recovery. Recent evidence has implicated mitochondria, organelles with a central role in energy metabolism and stress response, in stroke progression. Recognizing that stem cells offer a source of healthy mitochondria, potentially transferrable into ischemic cells, may provide a new therapeutic tool. To this end, deciphering cellular and molecular processes underlying dysfunctional mitochondria may reveal innovative strategies for stroke therapy. Here, we review recent studies capturing the intimate participation of mitochondrial impairment in stroke pathology, and showcase promising methods of healthy mitochondria transfer into ischemic cells, to critically evaluate the potential of mitochondria-based stem cell therapy for stroke.

Understanding the biology underlying the mechanisms and pathways regulating pancreatic β-cell development is necessary to understand the pathology of diabetes mellitus (DM), which is characterized by the progressive reduction in insulin producing β-cell mass. Pluripotent stem cells (PSCs) can potentially offer an unlimited supply of functional β-cells for cellular therapy and disease modeling of DM. Homeobox protein NKX6.1 is a transcription factor (TF) that plays a critical role in pancreatic β-cell function and proliferation. In human pancreatic islet, NKX6.1 expression is exclusive toβ-cells and is undetectable in other islet cells. Several reports showed that activation of NKX6.1 in PSC-derived pancreatic progenitors (MPCs), expressing PDX1 (PDX1⁺/NKX6.1⁺), warrants their future commitment to monohormonal β-cells. However, further differentiation of MPCs lacking NKX6.1 expression (PDX1⁺/NKX6.1^-) results in an undesirable generation of non-functional polyhormonal β-cells. The importance of NKX6.1 as a crucial regulator in MPC specification into functional β-cells directs attentions to further investigating its mechanism and enhancing NKX6.1 expression as a mean to increase β-cell function and mass. Here, we shed light on the role of NKX6.1 during pancreatic β-cell development and in directing the MPCs to functional monohormonal lineage. Furthermore, we address the transcriptional mechanisms and targets of NKX6.1 as well as its association with diabetes.

Immune checkpoint inhibitors (ICIs) have obtained durable responses in many cancers, making it possible to foresee their potential in improving the health of cancer patients. However, immunotherapies are limited at the moment to a minority of patients and there is a need for a better understanding of the basic molecular mechanisms and functions of pivotal immune regulatory molecules. Immune checkpoint cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and regulatory T (Treg) cells play pivotal roles in hindering the anticancer immunity. Treg cells suppress antigen-presenting cells (APCs) by depleting immune stimulating cytokines, producing immunosuppressive cytokines and constitutively expressing CTLA-4. CTLA-4 molecules bind with higher affinity to CD80 and CD86 than CD28 and act as competitive inhibitors of CD28 in APCs. The purpose of this review is to summarize state-of-the-art understanding of the molecular mechanisms underlining CTLA-4 immune regulation and the correlation of ICI response with CTLA-4 expression in Treg cells from preclinical and clinical studies for possibly improving CTLA-4-based immunotherapies, while highlighting the knowledge gap.

Background: Colorectal cancer (CRC) remains a leading cause of cancer-related morbidity and mortality in both sexes globally. This is not unconnected with the heterogeneity and plasticity of CRC stem cells (CRC-SCs) which stealthily exploit niche-related and (epi)genetic factors to facilitate metastasis, chemoresistance, tumor recurrence, and disease progression. Despite accumulating evidence of the role of dysregulated microRNAs in malignancies, the therapeutic efficacy of pharmacological-targeting of CRC-SC-associated microRNAs is relatively under-explored. Experimental approach: In this present study, we employed relatively new bioinformatics approaches, analyses of microarray data, western blot, RT-PCR, and functional assays to show that hsa-miR-324-5p expression is significantly suppressed in CRC cells, and inversely correlates with the aberrant expression of SOD2. Results: This converse hsa-miR-324-5p/SOD2 relationship is associated with enhanced oncogenicity, which is effectively inhibited by 4-AAQB as evidenced by inhibited cell viability and proliferation, as well as, attenuated migration, invasion and clonogenicity in 4-AAQB-treated DLD1 and HCT116 cells. We also showed that 4-AAQB-induced re-expression of hsa-miR-324-5p, akin to short-interfering RNA reduced SOD2 expression, correlates with the concurrent down-regulation of SOD2, N-cadherin, vimentin, c-Myc, and BcL-xL2, with concomitant up-regulation of E-cadherin and BAX2 proteins. Enhanced expression of hsa-miR-324-5p in the CRC cells suppressed their tumorigenicity in vitro and in vivo. Additionally, 4-AAQB synergistically potentiates FOLFOX anticancer effect by eliciting the re-expression of SOD2-suppressed hsa-miR-324 and inhibiting SOD2-mediated tumorigenicity. Conclusion: Our findings highlight the pre-clinical anti-CSC efficacy of 4-AAQB, with or without FOLFOX in CRC, and suggest a potential novel therapeutic strategy for CRC patients.

Imatinib became the standard treatment for chronic myeloid leukemia (CML) about 20 years ago, which was a major breakthrough in stabilizing the pathology and improving the quality of life of patients. However, the emergence of resistance to imatinib and other tyrosine kinase inhibitors leads researchers to characterize new therapeutic targets. Several studies have highlighted the role of histone deacetylase 6 (HDAC6) in various pathologies, including cancer. This protein effectively intervenes in cellular activities by its primarily cytoplasmic localization. In this review, we will discuss the molecular characteristics of the HDAC6 protein, as well as its overexpression in CML leukemic stem cells, which make it a promising therapeutic target for the treatment of CML.

The i-4-1-Health project is a One Health project on the prevalence and spread of antimicrobial resistance in the human and veterinary domain in the Dutch-Belgian cross-border region. This paper describes the main components of the laboratory protocol that was developed to standardise the microbiological methods used for the detection of intestinal carriage of highly-resistant microorganisms.

Transient receptor potential vanilloid (TRPV) channels act as sensors of pain, temperature, and other external stimuli. We have recently shown that DPV576, an aqueous mixture of nanodiamond (ND) and nanoplatinum (NP), can modulate the activity of TRPV on human primary keratinocytes, suggesting their potential as a possible pain modulator [1]. CD4+ T lymphocytes also express TRPV channels, and we sought with special interest to examine the effect of DPV576 in modulating the functions of TRPV channel expression and secretion of cytokines on human CD4+ T lymphocytes. Human primary CD4+ T cells were activated with anti CD3/CD28 with and without DPV576 at 1:25 and 1:100 dilutions for 24 hours in vitro. TRPV Receptor expression (TRPV1 and TRPV4) on CD4+ T cells was examined by flow cytometry. The capacity of DPV576 to modulate the activity of TRPV1 agonist capsaicin in CD4+ T cells was also determined. Activation of CD4+ T cells was determined by production of cytokines TNF-α, IFN-γ, and IL-10 using specific ELISA kits. DPV576 treatment of CD4+ T cells that were activated with anti CD3/CD28, resulted in increased expression of TRPV1 channel but had no effect on TRPV4. This was accompanied by increased secretion of IFN-g and reduced expression of TRPV1 in capsaicin activated CD4+ T cells. In addition, DPV576 inhibited the capsaicin, induced the production of both IFN-g and TNF-α, and enhanced the secretion of IL-10. We conclude that short term exposure to DPV576 inhibits the activity of TRPV1 channels in CD4+ T lymphocytes, which may suggest its possible beneficial use for pain management.

Thymic stromal lymphopoietin (TSLP) is a cytokine and is closely related to Interleukin (IL) - 7, and hTSLP can activation through the human thymus dendritic cell in thymic to indirectly promote the differentiation of natural Regulatory T cells (Tregs) of the thymus. In this study, we focused on recombinant TSLP to determine its effects on the differentiation of CD4+CD25-T cells separated from the thymus of myasthenia gravis (MG) patients. Our results demonstrated that exogenous TSLP could increase CD4+CD25+T/CD4+T cells ratio, up-regulate the expression of Foxp3 mRNA and protein expression in CD4+CD25+Treg cells. Furthermore, we found that CD4+CD25+ Treg cells induced by exogenous TSLP could secrete IL - 10, Transforming growth factor (TGF) - β and the ability to inhibit CD4+T cell proliferation improved. These results indicate that TSLP may promote the differentiation of thymic CD4+CD25-T cells of MG patient to CD4+CD25+Foxp3+ regulatory T cells and enhance the function of immune suppression.

Sickle cell disease (SCD) is the most common hereditary disorder of hemoglobin (Hb) that affects approximately a millions people worldwide. It is characterized by a single nucleotide substitution on the β-globin gene, leading to the production of abnormal sickle hemoglobin with multi-system consequences. Mutated Hb leads to profound changes in: i) red blood cell metabolism and physiology; ii) endothelial signaling; and iii) immune response. Oxidative stress is an important hallmark of SCD. It plays a key role in the pathophysiology of hemolysis, vessel occlusion and the following organ damage in sickle cell patients. For this reason, reactive oxidizing species and the (end)-products of their oxidative reactions have been proposed as markers of both tissue pro-oxidant status and disease severity. Although more studies are needed to clarify their role, antioxidant agents have been shown to be effective in reducing pathological consequences of the disease by preventing oxidative damage in SCD, i.e. by decreasing the oxidant formation or repairing the induced damage. An improved understanding of oxidative stress will lead to targeted antioxidant therapies that should prevent or delay the development of organ complications in this patient population.

By manipulating the various physico-chemical properties of amino acids, design of peptides with specific self-assembling properties has been emerging since more than a decade. In this context, short peptides possessing detergent properties (so-called “peptergents”) have been developed to self-assemble into well-ordered nanostructures that can stabilize membrane proteins for crystallization. In this study, the peptide with “peptergency” properties, called ADA8 extensively described by Zhang et al., is studied by molecular dynamics for its self-assembling properties in different conditions. In water, it spontaneously forms beta sheets with a β barrel-like structure. We next simulated the interaction of this peptide with a membrane protein, the bacteriorhodopsin, in the presence or absence of a micelle of dodecylphosphocholine. According to the literature, the peptergent ADA8 is thought to generate a belt of β structures around the hydrophobic helical domain that could help stabilize purified membrane proteins. Molecular dynamics is here used to challenge this view and to provide further molecular details for the replacement of detergent molecules around the protein. To our best knowledge, this is the first molecular mechanism proposed for ''peptergency''. In addition, our calculation approach should serve as a predicting tool for the design of beta peptergent with diverse amphipathic properties.

C-C Chemokine receptor type 5 (CCR5) is expressed on the CD4 T cell surface where CXCR4 and CCR5 expressions are controlled differently during the activation of T cells and with the binding of interleukin type-2 (IL-2). IL-2 can upregulate CCR1 and CCR2 in CD45R01 T cells and increase the T lymphocyte chemotaxis toward CC-chemokines. CD4+ T cells are either apart of the T helper 1 or Th1 lymphocytes that release interferon gamma (IFNγ) and lymphotoxin that provide cellular immunity to internal pathogens and T helper cells type 2 (Th2), which secrete interleukins 4 and 5 (IL-4 and IL-5). IL-4 and IL-5 cause an allergic and humoral immune response to parasites. Th2 lymphocytes use CCR3 chemokine receptors. CCR5 and CXCR3 chemokine receptors are specific for CD4+ Th1 and Th2 lymphocytes. CCR5Δ32 is a 32-base-pair deletion of the CCR5 gene. CCR5 is a co-receptor for the entrance of the human immunodeficiency virus-1 (HIV-1). CCR5Δ32 creates a malfunction of the CCR5 protein that can prevent HIV-1 infection. However, the CCR5Δ32 32-base-pair deletion is not prevalent and predominant in many populations worldwide and there also exist more genetic variations of CCR5 known as CCR5-SNPs. An alternative polymorphism was identified based on the CCR5 gene that was identified as a A to G (A/G) point mutation. This point mutation is located at the 59029 locus on the promoter that lowers the expression rate of CCR5. Gurdol et al. found activity at the promoter of CCR5/590029G was 45% lesser than the CCR5/59029A. The genetic variations of CCR5 SNPs also include: 2459G>SNP of CCR5, C101X, CCR5 gene position at -2273, and the A to G SNP mutation found in two South African blacks. Therefore, more studies are needed to find more and varied chemokine polymorphisms that are present in many diverse populations in the world. The aim of this literature review is to describe the immense impact of CCR5 SNP mutations on viral infection susceptibility, on the pathogenesis of chronic conditions, to endorse the increased discovery of more novel CCR5 SNPs, and to show the significant potential of anti-CCR5 therapies to treat multiple diseased conditions.

Along just over a century of research we moved from learning how to cultivate tissues in a dish to grasping the concepts for creating an entire brain in a vat. As we approach the divisive moment in which we can first detect signs of awareness in such artificially developed organoids, we need to lay foundation for what lays ahead. It is crucial that ethical, legal and moral implications of organoid research are clear and that boundaries are set to separate scientific progress from human life preservation. The largest obstacle may be the definition of consciousness itself, which has arguably been historically neglected by philosophy, psychology and neurosciences at large. One reason may be the difficulties posed by the underlying qualities of awareness, such as its subjective and heterogeneous nature. Another reason may lie on the possibly that consciousness is an overarching emergent property of our brain. For the time being, one can see brain organoids as philosophical zombies, physical analogues of the human brain which mimic sentient human reactions but lack experiential properties of sensation (a.k.a. qualia).

Nasopharyngeal carcinoma (NPC) has not been thoroughly studied, and the pathogenesis of NPC is unclear. Scientists have neither discovered effective therapies nor achieved a desirable prognosis. Some studies have found that the regulation of intra- and extracellular ion channels hinges directly on cell apoptosis, and treatment with Gambogenic acid (GNA) brings changes to the volume-sensitive outwardly rectifying chloride (VSOR Cl-) current of CNE-2Z cells recorded by the patch clamp method. Nevertheless, rarely have any researchers probed into the relevance between this variation and the anti-tumor mechanism of GNA. This paper is suggested that GNA activates the VSOR Cl- current on the CNE-2Z cell membrane, and the activation of VSOR Cl- currents by GNA in CNE-2Z cells is blocked by the chloride channel blockers DIDS and DCPIB. GNA induces the down-regulation of GRP78 and up-regulation of ATF4 as well as chop proteins, which is evidence for the induction of CNE-2Z cell apoptosis, and this correlates with ER stress. GNA can activate the VSOR Cl- channel and lead to the occurrence of ER stress, thus inducing the apoptosis of CNE-2Z cells and inhibiting the proliferation of CNE-2Z cells.

Diabetes mellitus (DM) is one of the most prevalent metabolic disorders. In order to replace the function of the destroyed pancreatic beta cells in diabetes, islet transplantation is the widely practiced treatment; however, it has several limitations. As an alternative approach, human pluripotent stem cells (hPSCs) can provide an unlimited source of pancreatic cells that have the ability to secrete insulin in response to high blood glucose level. However, determination of the appropriate pancreatic lineage candidate for the purpose of cell therapy for treatment of diabetes is still debated upon. While hPSC-derived beta cells are perceived as the ultimate candidate, the efficiency needs further improvement in order to obtain a sufficient number of glucose responsive β-cells for transplantation therapy. On the other hand, hPSC-derived pancreatic progenitors can be efficiently generated in vitro and can further mature into glucose responsive beta cells in vivo after transplantation. Herein, we discuss the advantages and predicted challenges associated with the use of each of the two pancreatic lineage products for diabetes cell therapy. Furthermore, we address co-generation of functionally relevant islet cell subpopulations and structural properties contributing to glucose responsiveness of beta cells, as well as the available encapsulation technology for these cells.

Reversible protonic ceramic cells (rPCCs) combine two different operation regimes, fuel cell and electrolysis cell modes, which allow reversible chemical-to-electrical energy conversion at reduced temperatures with high efficiency and performance. Here we present novel technological and materials science approaches, enabling a rPCC with symmetrical functional electrodes to be prepared using a single sintering step. The response of the cell fabricated on the basis of P–N–BCZD|BCZD|PBN–BCZD (where BCZD = BaCe_0.5Zr_0.3Dy_0.2O_3–δ, PBN = Pr_1.9Ba_0.1NiO_4+δ, P = Pr₂O₃, N = Ni) is studied at different temperatures and water vapor partial pressures (pH₂O) by means of volt-ampere measurements, electrochemical impedance spectroscopy and distribution of relaxation times analyses. The obtained results demonstrate that symmetrical electrodes exhibit classical mixed-ionic/electronic conducting behavior with no hydration capability at 750 °C; therefore, increasing the pH₂O values in both reducing and oxidizing atmospheres leads to some deterioration of their electrochemical activity. At the same time, the electrolytic properties of the BCZD membrane are improved, positively affecting the rPCC’s efficiency. The electrolysis cell mode of the rPCC is found to be more appropriate than the fuel cell mode under highly humidified atmospheres, since its improved performance is determined by the ohmic resistance, which decreases with pH₂O increasing.

Cardiovascular Diseases (CVDs) are still menacing and killing adults worldwide, notwithstanding the tremendous effort, to decrease their related mortality and morbidity. Lately, a growing body of evidences indicated that inflammation plays a pivotal role in the pathogenesis and complications of CVDs. A receptor of the immunoglobulin superfamily, triggering receptor expressed on myeloid cells -1 (TREM-1) was shown to induce and to amplify the inflammation in both acute and chronic diseases pathogenesis and progression and hence it is one of the important factors that complicates CVDs. Thus, studies endeavored to investigate the role played by TREM-1 in CVDs with respect to their etiologies, complications and possible therapeutics. We examined here, for the first time, the most relevant studies regarding TREM-1 involvement in CVDs. We summarized the finding after critically analyzing them and made some suggestions for furtherance of the investigations with the aim to utilize TREM-1 and its pathways for diagnostic, management and prognosis of CVDs. Overall, TREM-1 was found to be involved in the pathogenesis of acute and chronic cardiovascular conditions like Acute myocardial infraction (AMI) and atherosclerosis as well. Although most therapeutic approaches are yet to be elucidated, present research outcome displays a promising future to utilize TREM-1 pathway as potential target to understand and manage CVDs.

The study of neurodegenerative diseases using pluripotent stem cells requires new methods to assess neurodevelopment and neurodegeneration of specific neuronal subtypes. The cholinergic system, characterized by its use of the neurotransmitter acetylcholine, is one of the first to degenerate in Alzheimer’s disease and is also affected in frontotemporal dementia. We developed a differentiation protocol to generate basal forebrain cholinergic neurons (BFCNs) from induced pluripotent stem cells (iPSCs) aided by the use of small molecule inhibitors and growth factors. Ten iPSC lines were successfully differentiated into BFCNs using this protocol. The neuronal cultures were characterised through RNA and protein expression, and functional analysis of neurons was confirmed by whole-cell patch clamp. We have developed a reliable protocol using only small molecule inhibitors and growth factors, while avoiding transfection or cell sorting methods, to achieve a BFCN culture that expresses the characteristic markers of cholinergic neurons.

Human mesenchymal stem cells (hMSCs) constitute of cells having potential of self-renewal and proliferation and are commonly isolated from bone marrow aspirates of large bones. The osteogenic potential of these stem cells has been extensively exploited by scientists during the last many years for the biological evaluation of synthetic scaffolds with applications in tissue engineering. Current work aimed to synthesize N-arylhydrazone derivatives of orotic acid and their evaluation as stimulators of human mesenchymal stem cells. Some of the analogs show good to moderate proliferation rate.

Cells take decisions on their responses depending on the stimuli received by the surrounding extracellular environment, that provides the essential cues at the micro and the nano-lengthscales required for adhesion, orientation, proliferation and differentiation. In this study, discontinuous microcones on silicon (Si) and continuous microgrooves on polyethylene terephthalate (PET) substrates were fabricated via ultrashort-pulsed laser irradiation at various fluences, resulting in microstructures with different roughness and geometrical characteristics. The topographical models attained were specifically developed to imitate the guidance and alignment of Schwann cells for oriented axonal regrowth, towards nerve regeneration. At the same time, positive replicas of the silicon microstructures formed were successfully reproduced, via soft lithography, on the biodegradable polymer poly(lactide-co-glycolide) (PLGA). The anisotropic continuous (PET) and discontinuous (PLGA replicas) microstructured polymeric substrates were assessed in terms of their influence on the Schwann cells responses. It is shown that the developed micropatterned substrates enable control over the cellular adhesion, proliferation and orientation and are thus useful to engineer cell alignment in vitro. This property could be potentially useful in the fields of neural tissue engineering and for dynamic microenvironment systems that simulate in vivo conditions.

Stem cells derived from dental tissues—dental stem cells—are flavored due to their easy acquisition. Among them, dental pulp stem cells (DPSCs) extracted from the dental pulp have many advantages such as high proliferation and highly purified population. Although their ability for neurogenic differentiation has been highlighted and neurogenic differentiation using electrospun nanofibers (NFs) has been performed, graphene-incorporated NFs have never been applied for DPSC neurogenic differentiation. Here reduced graphene oxide (RGO)-polycaprolactone (PCL) hybrid electrospun NFs were developed and applied for enhanced neurogenesis of DPSCs. First, RGO-PCL NFs were fabricated by electrospinning with incorporation of RGO and alignments, and their chemical and morphological characteristics were evaluated. Furthermore, in vitro NF properties such as influence on the cellular alignments and cell viability of DPSCs were also analyzed. The influences of NFs on DPSCs neurogenesis was also analyzed. The results confirmed that an appropriate concentration of RGO promoted better DPSC neurogenesis. Furthermore, the use of random NFs facilitated contiguous junctions of differentiated cells, whereas the use of aligned NFs facilitated aligned junction of differentiated cells along the direction of NF alignments. Our findings showed that RGO-PCL NFs can be a useful tool for DPSC neurogenesis, which will help regeneration in neurodegenerative and neurodefective diseases.

A new mathematical model is presented to study the effects of macrophages on the bone fracture healing process. The model consists of a system of nonlinear ordinary differential equations that represents the interactions among classically and alternatively activated macrophages, mesenchymal stem cells, osteoblasts, and pro- and anti-inflammatory cytokines. A qualitative analysis of the model is performed to determine the equilibria and their corresponding stability properties. Numerical simulations are also presented to support the theoretical results and to monitor the evolution of a broken bone for different types of fractures under various medical interventions. The model can be used to guide clinical experiments and to explore possible medical treatments that accelerate the bone fracture healing process either by surgical interventions or drug administrations.

In the present study, we have systematically examined the clinical significance of Nectin-4 (encoded by the PVRL-4 gene), a marker for breast cancer stem cells (CSCs), in cancer metastasis and angiogenesis using a variety of human specimens, including invasive duct carcinoma (IDC) with multiple grades, several types of primary tumors to local and distant relapses, lymph node metastases and circulating tumor cells (CTCs). Nectin-4 was overexpressed in more than 92% of samples with 65.2% Nectin-4 positive cells. The level of expression was increased with increasing tumor grade (GI-III) and size (T1-4) of IDC specimens. More induction of Nectin-4 was noted in relapsed samples from a variety of tumors (colon, tongue, liver, kidney, ovary, buccal mucosa) in comparison to primary tumors, while paired adjacent normal tissues do not express any Nectin-4. A high expression of Nectin-4 along with other representative markers in CTCs and lymph node metastasis was also observed in cancer specimens. An increased level of Nectin-4 along with representative metastatic (CD-44, Sca1, ALDH1, Nanog) and angiogenic (Ang-I, Ang-II, VEGF) markers was noted in metastatic tumors (local and distant) in comparison to primary tumors that were correlated with different grades of tumor progression. In addition, greater expression of Nectin-4 was observed in secondary tumors (distant metastasis, e.g., breast to liver or stomach to gallbladder) in comparison to primary tumors. Nectin-4 was overexpressed at all stages of metastasis and angiogenesis, thus appearing to play a major role in tumor relapse through the PI3K-Akt-NFκβ pathway.

Beta thalassemia major (β-TM) disorder characterized by the lack, or severe reduction in the production of hemoglobin β-globin chains. The standard protocol for the management of β-TM is blood transfusion and iron chelation therapy to reduce the iron overload state. The present study aimed to investigate the relationships between two iron regulatory hormones, hepcidin (HEPC) and erythroferrone (ERFE) levels and iron status parameters (ISPs) in Iraqi patients with β-TM. ISPs and hormones were measured in sixty patients and compared with thirty healthy controls. The results indicated significant changes in different iron status parameters, while ferritin (FRT) with the ~11 fold increase showed the most change. Significant reduction in HEPC and increase in ERFE levels were detected in patients as compared to the control group, while no direct correlation was identified with the other measured ISPs. Receiver operating characteristic (ROC) analysis showed that the z-score of the composite of ERFE+FRT has a full diagnostic ability for β-TM. In conclusion, our finding indicated the correlation between different ISPs, FRT as the leading predictor of iron overload and tow main iron regulatory hormones.

Heat stress affects the granulosa cells (GCs) and ovarian follicular microenvironment, causing poor oocyte developmental competence and fertility. This study aimed to investigate the physical responses and global transcriptomic changes in bovine GCs to acute heat stress (43 ℃ for 2 h) in-vitro and gave essential insights into the general interaction at cell–stress nexus. Heat-stressed GCs exhibited transient proliferation senescence, resumed proliferation at 48 h post-stress. While post-stress immediate culture-media change had a relatively positive effect on proliferation resumption. Increased accumulation of reactive oxygen species and apoptosis was observed in heat stress group. In spite of the upregulation of pro-apoptotic and caspase executioner genes, antioxidants and anti-apoptotic genes were also upregulated in heat-stressed GCs. Progesterone and Estrogen hormones along with steroidogenic genes expression, declined significantly, in spite of the upregulation of genes involved in cholesterol synthesis. Out of 12385 differentially expressed genes (DEGs), 330 significant DEGs (75 upregulated, 225 downregulated) were subjected to KEGG functional pathway annotation, gene ontology enrichment, and STRING network analyses. Based on the manual query of DEGs, pathway and enrichment analyses, a vast interplay observed among all major signaling pathways strongly evidence the repression of cellular transcriptional and proliferation activity, averting the effects of heat stress through remodeling of cellular structural proteins and energetic-homeostasis. This study presents detailed responses of acute heat-stressed GCs at physical, transcriptional, and pathway levels and presents interesting insights into future studies regarding GCs adaptation and their interaction with oocyte and reproductive system at ovarian level.

We proposed a so-called Beta Kumaraswamy Burr Type X distribution which gives the extension of the Kumaraswamy-G class of family distribution. Some properties of this proposed model were provided, like: the expansion of densi- ties and quantile function. We considered the Bayes and maximum likelihood methods to estimate the parameters and also simulate the model parameters to validate the methods based on dierent set of true values. Some real data sets were employed to show the usefulness and exibility of the model which serves as generalization to many sub-models in the elds of engineering, medical, survival and reliability analysis.

BACKGROUND: Treatment failure in primary as well as metastatic cancer patients, caused by chemo and radio resistance, has truncated the research for the applicability of personalized medicine. The use of stem cells and cancer stem cells in such a treatment approach will be reviewed in this study. RESULTS: CRC stem cells prove to be a promising asset for CRC treatment optimization both by serving as biomarkers for the current therapy modalities by means of treatment personalization and patient/tumor stratification, as well as in the development of targeted therapies, selective for the stem cell population. Similar conclusions are drawn, regarding mesenchymal stromal cells and their effect in CRC therapy; while resident stromal cells of tumor microenvironment seem to promote the tumorigenic and metastatic processes in addition to conferring to the chemo- and radio resistance, under certain conditions they are able to improve the treatment outcome of CRC chemotherapy, e.g. by targeted enzyme/prodrug treatment of CRC cells. CONCLUSION: This review, truncates the dynamic potential of cancer stem cells and other stem cell types in CRC treatment personalization as well as, in the improvement of current treatment approaches opting to a higher therapeutic rate, improved prognosis, survival and quality of life for CRC patients.

Dengue virus (DENV), being one of the lethal pathogens in the hot climatic regions of the world, have been extensively studied to decipher its mechanism of pathogenesis and missing links of its life cycle. With respect to the entry of DENV, multiple receptors have been recognised in different cells of the human body. However, scientists still argue whether these identified receptors are the exclusive entry mediators for the virus. Adding to the complexity, DENV has been reported to be infecting multiple organ types in its human host. Also, more than one receptor in a particular cell has been discerned to take part in mediating the ingress of DENV. In this review, we aim to discuss about the different cells of the human immune system that support DENV infection and their corresponding receptors that DENV deploy to gain access to the cells.

Human cytomegalovirus (HCMV) is a β-herpes virus that is a significant pathogen within immune compromised populations. HCMV morbidity is induced through viral dissemination and inflammation. Typically, viral dissemination is thought to follow Fenner’s hypothesis where virus replicates at the site of infection, followed by replication in the draining lymph nodes, and eventually replicating within blood filtering organs. Although CMVs somewhat follow Fenner’s hypothesis, they deviate from it by spreading primarily through innate immune cells as opposed to cell free virus. Also, in vivo CMVs infect new cells via cell to cell spread and disseminate directly to secondary organs through novel mechanisms. We review the historic and recent literature pointing to CMV’s direct dissemination to secondary organs and the genes that it has evolved for increasing its ability to disseminate. We also highlight aspects of CMV infection for studying viral dissemination when using in vivo animal models.

To evaluate whether autologous mesenchymal cells, adipose derived stem cells and platelet-rich plasma, grafted into the supracoroideal space by surgical treatment according to Limoli retinal restoration technique (LRRT), can produce growth factors in order to exert a beneficial effect in retinitis pigmentosa (RP) patients. Twenty-one eyes underwent surgery and divided based on retinal foveal thickness ≤ 190 or >190 µm into group A and group B, respectively. The specific LRRT triad was grafted in a deep scleral pocket above the choroid of each eye. At 6-month follow-up, group B showed an improvement in residual close-up visus and sensitivity at microperimetry compared to group A. After an in-depth review of molecular biology studies concerning degenerative phenomena underlying the etiopathogenesis of RP, it can be confirmed that further research is needed on tapeto-retinal degenerations both from a clinical and molecular point of view to obtain better functional results. In particular, it is necessary to increase the number of patients, extend observation times, and treat subjects in the presence of still trophic retinal tissue to allow adequate biochemical and functional catering.

Grazing exclusion has been proved to be one of the main measures for rehabilitating degraded arid steppes. However, the effect of this management practice on plant species diversity and composition is ambiguous, specially under prolonged droughts. Concurrently considering the responses of individual plant species, diversity of functional groups, α-diversity, and β-diversity (and its components) may be crucial to the holistic understanding of grazing exclusion effects on plant communities under drought conditions. Here, we investigated the response of these diversity measures to short-term sheep exclusion under severe drought episode in arid steppes of Alfa-grass (Stipa tenacissima) with a long evolutionary history of livestock grazing. Individual species responses were tested based on species occurrence and abundance in either grazed or grazing-excluded steppes, in addition, we used indicator species analysis to assess the strength of the association between plant species and management type. Likewise, α-diversity, abundance- and incidence-based β-diversity, as well as the functional groups’ diversities were quantified using Hill Numbers and compared between the two management types. Sheep grazing exclusion enabled the recovery of various Alfa-steppe indicator species and improved the size of regional species pool, overall α-diversity, and the diversity of therophytes. This management practice decreased the abundance-based β-diversity and the nestedness-resultant fraction of the incidence-based β-diversity at the local scale, while at the landscape scale increased the abundance-based β-diversity and its balanced variation fraction and reduced the incidence-based β-diversity and its turnover component. Furthermore, protection from grazing altered β-diversities scaling patterns by maintaining higher balanced variation in species abundance at large spatial scale and greater abundance-gradient in species composition at the fine-scale. Our results suggest that the implementation of short-term grazing exclusion in degraded arid steppes would be the appropriate management practice for vegetation restoration and plant diversity conservation during prolonged drought periods.

The design of biomaterial platforms able to release bioactive molecules is mandatory in tissue repair and regenerative medicine. In this context, electrospinning is a user-friendly, versatile and low-cost technique, able to process different kinds of materials in micro- and nano-fibers with a large surface area-to-volume ratio for an optimal release of gaseous signalling molecules. Recently, the antioxidant and anti-inflammatory properties of the endogenous gasotramsmitter hydrogen sulfide (H2S), as well as its ability to stimulate relevant biochemical processes on the growth of mesenchymal stem cells (MSC), have been investigated. Therefore, in this work, new poly(lactic) acid fibrous membranes (PFM), doped and functionalized with H2S slow-releasing donors extracted from garlic, were synthetized. These innovative H2S-releasing mats were characterized for their morphological, thermal, mechanical and biological properties. Their antimicrobial activity and effects on the in vitro human cardiac MSC growth, either in the presence or in the absence of oxidative stress, were here assessed. On the basis of the results here presented, these new H2S-releasing PFM could represent promising and low-cost scaffolds or patches for biomedical applications in tissue repair.

Immunotherapy is an effective therapeutic option for several cancers. In the last years, the introduction of checkpoint inhibitors (ICIs) has shifted the therapeutic landscape in oncology and improved patient prognosis in a variety of neoplastic diseases. However, to date, the selection of the best patients eligible for these therapies, as well as the response assessment is still challenging. Patients are mainly stratified using immunohistochemical analysis of the expression of anti-gens on biopsy specimens, such as PD-L1 and PD-1, on tumor cells, on peritumoral immune cells, and/or in the tumor microenvironment (TME). Recently, the use and development of imaging biomarkers able to assess in-vivo cancer-related processes are becoming more important. Today, positron emission tomography (PET) with 2-deoxy-2-[18F]fluoro-D-glucose ([18F]FDG) is used routinely to evaluate tumor metabolism, and also to predict and monitor response to immunotherapy. Although highly sensitive, FDG-PET, in general, is rather unspecific. Novel radiopharmaceuticals (immuno-PET radiotracers) able to identify specific immune system targets are under investigation in pre-clinical and clinical settings. In this review, we will provide an overview of the main new immuno-PET radiotracers in development. We will also review the main players (immune cells, tumor cells, and molecular targets) involved in immunotherapy. Furthermore, we report current applications and the evidence of using [18F]FDG PET in immunotherapy, including the use of artificial intelligence (AI).

Cardiac hypertrophy is an important and independent risk factor for the development of heart failure. To better understand the mechanisms and regulatory pathways involved in cardiac hypertrophy, there is a need for improved in vitro models. In this study, we investigated how hypertrophic stimulation affected human induced pluripotent stem cell (iPSC)-derived cardiomyocytes (CMs). The cells were stimulated with endothelin-1 (ET-1) for 8, 24, 48, 72, or 96h. Parameters including cell size, ANP-, proBNP-, and lactate concentration were analyzed. Moreover, transcriptional profiling using RNA-sequencing was performed to identify differentially expressed genes following ET-1 stimulation. The results show that the CMs increase in size by approximately 13% when exposed to ET-1 in parallel to increases in ANP and proBNP protein and mRNA levels. Furthermore, the lactate concentration in the media was significantly increased indicating that the CMs consume more glucose, a hallmark of cardiac hypertrophy. Using RNA-seq, a hypertrophic gene expression pattern was also observed in the stimulated CMs. Taken together, these results show that hiPSC-derived CMs stimulated with ET-1 display a hypertrophic response. The results from this study also provide new molecular insights about the underlying mechanisms of cardiac hypertrophy and may help accelerate the development of new drugs against this condition.

This article focuses on the current state-of-the-art in the area of cellular and molecular biotechnology for over-production of clinically relevant therapeutic growth factors and how the technology can be used for the treatment of osteoarthritis (OA). Transfected and irradiated protein packaging cell lines may be used as “cellular factories” for large-scale production of therapeutic proteins and pro-anabolic growth factors, particularly in the context of cartilage matrix regeneration. We discuss the potential for new innovations in regenerative medicine for degenerative diseases of synovial joints using mammalian protein production platforms, specifically protein packaging cell lines, for over-producing growth factors for cartilage tissue regeneration and give recent examples. Mammalian protein production platforms that incorporate protein packaging cell lines are superior to bacterial expression systems and are likely to have a significant impact on the development of new biological therapies for treating focal cartilage defects and more generally for the treatment of degenerative joint diseases such as OA.

We profiled the transcriptomes of primary mouse cortical astrocytes cultured alone or co-cultured with immortalized precursor oligodendrocytes. The experimental set-up (insert systems) prevented formation of gap junction channels but allowed free exchange of the two culture media. The study complements our previously published reports that the genomic fabrics of major functional pathways in oligodendrocytes are substantially remodeled by the proximity of non-touching astrocytes. Here, we present new analysis indicating that the transcriptomic landscape of astrocytes likewise changes significantly in the proximity of non-touching oligodendrocytes. The research was stimulated by the reported transcriptomic similarity between the brains of Cx43KO and Cx32KO mice, both substantially different from that of the Cx36KO mice. Since the three connexins are expressed in different cell types (Cx43 in astrocytes, Cx32 in oligodendrocytes and Cx36 in neurons), altogether these findings support the idea of a “panglial transcriptomic syncytium” in the mouse brain. Going further, our results suggest that integration in a heterocellular tissue modulates not only the expression profile but also the expression control and networking of the genes in each cell phenotype.

We revisit the argument that link the efficiency of a solar cell to its reverse operation as a LED, in the case where the material is organic. In organic cells, exciton transport is an intermediate process between sunlight absorption and the generation of electric current. We show that quenching exciton radiation can be beneficial to cell efficiency, without contradicting the general rule prevailing for semiconductor cells. Our treatment allows us to discuss both bulk heterojunction and planar junctions.

Stem cells are undifferentiated cells which can give rise to any types of cells in our body. Hence, they have been utilized for various applications such as drug testing and disease modeling. However, for the successful of those applications, the survival and differentiation of stem cells into specialized lineages should be well controlled. Growth factors and chemical agents are the most common signals to promote the proliferation and differentiation of stem cells. However, those approaches holds several drawbacks such as the negative side effects, degradation or denaturation, and expensive. To address such limitations, nanomaterials have been recently used as a better approach for controlling stem cells behaviors. Graphene oxide is the derivative of graphene, the first 2D materials in the world. Recently, due to its extraordinary properties and great biological effects on stem cells, many scientists around the world have utilized graphene oxide to enhance the differentiation potential of stem cells. In this mini review, we highlight the key advances about the effects of graphene oxide on controlling stem cell growth and various types of stem cell differentiation. We also discuss the possible molecular mechanisms of graphene oxide in controlling stem cell growth and differentiation.

Mesenchymal stem cells (MSCs) have emerged as a promising treatment for inflammatory diseases. It is described that the immunomodulatory effect of MSCs takes place both by direct cell-to-cell contact and by means of soluble factors that leads to an increased accumulation of regulatory immune cells at the sites of inflammation. Similar efficacy of MSCs has been described regardless the route of administration used, the inflammation conditions and the MHC context. These observations arise the question as to whether the migration of the MSCs to the inflamed tissues is a pre-requisite to achieve their beneficial effect. To address this, we examined the biodistribution and the efficacy of intraperitoneal luciferase-expressing human expanded adipose derived stem cells (Luci-eASCs) in a mouse model of colitis. Luci-eASC-infused mice were stratified according to their response to the Luci-eASC treatment. According to the stratification criteria, there was a tendency to increase the bioluminescence signal in the intestine at the expense of a decrease in the bioluminescence signal in the liver in the `responder´ mice. These data thus suggest that the accumulation of the eASCs to the inflamed tissues is beneficial to achieve an optimal modulation of inflammation.

Our knowledge on the plastic functions of the serotonin (5-HT) receptor subtype 7 (5-HT7R) in the brain physiology and pathology considerably advanced in the last few years. A wealth of data show that the 5-HT7R is a key player in the establishment and remodeling of neuronal cytoarchitecture during development and in the mature brain, and its dysfunction is linked to neuropsychiatric and neurodevelopmental diseases. The involvement of this receptor in synaptic plasticity is further demonstrated by data showing that its activation allows to rescue long term potentiation (LTP) and long term depression (LTD) deficits in various animal models of neurodevelopmental diseases. In addition, it is becoming clear that the 5-HT7R is involved in inflammatory intestinal diseases, possibly playing a role in the gut-brain axis, and modulates the function of immune cells. In this review, we will mainly focus on recent findings on this receptor’s role in the structural and synaptic plasticity of the mammalian brain, although we will also illustrate novel aspects highlighted in gut and immune system.

Beta-lactam resistant bacteria, commonly resident in tertiary hospitals, have emerged as a worldwide health problem because of ready-to-eat vegetable intake. We aimed to characterize the genes providing resistance to beta-lactam antibiotics in Enterobacteriaceae, isolated from five commercial salad brands for human consumption in Mexico City. 25 samples were collected, grow in blood agar plates, the bacteria were biochemistry identified and antimicrobial susceptibility testing was done, the carried family genes were identified by endpoint PCR and the specific genes were confirmed with WGS by NGS. 12 positive cultures were identified and their microbiological distribution was as follows, 8.3% for Enterobacter aerogene (n=1), 8.3% for Serratia fonricola (n=1), 16.7% for Serratia marcesens (n=2), 16.7% for Klebsiella pneumoniae (n=2), and 50% (n=6) for Enterobacter cloacae. The endpoint PCR results showed 11 colonies positive for blaBIL (91.7%), 11 for blaSHV (91.7%), 11 for blaCTX (97.7%), 12 for blaDHA (100%),4 for blaVIM (33.3%), 2 for blaOXA (16.7%), 2 for blaIMP (16.7%), 1 for blaKPC (8.3%) and 1 for blaTEM (8.3%) gene, all samples were negative blaROB, blaCMY, blaP, blaCFX and blaLAP gene. The sequencing analysis revels a specific genotypes for Enterobacter cloacae (blaSHV-12, blaCTX-M-15, blaDHA-1, blaKPC-2); Serratia marcescens (blaSHV-1, blaCTX-M-3, blaDHA-1, blaVIM-2); Klebsiella pneumoniae (blaSHV-12, blaCTX-M-15, blaDHA-1); Serratia fonticola (blaSHV-12, blaVIM-1, blaDHA-1) and Enterobacter aerogene (blaSHV-1, blaCTX-M-1, blaDHA-1, blaVIM-2, blaOXA-9). Our results indicate that beta-lactam resistant bacteria have acquired integrons with a different number of genes that providing panresistance to beta-lactam antibiotics, including penicillins, oxacillins, cefalosporins, monobactams, carbapenems and imipenems.

In the last two decades, the continuous ever growing demand for energy has determined a significant development in the production of photovoltaic (PV) modules. Anyway, a critical and very important issue in the module design process is the adoption of suitable encapsulant materials and technologies for cell embedding. Therefore, adopted encapsulants have a significant impact on modules efficiency, stability and reliability, and to ensure the unchanged performance of PV modules in time, the encapsulant materials must be selected properly. The selection of encapsulant materials must maintain a good balance between the encapsulant performance in time and costs, related to materials production and technologies for cells embedding. However, the encapsulants must ensure excellent isolation of active photovoltaic elements by the environment, preserving accurately the PV cells against humidity, oxygen and accidental causes that may compromise the PV modules function. This review provides an overview of different encapsulant materials, their main advantages and disadvantages in adoption for PV production, and also in relation to used encapsulant technologies for cell embedding, additives and the interaction of these materials with other PV components.

Remanufacturing is a viable option to extend the useful life of an end-of-use product or its parts, ensuring sustainable competitive advantages under the current global economic climate. Challenges typical to remanufacturing still persist, despite its many benefits. According to the European Remanufacturing Network a key challenge is lack of accurate, timely and consistent product knowledge as highlighted in a 2015 survey of 188 European remanufacturers. With more data being produced by electric and hybrid vehicles, this adds to the information complexity challenge already experienced in remanufacturing. Therefore, it is difficult to implement real-time and accurate remanufacturing for the shop floor; there are no papers that focus on this within an electric and hybrid vehicle environment. To address this problem this paper attempts to (1) identify the required parameters/ variables needed for fuel cell remanufacturing by means of interviews (2) rank the variables by Pareto analysis (3) develop a casual loop diagram for the identified parameters/ variables to visualise its impact on remanufacturing (4) model a simple stock and flow diagram to simulate and understand data and information-driven schemes in remanufacturing.

Probiotics make up a large and growing segment of the commercial market of dietary supplements and are touted as offering a variety of human health benefits. Some of the purported positive impacts of probiotics include, but are not limited to, stabilization of the gut microbiota, prevention of gastrointestinal disorders and modulation of the host immune system. Current research suggests that the immunomodulatory effects of probiotics are strain specific and vary in mode of action. Here, we examined the immunomodulatory properties of Bacillus subtilis strain DE111 in a healthy human population. In a randomized, double blind, placebo-controlled four-week intervention, we examined peripheral blood mononuclear cells (PBMCs) at basal levels pre- and post-treatment as well as in response to stimulation with bacterial lipopolysaccharide (LPS). We observed an anti-inflammatory effect of B. subtilis, manifested as a decrease in immune cell populations within the basal state along with an increase in anti-inflammatory immune cells in response to LPS stimulation. Overall gastrointestinal health, microbiota, and circulating and fecal markers of inflammation and gut barrier function were largely unaffected by DE111 treatment. These data suggest that the novel probiotic B. subtilis DE111 may have clinical applications in modulating immune homeostasis via anti-inflammatory mechanisms.

Integrated photovoltaic-fuel cell (IPVFC) systems, amongst other integrated energy generation methodologies are renewable and clean energy technologies that have received diverse research and development attentions over the last few decades due to their potential applications in a hydrogen economy. This article systematically updates the state-of-the-art of IPVFC systems and provides critical insights into the research and development gaps needed to be filled/addressed to advance these systems towards full commercialisation. The design methodologies, renewable energy-based microgrid and off-grid applications, energy management strategies, optimisations and the prospects as self-sustaining power source were covered. IPVFC systems could play an important role in the upcoming hydrogen economy since they depend on solar hydrogen which has almost zero emissions during operation. Highlighted herein are the progresses as well as the technical challenges requiring research efforts to solve to realise numerous potential applications of IPVFC systems such as in unmanned aerial vehicles, hybrid electric vehicles, agricultural applications, telecommunications, desalination, synthesis of ammonia, boats, buildings, and distributed microgrid applications.

Angiotensin-converting enzyme 2 (ACE2) is an important player of the renin-angiotensin-aldosterone system (RAAS) in regulating the conversion of angiotensin II into angiotensin (1-7). While expressed on the surface of human cells, such as lung, heart, kidney, neurons, and endothelial cells (EC), ACE2 is the entry receptor for SARS-CoV-2. Here, we would like to highlight that ACE2 is predominant on the EC membrane. Many of coronavirus disease 2019 (COVID-19) symptoms have been associated with the large recruitment of immune cells, directly affecting EC. Additionally, cytokines, hypoxia, and complement activation can trigger the activation of EC leading to the coagulation cascade. The EC dysfunction plus the inflammation due to SARS-CoV-2 infection may lead to abnormal coagulation, actively participating in thrombo-inflammatory processes resulting in vasculopathy and indicating poor prognosis in patients with COVID-19. Considering the intrinsic relationship between EC and the pathophysiology of SARS-CoV-2, EC-associated therapies such as anticoagulants, fibrinolytic drugs, immunomodulators, and molecular therapies have been proposed. In this review, we will discuss the role of EC in the lung inflammation and edema, in the disseminate coagulation process, ACE2 positive cancer patients, and current and future EC-associated therapies to treat COVID-19.

Blood cell analysis is a crucial diagnostic process in medical practice. In particular, detecting white blood cells (WBCs) is essential for diagnosing of many diseases. The manual screening of blood films is a time-consuming and subjective process, which can lead to inconsistencies and errors. Therefore, automated detection of blood cells can improve the accuracy and efficiency of the screening process. In this study, an explainable Vision Transformer (ViT) model was proposed for the automatic detection of WBCs from blood films. The proposed model utilizes the self-attention mechanism to extract relevant features from the input images and leverages transfer learning by incorporating pre-trained model weights to improve its performance. The proposed model achieved a classification accuracy of 99.40% for five distinct types of WBCs and exhibited potential in reducing the time required for manual screening of blood films by pathologists. Upon examination of the misclassified test samples, it was observed that incorrect predictions were correlated with the presence or absence of granules in the cell samples. To validate this observation, the dataset was divided into two classes, namely Granulocytes and Agranulocytes, and a secondary training process was conducted. The resulting ViT model trained for binary classification achieved an accuracy of 99.70%, recall of 99.54%, precision of 99.32%, and F-1 score of 99.43% during the test phase. To ensure the reliability of the ViT model's multi-class classification of WBCs, the pixel areas that the model focuses on in its predictions are visualized through the Score-CAM algorithm.

Cachexia is a syndrome characterized by an ongoing loss of skeletal muscle mass associated with poor patient prognosis in non-small cell lung cancer (NSCLC). However, prognostic cachexia biomarkers in NSCLC are unknown. Here, we analyzed computed tomography (CT) images and tumor transcriptome data to identify potentially secreted cachexia biomarkers (PSCB) in NSCLC patients with low-muscularity. We integrated radiomics features (pectoralis muscle, sternum, and T10 vertebra) from CT of 89 NSCLC patients, which allowed us to identify an index for screening muscularity. Next, a tumor transcriptomic-based secretome analysis from these patients (discovery set) was evaluated to identify potential cachexia biomarkers in patients with low-muscularity. The prognostic value of these biomarkers for predicting recurrence and survival outcome was confirmed using expression data from eight lung cancer datasets (validation set). Finally, C2C12 myoblasts differentiated into myotubes were used to evaluate the ability of the selected biomarker, IL-8, in inducing muscle cell atrophy. We identified 75 over-expressed transcripts in patients with low-muscularity, which included IL6, CSF3, and IL8. Also, we identified NCAM1, CNTN1, SCG2, CADM1, IL8, NPTX1, and APOD as PSCB in the tumor secretome. These PSCB were capable of distinguishing worse and better prognosis (recurrence and survival) in NSCLC patients. IL8 was confirmed as a predictor of worse prognosis in all validation sets. In vitro assays revealed that IL-8 promoted C2C12 myotube atrophy. Tumors from low-muscularity patients presented a set of upregulated genes encoding for secreted proteins, including pro-inflammatory cytokines that predict worse overall survival in NSCLC. Among these up-regulated genes, IL8 expression in NSCLC tissues was associated with worse prognosis and the recombinant IL-8 was capable of triggering atrophy in C2C12 myotubes.

In this article, our main purpose is to establish a new extension of Mittag-Leffler function by using the known extended beta function $\mathbf{B}_{\omega}(a,b;p)$ introduced in [1]. It led to a novel extension of the applicability of Mittag-Leffler function that introduced them as distributions defined for a specific set of functions. We also, investigate some of its important properties, namely recursion relation, Mellin transform and differential formulas.

The Hedgehog (Hh) signaling pathway plays an important role in embryonic and postnatal vascular development and in maintaining the homeostasis of organs. Under physiological conditions, Sonic Hedgehog (Shh), a secreted protein belonging to the Hh family, regulates endothelial cell growth, promotes cell migration, and stimulates the formation of new blood vessels. The present review highlights recent advances made in the field of Shh signaling in endothelial progenitor cells (EPCs). The canonical and non-canonical Shh signaling pathways in EPCs and endothelial cells (ECs) related to homeostasis, Shh signal transmission by extracellular vesicles (EVs) or exosomes containing single-strand non-coding miRNAs, and impaired Shh signaling in cardiovascular diseases are discussed. As a promising therapeutic tool, the possibility of using the Shh signaling pathway for the activation of EPCs in patients suffering from cardiovascular diseases is further explored.

A series of D–π–A diketopyrrolopyrrole (DPP)-based small molecules have been designed for organic light-emitting diodes (OLEDs) and organic solar cells (OSCs) applications. Appling the PBE0/6-31G(d,p) method, the ground state geometry and relevant electronic properties were investigated. The first excited singlet state geometry and the absorption and fluorescent spectra were simulated at the TD-PBE0/6-31G(d,p) level. The calculated results reveal that the photophysical properties are affected through the introduction of different end groups. Furthermore, the electronic transitions corresponding to absorption and emission exhibit intramolecular charge transfer feature. It was disclosed that the designed molecules act not only as luminescent for OLEDs, but also donor materials in OSCs. Moreover, they also can be used as potential electron transfer materials using for OLEDs and OSCs.

Crimean-Congo hemorrhagic fever virus is one the most important and wide spread tick-borne viruses. Very little is known about the transmission from the tick and the early aspects of pathogenesis. Here, we generate human cutaneous antigen presenting cells: dermal dendritic cells and Langerhans cells, from umbilical cord progenitor cells. In order to mimic the environment created during tick feeding, tick salivary gland extract was generated from semi-engorged Hyalomma marginatum ticks. Our findings indicate that human dermal dendritic cells and Langerhans cells are susceptible and permissive to Crimean-Congo hemorrhagic fever virus infection, however, to different degrees. Infection leads to cell activation and cytokine/chemokine secretion, although these responses vary between the different cell types. Hyalomma marginatum salivary gland extract had minimal effect on cell responses, with some synergy with viral infection with respect to cytokine secretion. However, salivary gland extract appeared to inhibit antigen presenting cell (APC) migration. Based on the findings here we hypothesize that human dermal dendritic cells and Langerhans cells serve as early target cells. Rather affecting Crimean-Congo hemorrhagic fever virus replication, tick saliva likely immunomodulates and inhibits migration of these APC from the feeding site.

Discovery of inhibitors for endothelial-related transcription factors can contribute to the development of angiogenic therapies that treat diseases ranging from cardiovascular to cancer. The role of transcription factor Vezf1 in vascular development and regulation of angiogenesis has been defined by several earlier studies. Through construction of a computational model for Vezf1, work here has identified a novel small molecule drug capable of inhibiting Vezf1 from binding to its cognate DNA binding site. Using structure-based design and virtual screening of the NCI Diversity Compound Library, 12 shortlisted compounds were tested for their ability to interfere with the binding of Vezf1 to DNA using electrophoretic gel mobility shift assays. We identified one compound, T4, which has an IC50 of 20uM. Using murine endothelial cells, MSS31, we tested the effect of T4 on endothelial cell viability and angiogenesis by using tube formation assay. Our data show that addition of T4 in cell culture medium does not affect cell viability at concentrations lower or equal to its IC 50 but strongly inhibits the network formation by MSS31 in the tube formation assays. Given its potential efficacy, this inhibitor has significant therapeutic potential in several human diseases raging from wound healing to cancer.

: Glioblastoma (GBM) is the most common and most aggressive primary brain tumor with a very high rate of recurrence and a median survival of 15 months after diagnosis. Abundant evi-dence suggests that a certain sub-population of cancer cells harbors a stem-like phenotype and is likely responsible for disease recurrence, treatment resistance and potentially even for the infil-trative growth of GBM. GBM incidence has been negatively correlated with the serum levels of 25-hydroxy-vitamin D3, while the low pH within tumors has been shown to promote the ex-pression of the vitamin D3-degrading enzyme 24-hydroxylase, encoded by the CYP24A1 gene. Therefore, we hypothesized that calcitriol can specifically target stem-like glioblastoma cells and induce their differentiation. Here, we show using in vitro limiting dilution assays, quantita-tive real-time PCR and ex vivo adult organotypic brain slice transplantation cultures that thera-peutic doses of calcitriol, the hormonally active form of vitamin D3, reduces stemness to varying extent in a panel of investigated GSC lines and effectively hinders tumor growth of responding GSCs ex vivo. We further show that calcitriol synergizes with Temozolomide ex vivo to com-pletely eliminate some GSC tumors. These findings indicate that calcitriol carries potential as an adjuvant therapy for a subgroup of GBM patients and should be analyzed in more detail in fol-low-up studies.

Aberration in microRNA (miRNA) expression or DNA methylation is a causal factor for polycystic ovarian syndrome (PCOS), a common endocrine disorder and leading cause of infertility. However, the epigenetic interactions between miRNA and DNA methylation remain unexplored in PCOS. In this study, we conducted an integrated analysis of RNA-seq, miRNA-seq and MBD-seq on ovarian granulosa cells of PCOS and control groups to reveal the epigenetic interactions involved in the pathogenesis of PCOS. Firstly, we identified 830 genes and 30 miRNAs that were expressed differently in PCOS, and seven miRNAs were found to negatively regulate targeted mRNA expression. Next, in total, 130 miRNAs were found to be significantly differently methylated in promoter regions, while 13 were found to be associated with miRNA expression. Furthermore, the promoter hypermethylation of miR-429, miR-141-3p, and miR-126-3p was proven to suppress miRNA expression and therefore upregulate their corresponding genes, including XIAP, BRD3, MAPK14 and SLC7A5. Our results demonstrate that DNA methylation regulates miRNA expression and therefore controls its corresponding gene expression. The reactivation of the transcription of epigenetically silenced genes may be one of the key elements in PCOS pathogenesis. Meanwhile, the epigenetic mechanisms underlying the regulation of miRNA expression can provide a potential therapeutic target for PCOS in the future.

A new compound containing a triene, a tetrahydropyran ring and glycine ester functionalities, restricticin B (1), together with four known compounds (2-5) were obtained from the EtOAc extract of the marine fungus Penicillium janthinellum. The planar structure of 1 was determined by detailed analyses of MS, 1D and 2D NMR data. The relative and absolute configurations of 1 were established via analyses of NOESY spectroscopy data, comparison of optical rotation values with those of restricticin derivatives reported and electronic circular dichroism (ECD). All the compounds were screened for their anti-neuroinflammatory effects in lipopolysaccharide (LPS)-induced BV-2 microglia cells. Restricticin B (1) and N-acetyl restricticin (2) exhibited anti-neuroinflammatory effects by suppressing the production of pro-inflammatory mediators in activated microglial cells.

Zika virus (ZIKV) is a flavivirus that originated in Africa but emerged in Latin America in 2015. In this region, other flaviviruses such as Dengue (DENV), West Nile, and Yellow Fever Virus (YFV) also circulate, allowing for possible antigenic cross-reactivity to impact viral infections and immune responses. Studies have found antibody mediated enhancement between DENV and ZIKV, but the impact of YFV antibodies on ZIKV infection has not been fully explored. ZIKV infections cause congenital syndromes, such as microcephaly, necessitating further research into ZIKV vertical transmission through the placental barrier. Recent advancements in biomedical engineering have generated co-culture methods that allow for in vitro recapitulation of the maternal: fetal interface. This study utilized a transwell assay, which is a co-culture model utilizing human placental syncytiotrophoblasts, fetal umbilical cells, and a differentiating embryoid body to replicate the maternal: fetal axis. To determine if cross reactive YFV vaccine antibodies impact the pathogenesis of ZIKV across the maternal fetal axis, maternal syncytiotrophoblasts were inoculated with ZIKV or ZIKV incubated with YFV vaccine anti-sera, and viral load was measured 72 hours post inoculation. Here we report that BeWo and HUVEC cells are permissive to ZIKV and that the impact of YFV post-vaccination antibodies on ZIKV replication is cell line dependent. Embryoid bodies are also permissive to ZIKV and the presence of YFV antibodies collected 1 to 6 months post vaccination enhances ZIKV infection. Our data show that each of the cell lines and EBs have a unique response to ZIKV complexed with post-vaccination serum suggesting there may be cell-specific mechanisms that impact congenital ZIKV infections. Since ZIKV infections can cause severe congenital syndromes, it is crucial to understand any potential enhancement or protection offered from cross-reactive, post-vaccination antibodies.

Protein glycation is usually referred to as an array of non-enzymatic post-translational modifications, formed by reducing sugars and carbonyl products of their degradation. Resulting advanced glycation end products (AGEs) represent a heterogeneous group of covalent adducts, known for their pro-inflammatory effects in mammals, and impacting on pathogenesis of metabolic diseases and ageing. In plants, AGEs are the markers of tissue ageing and response to environmental stressors, the most prominent of which is drought. Although water deficit enhances protein glycation in leaves, its effect on seed glycation profiles is still unknown. Moreover, the effect of drought on biological activities of seed protein in mammalian systems is still unstudied in respect of glycation. Therefore, here we address the effects of a short-term drought on the patterns of seed protein-bound AGEs and accompanying alterations in pro-inflammatory properties of seed protein in the context of seed metabolome dynamics. A short-term drought, simulated as polyethylene glycol-induced osmotic stress and applied at the stage of seed filling, resulted in dramatic suppression of primary seed metabolism, although secondary metabolome was minimally affected. This was accompanied with significant suppression of NF-kB activation in human SH-SY5Y neuroblastoma cells after a treatment with protein hydrolyzates, isolated from the mature seeds of drought-treated plants. This effect could not be attributed to formation of known AGEs. Most likely, the prospective anti-inflammatory effect of short-term drought is related to antioxidant effect of unknown secondary metabolite protein adducts, or down-regulation of unknown plant-specific AGEs due to suppression of energy metabolism during seed filling.

Endo-reticular stress induces the unfolded protein response including a highly conserved set of genes crucial for cell survival against a variety of onslaughts. Among the activated stress response genes is Ire1, which undergoes auto-phosphorylation and acquires a regulated Ire1-dependent mRNA decay activity. Ire1P non-canonically splices the mRNA for Xbp1 in the cytoplasm. This spliced Xbp1 serves as mRNA encoding a transcription factor for unfolded protein response genes. Meanwhile the mRNA decay function of Ire1P degrades other cellular mRNAs and can cause changes to the translation machinery by altering regulators in a cell specific manner. Naïve splenic B cells differentiate into Antibody Secreting Cells and activate Ire1 phosphorylation early on after LPS stimulation, within 18 hrs. When Ire1 is activated in B cells, in addition to Xbp1 splicing, there are large-scale changes in mRNA; inhibition of the mRNA degradation function of Ire1 both reduces the number and changes the type of genes involved in altered splicing patterns, including factors for snRNA transcription. Some of the splicing changes seen at 18 hrs after LPS persist into the late stages of antibody secretion, up to 72 hrs, while others are supplanted by new splicing changes introduced by the induction of ELL2, a transcription elongation factor. ELL2 changes mRNA processing patterns and is necessary for Immunoglobulin secretion. RNA splicing patterns in antibody secreting cells are thus shaped by endo-reticular stress, ELL2 induction, and are associated with changes in the levels of snRNAs.

The World Health Organization identifies alcohol as a cause in several neoplasias of the oro-pharynx cavity, esophagus, gastrointestinal tract, larynx, liver, or female breast. This study re-views ethanol's nonoxidative and oxidative metabolism and one-carbon metabolism that en-compasses both redox and transfer reactions that influence crucial cell proliferation machinery. Ethanol favors the uncontrolled production and action of free radicals that interfere with the maintenance of essential cellular functions. We focus on the generation of protein, DNA, and lipid adducts that interfere with the cellular processes related to growth and differentiation. Ethanol's effects on stem cells responsible for building and repairing tissues are reviewed. Cancer stem cells suffer disturbances related to the expression of cell surface markers, enzymes, and transcription factors after ethanol exposure with consequent dysregulation of mechanisms related to cancer metastasis or resistance to treatments. Our analysis aims to underlie and discuss potential targets that show more sensitivity to ethanol's action and identify specific metabolic routes and metabolic realms that may be corrected to recover metabolic homeostasis after pharmacological interven-tion. Specifically, research should pay attention to reestablish metabolic fluxes by fine-tuning the functioning of specific pathways related to one-carbon metabolism and antioxidant processes.

Chronic gastro-abdominal pain with altered bowel habits are associated with pathologies including gastroenteritis, autoimmune and inflammatory bowel disease, and irritable bowel syndrome (IBS). In IBS, diagnostic evidence of infection or inflammation are absent, yet symptoms nonetheless include chronic abdominal pain and alterations of stool frequency and consistency, with most common subtypes including diarrhea-predominant (IBS-D) or constipation predominant (IBS-C). [1, 2] IBS is a common clinical complaint in westernized nations, with females more frequently diagnosed than males [3]. Obesity is also associated with increased likelihood of chronic pain [4], and is associated with intestinal dysbiosis, and systemic inflammatory signatures [5]. Improving personalized medicine therefore requires patient stratification based on a combination of biological factors contributing to the individual’s symptom and biomarker spectrum. The “buffy coat” method isolates leukocytes and PBMCs from whole blood, comprises the immune cell population in peripheral blood. These cells are relatively inactive but are primed to respond to generalized and localized immune activation signals; they are under active investigation as diagnostic biomarkers [6]. Collection of buffy coat is a standard method in clinical laboratories; detection of immune activation via RNA expression biomarkers will be informative of differential biological response, and be tractable to collect in clinical settings. Results of differential expression, pathway analysis, and cell-type abundance analysis from buffy coat RNA, is presented here using variables for BMI, Gender, and IBS-subtype from publicly available Nanostring RNA expression and phenotypic data from the NCBI GEO database.

The landscape of therapeutic measures to treat multiple myeloma has undergone a seismic shift since the dawn of the current century. This has been driven largely by the introduction of new classes of small molecules, such as proteasome blockers (e.g., bortezomib) and immunomodulators (e.g., lenalidomide), as well as by immunotherapeutic agents starting with the anti-CD38 monoclonal antibody daratumumab in 2015. Recently, other immunotherapies have been added to the armamentarium of drugs available to fight this malignancy. These include the bispecifics teclistamab, talquetamab, and elranatamab, and the chimeric antigen receptor (CAR) T-cell products idecabtagene vicleucel (ide-cel) and ciltacabtagene autoleucel (cilta-cel). While the accumulated benefits of these newer agents have resulted in a more than doubling of the disease’s five-year survival rate to nearly 60% and improved quality of life, the disease remains incurable, as patients become refractory to the drugs and experience relapse. This review covers the current scope of anti-myeloma immunotherapeutic agents, both those in clinical use and in development. Included in the discussion are additional monoclonal antibodies (mAbs), antibody-drug conjugates (ADCs), bi- and multi-targeted mAbs, and CAR T-cells and emerging natural killer (NK) cells, including products intended for “off-the-shelf” (allogeneic) applications. Emphasis is placed on the benefits of each along with the challenges that need to be surmounted if MM is to be cured.

Sporotrichosis is a subcutaneous mycosis affecting humans and other animals that can be transmitted a zoonosis with cats as the main vector. The conventional anti-fungal therapy is especially inefficient in immunocompromised patients, who tend to develop the most severe forms of the disease, thus prompting the search for alternative therapies. Given their antigen-presenting properties, dendritic cells (DCs) have been used in both prophylactic and therapeutic vaccination strategies. Hence, this study aims to assess the use of DCs as a prophylactic tool in sporotrichosis by evaluating the immune profile induced by Sporothrix schenckii cell wall proteins (SsCWP)-stimulated bone-marrow-derived DCs (BMDCs). Mouse BMDCs were stimulated with SsCWP for 24 hours and analyzed for the surface expression of co-stimulatory molecules and TLR-4, as well as the secretion of proinflammatory cytokines and IL-10. Following that, activated BMDCs were cocultured with splenocytes for 72 hours and had the same cytokines measured in the supernatant. SsCWP-stimulated BMDCs showed higher expression of CD80, CD86, and CD40, but not TLR-4, and higher secretion of IL-6, IL-17A, and TNF. On the other hand, higher levels of IFN-γ, IL-10, and IL-2 were found in the supernatants of the coculture as compared with the BMDCs alone; TNF secretion was almost completely abrogated, whereas IL-6 was only partially inhibited and IL-17A was unaffected. Our results thus suggest SsCWP-stimulated BMDCs are able to induce a Th1-prone cytokine profile, known to be protective against other fungal diseases. This result could lead to evaluate the development of prophylactic and/or therapeutic DC-based tools against sporotrichosis.

Intratumoral heterogeneity is a major ongoing challenge in the effective therapeutic targeting of cancer. Accumulating evidence suggests that a fraction of cells within a tumor termed Cancer Stem Cells (CSCs) are primarily responsible for this diversity resulting in therapeutic resistance and metastasis. Adding to this complexity, recent studies have shown that there can be different subpopulations of CSCs with varying biochemical and biophysical traits resulting in varied dissemination and drug-resistance potential. Moreover, cancer cells can exhibit a high level of plasticity or the ability to dynamically switch between CSC and non-CSC states or among different subsets of CSCs. The molecular mechanisms underlying such plasticity has been under extensive investigation and the trans-differentiation process of Epithelial to Mesenchymal transition (EMT) has been identified as a major contributing factor. Besides genetic and epigenetic factors, CSC plasticity is also shaped by non-cell-autonomous effects such as the tumor microenvironment. In this review, we discuss the recent developments in understanding CSC plasticity in tumor progression at biochemical and biophysical levels, and the latest in silico approaches being taken for characterizing cancer cell plasticity with implications in improving existing therapeutic approaches.

This study aimed to evaluate the physico-chemical properties, biocompatibility and bioabsorption of 3 different new membranes for bone guided regeneration (PLGA associated with hydroxyapatite and beta-TCP) with three thicknesses (200, 500 and 700 µm) implanted in mice subcutaneously. Scanning electron microscopy (SEM), X-ray diffraction (XRD), Fourier transform infrared spectroscopy (FTIR) and the quantification of Carbon, Hidrogen and Nitrogen were used to characterize the physico-chemical properties. One hundred Balb-C mice were divided into 5 experimental groups: Group 1 - Sham (without implantation); Group 2 - 200 μm; Group 3 - 500 μm; Group 4 - 700 μm; and Group 5 - Pratix®. Each group was subdivided into four experimental periods (7, 30, 60 and 90 days). Samples were collected and processed for histological and histomorphometrical evaluation. The membranes showed no moderate or severe tissue reactions in the experimental periods studied. The 500 μm membrane did not show tissue reaction for any experimental periods studied. The 200 μm membrane membranes began to exhibit fragmentation after 30- day, while the 500 and 700 µm membranes started the fragmentation at 90-day. All membranes studied were biocompatible, and the 500µm membrane showed the best results being a promissory membrane for bone guided regeneration.

White shrimps are susceptible to outbreaks of vibriosis because they do not have any adaptive immune system, they only have a non-specific innate immune system. The administration of EPS from microalgae Porphyridium cruentum (synonym: P. purpureum) on shrimps Litopenaeus vannamei was investigated to determine the effect of this immunostimulant on their non specific immune response and to test if EPS can be used as a protective agent for shrimp related to Vibrio infection. EPS was given to shrimps by immersion method on day 1 and booster on day 8. Shrimp hemocytes were taken on day 1 (EPS administration), day 7 (no treatment), day 8 (EPS booster) and day 9 (Vibrio infection) and tested for their immune response on each treatment. Result shows an increase in values ​​of all immune parameters in line with the increasing EPS concentration, except the Differential Haemocyte Count (DHC). In detail, an increase was noted in total hemocytes (THC) value, Phagocytotic Activity (PA), Respiratory Burst (RB) in line as the EPS concentration increase. Although there is a decrease after the infection, the value obtained is not lower than the control value. These results indicate that EPS from Porphyrydium enhances immune parameters in shrimp rapidly and has the ability as an immunostimulant or an immunomodulator. It is a good modulator for the non specific immune cells of Pacific white shrimps, and it can be used as a preventive agent against Vibrio.

Background: Oral squamous cell carcinoma (OSCC), with poor prognosis and high mortality rates, is one of the most diagnosed head and neck cancers. Cancer stem cells (CSCs) - epithelial-to-mesenchymal transition (EMT) loop is increasingly implicated in the therapy-resistance, relapse, and metastasis of OSCC patients. Accumulating evidence indicate that aberrantly expressed CD47 is associated with cell-death evasion, invasion and cancer metastasis; however, the role of CD47 in the modulation of CSCs-like phenotypes, including therapy-resistance and metastasis, with its underlying mechanism in OSCC remains largely underexplored. Methods: This study investigated the CSCs- modulating potential of CD47 in OSCC cell lines SAS, TW2.6, HSC-3 and FaDu using bioinformatics approach, immunoblotting, immunofluorescence staining, migration, invasion, colony and orosphere formation, as well as radiosensitivity assays. Results: We demonstrated that the characteristic ectopic expression of CD47 in OSCC patients was associated with ~ 20% 2-year survival disadvantage (p = 0.01) and positively correlated with the expression of pluripotency factors; while shRNA silencing of CD47 significantly suppressed cell viability and markedly inhibited orosphere formation, resulting in smaller and fewer orospheres, and downregulated CD133, SOX2, OCT4 and c-Myc mRNA and protein expression levels. We also showed that CD47 downregulation attenuates EMT, migration and clonogenicity of OSCC cells, with associated E-cadherin upregulation and suppression of Vimentin, Slug, Snail, and N-cadherin expression. Conclusion: Of therapeutic relevance, combined with radiotherapy, CD47 knockdown enhanced the anti-OSCC effect of radiotherapy. Thus, we demonstrate the therapeutic feasibility of a CD47-mediated anti-CSCs strategy, and suggest a role for CD47 suppression in potentiating the therapeutic efficacy of radiation therapy in OSCC patients.

Over the last decades, cellular immunotherapy has revealed its curative potential. However, the inherent physiological characteristics of immune cells can limit the potency of this approach. Best defined in T cells, dysfunction associated with terminal differentiation, exhaustion, senescence, and activation-induced cell death undermine adoptive cell therapies. In this review, we concentrate on how the multiple mechanisms that articulate the various forms of immune dysfunction impact cellular therapies primarily involving conventional T cells, but also other lymphoid subtypes, in addition to the various strategies put in place to circumvent these effects. The repercussions of immune cell dysfunction across the full life cycle of cell therapy, from the source material, during manufacturing, and after adoptive transfer are discussed. Applicable to cellular products prepared from native and unmodified immune cells, as well as genetically engineered therapeutics, the understanding and potential modulation of dysfunctional features is key to the development of improved cellular immunotherapies.

The natural products and conventional chemotherapeutic drugs are believed to increase the cure rates of anti-cancer treatment while reducing their toxicity. The current study investigates the cytotoxic and apoptogenic effects of bioactive compounds from Monotheca buxifolia on Hep G2 cell lines. The effect on the viability of Hep G2 cells was evaluated by MTT assay; Morphological changes were studied, the apoptotic activity was demonstrated through Annexin-V-FITC/ PI, a molecular dynamics simulation study was conducted to explore the binding pattern of the compounds in the active site of the PPRAδ protein. The isolated compounds lauric acid, oleanolic acid, and bis(2-ethylhexyl) phthalate inhibited the growth of hepatocellular cancer cells, as determined by MTT assay and annexin V-FITC/PI. The IC50 value for lauric acid was 56.4584 ± 1.20 µg/ml, that for oleanolic acid was 31.9421 ± 1.03 µg/ml, and that for bis(2-ethylhexyl) phthalate was 83.8019 ± 2.18 µg/ml. After 24 h of treatment, 29.5% of Hep G2 cells treated with lauric acid, 52.1% of those treated with oleanolic acid, and 22.4% of those treated with bis(2-ethylhexyl) phthalate were apoptotic. Morphological assay and Hoechst staining microscopy revealed the morphological alterations of cell membrane accompanied by nuclear condensation after treatment. The high fluctuation indicates the high potency and adopting various interactions, and vice versa, the oleanolic acid showed highly residues fluctuation, which remains stable in the active site of PPARδ protein and involved in various interactions while remaining locally fluctuated in the binding site the other two compounds. In conclusion, a significant apoptogenic effect was exhibited by lauric acid, oleanolic acid, and bis(2-ethylhexyl) phthalate against HepG2 cells in inducing apoptosis. Our findings indicate that these bioactive compounds hold promise as potential therapeutic for hepatocellular carcinoma.

Patients with glioblastoma (GB), a highly aggressive brain tumor, have a median survival of 14.6 months following neurosurgical resection with adjuvant chemoradiotherapy. Quiescent GB cancer stem cells (CSCs) invariably cause local recurrence. These GB CSCs that can be identified by embryonic stem cell markers express components of the renin-angiotensin system and are associated with circulating CSCs. Despite the presence of circulating CSCs, GB rarely develops distant metastasis outside the central nervous system. This paper reviews the current literature on GB growth inhibition in relation to CSCs, circulating CSCs, the RAS and the novel therapeutic approach by repurposing drugs that target the renin-angiotensin system to improve overall symptom-free survival and maintain quality of life.

Dendritic cells (DCs) are the professional antigen-presenting cells that recognize and present antigens to naïve T cells to induce antigen-specific adaptive immunity. Among the T-cell subsets, T helper type 2 (Th2) cells produce the humoral immune responses required for protection against helminthic disease by activating B cells. DCs induce a Th2 immune response at a certain immune environment. Basophil, eosinophil, mast cells, and type 2 innate lymphoid cells also induce Th2 immunity. However, in the case of DCs, controversy remains regarding which subsets of DCs induce Th2 immunity, which genes in DCs are directly or indirectly involved in inducing Th2 immunity, and the detailed mechanisms underlying induction, regulation, or maintenance of the DC-mediated Th2 immunity against allergic environments and parasite infection. A recent study has shown that a genetic defect in DCs causes an enhanced Th2 immunity leading to a severe atopic dermatitis. We summarize the Th2 immune-inducing DC subsets, the genetic and environmental factors which involved in DC-mediated Th2 immunity, and current therapeutic approaches for Th2-mediated immune disorders. This review is to provide an improved understanding of DC-mediated Th2 immunity and Th1/Th2 immune balancing, leading to control over their adverse consequences.

Clinical pathogens especially Gram-negative bacteria developing resistance to third-generation cephalosporins are making the clinical outcome more complicated and serious. This study was undertaken to evaluate the distribution of extended-spectrum beta-lactamases in Tamil Nadu regions in India. For this study, clinical samples were collected from five different hospitals located in Tamil Nadu and ESBL producing Gram-negative isolates were characterized. Minimal inhibitory concentration (MIC) was performed using cefotaxime and ceftazidime. The blaESBL producing genes were screened using multiplex PCR for the genes, CTX-M group-1,-2,-8,-9,-26. Conjugation studies were performed using E. coli AB1157 as a recipient for the isolates harbouring plasmid-borne resistance following broth-mating experiment. In total, 1500 samples were collected and 599 Gram-negative bacteria were isolated that included Escherichia coli (n=233), Klebsiella pneumoniae (n=182), Pseudomonas aeruginosa (n=79), Citrobacter spp. (n=30), Proteus mirabilis (n=28), Salmonella spp. (n=21), Acinetobacter baumannii (n=12), Serratia spp. (n=6), Shigella spp. (n=4), Morganella morganii (n=3) and Providencia spp. (n=1). MIC results showed that 358 isolates were resistant to cefotaxime and ceftazidime. Further, ESBL gene amplification results showed that 19 isolates had CTX-M group-1 gene including E. coli (n=16), K. pneumoniae (n=2) and P. aeruginosa (n=1) whereas one M. morganii isolate had CTX-M group-9 gene in their plasmid. Through conjugation studies, 12/20 isolates were found to be involved in the transformation of its plasmid-borne resistance gene. Our study highlighted the role of horizontal gene transfer in the dissemination of plasmid-borne blaCTX-M resistance genes among ESBL producing isolates.

Medullary thyroid carcinomas (MTCs) are rare thyroid tumors occurring in both sporadic and hereditary forms and whose pathogenesis is related to RET proto-oncogene alterations. MTCs originate from parafollicular cells, which produce calcitonin that represents the biochemical activity of MTC. Total thyroidectomy is the main treatment for MTC and often cures patients with confined diseases. In cases of metastasis, the approach depends on the rate of progression of disease. We report a case of a 54 years old female with a single, incidentally discovered, thyroid nodule of 1 cm, classified as suspicious MTC after a stimulation test with i.v. calcium. After surgery, we examined the nodule using immunohistochemistry, immunofluorescence and electron microscopy. In addition to calcitonin, we found that it expressed intracellular positivity for the RTK receptors ERBB1 and ERBB2. Consistently with MTC features, ultrastructural examination of the tumor displayed heterogeneous spindle-shaped cells containing two groups of secretory granules. Due to the significant correlation found between high ERBB1/ERBB2 levels in MTCs and extrathyroidal growth, the detection of ERBB1 and ERBB2 expression suggests that the two oncoproteins may possibly be involved in tumor proliferative responses and/or differentiation of C-cells. The biological, prognostic and therapeutic significance of these patterns would merits further investigations.

In this brief communication, we propose the concept that capillary regression may represent a primary pathogenic process underlying COVID-19 infection, particularly in the serious and life-threatening manifestations of the disease. We suggest that the marked elevations of pro-inflammatory mediators that are observed in these seriously ill patients may directly induce capillary regression and endothelial cell (EC) loss. Recent autopsy studies are demonstrating EC loss leading to widespread microthrombi and associated tissue damage. Recent work has indicated that interleukin-1 beta (IL-1β), tumor necrosis factor-alpha (TNFα), and thrombin, individually and in combination, can potently cause capillary tube regression in experimental models in vitro and in vivo. Other pro-inflammatory mediators including interferon gamma (IFNγ), interleukin-4 (IL-4), and interleukin-13 (IL-13) were also shown to be pro-regressive and could be relevant mediators in COVID-19 patients. Interestingly, combinations of pharmacologic agents were identified that reduced capillary regression and protected capillary tube networks against these pro-inflammatory mediators. Such an approach might be an important therapeutic option going forward to treat key disease states where capillary regression plays a major underlying pathogenic role. Finally, if capillary regression is occurring in response to these pro-inflammatory mediators during COVID-19 infection, we suggest that combinations of blocking agents directed to these key pro-regressive mediators might be necessary to appropriately treat patients.