Non-melanomatous skin cancers (NMSCs), which include basal and squamous cell carcinoma (BCC and SCC respectively), represent a significant burden on the population as well as an economic load to the health care system, yet treatments of these preventable cancers remain ineffective. Although primary prevention is possible through minimising sunlight exposure, the World Health Organisation estimates that between 2 and 3 million new cases of NMSCs are diagnosed each year, accounting for 1 in 3 of all newly diagnosed cancers. Furthermore, studies have estimated there has been a 2-fold increase in the incidence of NMSCs between 1960s and 1980s. The increase in cases of NMSCs as well as the lack of effective treatments makes the need for novel therapeutic approaches all the more necessary. To rationally develop more targeted treatments for NMSCs, a better understanding of the cell of origin, in addition to the underlying pathophysiological mechanisms that govern the development of these cancers, is urgent. NMSCs are generally thought to arise from specific types of stem cells that become the source of clonal expansion of tumourigenic cells. Previous research on SCC has alluded to these stem cells being localised in the basal compartment of the skin, which ordinarily houses the progenitor cells that contribute towards wound healing and normal cell turnover of overlying epidermal skin layers. More recent research has suggested that commitment to differentiation, which requires exiting the basal, progenitor-cell compartment, is a reversible mechanism. Genetic modifications engage differentiated cells into dedifferentiation, converting them into cancer-initiating cells (CICs) and thereby promoting a tumourigenic environment. Here we explore the most recent developments in the understanding of skin SCC cell of origin, and discuss a case study illustrating the loss of the Grainy-head like 3 (GRHL3) transcription factor in suprabasal layers, which confers a tendency towards tumour development and thereby challenging the “stem cell” theory of tumourigenesis.

This paper presents data supporting the IC Regimen for potentiating the effectiveness of lorlatinib in treating ALK positive cancers, and specifically non-small cell lung cancer. Lorlatinib is an effective treatment for ALK driven non-small cell lung cancer and other ALK driven cancers. Lorlatinib inhibits ALK kinase and achieves good brain tissue levels, a common site for metastases in lung cancers. However, resistance to lorlatinib usually supervenes and the cancer awakens and starts growing again, resistant to lorlatinib. This paper analyses data indicating that adding two common generic drugs, itraconazole and cilostazol, to lorlatinib treatment may delay resistance development. Itraconazole is marketed worldwide as a generic antifungal drug that also inhibits Hedgehog signaling, CYP3A4, and the p-gp efflux pump. Cilostazol is a generic anti-thrombosis, phosphodiesterase 3 inhibiting drug that carries minimal bleeding risk. Cilostazol may enhance lorlatinib by deprivation of trophic growth factors supplied by platelets. Itraconazole may enhance lorlatinib effectiveness by reducing or stopping a Hedgehog centered amplifying feedback loop with ALK kinase. The combination of metastatic non-small cell lung cancer being a low-survival disease and the general safety itraconazole plus cilostazol augmentation, make a clinical trial of this trio worthwhile.

The fuel cell particularly the Proton Exchange Membrane Fuel Cell (PEMFC) is a new energy technology that plays a critical role in achieving market viability. The PEMFC has high power density, zero CO₂ emissions, and high conversion efficiency. However, with uniform distribution of fuel in PEMFC, we can improve the performance and reduce the cost. The PEMFC will be more efficient and effective in terms of renewable energy as a byproduct only water. Metal foam is used as an alternative for the channels in PEMFC. The model of PEMFC was established by using the ANSYS Fluent 3D Model. Then we proposed four configurations of PEMFC. The outcome demonstrates that Case IV provided outstanding performance if it is compared with the other three cases. In terms of power density, Case IV provided a high power density that is double that of Case I. The porosity of metal foam was investigated. The 0.6 porosity value is found as the optimal value. The uniform distribution of the fuel can be achieved at this value which leads to the outstanding current density.

Separase is a key cysteine protease to separate sister chromatids through digestion of cohesion ring that inhibits chromosome segregation as trigger of metaphase–anaphase transition in eukaryotes and highly regulated its activity by binding with securin and cyclinB-CDK1 complex. Those bindings prevent proteolytic activity of separase until the onset of anaphase. Chromosome missegregation and aneuploidy are frequently observed in malignancies. However, there are some difficulties for biochemical examinations due to instability of separase in vitro and a few spatiotemporal resolution approaches monitoring live separase activity throughout mitotic processes. Here we have developed FRET-based molecular sensors including GFP variants with separase cleavable sequences as donor and covalently attached fluorescent dye as acceptor molecules applicable to conventional live cell imaging and flow cytometric analysis because of efficient live cell uptake. We investigated performance of equivalent molecular sensors localized or not localized inside nucleus under cell cycle control using flow cytometry. Synchronized cell cycle progression rendered significant separase activity detections in both molecular sensors. We obtained consistent outcomes with localized molecular sensor introduction and cell cycle control by fluorescent microscopic observations. We thus established live cell separase activity monitoring systems specifically or statistically that could lead to elucidate separase properties in detail.

The Hippo pathway plays crucial roles in governing various biological processes during tumorigenesis and metastasis. Within this pathway, upstream signaling stimuli activate a core kinase cascade, involving MST1/2 and LATS1/2, which subsequently phosphorylates and inhibits the transcriptional co-activators YAP and its paralog TAZ. This inhibition modulates the transcriptional regulation of downstream target genes, impacting cell proliferation, migration, and death. Despite the acknowledged significance of protein kinases in the Hippo pathway, the regulatory influence of protein phosphatases remains largely unexplored. In this study, we conducted the first gain-of-functional screen for protein tyrosine phosphatases (PTPs) regulating the Hippo pathway. Utilizing a LATS kinase biosensor (LATS-BS), a YAP/TAZ activity reporter (STBS-Luc), and a comprehensive PTP library, we identified numerous novel PTPs that play regulatory roles in the Hippo pathway. Subsequent experiments validated PTPN12, a master regulator of oncogenic receptor tyrosine kinases (RTKs), as a previously unrecognized negative regulator of the Hippo pathway effectors, oncogenic YAP/TAZ, influencing breast cancer cell proliferation and migration. In summary, our findings offer valuable insights into the roles of PTPs in the Hippo signaling pathway, significantly contributing to our understanding of breast cancer bi-ology and potential therapeutic strategies.

Sarcomas are a group of malignancies of mesenchymal origin with plethora of subtypes. Given the sheer heterogeneity of various subtypes and rarity of the disease, management of sarcomas has been challenging with poor patient outcomes. Surgery, radiation therapy and chemotherapy have remained the backbone of treatment in patients with sarcoma. The introduction of immunotherapy has rev-olutionized the treatment of various solid and hematological malignancies. In this review, we discuss basics of immunotherapy and immune microenvironment in sarcomas, various modalities of im-munotherapy such as immune checkpoint blockade, oncolytic viruses, cancer targeted antibodies, vaccine therapy and adoptive cell therapies like CAR T-cell therapy, T cell therapy, TCR therapy.

The human immunodeficiency virus 1 (HIV-1) viral protease (PR) is one of the most studied viral enzymes, and approval of drugs targeting its catalytic activity opened the door to the develop-ment of highly active antiretroviral therapy (HAART). Despite the fact that its crucial role in viri-on maturation is well characterized, an increasing body of research is starting to focus on its abil-ity to cleave host cell proteins, based on recent advances in proteomics and genomics technologies. Such findings are apparently in contrast with the dogma of HIV-1 PR activity being restricted to the interior of nascent virions, and suggest catalytic activity within the host cell environment. Given the limited amount of PR present in the virion at the time of infection, it is tempting to specu-late that such events mainly occur during viral late gene expression, mediated by newly synthe-sized Gag-Pol polyprotein precursors, rather than at a very early stage of infection, before pro-viral integration. Among cellular targets of HIV-1 PR, three major clusters can be identified: pro-teins involved in viral and cellular translation, those controlling cell survival, and restriction fac-tors responsible for innate/intrinsic antiviral responses. Indeed, by cleaving host cell translation initiation factors HIV-1 PR can impair cap-dependent translation, thus promoting IRES-mediated translation of late viral transcripts and viral production, while by targeting several apoptotic fac-tors it modulates cell survival, thus promoting immune evasion and viral dissemination. Addi-tionally, HIV-1 PR counteracts restriction factors incorporated in the virion that would otherwise interfere with nascent virus vitality. Thus, HIV-1 PR appears to modulate host cell function at dif-ferent times and locations during its life cycle, to ensure efficient viral persistency and propaga-tion. This kind of PR-mediated host cell modulation is found in a plethora of different viruses and HIV-1 is no exception, and although we are far from having a complete picture, it is clear that the PR has a multifaceted role in interfering with host machineries to better suit viral replication, and is a field that needs to be explored further.

Background: The phase III KEYNOTE-604 study confirmed the benefit of pembrolizumab combined with chemotherapy in the first-line treatment of extensive-stage small-cell lung cancer(ES-SCLC). Intergrated the clinical benefits of pembrolizumab and its high cost into account, this study aim to assess the cost-effectiveness of adding pembrolizumab to standard first-line etoposide-platinum (EP) for patients with ES-SCLC from the the US payer perspective. Methods: A Markov model was developed to compared the costs and quality-adjusted life-years (QALYs) of pembrolizumab plus EP and placebo plus EP over a 10-year time horizon. Clinical efficacy, treatment utilization and safety data were pooled from the KEYNOTE-604 trial. Utilities were obtained from published resources. Costs were mainly collected from Medicare in 2020. Sensitivity analyses were performed to examined the robustness of our model. Results: Adding pembrolizumab to standard first-line EP, resulted in better effectiveness than the use of EP alone for ES-SCLC by 0.22 QALYs. Pembrolizumab plus EP was dominated economically by placebo plus EP, leading to an incremental cost-effectiveness ratio(ICER) of $334,373/ QALY. Deterministic sensitivity analyses indicated that the uncertainty in model parameters exerts no substantial effect on our results. Probability sensitivity analysis indicated that probabilities for pembrolizumab plus EP being cost-effective within a wide rang of willingness to pay were modest. Conclusion: From the US payer perspective, the first-line treatment for ES-SCLC with pembrolizumab plus EP was not cost-effective compare with placebo plus EP. Although pembrolizumab combination chemotherapy was beneficial to the survival of ES-SCLC, price reduction may be the necessary measure to improve its cost-effectiveness.

Cancer stem cells (CSCs) have been identified in many cancer types. This study identified and characterized CSCs in head and neck metastatic malignant melanoma (HNmMM) to regional lymph nodes using induced pluripotent stem cell (iPSC) markers. Immunohistochemical (IHC) staining performed on 20 HNmMM tissue samples demonstrated expression of iPSC markers OCT4, SOX2, KLF4 and c-MYC in all samples while NANOG was expressed at low levels in two samples. Immunofluorescence (IF) staining demonstrated an OCT4+/SOX2+/KLF4+/c-MYC+ CSC subpopulation within the tumor nests (TNs) and another within the peritumoral stroma (PTS) of HNmMM tissues. IF also showed expression of NANOG by some OCT4+/SOX2+/KLF4+/c-MYC+ cells within the TNs in an HNmMM tissue sample that expressed NANOG on IHC staining. In situ hybridization (n=6) and reverse-transcription quantitative polymerase chain reaction (n=5) on the HNmMM samples confirmed expression of all five iPSC markers. Western blotting of four primary cell lines derived from four of the 20 HNmMM tissue samples showed expression of SOX2, KLF4, and c-MYC but not OCT4 and NANOG, and three of these cell lines formed tumorspheres in vitro. We demonstrate the presence of two putative CSC subpopulations within HNmMM, which may be a novel therapeutic target in the treatment of this aggressive cancer.

Cancer cell lines are widely used as in vitro models of tumorigenesis, facilitating fundamental discoveries in cancer biology and translational medicine. Currently, there are few options for glioblastoma (GBM) treatment and limited in vitro models with accurate genomic and transcriptomic characterization. Here, a detailed characterization of a new GBM cell line, namely AHOL1, was conducted in order to fully characterize its molecular composition based on its copy number alteration (CNA) and transcriptome profiling, followed by the validation of key elements associated with GBM tumorigenesis. Large numbers of CNAs and differentially expressed genes (DEGs) were identified. CNAs were distributed throughout the genome, including gains at Xq11.1-q28, Xp22.33-p11.1, Xq21.1-q21.33, 4p15.1-p14, 8q23.2-q23.3 and losses at Yq11.21-q12, Yp11.31-p11.2 and 12p13.31 positions. Nine druggable genes were identified, including HCRTR2, ETV1, PTPRD, PRKX, STS, RPS6KA6, ZFY, USP9Y and KDM5D. By integrating DEGs and CNAs, we identified 57 overlapping genes enriched in fourteen pathways. Altered expression of several cancer-related candidates found in the DEGs-CNA dataset was confirmed by RT-qPCR. Taken together, this first comprehensive genomic and transcriptomic landscape of AHOL1 provides unique resources for further studies and identifies several druggable targets that may be useful for therapeutics and biologic and molecular investigation of GBM.

The field of solar technology has experienced remarkable advancements, transforming from early photovoltaic discoveries to a diverse array of high-efficiency, cost-effective solutions. This review explores the evolution of solar technology, detailing its development from the initial discovery of the photovoltaic effect to contemporary innovations. The current generation of solar technologies, including silicon photovoltaic cells, thin-film solar cells, perovskite solar cells, bifacial panels, concentrated solar power, and building-integrated photovoltaics, is examined for their efficiencies, applications, and contributions to the renewable energy landscape. Future prospects highlight promising trends such as next-generation photovoltaics, advanced energy storage solutions, agrivoltaics, floating solar farms, and artificial photosynthesis. Despite the progress, challenges related to efficiency, stability, scalability, cost, grid integration, environmental impact, policy support, and public acceptance remain. Addressing these challenges through continued research, supportive policies, and collaborative efforts is crucial for realizing the full potential of solar technology. This review underscores the importance of solar energy in achieving a sustainable future and emphasizes the need for ongoing innovation and commitment to overcome existing barriers.

Depression is the most common chronic mental illness and is characterized by low mood, insomnia, and affective disorders. However, the pathological mechanisms of depression remain unclear. Numerous studies have suggested that the ghrelin/GHSR system may be involved in the pathophysiologic process of depression. Ghrelin plays a dual role in the experimental animals, increasing depressed behavior and decreasing anxiety. By combining several neuropeptides and traditional neurotransmitter systems to construct neural networks, it modifies signals connected to depression. The present review emphasizes the role of ghrelin in neuritogenesis, astrocyte protection, inflammatory factor production, and endocrine disruption in depression. Furthermore, ghrelin/GHSR can activate multiple signaling pathways to produce antidepressant effects, including cAMP/CREB/BDNF, PI3K/Akt, Jak2/STAT3, and p38-MAPK. Given the antidepressant effects of ghrelin/GHSR1a system, it is expected to become a potential therapeutic target for the treatment of depression.

Cancer is a disease that encompasses multiple and different malignant conditions and is among the leading causes of death in the world. Therefore, the search for new pharmacotherapeutic options and potential candidates that can be used as treatments or adjuvants to control this disease is urgent. Natural products, especially those obtained from plants, have played an important role as a source of specialized metabolites with recognized pharmacological properties against cancer, therefore, they are an excellent alternative to be used. The objective of this research was to evaluate the action of the monoterpene isoespintanol (ISO) against the human tumor cell lines MDA-MB-231, A549, DU145, A2780, A2780-cis and the non-tumor line MRC-5. Experiments with MTT and fluorescence with propidium iodide (PI), DAPI and green plasma revealed the cytotoxicity of ISO against these cells; furthermore, morphological and chromogenic studies revealed the action of ISO on cell morphology and the inhibitory capacity on reproductive viability to form colonies in MDA-MB-231 cells. Likewise, 3D experiments validated the damage in these cells caused by this monoterpene. These results serve as a basis for progress in studies of the mechanisms of action of these compounds and the development of derivatives or synthetic analogues with a better antitumor profile.

Some global difficulties in the modern period include energy storage conversion. Researchers have looked to renewable energy resources to discover long-term answers to this dilemma. Fuel cells are one example of prospective energy producing technology. Although these technologies appear to be very enticing, they are known to be expensive due to high expenses. Catalyst costs, as well as concerns concerning energy density. Pt based Electrocatalysts have traditionally been used to drive ORR and offer efficient power outputs. However, cost constraints have limited the use of these electrocatalysts, rendering them inefficient. Apart from the high price, Pt-based Electrodes are prone to time-dependent drift and CO deactivation, both of which occur gradually. Electrocatalysts deteriorate over time, reducing the efficiency of fuel cells. This is why alternative electrocatalysts are in high demand for future energy applications. This review covers the comparative study of Platinium and Non-Platinium based electrocatalyst in fuel cells, their shortcomings and recent advancement for efficient and optimized electrocatalyst.

The quality of cellular products used in biological research can directly impact the ability to ob-tain accurate results. Epstein-Barr virus (EBV) is a latent virus that spreads extensively world-wide, and cell lines used in experiments may carry EBV and pose an infection risk. The presence of EBV in a single cell line can contaminate other cell lines used in the same laboratory, affecting experimental results. We developed three EBV detection systems: (1) a polymerase chain reac-tion (PCR)-based detection system, (2) a recombinase polymerase amplification (RPA)-based de-tection system, and (3) a combined RPA-lateral flow assay (LFA) detection system. The mini-mum EBV detection limits were 1×103 copy numbers for the RPA-based and RPA-LFA systems and 1×104 copy numbers for the PCR-based system. Both the PCR and RPA detection systems were applied to 192 cell lines, and the results were consistent with those obtained by the EBV assay methods specified in the pharma-ceutical industry standards of the People's Republic of China. 10 EBV-positive cell lines were identified. The combined RPA-LFA system is simple to operate, allowing for rapid results visualization. This system can be implemented in laborato-ries and cell banks as part of a daily quality control strategy to ensure cell quality and experi-mental safety and may represent a potential new technique for the rapid detection of EBV in clinical samples.

This study was conducted to recover valuable metals (silicon and silver) using acid leaching and substitution reactions with copper powder from the pulverized solar cell separated from the PV ribbon. Leaching experiments were conducted according to nitric acid concentration by molar solution as 1M, 2M, and 3M using an ultrasonic cleaner at a reaction temperature of 60 °C for the leaching times of 30 to 120 minutes. Si phases were detected at all leaching reaction times, it was confirmed that the aluminium was removed effectively if the nitric acid leaching time was more than 30 minutes, and silicon with a purity above 99% could be recovered. The silver was precipitated by adding copper, which has greater reducibility than Cu, Al, Si, Pb, and Sn. When the addition of copper powder was 0.75 and 1.0 g, precipitate was produced 0.23 and 0.55 g, respectively. The optimal condition for the recovery of silver by the addition of copper powder was 1 g, where is recovery rate reached 93.3%.

Cancer is the second leading cause of death worldwide. Key to cancer initiation and progression is the crosstalk between cancer cells and their microenvironment. The extracellular matrix (ECM) is a major component of the tumour microenvironment and integrins, main cell-ECM adhesion receptors, are involved in every step of cancer progression. However, accumulating evidence has shown that integrins can act as tumour promoter but also as tumour suppressor factors, revealing that the biological roles of integrins in cancer are complex. This incites a better understating of integrin function in cancer progression. To achieve this goal, simple model organisms, such as Drosophila, offer a great potential to unravel underlying conceptual principles. Here, we find that in the Drosophila wing disc epithelium the PS integrins act as suppressors of tumours induced by a gain of function of the oncogenic form of Ras, RasV12. We show that PS integrin depletion enhances the growth, delamination and invasive behaviour of RasV12 tumour cells, as well as their ability to affect the tumour microenvironment. These results strongly suggest that integrin function as tumour suppressors might be evolutionary conserved. Drosophila can be used to understand the complex tumour modulating activities conferred by integrins, thus facilitating drug development.

Background: Diffuse large B-cell lymphoma is the most common type of non-Hodgkin's lymphoma. Due to the variety of clinical manifestations, accurate diagnosis can be challenging. Here, we present a case of DLBCL that was initially misdiagnosed as a hematoma, highlighting the importance of considering malignancy in the setting of non-responsive soft tissue swelling. Methods: A 76-year-old man presented to the emergency department with right periorbital swelling and ecchymosis. The symptoms first appeared after an injury and did not resolve spontaneously. The patient was taking warfarin for atrial fibrillation. A facial bone CT revealed a large irregular homogeneous mass. An extraconal hematoma was suspected based on clinical history and radiologic findings. Incision and drainage were performed, resulting in evacuation of old blood. Despite continued drainage, the patient's symptoms worsened. A comparison with the previous CT revealed an increase in the size of the lesion. As a result, a surgical excisional biopsy was performed. Results: Biopsy of the mass showed a diffuse infiltrate of lymphocytes around the tissue. The diagnosis of diffuse large B-cell lymphoma was confirmed pathologically. The patient was referred to hematology for further management. Conclusions: DLBCL is a rare disease associated with a poor prognosis. Due to the previous injury and the use of anticoagulants, the patient was initially misdiagnosed as having a hematoma. This delayed the prompt diagnosis and affected the timing of treatment initiation. We must be aware that a malignant mass is a potential cause of unresponsive soft tissue swelling.

Zero-emission trucks for regional and long haul missions are an option for fossil-free freight. The viability of such powertrains and system solutions was studied conceptually in project ESCALATE for trucks with GVW of 40 tonnes and beyond through various prime mover combinations. The study covers battery and fuel cell power sources with different degrees of battery electric as well as H2 and fuel cell operation. As a design basis, two different missions with a single-charge/H2 refill were analysed. The first mission was the VECTO long haul profile repeated up to 750 km, whereas the second was a real 520 km on-road mission in Finland. Based on the simulated energy consumption on the driving cycle, on-board energy demand was estimated, and the initial single-charge operational scenarios were analysed with five different power source topologies. The traction motors of the tractor were dimensioned so that a secondary mission of GVW up to 76 tons on a shorter route can be operated. Based on the powertrain and vehicle model, various infrastructure options for charging and H2 refuelling strategy as well as various operative scenarios with indicative total cost of ownership (TCO) were analysed.

Background – Endobronchial squamous cell carcinoma is one of the most common types of tumors with such a location. Patients often present in advanced stages of the disease, which leads to a targeted therapeutic attitude of pneumonectomy, most of the time. Practicing a lung parenchyma-preserving surgery led us to do this review. Material and Methods - We used three search platforms SCIENCE, MEDLINE and PubMed, in order to identify studies presenting case reports, studies and reviews on endobronchial squamous cell carcinoma. We identified clinical and paraclinical features of endobronchial squamous cell carcinoma. All selected articles were in English and contained clinical criteria of endobronchial squamous cell carcinoma, autofluorescence bronchoscopy in endobronchial squamous cell carcinoma, imaging features of endobronchial squamous cell carcinoma, blood tumor markers specific for lung squamous cell carcinoma, histopathological features of endobronchial squamous cell carcinoma. Results - 73 articles were analyzed, from which 47 articles were selected as bibliographic references. We have presented the criteria found for endobronchial squamous cell carcinoma in order to highlight the main characteristics and high reliability technologies for the detection of this type of cancer. Conclusions – The current literature review highlights the clinical and paraclinical characteristics of endobronchial squamous cell carcinoma. It aims to open new horizons for research and early detection, frequent practice of lung parenchymal preservation surgery.

Osteitis fibrosa cystica (OFC) and Brown Tumour are two related but distinct types of bone lesions that result from overactivity of osteoclasts most often associated with chronic kidney disease (CKD). Despite their potential consequences, these conditions are poorly understood because of their rare prevalence and variability in their clinical manifestation. Canonically, OFC and Brown Tumours are caused by secondary hyperparathyroidism in CKD. Recent literature showed that multiple factors such as hyperactivation of the renin-angiotensin-aldosterone system and chronic inflammation may also contribute to the occurrence of these diseases through osteoclast activation. Moreover, hotspot KRAS mutations were identified in these lesions placing them in the spectrum of RAS-MAPK-driven neoplasms, while until recently thought to be reactive lesions. Some risk factors contributed to the occurrence of OFC and Brown Tumour such as age, gender, comorbidities, and certain medications. The diagnosis of OFC and Brown Tumour includes clinical symptoms involving chronic bone pain and laboratory finding of hyperparathyroidism. In radiological imaging, the X-ray and Computed tomography (CT) scan could show lytic or multi-lobular cystic alterations. Histologically both lesions are characterized by clustered osteoclast in a fibrotic hemorrhagic background. Based on the latest understanding of the mechanism of OFC, this review elaborates on the manifestation, diagnosis, and available therapies that can be leveraged to prevent the occurrence of OFC and Brown Tumour.

IQGAP1 is a multi-functional scaffold protein. However, its role in B cell development and function is not known. Here, we demonstrate Iqgap1mice contained significantly increased numbers of B220+ B, B220+IgM pro/pre-B, and B220+IgM+ immature-B cells in the bone marrow. Here, we show IQGAP1 as the essential scaffold that regulates early B cell development and function. Iqgap1mice contained significantly increased numbers of B220+ B, B220+IgM pro/pre-B, and B220+IgM+ immature-B cells in the bone marrow. New-forming and follicular B cell numbers were increased, while the marginal zone B cell numbers were significantly reduced in the spleen of the Iqgap1mice. Lack of IQGAP1 reduced T-dependent and T-independent humoral responses. Mechanistically, the lack of IQGAP1 considerably decreased the phosphorylation of Mek1/2, Erk1/2, and Jnk1/2. B cells from Iqgap1mice failed to suppress IL-7R-mediated activation of Stat5a/b, an essential step for cell-cycle exit and initiate light-chain recombination, leading to a reduction in RS rearrangement frequency. Lack of IQGAP1 resulted in a significant reduction of IRF4 and IRF8 in BM B cells. Our study provides the first evidence that IQGAP1-based signalosome is essential for the development and functions of B cells.

The Zika virus (ZIKV) epidemic brought new discoveries regarding arboviruses, especially flaviviruses, as ZIKV was described as sexually and vertically transmitted. The latter shows severe consequences for the embryo/fetus, such as congenital microcephaly and deficiency of the neural system, currently known as Congenital ZIKV Syndrome (CZS). To better understand ZIKV dynamics in trophoblastic cells present in the first trimester of pregnancy (BeWo, HTR-8, and control cell HuH-7), an experiment of viral kinetics was performed for African MR766 low passage and Asian-Brazilian IEC ZIKV lineages. The results were described independently, and demonstrated that the three placental cells lines are permissive and susceptible to ZIKV. We noticed cytopathic effects that are typical in vitro viral infection in BeWo and HTR-8. Regarding kinetics, MR766lp showed peaks of viral loads in 24 and 48 hpi for all cell types tested, as well as marked cells death after peak production. On the other hand, HTR-8 lineage inoculated with ZIKV-IEC exhibited increased viral production in 144 hpi, with a peak between 24 and 96 hpi. Furthermore, IEC had peak variations of viral production for BeWo in 144 hpi. Both cells types continued alive during the process of viral replication. Considering such in vitro results, the hypothesis that maternal-fetal transmission is probably a way of virus transmission between the mother and the embryo/fetus is maintained.

Autoimmune disorders and some types of blood cancer originate when B lymphocytes malfunction. In particular, when B cells produce antibodies recognizing the body’s proteins, it leads to various autoimmune disorders. And when B cells of various developmental stages transform into cancer cells, it results in blood cancers, including multiple myeloma, lymphoma, and leukemia. Thus, new methods of targeting B cells are required for various patient groups. Here, we used protein kinase inhibitors alectinib, brigatinib, ceritinib, crizotinib, entrectinib, and lorlatinib previously approved as drugs treating anaplastic lymphoma kinase (ALK)-positive lung cancer cells. We hypothesized that the same inhibitors will efficiently target leukocyte tyrosine kinase (LTK)-positive, actively protein-secreting mature B lymphocytes, including plasma cells. We isolated CD19-positive human B cells from the blood of healthy donors and used two alternative methods to stimulate cell maturation toward plasma cells. Using cell proliferation and flow cytometry assays, we found that ceritinib and entrectinib eliminate plasma cells from B cell populations. Alectinib, brigatinib, and crizotinib also inhibited B cell proliferation, while lorlatinib had no or limited effect on B cells. More generally, we concluded that several drugs previously developed to treat ALK-positive malignant cells can be also used to treat LTK-positive B cells.

Ovine footrot is a complex multifactorial infectious disease, causing lameness in sheep with major welfare and economic consequences. Dichelobacter nodosus is the main causative bacterium, however, footrot is a polymicrobial disease with Fusobacterium necrophorum, Mycoplasma fermentans and Porphyromonas asaccharolytica also associated. There is limited understanding of the host response involved. Proinflammatory mediators interleukin (IL)-1β and C-X-C Motif Chemokine Ligand 8 (CXCL8) have been shown to play a role in the early response to D. nodosus in dermal fibroblasts and interdigital skin explant models. To further understand the response of ovine skin to bacterial stimulation, and to build the understanding of the role of the cytokines and chemokines identified in transcriptomic data, primary ovine interdigital fibroblasts and keratinocytes were isolated, cultured and stimulated with lipopolysaccharide (LPS), D. nodosus or F. necrophorum in the presence and absence of M. fermentans, whilst measuring mRNA expression and protein release of CXCL8 and, IL-1β. Stimulation with LPS, D. nodosus or F. necrophorum resulted in increased transcript levels of IL-1β and CXCL8 in M. fermentans free cells, however, only an increase in CXCL8 protein release was observed. No IL-1β protein release was detected despite increases in IL-1β mRNA, suggesting the signal for intracellular pre-IL-1β processing may be lacking when culturing primary cells in isolation. Keratinocytes and fibroblasts naturally infected with M. fermentans showed little response to LPS, a range of D. nodosus preparations or heat-inactivated F. necrophorum. Primary single cell culture models complement ex vivo organ culture models to study different aspects of the host response to D. nodosus. Ovine keratinocytes and fibroblasts infected with M. fermentans had a reduced response to experimental bacterial stimulation. However, in the case of footrot where Mycoplasma spp. are associated with diseased feet, this natural infection gives important insights into the impact of multiple pathogens on the host response.

Thermodynamic studies consider living entities as dissipative structures. Organisms maintain and develop an orderly structure by exchanging matter, energy, and entropy with the surrounding environment; thus, maintaining life and growth. For a single cell, the temperature, volume, content concentration, and content complexity are four control variables. For warm-blooded animals, both temperature and content concentration are assumed to be constant, and only volume and content complexity, i.e., various proteins, nucleic acids, and small molecular substances in the cell and their interactions, are considered as acting variables. Thus, the potential function of a single cell should conform to the cusp catastrophe model. As the studies on the specific mathematical models of the relationship between the volume and content complexity are not available, we could not propose specific methods for the specific variants of the potential function of this cusp catastrophe model. We could only present our approximate results based on the basic characteristics of the cusp catastrophe model. We speculated that when a single cell is in a stable state, it cannot undergo differentiation, dedifferentiation, and division. These behaviors occur only when the cell enters an unstable state. Based on this speculation, we divided somatic cells of warm-blooded animals into two types, namely stable cells and non-steady cells. If we consider a warm-blooded animal as a whole dissipative structure, its control variables should have steady-state cells, non-steady-state cells, and negative entropy input. If we assume that the negative entropy input is constant, the proportion of non-steady cells and the total number of cells can be used as the control variables of the potential function. For warm-blooded animals, their potential function also conforms to the cusp catastrophe model. Because the studies on the relationship between the proportion of non-steady-state cells and the total cell number are rare, we could not propose specific methods for the variation of the potential function of this cusp catastrophe model. We could only present our approximate results according to the basic characteristics of the cusp catastrophe model. We speculated that as individuals, animals should be in a stable state during development. Once they enter an unstable state, they will fall ill or die. For humans, the proportion of non-steady cells decreases during the growth process from a fertilized egg to old age. From the fertilized egg to adulthood, the total cell number increases; however, in old age, the total cell number begins to decrease gradually. The entire developmental curve will gradually enter an unstable state. We speculated that once the developmental curve of a human enters an unstable state, it is death for the elderly.

Cell death by apoptosis is a major cellular response, in the control of tissue homeostasis and as a defense mechanism in case of cellular aggression like an infection. Cell self-destruction is part of antiviral responses, aimed at limiting the spread of a virus. Although it may contribute to the deleterious effects in infectious pathology, apoptosis remains a key mechanism for viral clearance and resolution of infection. The control mechanisms of cell death processes by viruses have been extensively studied. Apoptosis can be triggered by different viral determinants, through different pathways, as a result of virally induced cell stresses and innate immune responses. Zika virus (ZIKV) induces Zika disease in humans which has caused severe neurological forms, birth defects and microcephaly in newborns during the last epidemics. ZIKV also surprised by revealing an ability to persist in the genital tract and in semen, thus being sexually transmitted. Mechanisms of diverting antiviral responses such as the interferon response, the role of cytopathic effects and apoptosis in the etiology of the disease have been widely studied and debated. In this review, we examined the interplay between ZIKV infection of different cell types and apoptosis and how the virus deals with this cellular response. We illustrate a duality in the effects of ZIKV-controlled apoptosis, depending on whether it occurs too early or too late, respectively in neuropathogenesis, or in long-term viral persistence. We further discuss a prospective role for apoptosis in ZIKV-related therapies, and the use of ZIKV as an oncolytic agent.

Light microscopy is indispensable for analysis of bacterial spatial organization. However, imaging in bacteria is difficult due to their small sizes and the fact that most species are non-spherical, meaning they typically lie horizontally on a microscope coverslip. This is especially problematic when considering that many essential bacterial processes—such as cell division—occur along the short axes of these cells, and so are viewed side-on by standard microscopy. We recently developed a pair of methods to overcome this problem by forcing cells to stand vertically during imaging, named VerCINI (Vertical Cell Imaging by Nanostructured Immobilisation) and µVerCINI (Microfluidic VerCINI). The concept behind both methods is that cells are imaged while confined vertically inside cell traps made from a nanofabricated mould. By doing so, the short axes of the cells are rotated parallel to the microscope imaging plane and are imaged with high resolution. μVerCINI combines the vertical cell confinement with microfluidics so that vertical imaging can be done during fluid exchange, such as during antibiotic perturbations. Here, we provide a practical guide to implementing both VerCINI and µVerCINI, with detailed protocols and experience-based tips so that interested researchers can easily use one or both imaging methods to complement their current approaches.

Background: Thousands of genetic variants have been associated with hematological traits, though target genes remain unknown at most loci. Also, limited analyses have been conducted in African ancestry and Hispanic/Latino populations; hematological trait associated variants more common in these populations have likely been missed. Methods: To derive gene expression prediction models, we used ancestry-stratified datasets from the Multi-Ethnic Study of Atherosclerosis (MESA, including N=229 African American and N=381 Hispanic/Latino participants, monocytes) and the Depression Genes and Networks study (DGN, N = 922 European ancestry participants, whole blood). We then performed a transcriptome-wide association study (TWAS) for platelet count, hemoglobin, hematocrit, and white blood cell count in African (N = 27,955) and Hispanic/Latino (N = 28,324) ancestry participants. Results: Our results revealed 24 suggestive signals (p < 1×10^(-4)) that were conditionally distinct from known GWAS identified variants and successfully replicated these signals in European ancestry subjects from UK Biobank. We found modestly improved correlation of predicted and measured gene expression in an independent African American cohort (the Genetic Epidemiology Network of Arteriopathy (GENOA) study (N=802), lymphoblastoid cell lines) using the larger DGN reference panel; however, some genes were well predicted using MESA but not DGN. Conclusions: These analyses demonstrate the importance of performing TWAS and other genetic analyses across diverse populations and of balancing sample size and ancestry background matching when selecting a TWAS reference panel.

Unanticipated errors in scientific research data can be attributed to the unwarranted assumption of uniformity in the polystyrene surface that is ubiquitously used in tissue culture flasks and dishes. We have shown that when adherent cells are subjected to fluid shear force, equivalent to rinsing the culture with a balanced salt solution, cells on some areas of the polystyrene surface will immediately rupture while still adherent on the surface. This heterogeneity on the polystyrene surface can cause unexpected variability in experimental results and in replicating experiments among labs. In this paper a novel quantitative method is described to measure the degree of heterogeneity on the polystyrene surface of tissue culture flasks. The results show significant variation among several brands of tissue culture flasks as well as large variability within the production lot of a manufacturer. The assay method involves loading the cells with a fluorescent marker that is released upon membrane rupture. Cell membrane rupture also causes the loss of marker proteins used in Westernblots. This novel assay method can be used to monitor the batch consistency and the manufacturing process of flasks and dishes. It may also be used to test new biomaterials.

In this study, the elastic properties of composite materials are investigated, considering the effects of separation of fiber-matrix joint boundary and matrix failure. In this method, by assuming periodic microstructure and using a linear approximation of the displacement field by applying continuity and equilibrium conditions, the composite fiber composite relation is determined. The effect of separation is assumed by introducing tangential and normal scalar parameters in the equations by assuming the displacement field jump at the common boundary. In order to express the effect of matrix micro-cracks, the fracture mechanics framework of continuous environments was used and the micro-cracks parallel to the fibers, perpendicular to the fibers and in the thickness direction with scalar parameters were expressed. At the end of the effect of these parameters the results are presented in graphs. The results show that the presence of defective joint at the joint boundary and the matrix micro-components reduce the hardness of the composite and thus it’s bearing load, which is more significant at the defective joint state.

The paper presents the author’ original modification of the residual method in order to construct an efficient tool for assessing the condition of photovoltaic cells, in particular – panels made of amorphous cells which are characterized by significant random operation parameter changes. The solution constructed has been verified through experiments, which show the usefulness of the proposed methodology as it allows to minimize the risk of obtaining false diagnostic information in the process of assessing the condition of photovoltaic panels.

Excretion and osmoregulation are fundamental processes of the organism, as they prevent the accumulation of toxic waste products in the body and control the osmotic differences between the cells and the environment. In most of the animals these phenomena are taking place through specialized organs, namely excretory organs, composed of diverse cell types that are performing tasks such as secretion and ultrafiltration. Although the morphology and embryology of excretory organs can differ dramatically, the common spatial arrangement of structural proteins and transporters as well as the similar transcriptional developmental programs underlying their formation suggests the homology of their cell types. In this chapter we discuss the current understanding of the evolution of excretory organsfrom a comparative morphological, developmental and functional perspective, flanked by an additional, cell-type perspective. We argue that a putative homologization of certain excretory cell types does not necessarily reflect the homology of the resulting organs, and that integrating all different levels of comparison is crucial for addressing evolutionary questions.

Multinucleate cells can be produced in Dictyostelium by electric-pulse induced fusion. In these cells unilateral cleavage furrows are formed at spaces between areas that are controlled by aster microtubules. A peculiarity of unilateral cleavage furrows is their propensity to join laterally with other furrows into rings to form constrictions. This means, cytokinesis is biphasic in multinucleate cells, the final abscission of daughter cells being independent of the initial direction of furrow progression. Myosin-II and the actin-filament cross-linking protein cortexillin accumulate in the unilateral furrows, as they do in the normal cleavage furrows of mononucleate cells. Myosin-II is not essential for cytokinesis, but stabilizes and confines the position of the cleavage furrows.

Bio-devices are designed to allow biological matter to perform in vitro almost the same functions it performs in vivo. Therefore, they can benefit from the specificities of such materials and are expected to perform better than traditional devices. On the other hand, the integration of biological material with electronic/electrochemical instrumentation requires careful attention and can produce unconventional results. In this paper, we describe the impedance response of an electrochemical cell that converts sunlight into electrical power. It uses the photosynthetic system known as Reaction Center, which is the core of photosynthesis in several living beings. Under illumination, an abrupt transformation drives the cell electrical response from insulator to conductor and a photocurrent is observed. The impedance spectrum shows a peculiar shape which significantly modifies with the protein activation. It has been analyzed by means of a graphical/analytical/ numerical procedure. The modelling identifies an analogue electrical circuit, whose parameters give quantitative information about the underlying process. Finally, an appropriate normalization of data is proposed which validates data in dark and light and can be useful as a fast screening of measurements.

Recently, some authors have developed a shell-less culture system for chick embryos by using a plastic lm as culture vessels. We will show that velocity of rotation of vessels in incubator and temperature have direct relations with growth of chick embryos. We also obtain a mathematical relation between velocity, temperature and rate of growth of chick embryo.

The wide range of applications of nanoparticles (NPs) has increased the probability of environmental and occupational exposure. In a previous comparative study on cell line A549, we observed that oxidative stress caused by Co₃O₄ NPs affects the energetic homeostasis and the detoxification capacity, preventing autophagy induced by TiO₂ NPs. In this study, we have investigated the effects of NPs on the cell cycle.Cytofluorimetric analysis showed a slow-down of the cell cycle progression for both NPs, with increases in the percentage of resting cells in the G0/G1. These observations were confirmed by a reduced expression of all cyclins, especially of CCNE1 and CDK2, involved in the late stages of the G1 phase, coupled with a significant increase in the expression of p21 only for Co₃O₄ NP exposure. On the contrary, the effects of TiO₂ NPs were modest. Cell cycle related miRNA-34a, miRNA-126 and miRNA-1290 resulted increased at different early time-points (4-8h) but were down-expressed at 24h-48h only after TiO₂ NP exposure. Our results show that NPs have an antiproliferative effect and deregulate cell cycle on A549 cells. These effects should not be underestimated because regulation of cycle progression is crucial for cell survival and repair of genetic damage.

Dengue virus is a global health problem most prevalent in tropical and subtropical regions. However, after the approval of two vaccines, Dengvaxia, TV003/TV005 of Takeda, for its prevention, problems were reported, like enhanced risks of infection or less efficiency of protection. Since then, more struggles have been in demand for the development of better vaccines. Here, we conducted a new design through an in-silico strategy. Initially, epitopes were chosen based on their antigenicity, immunogenicity, and binding affinity with MHC molecule, while excluded with allergenicity, toxicity and potential risk of antibody dependent enhancement. Subsequently, a core antigen was constructed with selected epitopes and linked with distinct adjuvant proteins to achieve three candidate vaccines, PSDV-1~3. PSDV-2 was chosen for further validation based on their advantage in physicochemical and structural properties. With a panel of simulations, this artificial protein showed tight binding with pattern recognition receptors, good stability, robust immune induction, and ultimately was confirmed as a high quality vaccine candidate. The plasmid for its recombinant expression was then designed accordingly. With our new design, one more choice was obtained for the effective protection from Dengue virus. Further experimental validations are still require to confirm it protection capacity and safety.

Adult mesenchymal stem cells (MSCs) are a promising cell source for tissue regeneration. However, ex vivo expansion results in cell senescence; cells lose their proliferation and differentiation capacity. Fetal MSCs can be an alternative due to their robust proliferation and differentiation capacities as well as immune privilege properties. Given the rejuvenation effect of decellularized extracellular matrix (dECM) on adult MSCs, it remains unknown whether dECM influences the regenerative potential of fetal stem cells. In this study, passage five fetal nucleus pulposus cells (fNPCs) and fetal synovium-derived stem cells (fSDSCs) were expanded on dECMs deposited by fNPCs (NECM) and fSDSCs (SECM) for one passage with expansion on tissue culture plastic (Plastic) as a control. We found that dECM expanded fNPCs and fSDSCs exhibited both similarities and differences in expression of stemness genes and surface markers. Expanded fNPCs yielded more differentiated pellets after chondrogenic induction but no adipogenic differentiation following adipogenic induction in both Plastic and dECM groups than the corresponding fSDSC group. Despite a significant increase in fNPCs, dECM expanded fSDSCs exhibited no increase in chondrogenic potential; however, compared to the Plastic group, dECM expanded fSDSCs exhibited a small increase in osteogenic potential and a great increase in adipogenic potential. These results suggest that fNPCs are more sensitive to NECM rejuvenation for cartilage tissue engineering and regeneration; in contrast, dECMs exhibited limited effects on fSDSC rejuvenation in chondrogenic capacity except for enhanced adipogenic capacity following expansion on SECM.

An automatic recognizing system of white blood cells can assist hematologists in the diagnosis of many diseases, where accuracy and efficiency are paramount for computer-based system. In this paper, we present a new image processing system to recognize the five types of white blood cells in peripheral blood with marked improvement in efficiency when juxtaposed against mainstream methods. The prevailing deep learning segmentation solutions often utilize millions of parameters to extract high-level image features and neglect the incorporation of prior domain knowledge, which consequently consume substantial computational resources and increase the risk of overfitting, especially when limited medical image samples are available for training. To address these challenges, we propose a novel memory-efficient strategy that exploits graph structures derived from the images. Specifically, we introduce a lightweight superpixel-based Graph Neural Network (GNN) and break new ground by introducing superpixel metric learning to segment nucles and cytoplasm. Remarkably, our proposed segmentation model (SMGNN) achieves state-of-the-art segmentation performance while utilizing at most 10000$\times$ less than the parameters compared to existing approaches. The subsequent segmentation-based cell type classification processes show satisfactory results that such automatic recognizing algorithms are accurate and efficient to execeute in hematological laboratories.

Background: Although metastatic GCT is highly curable with initial cisplatin-based chemotherapy (CT), 20-30% of patients relapse. Salvage CT options include conventional (CDCT) and high dose chemotherapy (HDCT), however definitive comparative data remains lacking. We aimed to characterize the contemporary practice patterns of salvage CT across Canada. Methods: We conducted a 30-question online survey for Canadian medical and hematological oncologists with experience in treating GCT, assessing treatment availability, patient selection, and management strategies used for relapsed GCT patients. Results: Respondents included 30 staff; from 18 cancer centers across provinces. The most common CDCT regimens used were TIP (64%) and VIP (25%). HDCT was available for (70%) in 13 centers. HDCT regimen used included carboplatin and etoposide for 2 cycles (76% in 7 centers), 3 cycles (6% in two centers), and the TICE protocol (11%, in 2 centers). “Bridging” CDCT was used by 65% respondents. Post HDCT treatments considered include surgical resection for residual disease (87.5%), maintenance etoposide (6.3%) and sur-veillance only (6.3%). Conclusions: HDCT is the most commonly used GCT salvage strategy in Canada. Significant differences exist in the treatment availability, selection and delivery of HDCT, highlighting the need for standardization of care for patients with relapsed testicular GCT.

Calcium-activated potassium channels (KCa) are the important participants in calcium signaling pathways due to their ability to be activated by increase of the intracellular free calcium concentration. KCa channels are involved in the regulation of various processes in the cells under normal, as well as pathophysiological conditions, including oncotransformation. Previously, with the use of patch-clamp method, we registered the KCa activity in the plasma membrane of human myeloid leukemia K562 cell line. Here, we performed the molecular and functional identification of KCa channels and have uncovered their role in proliferation, migration and invasion of K562 cells. Using a combined approach, we identified the functional activity of SK2, SK3 and IK channels in the plasma membrane of the cells. Selective SK and IK channel inhibitors, apamin and TRAM-34, reduced the proliferative, migratory and invasive capabilities of human myeloid leukemia cells. At the same time, the viability of K562 cells was not affected by KCa channel inhibitors. Our data imply that SK/IK channel inhibitors could be used to slow down the proliferation and spreading of leukemia cells that express functionally active KCa channels in the plasma membrane.

The most widely spread and neglected zoonotic disease – Leptospirosis, with an estimated 1.03 million cases and 58,900 deaths occurring annually, is a concern and can be prevented only by effective immunization. Due to the urgent need for a novel vaccine, various research organizations have been evaluating the protective immune response elicited by recombinant vaccines. In this study amino-acid sequences of Outermembrane protein (OMPL) 1, LipL 32, 41 and 46 from ten pathogenic serovars of Leptospira were selected to obtain epitopes that induce CD4+ and CD8+ T cell responses by binding to the MHC molecules. These B cell and T cell epitopes were used to design multi-epitope vaccine to which an adjuvant sequence was added at the N-terminal end and appropriate linkers were used to join the different epitopes to increase the efficiency of the vaccine constructs. Using an immuno-informatics approach, constructs were analyzed for the physiochemical properties, secondary and tertiary structure and its validation, docking with different receptors and prediction of binding affinity for each docked complex, followed by molecular dynamics simulation. Taking in consideration all the results, multi-epitope constructs designed may prove to be promising vaccine candidates against Leptospirosis and warrants experimental validation.

Epithelial-mesenchymal transition (EMT) networks are essential in acquiring the drug resistance and cancer malignant features in cancer stem cells (CSCs). In this regard, gene expression profiles in diffuse- and intestinal-type gastric cancer (GC) have been analyzed to reveal the network pathways in EMT and CSCs, since the diffuse-type GC has much more mesenchymal features than intestinal-type GC that has the intestinal features. The study results revealed that the activation state of several canonical pathways related to cell cycle regulation was altered. The canonical pathway on Cell cycle: G1/S checkpoint regulation was activated in diffuse-type GC, and canonical pathways on Cell cycle control of chromosomal replication and Cyclins and cell cycle regulation were activated in intestinal-type GC. Canonical pathway related to Role of BRCA1 in DNA damage response was activated in intestinal-type GC, where BRCA1, which is related to G1/S phase transition was up-regulated in intestinal-type GC. Several microRNAs (miRNAs), including mir-10, mir-17, mir-19, mir-194, mir-224, mir-25, mir-34, mir-451, and mir-605, were identified to have direct relationships of RNA-RNA interaction in Cell cycle: G1/S checkpoint regulation pathway. Additionally, cell cycle regulation may be altered in EMT conditions. The alterations in activation states of the pathways related to cell cycle regulation in diffuse- and intestinal-type GC would indicate the significance of cell cycle regulation in EMT.

This study investigated the roles of low-molecular-weight fucoidan (LMWF) in enhancing the anti-cancer effects of fluoropyrimidine-based chemotherapy. HCT116 and Caco-2 cells were treated with LMWF and 5-FU. Cell viability, cell cycle, apoptosis, and migration were analyzed in both cell types. Potential mechanisms underlying how LMWF enhances the anti-cancer effects of fluoropyrimidine-based chemotherapy were also explored. The cell viability of HCT116 and Caco-2 cells was significantly reduced after treatment with a LMWF-5-FU combination. In HCT116 cells, LMWF enhanced the suppressive effects of 5-FU on cell viability through the 1) induction of cell cycle arrest in the S phase and 2) late apoptosis mediated by the Jun-N-terminal kinase (JNK) signaling pathway. In Caco-2 cells, LMWF enhanced the suppressive effects of 5-FU on cell viability through both c-mesenchymal–epithelial transition (MET)/ Kirsten Rat Sarcoma virus (KRAS)/ extracellular signal-regulated kinase (ERK) and c-MET/ phosphatidyl-inositol 3-kinases (PI3K)/ protein kinase B (AKT) signaling pathways. Moreover, LMWF enhanced the suppressive effects of 5-FU on tumor cell migration through the c-MET/ matrix metalloproteinase (MMP)-2 signaling pathway in both HCT116 and Caco-2 cells. Our results demonstrated that LMWF is a potential complementary therapy for enhancing the efficacies of fluoropyrimidine-based chemotherapy in colorectal cancers (CRCs) with the wild-type or mutated KRAS gene through different mechanisms. However, in vivo studies and in clinical trials are required to validate the results of the present study.

Progression of oral squamous cell carcinoma (OSCC) has been associated with an escape of tumor cells from the host immune surveillance due to an increased knowledge of its underlying molecular mechanisms and its modulation by the tumor microenvironment and immune cell repertoire. In this study the expression of HLA class I (HLA-I) antigens and of components of the antigen processing machinery (APM) was analyzed in 160 pathologically classified human papilloma virus (HPV)-negative OSCC lesions and correlated to the intra-tumoral immune cell response, IFN- signaling and to the patients outcome. A heterogeneous, but predominantly lower constitutive protein expression of HLA-I APM components was found in OSCC sections when compared to non-neoplastic cells. Tumoral HLA-I APM component expression was further categorized into the three major phenotypes HLA-Ihigh/APMhigh, HLA-Ilow/APMlow and HLA-Idiscordant high/low/APMhigh. In the HLA-Ihigh/APMhigh group, the highest frequency of intra-tumoral CD8+ T cells and lowest number of CD8+ T cells close to FoxP3+ cells was found. Patients within this group presented the most unfavorable survival, which was significantly evident in stage T2 tumors. Despite a correlation with the number of intra-tumoral CD8+ T cells, tumoral JAK1 expression as a surrogate marker for IFN- signaling was not associated with HLA-I/APM expression. Thus, the presented findings strongly indicate the presence of additional factors involved in the immunomodulatory process of HPV-negative OSCC with a possible tumor-burden-dependent complex network of immune escape mechanisms beyond HLA-I/APM components and T cell infiltration in this tumor entity.

Progression of oral squamous cell carcinoma (OSCC) has been associated with an escape of tumor cells from the host immune surveillance with growing evidence of its underlying molecular mechanisms and its interaction with the immune cell control. In this study the expression of HLA class I (HLA-I) antigens and of components of the antigen processing machinery (APM) was analyzed in 160 consecutive human papilloma virus (HPV)-negative OSCC lesions and correlated to tumor specific parameters, the intratumoral immune cell response and to the patients outcome. A heterogeneous, but predominantly lower constitutive protein expression of HLA-I APM components was seen in OSCC sections when compared to non-neoplastic cells. Based on the expression levels of HLA-I APM components three main OSCC subgroups were detected and categorized into HLA-Ihigh/APMhigh, HLA-Ilow/APMlow and HLA-Idiscordant high/low/APMhigh phenotypes. In the HLA-Ihigh/APMhigh group, the highest frequency of intratumoral CD8+ T cells and lowest number of CD8+ T cells close to FoxP3 cells was found. Despite being associated with the highest T cell infiltration, patients within this group presented the most unfavorable survival, which was most evident in stage T2 tumors. Thus, the presented findings strongly indicate the presence of additional factors involved in the immunomodulatory process of HPV-negative OSCC with a possible tumor-burden-dependent complex network of immune escape mechanisms beyond HLA-I/APM components and T cell infiltration in this tumor entity.

Coronavirus disease (COVID-19) is a new discovered strain where WHO officially declares the disease as COVID-19 while the virus responsible for it called Severe Acute Respiratory Syndrome Coronavirus 2 or SARS-CoV-2. The incubation period of this disease is between 14 days. Ordinary clinical symptoms that reported around the world include fever, cough, fatigue, diarrhoea and vomiting as well as asymptomatic for certain people. Infection is spread mainly through broad droplets. In early March 2020, WHO again has announced that COVID-19 is a pandemic with currently no specific treatment. The potential use of SARS-COV-2 proteome as a vaccine candidate by analysing through B-cell and T-cell antigenicity by using a immunoinformatics approach as a vaccine development early stage. In this study, we used consensus sequence for SARS-COV-2 proteome that was retrieved from NCBI database. VaxiJen 2.0 was mainly used to identify the antigenic property of SARS-COV-2 proteins. IEDB then used to analyse the B-cell epitope, the presence of T cell immunogenic epitope in SARS-COV-2 proteins was obtained by using compromise method of MHC class I and II tools that accessible respectively using ProPred-1 server and MHC II Binding Prediction in IEDB database. The best epitopes of B and T-cell epitopes were predicted with high antigencity and the information is disseminated through web-based database resource (https://covid-19.omicstutorials.com/epitopes/). This study will be useful to find a new epitope-based candidate for SARS-COV-2. However, further study needs to be done for the next stages of vaccine development.

Malignant tumors behave dynamically as cell communities governed by ecological principles. Massive sequencing tools are unveiling the true dimension of the heterogeneity of these communities along their evolution in most human neoplasms, clear cell renal cell carcinomas (CCRCC) included. Although initially thought to be purely stochastic processes, very recent genomic analyses have shown that temporal tumor evolution in CCRCC may follow some deterministic pathways that give rise to different clones and sub-clones randomly spatially distributed across the tumor. This fact makes each case unique, unrepeatable and unpredictable. Precise and complete molecular information is crucial for patients with cancer since it may help in establishing a personalized therapy. Intratumor heterogeneity (ITH) detection relies on the correctness of tumor sampling and this is part of the pathologist’s daily work. International protocols for tumor sampling are insufficient today. They were conceived decades ago, when ITH was not an issue, and have remained unchanged until now. Noteworthy, an alternative and more efficient sampling method for detecting ITH has been developed recently. This new method, called multisite tumor sampling (MSTS), is specifically addressed to large tumors that are impossible to be totally sampled, and represent an opportunity to improve ITH detection without extra costs.

In the last two decades, the discovery of various pathways involved in renal cell carcinoma (RCC) have led to the development of biologically-driven targeted therapies. Hypoxia inducible factors (HIFs), angiogenic growth factors, von Hippel-Lindau (VHL) gene mutations and oncogenic miRNAs play essential roles in the pathogenesis and drug resistance of clear cell renal cell carcinoma. These insights have led to the development of VEGF inhibitors, mTOR inhibitors and immunotherapeutic agents which have significantly improved outcomes of patients with advanced RCC. HIF inhibitors will be a valuable asset in the growing therapeutic armamentarium of RCC. Various histone deacetylase (HDAC)inhibitors, including selenium and agents such as PT2385 and PT2977, are being explored in various clinical trials as potential HIF inhibitors to ameliorate the outcomes of RCC patients. In this article, we will review the current treatment options and highlight the potential role of selenium in the modulation of drug resistance biomarkers expressed in ccRCC tumors.

We examine the impact of temperature (T) on the Seebeck coefficient S, i.e., the T dependence of S for the single-component molecular conductor Pd(dddt)_2] (dddt = 5,6-dihydro-1,4-dithiin-2,3-dithiolate) with a half-filled band, where the coefficient is obtained from a ratio of the thermal conductivity to the electrical conductivity. The conductor exhibits Dirac electrons with a nodal line, which shows the energy variation around the chemical potential and the density of states (DOS) with a minimum. Using a three-dimensional tight-binding (TB) model in the presence of both impurity and electron--phonon (e--p) scatterings, we study the Seebeck coefficient S_y for the molecular stacking and the most conducting direction. The impact of T on S_y exhibits a sign change, where S_y > 0 with a maximum at high temperatures and S_y < 0 with a minimum at low temperatures. The T dependence of S_y suggests that the contribution from the conduction (valence) band is dominant at low (high) temperatures.The result is examined using a spectral conductivity \sigma_y(\epsilon,T) as a function of the energy $\epsilon$ close to the chemical potential \mu. Further, the Seebeck coefficients for perpendicular directions (x and z) are examined, to show both S_x and S_z being positive and no sign change in contrast to S_y.

During the COVID-19 pandemic, the circulation of non–SARS-CoV-2 respiratory viruses changed throughout the world. This study aimed to analyze the effect of respiratory syncytial virus (RSV), metapneumovirus (MPV), rhinovirus (RV), and parainfluenza (PIV)-3 single infection, dual co-infection, and viral load on cytokine and chemokine expression in 300 Mexican patients with ARIs negative for SARS-CoV-2. Molecular detection and viral load were performed by RT-qPCR. Cytokine and chemokine expression was determined in samples positive for single RSV, MPV, RV, or PIV-3 infection, and in the most frequent dual co-infections, by a cytokine panel using a magnetic-bead-based multiplex immunoassay. Of the patients positive for viral infection, 91.7% had a single infection and 8.3% had dual co-infections. In this study, RSV was the respiratory virus with the highest prevalence, and the most common dual co-infection was RV+RSV. On the other hand, RV infections had the highest viral loads compared to the other viruses detected. FGF basic, MIP-1α IL-8, IP-10, MCP-1, IFN-γ, and RANTES showed differential expression between single infections and dual co-infections compared to healthy patients. We report, for the first time, the circulation of non-SARS-CoV-2 viruses in the south of Mexico and the cytokine and chemokine profiles associated with these viruses.

The optical reflection characteristics of asphalt pavement are an important influencing factor in road lighting design, and the macro and micro textures of asphalt pavement significantly affect its reflection characteristics. To investigate the impact of texture parameters on the retroreflection coefficient of asphalt pavement, this study obtained the macroscopic and microscopic texture properties of rutting board specimens and on-site asphalt pavement using a pavement texture tester. The macro- and microtexture parameters, such as macroscopic texture distribution density (D1), microscopic texture distribution density (D2), profile height root-mean-square (Rq), profile slope root-mean-square (Δq), skewness Rsk and kurtosis Rku, were measured, and the corresponding retroreflection coefficient RL was measured using a retro-reflectometer. In the laboratory ex-periments, rutting specimens of AC-13, SMA-13, and OGFC-13 asphalt mixtures were formed. The changes in texture parameters and retroreflection coefficient of different rutting specimens before and after crushing were studied, and a factor influence model between macro- and microtexture parameters and RL was established. And the correlation models of texture index and RL of asphalt pavement are further established. The results showed that in the single factor model, the param-eters can be used to characterize RL with high prediction accuracy, whereas for the on-site meas-urements, the three parameters of Δq, Rsk, and Rku can characterize the RL well. The nonlinear model established on the basis of the B-P neural network algorithm improves its prediction ac-curacy. This research can provide ideas for optimizing the reflection characteristics of asphalt pavement and further provide a decision-making basis for road lighting design.

Bloodstream infection is a major health problem worldwide, with extremely high mortality. Detecting infection in the early stage is challenging due to the extremely low concentration of bacteria in the blood. Digital PCR provides unparalleled sensitivity and can achieve absolute quantification, but it is time-consuming. Moreover, the presence of unavoidable background signals in negative controls poses a significant challenge for single-molecule detection. Here, we propose a novel strategy called “Ultrafast flexible thin tube-based droplet digital PCR (utPCR)” that can shorten the digital PCR process from 2 hours to only 5 minutes, with primer annealing/extension time reduced from minutes to only 5 seconds. Importantly, the ultrafast PCR eliminates the nonspecific amplification and thus enables single-molecular detection. The utPCR enabled sensitive detection and digital quantification of E. coli O157 in the high background of 106-fold excess of E. coli K12 cells. Moreover, this method also displayed the potential to detect rare pathogens in blood samples, and the limit of detection (LOD) could be as low as 10 CFU per mL of blood without false positive results. Considering ultrafast (<5 min) and highly sensitive (single-molecule detection), the utPCR holds excellent prospects in the next generation of molecular diagnosis.

It is important for food recognition to separate each ingredient within a food image at the pixel level. In this paper, we propose a new approach to segment ingredients by utilizing a CNN-based Single-Ingredient Classification Model. In detail, we firstly introduce a standardized biological-based hierarchical ingredient structure and construct a single-ingredient image dataset based on this structure. Then, we build a single-ingredient classification model based on a novel convolutional neural network (CNN) architecture that utilizes an attention mechanism. Afterwards, we propose a new framework for segmentation using the above single-ingredient classification model as the backbone. In this framework, two methods are involved in segmenting ingredients in the food images. We introduce five evaluation metrics (IoU, Dice, Purity, Entirety, Loss of GTs) to assess the performance of ingredient segmentation in terms of ingredient classification. Extensive experiments demonstrate the effectiveness of the proposed method, achieving an maximal mIoU of 0.65, mDice of 0.77, mPurity of 0.83, mEntirety of 0.80, and mLoGTs of 0.06 on the FoodSeg103 dataset. The results confirm that our CNN-based architecture achieves higher segmentation performance compared to ResNet18 and EfficientNet-B0 when used as the backbone for ingredient segmentation. We believe that our ingredient segmentation approach lays the foundation for subsequent ingredient recognition.

The refractive index of solids guages their transparency to incident light, while the energy gap determines the threshold for light absorption. This paper provides a mathematical formulation for the relationship between refractive index and energy gap. It is also established that this formulation aided in the unification of the Moss, Ravindra, and Herve-Vandamme relationships.

Hypertrophic Cardiomyopathy (HCM) is a common inherited disorder that can lead to heart failure and sudden cardiac death, characterized at the histological level by focal areas of myocyte disarray, hypertrophy and fibrosis, and few disease-targeted therapies exist. To identify, focal, spatially restricted alterations in transcriptional pathways and reveal novel therapeutic targets, we performed a spatial transcriptomic analysis of areas of focal myocyte disarray compared to areas of normal tissue, using a commercially available platform (GeoMx, nanoString). We analyzed surgical myectomy tissue from four patients with HCM and control interventricular septum tissue from two unused organ donor hearts that were free of cardiovascular disease. Histological sections were reviewed by an expert pathologist and 72 focal areas with varying degrees of myocyte disarray (normal, mild, moderate, severe) were chosen for analysis. Areas of interest were interrogated with the Human Cancer Transcriptome Atlas designed to profile 1800 transcripts. Differential expression analysis revealed significant changes in gene expression between HCM and Control tissue, and functional enrichment analysis indicated these genes were primarily involved in interferon production and mitochondrial energetics. Within HCM tissue, differentially expressed genes between areas of mild and moderate disarray were enriched for genes related to mitochondrial energetics (moderate disarray) and response to oxygen/cytokine levels (mild disarray). The comparison between areas of moderate and severe disarray were enriched for genes related to the c-Jun N-terminal kinase (JNK) cascade in severe disarray. Analysis of ligand-receptor pair gene expression revealed that HCM tissue exhibited downregulation of platelet-derived growth factor (PDGF), NOTCH, junctional adhesion molecule, and CD46 signaling, while showing upregulation of fibronectin, CD99, cadherin, and amyloid precursor protein signaling. A deconvolution analysis utilizing the matched single nuclei RNA-sequencing (snRNA-seq) data to determine cell type composition in areas of interest revealed significant differences in fibroblast and vascular cell composition in areas of severe disarray when compared to normal areas in HCM samples. Cell composition in normal areas from control tissue was also divergent from normal areas in HCM samples, which was consistent with the differential expression results. Overall, our data identify novel and potential disease-modifying targets for therapy in HCM.

We developed a transparent and flexible electrochemical sensor using a platform based on a network of single-walled carbon nanotubes (SWCNTs) for the non-enzymatic detection of hydrogen peroxide (H2O2) released from living cells. We decorated the SWCNT network on a poly(ethylene terephthalate) (PET) substrate with platinum nanoparticles (PtNPs) using a potentiodynamic method. The PtNP/SWCNT/PET sensor synergized the advantages of a flexible PET substrate, a conducting SWCNT network, and a catalytic PtNP, and demonstrated good biocompatibility and flexibility, enabling cell adhesion. The PtNP/SWCNT/PET-based sensor demonstrated enhanced electrocatalytic activity towards H2O2 as well as excellent selectivity, stability, and reproducibility. The sensor exhibited a wide dynamic range of 500 nM to 1 M, with a low detection limit of 228 nM. In addition, Furthermore, the PtNP/SWCNT/PET sensor remained operationally stable even after bending at various angles (15°, 30°, 60°, and 90°) with no noticeable loss of current signal. These outstanding characteristics enabled the PtNP/SWCNT/PET sensor to be practically applied for the direct culture of HeLa cells and the real-time monitoring of H2O2 release by the HeLa cells under drug stimulation.

Purpose: The purpose of this study was to evaluate the dosimetric impact of multiple channels compared to a single channel in high dose rate (HDR) vaginal cuff brachytherapy (VCBT). Methods and materials: Sample plans of HDR VCBT from both single and multiple channel cylinders at 2.5, 3.0 and 3.5 cm in diameter were created and analyzed. The doses were prescribed either at the 0.5 cm depth with 5.5 Gy for 4 fractions or at the cylinder surface with 8.8 Gy for 4 frac¬tions, in various treatment lengths ranging from 3 to 8 cm. A 0.5 cm ring target volume called PTV_Eval was contoured for each plan and served as the target volume for dosimetric evaluation. Mean doses and the doses covering 90% (D90), 10% (D10), and 5% (D5) of PTV_Eval were calculated and compared. The same treatment lengths, same prescription regimens, same target volume contouring and same plan evaluation methods were repeated for the similar size single channel and multiple channel cylinders. Results: The mean doses of both regimens with the multi-channel cases (6.3 to 7.1 Gy) were comparable to single channel ones (6.4 and 7.5 Gy). The ranges of D90, D10 and D5 were from 3.654 to 5.04 Gy, 8.44 to 10.08 Gy and 8.84 to 10.86 Gy in the multi-channel cases, but from 5.36 to 5.76 Gy, 7.40 to 9.97 Gy and 8.16 to 11.93 Gy in the single channel cases, respectively. Conclusion: The single channel and multiple-channel cylinder deliver a similar mean dose, but with marked heterogeneity in D90, D5 and D10 for the same prescription dose and target volume. Multi-channel cylinders adequately cover the target volume, but given the heterogeneity, increased treatment time and cost are best suited for asymmetric target volumes.

Background: Carbapenem-resistant Klebsiella pneumoniae (CRKP) is a serious public health issue. Aim of the study was to identify the antimicrobial resistance and accessory genes, the clonal relatedness and the evolution dynamics of selected CRKP isolates recovered in an adult and a pediatric intensive care unit of a tertiary hospital in Greece. Methods: Twenty-four CRKP isolates recovered during 2018-2022 were included in the study. Next-generation sequencing was performed using the Ion Torrent PGM Platform. The identification of the plasmid content, MLST and antimicrobial resistance genes, as well as the comparison of multiple genome alignments and the identification of core genome single-nucleotide polymorphism sites, were performed applying various bioinformatics software. Results: The isolates belonged to eight sequence types 11, 15, 30, 35, 39, 307, 323, and 512. A variety of carbapenemases (KPC, VIM, NDM and OXA-48) and resistance genes were detected. CRKP strains shared visually common genomic regions with the reference strain (NTUH-K2044). ST15, ST323, ST39, and ST11 CRKP isolates presented on average 17, 6, 16 and 866 recombined SNPs, respectively. All isolates belonging to ST15, ST323 and ST39 were classified in distinct phylogenetic branches, while ST11 isolates were assigned to a two-subclade branch. For large CRKP sets, the phylogeny seems to change approximately every seven SNPs. Conclusion: The current study provides insight into the genetic characterization of CRKP isolates in the ICUs of a tertiary hospital. Our results indicate clonal dispersion of ST15, ST323, and ST39 and highly diverged ST11 isolates.

Unlike aerial or terrestrial navigation, the Global Navigation satellite system (GNSS) is not available underwater. This is a big challenge for underwater navigation. The inertial navigation system (INS) aided by the single-beacon acoustic positioning system (APS) provides one solution, but the long-range case is limited by low SNR conditions. Inspired by passive synthetic aperture detection, we proposed a new tightly coupled navigation algorithm based on spatial synthesis and one-way-travel-time (OWTT) range measurement. We design two estimators: the DOA/Range estimator using the model-based method and the tightly coupled INS/APS navigation estimator. Based on the improved UKF, all information is combined. Simulation is carried out in MATLAB. Compared with range-only tightly coupled INS/APS navigation, synthetic long baseline (SLBL) algorithm and Doppler velocity logger (DVL) aided centralized extended Kalman filter (CEKF) based single beacon INS/OWTT navigation, the proposed method's performance is proven. The main contributions of this work are: 1. Propose a new architecture of underwater integrated navigation; 2. Apply the passive acoustic detecting method in the navigation to improve accuracy. 3. Apply the tightly coupled method to improve availability.

In this paper, four types of open service signals of BDS-3 satellite (B1I, B1C, B2a, and B3I) and B2I signals broadcasted by BDS-2 satellites were used in the time frequency transfer and positioning experiments with signal coexisting in BDS system, and the single frequency PPP (precise point positioning) method was used. Modified GRoup And PHase Ionospheric Correction (GRAPHIC) method was proposed and verified by the experiment. The results show that 18 selected stations can achieve decimeter-level positioning results with single frequency. Compared with the general observation method, the proposed modified GRAPHIC method improves the stability and precision of positioning and timing significantly, and the positioning accuracy of 5 frequency signals is increased 40.4%, 32.2%, 80.3%, 12.4%, and 10.3%, respectively. The frequency stability can reach the same accuracy as that of dual-frequency with BDS in the current state.

Hypertrophic Cardiomyopathy (HCM) is a common inherited disorder characterized by unexplained left ventricular hypertrophy, with or without left ventricular outflow tract (LVOT) obstruction. Single nuclei RNA-sequencing (snRNA-seq) of both obstructive and nonobstructive HCM patient samples have revealed alterations in communication between various cell types but a direct and integrated comparison between the two HCM phenotypes has not been reported. We performed a bioinformatic analysis of HCM snRNA-seq datasets from obstructive and nonobstructive patient samples to identify differentially expressed genes and distinctive patterns of intercellular communication. Differential gene expression analysis revealed 37 differentially expressed genes, predominantly in cardiomyocytes but also in other cell types, relevant to aging, muscle contraction, cell motility and the extracellular matrix. Intercellular communication was generally reduced in HCM, affecting the extracellular matrix, growth factor binding, integrin binding, PDGF binding and SMAD binding, but with increases in adenylate cyclase binding, calcium channel inhibitor activity, and serine-threonine kinase activity in nonobstructive HCM. Increases in neuron to leukocyte and dendritic cell communication, in fibroblast to leukocyte and dendritic cell communication and in endothelial cell communication to other cell types, largely through changes in expression of integrin-b1 and its cognate ligands, were also noted. These findings indicate both common and distinct physiological mechanisms affecting the pathogenesis of obstructive and nonobstructive HCM and provide opportunities for personalized management of different HCM phenotypes.

The City of Meycauayan is considered as one of the most polluted cities in the developing world on the account of industrial discharges of toxic materials to the environment. This work investigated the sources of the heavy metal pollution by analyzing soil and sediment samples for heavy metals (Cr, Hg, Ni, and Pb) together with selected environmental indicators (TN, TOM, and TP) located along the Meycauayan River. Hierarchical cluster analysis (HCA), principal components analysis (PCA), and Pearson correlation analysis (CA) were used to identify the sources of the metals. Results showed delineated locations of severe levels of heavy metal pollution downstream because of the concentration of industrial activities. Cr contributed more than any other heavy metals analyzed due to proliferation of tanneries discharging untreated wastewaters to the river. Significant inputs of Pb and Hg from Pb-acid battery recycling and gold smelting industries were also found. Risk assessments indicated severe levels of heavy metal pollution where industrial activities are concentrated. The mean Cr, Pb, Ni, and Hg in the sampling locations have mean incidences of toxicity of 91.7 %, 53.6 %, 27.7 %, and 70.0 %, respectively. Our study showed a serious need to address heavy metal pollution in Meycauayan.

Deep convolutional neural network (CNN) has shown their great advantages in the single image deraining task. However, most existing CNN-based single image deraining methods still suffer from residual rain streaks and details lost. In this paper, we propose a deep neural network including the Multi-scale feature extraction module and the channel attention module, which are embed in the feature extraction sub-network and the rain removal sub-network respectively. In the feature extraction sub-network, the Multi-scale feature extraction module is constructed by a Multi-layer Laplacian pyramid, and is then integrated multi-scale feature maps by a feature fusion module. In the rain removal sub-network, the channel attention module, which assigns different weights to the different channels, is introduced for preserving image details. Experimental results on visually and quantitatively comparison demonstrate that the proposed method performs favorably against other state-of-the-art approaches

We report herein high-resolution x-ray diffraction measurements of basal plane bending of homoepitaxial single-crystal diamond (SCD). The results reveal that growth parameters such as temperature, growth time and basal plane bending of the substrate affect the basal plane bending of SCD. First, the basal plane bending of SCD depends mainly on the substrate itself. The basal plane bending of SCD becomes more severe with increasing basal plane bending of the substrate and this type of basal plane bending cannot be recovered. The SCD growth experiments show that the basal plane bending increases at high temperature and with increasing growth time. Finally, to understand the mechanism behind basal plane bending, we investigate the substrate-surface temperature distribution as a function of basal plane bending of SCD fabricated by chemical vapour deposition (CVD). This allows us to propose a bending model and understand the origin of basal plane bending. The results indicate that an uneven temperature distribution on the substrate surface is the main cause of the CVD diamond base-plane bending.

The asymmetry in the dynamics of an electro-pneumatic actuating device consisting of an electro-pneumatic transducer and a single-action pneumatic actuator was unexpectedly found experimentally. This asymmetry manifests in response to large step excitations. The dynamic asymmetry effect is understood as a change in the shape of the response of an actuator depending on the direction of the actuators stem movement. The questions appears: How to explain this effect? Does this phenomenon reflect thermodynamic air processes? Is it connected with air-to-mechanical energy conversion? Together, six working hypotheses explaining this effect were formulated. The asymmetry was studied in detail using analytical and simulation modeling, as well as experimental research. In this respect, a nonlinear analytical model was developed, tuned, and later solved using simulations. The simulation model was verified based on the experiment data. In addition, the problem of the efficiency in the energy conversion of a single-action actuator was discussed and, in result, the maximum theoretical energy efficiency was determined. Subsequently, all six working hypotheses were verified. Finally, the hypothesis explaining asymmetry as an effect of the different thermodynamic air processes in both actuator’s stem travel directions was confirmed.

Single nucleotide polymorphisms (SNP) are associated with diseases and drug response variabilities in humans. Elucidating the damaging and disease-associated SNPs using wet-laboratory approaches can be challenging and resource-demanding due to the large number of SNPs in the human genome. Due to the growth in the field of computational biology and bioinformatics, algorithms have been developed to help screen and filter out the most deleterious SNPs that are worth considering for wet-laboratory studies. Here we review the existing in-silico based methods used to predict and characterize the effects of SNPs on protein structure and function. This cutting-edge approach will facilitate the search for novel therapeutics, help understand the etiology of diseases and fast-track the personalized medicine agenda.

Nanoparticles of platinum-group metals (PGM) on carbon supports are widely used as catalysts for a number of chemical and electrochemical conversions on laboratory and industrial scale. The newly emerging field of single atom catalysis focuses on the ultimate level of metal dispersion, i.e. atomically dispersed metal species anchored on the substrate surface. However, the presence of single atoms in traditional nanoparticle-based catalysts remains largely overlooked. In this work we use aberration-corrected scanning transmission electron microscope to investigate four commercially available nanoparticle-based PGM/C catalysts (PGM = Ru, Rh, Pd, Pt). We show that in addition to nanoparticles, single atoms are also present on the surface of carbon substrates. These observations raise questions about the role that single atoms play in conventional nanoparticle PGM/C catalysts. We critically discuss the observations with regard to the quickly developing field of single atom catalysis.

Single valued neutrosophic set has king power to express uncertainty characterized by indeterminacy, inconsistency and incompleteness. Most of the existing single valued neutrosophic cross entropy bears an asymmetrical behavior and produce an undefined phenomenon in some situations. In order to deal with these disadvantages, we propose a new cross entropy measure under single valued neutrosophic set (SVNS) environment namely SN- cross entropy and prove its basic properties. Also we define weighted SN-cross entropy measure and investigate its basic properties. We develop a new multi attribute group decision making (MAGDM) strategy for ranking of the alternatives based on the proposed weighted SN-cross entropy measure between each alternative and the ideal alternative. Finally, a numerical example of MAGDM problem of investment potential is solved to show the validity and efficiency of proposed decision making strategy. We also present comparative anslysis of the obtained result with the results obtained form the existing solution strategies in the solution.

A gold(I) complex with a triphenylphosphine and a monodentate N,N-dimethyldithiocarbamate ligand was synthesized and characterized by Raman spectroscopy and single crystal X-ray diffraction. DFT calculations (Gaussian 09, PBE1PBE/Lanl2dz) were undertaken for a single complex in the gas-phase. The DFT-optimized structure is in good agreement with the crystal structure and the DFT-calculated Raman spectrum also is in excellent agreement with the experimental spectrum. Assignments of the Raman peaks are based on these DFT calculations. Frontier molecular orbitals were calculated and their nature is discussed.

Alzheimer’s Disease (AD) is a debilitating neurodegenerative disease characterized by the accumulation of extracellular amyloid-β peptides (Aβ) within the cerebral parenchyma and vasculature, the latter termed cerebral amyloid angiopathy (CAA). This study utilized confocal imaging to investigate heparan sulfate (HS) within the cerebrovasculature and its potential associations with CAA, gender, and ApoE4 genotype. Our investigation revealed elevated levels of HS in the cerebrovasculature of AD patients with severe CAA. Additionally, these patients exhibited higher colocalization of HS with Aβ in the cerebrovasculature, including both endothelial and vascular smooth muscle cell compartments. Intriguingly, a reversal in the polarized expression of HS within the cerebral vasculature was detected in AD patients with severe CAA, suggesting a potential role in CAA development. Furthermore, male patients exhibited lower levels of both parenchymal and cerebrovascular HS. Additionally, ApoE4 carriers displayed heightened cerebrovascular Aβ expression and a tendency of elevated cerebrovascular HS levels in AD patients with severe CAA. Overall, these findings shed light on the intricate interplay between HS, Aβ, ApoE, and vascular pathology in AD, underscoring the potential roles of cerebrovascular HS in CAA development and AD pathology. Further exploring the underlying mechanisms may present novel therapeutic avenues for AD treatment.

The term neuroinflammation defines the reactions of astrocytes and microglia to alterations in homeostasis in the diseased central nervous system (CNS), the exacerbation of which contributes to the neurodegenerative effects of Alzheimer's disease (AD). Local environmental conditions, such as the presence of proinflammatory molecules, mechanical properties of the extracellular matrix (ECM) and local cell-cell interactions, are determinants of glial cell phenotypes. In AD, the load of the cytotoxic/proinflammatory amyloid β peptide (Aβ) is a microenvironmental component increasingly growing in the CNS, imposing time-evolving challenges on resident cells. This study aimed at investigating the temporal and spatial variations of the effects produced by this process on astrocytes and microglia, either directly or by interfering in their interactions. Ex vivo confocal analyses of hippocampal sections from the mouse model TgCRND8 at different ages have shown that overproduction of Aβ peptide induced early and time persistent disassembly of functional astroglia syncytium and promoted a senile phenotype of reactive microglia, hindering Aβ clearance. In the late stages of disease, these patterns were altered in the presence of Aβ-plaques, surrounded by typically reactive astrocytes and microglia. Morphofunctional characterization of peri-plaque gliosis revealed a direct contribution of astrocytes in plaque buildup that might result in shielding Aβ-peptide cytotoxicity and, as a side effect, in exacerbating neuroinflammation.

Chondroitin sulfate (CS) proteoglycan 4 (CSPG4) is a cell surface proteoglycan that is currently under investigation as a marker of cancer malignancy, and as a potential target of anticancer drug treatment. CSPG4 acts as a driver of tumourigenesis by regulating turnover of the extracellular matrix (ECM) to promote tumour cell invasion, migration as well as inflammation and angiogenesis. While CSPG4 has been widely studied in certain malignancies, such as melanoma, evidence is emerging from global gene expression studies, which suggests a role for CSPG4 in squamous cell carcinoma (SCC). While relatively treatable, lack of widely agreed upon diagnostic markers for SCCs is problematic, especially for clinicians managing certain patients, including those who are aged or infirm, as well as those with underlying conditions such as epidermolysis bullosa (EB), for which a delayed diagnosis is likely lethal. In this review, we have discussed the structure of CSPG4, and quantitatively analysed CSPG4 expression in the tissues and pathologies where it has been identified. The aim of this review has been to collate the information available from functional studies and recent transcriptome analysis to determine the usefulness of CSPG4 expression as a diagnostic marker and therapeutic target in management of malignant SCC.

Turner syndrome (TS) is a chromosomal disorder that is caused by a missing or structurally ab-normal second sex chromosome. Subjects with TS are at an increased risk of developing intrauterine growth retardation, low birth weight, short stature, congenital heart diseases, infertility, obesity, dyslipidemia, hypertension, insulin resistance, type 2 diabetes mellitus, metabolic syndrome, and cardiovascular diseases (stroke and myocardial infarction). The underlying pathogenetic mechanism of TS is unknown. The assumption that X chromosome-linked gene haploinsufficiency is associated with the TS phenotype is questioned since such genes have not been identified. Thus, other pathogenic mechanisms have been suggested to explain this phenotype. Morphogenesis encompasses a series of events that includes cell division, the production of migratory precursors and their progeny, differentiation, programmed cell death, and integration into organs and systems. The precise control of the growth and differentiation of cells is essential for normal development. The cell cycle frequency and the number of proliferating cells are essential in cell growth. 45,X cells have a failure to proliferate at a normal rate, leading to a decreased cell number in a given tissue during organogenesis. A convergence of data indicates an association between a prolonged cell cycle and the phenotypical features in Turner syndrome. This review aims to examine old and new findings concerning the relationship between a prolonged cell cycle and TS phenotype. These studies reveal a diversity of phenotypic features in TS that could be explained by reduced cell proliferation. The implications of this hypothesis for our understanding of the TS phenotype and its pathogenesis are discussed. It is not surprising that 45,X monosomy leads to cellular growth pathway dysregulation with profound deleterious effects on both embryonic and later stages of development. The prolonged cell cycle could represent the beginning of the pathogenesis of TS, leading to a series of phenotypic consequences in embryonic/fetal, neonatal, pediatric, adolescence, and adulthood life.

Cost-effective and functionalized scaffolds are in high demand for stem-cell-based regenerative medicine to treat refractory bone defects in craniofacial abnormalities and injuries. One potential strategy is to utilize pharmacological and cost-effective plant polyphenols and biocompatible proteins, such as gelatin. Nevertheless, the use of chemically modified proteins with plant polyphenols in this strategy has not been standardized. Here, we demonstrated that gelatin chemically modified with epigallocatechin gallate (EGCG), the major catechin isolated from green tea, can be a useful material for dedifferentiated fat cells and adipose-derived stem cells and can induce bone regeneration in a rat congenial cleft-jaw model in vivo. Vacuum-heated gelatin sponge modified with EGCG (vhEGCG-GS) induced superior osteogenesis from these two cell types compared with vacuum-heated gelatin sponge (vhGS). The EGCG-modification converted the water wettability of vhGS to a hydrophilic property (contact angle: 110° to 3.8°) and the zeta potential to a negative surface charge; the modification enhanced the cell adhesion property and promoted calcium phosphate precipitation. These results suggest that the EGCG-modification with chemical synthesis can be a useful platform to modify the physicochemical property of gelatin. This alteration is likely to provide a preferable microenvironment for multipotent progenitor cells, inducing superior bone formation in vivo.

Single-phase-to-ground fault in non-effectively grounded systems poses serious public safety concern. Along with increasing deployment of low-voltage (LV) sensors, new opportunities and ways are created for solving this traditional problem in distribution systems. A new approach, identifying primary single-phase-to-ground line fault and locating it through measurement data from smart sensors deployed in the secondary side of distribution transformers, is proposed in this paper. When a fault occurs in primary distribution feeder, the transient aerial mode voltage (AMV) of each LV smart sensor is calculated. The fault line can be identified by an abrupt change value of AMV at LV side. Next, by finding the position of the maximum value of this AMV from LV sensors on the fault line, the fault location can be pinpointed to two neighboring distribution transformers. The proposed method has been proven to be efficient and reliable by simulation studies.

The state detection of power cable is very important to ensure the reliability of power supply. Traditional sensors are mostly based on electric field detection, the operation is complex, and its efficiency needs to be improved. This paper optimizes the design and development of the magnetic field detection sensor for AC power cables. Firstly, through the establishment of the magnetic field sensor model, it is determined that permalloy is the material of the magnetic core, the optimal aspect ratio of the magnetic core is 20, and the ratio of coil length to core length is 0.3. Secondly, the coil simulation model is established, and it is determined that the optimal number of turns of the coil is 11000 turns, the diameter of the enamelled copper wire is 0.08mm, and the equivalent magnetic field noise of the sensor is 0.06pT. Finally, the amplifying circuit based on negative magnetic flux feedback is designed and the sensor is assembled, and the experimental circuit is built for sensitivity test. the results show that the sensitivity of the magnetic field sensor is 327.6mV/μT. The sensor designed in this paper has the advantages of small size, high sensitivity, easy to carry and high reliability.

Background and Objectives: Rheumatic diseases often exhibit a complex pattern of comorbidities, including the increased occurrence of emotional disorders like anxiety and depression, which are closely related to the presence of chronic pain. Therefore, a multimodal approach is necessary for treatment, targeting both the physical and psychological functioning. Due to the increased burden within the healthcare context that emerged during the post-pandemic period, the need to adjust the content and length of psychological interventions became ubiquitous. In this way, the main objective of this study was to investigate the efficiency of a single-session, process-based psychological intervention for patients with rheumatic conditions and emotional comorbidities in a naturalistic, in-patient setting. Materials and Methods: After the screening, a total of 31 participants (Mage = 58.9, SD = 12.03) completed the single session intervention. The therapeutic protocol relied on a process-based cognitive-behavioural therapy framework aiming to improve cognitive, emotional and behavioural functioning. Assessments were conducted prior to the intervention, post-intervention and one month following the hospitalization. Results: Immediately after the intervention, significant reductions in dysfunctional cognitive and emotional processes, along with the improvement of behavioural strategies were observed. At the one-month telephonic evaluation, participants reported decreased pain, state anxiety and state depression levels. Conclusions: The single-session, process-based approach represents a promising intervention in healthcare contexts, targeting important psychopathological mechanisms in patients with rheumatic conditions. Future studies could clarify the extent to which these outcomes persist over time and their specific associations with anxiety and depressive symptoms, by using more controlled and rigorous trial designs.

In the paper the experimental methodology for the single-crystal circular plate deformation measurement and subsequent procedure for mechanical properties quantitation are developed. The procedure is based on a new numerical-analytical solution of nonlinear boundary-value problem for finite deformations of a circular anisotropic plate. Using the developed method, a study of the deformation of single-crystal circular plates formed on the basis of a silicon-on-insulator structure was carried out. The values of residual stresses are determined and it is shown that the presence of these stresses increases the flexural rigidity of the plate in several times.

The authors of the article analyze the existing methods and models of technological preparation of machine-building industries. The structure of a three-level simulation model with network-centric control, the structures of individual elements of the simulation model and the process of simulation modeling are described. The criteria for choosing a rational option for the processing technological route have been determined. During the research, a simulation program was implemented in C++. It allows you to select the optimal scenario for the operation of a production site based on two criteria: time and cost. The volume of implementation is about 2x103 lines of code. A diagram of the modeling algorithm for the implemented program, a description of the classes and their interactions are given in the article. The developed simulation model was tested at a machine-building enterprise using the example of the “Pusher” part, manufactured under single-unit production condi-tions. The technological equipment used for the manufacture of this part was formed in the form of input data of the simulation model. The results of simulation modeling for the selected part are described. For each variant of the technological processing route, the values of variable costs and the duration of the production cycle were determined.

Human Ribonuclease (RNase) 6 is a monocyte and macrophage-derived protein with potent an-timicrobial activity toward uropathogenic bacteria. The RNASE6 gene is heterogeneous in hu-mans due to the presence of single nucleotide polymorphisms (SNPs). RNASE6 rs1045922 is the most common non-synonymous SNP, resulting in a G to A substitution that determines an ar-ginine (R) to glutamine (Q) transversion at position 66 in the protein sequence. By structural analysis we observed that R66Q substitution significantly reduces the positive electrostatic charge at the protein surface. Here, we generated both recombinant RNase 6 -R66 and -Q66 protein variants and determined their antimicrobial activity toward uropathogenic Escherichia coli (UPEC), the most common cause of UTI. We found that the R66 variant, encoded by the major SNP rs1045922 allele, exhibited superior bactericidal activity in comparison to the Q66 variant. The higher bactericidal activity of R66 variant correlated with an increase in the protein lipopolysac-charide binding and bacterial agglutination abilities, while retaining the same enzymatic effi-ciency. These findings encourage further work to evaluate RNASE6 SNP distribution and its impact in UTI susceptibility.

Currently Single Board Computers (SBCs) are sufficiently powerful to run Real-Time Operating Systems (RTOSs) and applications with real-time attributes and requirements. SBCs serve as a foundation in Industrial Internet of Things (IIoT). The NXP Semiconductors produces a series of SBCs based on ARM-processors for a variety of industrial applications. The continuous increase in real-time data generated by IoT devices adds further research issues about the efficiency of such systems and applications. The purpose of this research was to investigate the timing performance of an NXP TWR-K70F120M device with μClinux OS on running concurrently tasks with real-time features and constraints. A custom-built multithreaded application with specific compute-intensive sorting and matrix operations was developed and applied to obtain measurements in specific timing metrics, including task’s execution time, threads waiting time, and response time, under different threads variations. The performance of this device was additionally benchmarked and validated against favorite platforms, a Raspberry Pi4 and BeagleBone AI SBCs. The experimental results showed that this device stands well both in terms of timing and efficiency metrics. Execution times were quite lower than the others, by approximately 56% in the case of two threads, and by 29% in the case of thirty-two threads configurations.

Prostate-specific membrane antigen (PSMA) is a well validated prostate cancer marker, but reported PSMA-targeted tracers derived from the Lys-urea-Glu pharmacophore including the clinically validated [99mTc]Tc-EDDA/HYNIC-iPSMA have high off-target uptake in kidneys, spleen and salivary glands. In this study, we synthesized and evaluated three novel 99mTc-labeled PSMA-targeted tracers and investigated if the tracers derived from the Lys-urea-Aad pharmacophore could have minimized uptake in off-target organs/tissues. In vitro competition binding assays showed that compared with HYNIC-iPSMA, the three novel ligands had slightly weaker PSMA binding affinity (average Ki = 3.11 vs 8.96 - 11.6 nM). Imaging and ex vivo biodistribution studies in LNCaP tumor-bearing mice showed that [99mTc]Tc-EDDA/HYNIC-iPSMA and the three novel tracers successfully visualized LNCaP tumor xenografts in SPECT images and were excreted mainly via the renal pathway. The average tumor uptake at 1 h post-injection varied from 5.40 to 18.8 %ID/g, and the tracers derived from the Lys-urea-Aad pharmacophore had much lower uptake in spleen and salivary glands. Compared with the clinical tracer [99mTc]Tc-EDDA/HYNIC-iPSMA, the Lys-urea-Aad derived [99mTc]Tc-EDDA-KL01127 had lower background uptake and superior tumor-to-background contrast ratios, and is therefore promising for clinical translation to detect prostate cancer lesions with SPECT.

Achieving high-yield potential is always the ultimate objective of any breeding program. However, various abiotic stresses like salinity, drought, cold, flood, and heat hampered rice productivity tremendously. Salinity is one of the most important abiotic stresses that adversely affect rice grain yield. The present investigation was undertaken to dissect new genetic loci, which are responsible for salt tolerance at the early seedling stage in rice. A bi-parental mapping population (F2:3) was developed from the cross between BRRI dhan28/Akundi, where BRRI dhan28 (BR28) is a salt-sensitive irrigated (boro) rice mega variety and Akundi is a highly salinity tolerant Bangladeshi origin indica rice landrace that is utilized as a donor parent. We report stable QTLs for salt tolerance from a common donor (Akundi) irrespective of two different genetic backgrounds (BRRI dhan49/Akundi and BRRI dhan28/Akundi). A robust 1k-Rice Custom Amplicon (1k-RiCA) SNP marker genotyping platform was used to genotype this bi-parental population. After eliminating markers with high segregation distortion, 886 polymorphic SNPs built a genetic linkage map covering 1526.5 cM of whole rice genome with an average SNP density of 1.72 cM for the 12 genetic linkage groups. A total of 12 QTLs for nine different salt tolerance-related traits were identified using QGene and inclusive composite interval mapping of additive and dominant QTL (ICIM-ADD) under salt stress on seven different chromosomes. All of these 12 new QTLs found unique, as no other map from the previous study has reported these QTLs in the similar chromosomal location and found them different from extensively studied Saltol, SKC1, OsSalT and salT locus. Twenty-eight significant digenic/epistatic interactions identified between chromosomal regions linked to or unlinked to QTLs. Akundi acts like a new alternate donor source of salt tolerance except for other usually known donors like Nona Bokra, Pokkali, Capsule, and Hasawi used in salt tolerance genetic analysis and breeding programs worldwide, including Bangladesh. Integration of the seven novel and stable QTLs (qSES1, qSL1, qRL1, qSUR1, qSL8, qK8, qK1) reported in this investigation will expedite the cultivar development that is highly tolerant to salt stress.

The frequency of selected polymorphisms, one in each gene coding for proteins with antioxidative properties (CAT, SOD2, GPX1, NQO1) was compared between patients suffering from pain-related temporomandibular disorders (TMDp;n=85) and control subjects (CTR;n=85). According to the Oral Behaviours Checklist score participants were divided into high-frequency parafunction (HFP;n=98) and low-frequency parafunction (LFP;n=72) groups. In addition, we have investigated the association of selected polymorphisms with participants' psychological (anxiety, depression) and psychosomatic (hypervigilance, somatosensory amplification) characteristics. Polymorphisms rs1001179, rs4880, rs1050450, rs689452 were genotyped using the genomic DNA extracted from buccal mucosa swabs and real-time TaqMan genotyping assays. No differences in genotype distribution between TMDp patients and control subjects were found. Still, TMDp patients who were homozygous for minor allele A, related to the GPX1 polymorphism rs1050450 reported significantly more waking-state oral behaviours compared to GA+GG genotype carriers (score: 30 vs. 23, p=0.019). Frequency of genotype AA for rs1050450 polymorphism was higher in HFP compared to LFP participants (14.3% vs. 4.2%, p =0.030). Most important predictors of waking-state oral behaviours were depression, anxiety, AA genotype (rs1050450) and female sex. Explored genetic factors were not found to be significant risk factors for either TMDp or sleep-related oral behaviours. The association of waking-state oral behaviours with selected gene polymorphisms additionally supports previous assumptions that the daytime bruxism is more closely linked to various stress manifestations, which might also be reflected through the variability related to cellular antioxidative activity.

Like 18F-FDG, 99mTc-1-thio-D-glucose (99mTc-TG) also binds to GLUT receptors. The aim of this Phase I study was to evaluate the safety, biodistribution and dosimetry of 99mTc-TG. Twelve lym-phoma patients were injected with 729±102 MBq 99mTc-TG. Whole-body planar imaging was per-formed in 10 patients at 2, 4, 6 and 24 h after injection. In all 12 patients SPECT/CT (at 2 h) and SPECT (at 4 and 6 h) imaging was performed. Vital signs and possible side effects were monitored during imaging and up to 7 days after injection. 99mTc-TG injections were well tolerated and no side effects or alterations in blood and urine analyses data were observed. The highest absorbed dose was in the kidneys and urinary bladder wall, followed by the adrenals, prostate, bone mar-row, lungs, myocardium, ovaries, uterus, liver and gall bladder wall. 99mTc-TG SPECT/CT re-vealed foci of high activity uptake in the lymph nodes of all nine patients with known nodal le-sions. Extranodal lesions were detected in all nine cases. In one patient, a lesion in the humerus head, which was not detected by CT, was visualized using 99mTc-TG. Potentially, 99mTc-TG SPECT can be considered as an additional diagnostic method for imaging GLUT receptors in lymphoma patients.

Poly(2-methoxyethyl acrylate) (PMEA) and poly(ethylene oxide) (PEO) have protein-antifouling properties and blood compatibility. ABA triblock copolymers (PMEAn-PEO11340-PMEAn (MEOMn)) were prepared using single-electron transfer-living radical polymerization (SET-LRP) using a bi-functional PEO macroinitiator. Two types of MEOMn composed of PMEA blocks with a degree of polymerization (DP = n) of 85 and 777 were prepared using the same PEO macroinitiator. MEOMn formed flower micelles with a hydrophobic PMEA (A) core and hydrophilic PEO (B) loop shells in diluted water with a similar appearance to petals. The hydrodynamic radii of MEOM85 and MEOM777 were 151 and 108 nm, respectively. The PMEA block with a large DP formed a tightly packed core. The aggregation number (Nagg) of the PMEA block in a single flower micelle for MEOM85 and MEOM777 was 156 and 164, respectively, which were estimated using a light scat-tering technique. The critical micelle concentrations (CMCs) for MEOM85 and MEOM777 were 0.01 and 0.002 g/L, respectively, as determined by the light scattering intensity and fluorescence probe techniques. The size, Nagg, and CMC for MEOM85 and MEOM777 were almost the same inde-pendent of hydrophobic DP of the PMEA block.

Single-molecule fluorescence detection (SMFD) experiments are useful in distinguishing sub-populations of molecular species when measuring heterogeneous samples. One experimental platform for SMFD is based on a confocal microscope, where molecules randomly traverse an effective detection volume. The non-uniformity of the excitation profile and the random nature of Brownian motion, produce fluctuating fluorescence signals. For these signals to be distinguished from the background, burst analysis is frequently used. Yet, the relation between the results of burst analyses and the underlying information of the diffusing molecules is still obscure and requires systematic assessment. In this work we performed three-dimensional Brownian motion simulations of SMFD, and tested the positions at which molecules emitted photons that passed the burst analysis criteria for different values of burst analysis parameters. The results of this work verify which of the burst analysis parameters and experimental conditions influence both the position of molecules in space when fluorescence is detected and taken into account, and whether these bursts of photons arise purely from single molecules, or not entirely. Finally, we show, as an example, the effect of bursts that are not purely from a single molecule on the accuracy in single-molecule Förster resonance energy transfer measurements.

The nuclear lamina consists of a dense fibrous meshwork made of nuclear lamins, Type V intermediate filaments, and is ~14 nm thick according to recent cryo-electron tomography studies. Recent advances in light microscopy have extended the resolution to a scale allowing for the fine structure of the lamina to be imaged in the context of the whole nucleus. We review quantitative approaches to analyze the imaging data of the nuclear lamina as acquired by structured illumination microscopy (SIM) and single molecule localization microscopy (SMLM), as well as the requisite cell preparation techniques. In particular, we discuss the application of steerable filters and graph based methods to segment the structure of the four mammalian lamin isoforms (A, C, B1, and B2) and extract quantitative information.

The three-dimensional single fin configuration finds application in an intake geometry where the cowl-shock wave interacts with the side-wall boundary-layer. Accurate numerical simulation of such three-dimensional shock/turbulent boundary-layer interaction flows, which are characterized by the appearance of strong crossflow separation, is a challenging task. Reynolds-averaged Navier-Stokes computations using the shock-unsteadiness modified Spalart-Allmaras model is carried out at Mach of 5 at large fin angle of 23^◦. The computed results using the modified model are compared to the standard Spalart-Allmaras model and validated against the experimental data. The focus of work is to implement the modified model and to study the flow physics in detail in the complex region of swept-shock-wave turbulent boundary-layer interaction in terms of the shock structure, expansion fan, shear layer and the surface streamlines. The flow structure is correlated to the wall pressure and skin friction in detail. It is observed that the standard model predicts an initial pressure location downstream of the experiments. The modified model reduces the eddy viscosity at the shock and predicts close to the experiments. Overall, the surface pressure using modified model is predicted accurately at all the locations. The skin friction is under predicted by both the models in the reattachment region and is attributed to the poor performance of turbulence models due to flow laminarization.

The growing attention for plug-in electric vehicles, and the associated high-performance demands, have initiated a development trend towards highly efficient and compact on-board battery chargers. These isolated ac-dc converters are most commonly realized using two conversion stages, combining a non-isolated power factor correction (PFC) rectifier with an isolated dc-dc converter. This, however, involves two loss stages and a relatively high component count, limiting the achievable efficiency and power density and resulting in high costs. In this paper a single-stage converter approach is analyzed to realize a single-phase ac-dc converter, combining all functionalities into one conversion stage and thus enabling a cost-effective efficiency and power density increase. The converter topology consists of a quasi-lossless synchronous rectifier followed by an isolated dual active bridge (DAB) dc-dc converter, putting a small filter capacitor in between. To show the performance potential of this bidirectional, isolated ac-dc converter, a comprehensive design procedure and multi-objective optimization with respect to efficiency and power density is presented, using detailed loss and volume models. The models and procedures are verified by a 3.7 kW hardware demonstrator, interfacing a 400 V dc-bus with the single-phase 230 V, 50 Hz utility grid. Measurement results indicate a state-of-the-art efficiency of 96.1% and power density of 2.2 kW/dm³, confirming the competitiveness of the investigated single-stage DAB ac-dc converter.

The use of chimeric antigen receptor (CAR) in natural killer (NK) cells for cancer therapy is gaining momentum, marking a significant shift in cancer treatment. This review aims to explore the potential of CAR-NK cell therapy in cancer immunotherapy, providing a fresh perspective. It discusses the innovative approaches in CAR-NK cell design and engineering, particularly targeting refractory or recurrent cancers. By comparing CAR-NK cells with traditional therapies, the review highlights their unique ability to tackle tumor heterogeneity and immune system suppression. Additionally, it explains how novel cytokines and receptors can enhance CAR-NK cell efficacy, specificity, and functionality. The review underscores the advantages of CAR-NK cells, including reduced toxicity, lower cost, and broader accessibility compared to CAR-T cells, along with their potential in treating both blood cancers and solid tumors.

C. albicans Dfg5 and Dcw1 are homologous cell wall alpha-1,6-mannosidases with important functions. Our past studies have shown that Dfg5 and Dcw1 function in cell wall biogenesis via cross-linking of glycoproteins into the cell wall, thus playing a key role in cell wall integrity. Additionally, Dfg5 and Dcw1 are required for hyphal morphogenesis. However, the exact functions of Dfg5 and Dcw1 in cell wall integrity, hyphal morphogenesis, and pathogenesis were not known. In this study, we determined the relation of Dfg5 and Dcw1 with Hog1 MAPK, that plays a key role in cell wall integrity via regulation of chitin synthesis in C. albicans. Additionally, we also determined the effect of dfg5 and dcw1 mutations on gene expression of transcriptional regulators of hyphal morphogenesis. Furthermore, we determined the effects of dfg5 and dcw1 mutations on pathogenesis in a mouse model of oral candidiasis. Our results demonstrate that dfg5 and dcw1 mutations, as well as hog1 knock-out mutation result in dysregulation of chitin synthesis resulting in a cell separation defect. The heterozygous and conditional mutations of dfg5 and dcw1 result in decreased levels of Cst20, a positive regulator of hyphal morphogenesis. However, mutations of dfg5 and dcw1 mutations resulted in increased levels of all the five negative regulators of hyphal morphogenesis – Tup1, Nrg1, Mig1, Rbf1 and Rfg1. However, Tup1 levels were significantly higher than other negative regulators indicating that Dfg5 and Dcw1 function in hyphal morphogenesis by repression of Tup1. Finally, dfg5 and dcw1 mutations affected the ability of C. albicans to cause oral candidiasis in mice. Thus, cell wall glycosidases, Dfg5 and Dcw1, are required for virulence and pathogenesis and represent novel drug targets.

Androgenetic alopecia is a genetic disorder caused by an excessive response to androgens. This alopecia is the most common cause of progressive hair loss in men and causes low self-esteem in patients. In this study we used various methods, including quantitative PCR, flow cytometry, ELISA, and immunocytochemistry, to evaluate the biological effects of germinated hemp seeds extract and exosomes derived from calli of germinated hemp seeds. This research reveals pre-ventive functions of two biomaterials (GE2000: 2000 ug/mL germinated hemp seeds extract; E40: 40 ng/mL exosomes derived from calli of germinated hemp seeds) for androgenetic alopecia through three biochemical categories: genetic modulation in hair follicle dermal papilla stem cells (HFDPSCs), cellular differentiation, and modulation of immune systems. Despite exposure to dihydrotestosterone (DT), two materials upregulated alopecia preventing genes including Wnt, β-catenin, and TCF in HFDPSCs. Conversely, alopecia activating genes (STAT1, 5α-reductase type 1, and IL-15R) were suppressed. Moreover, two materials suppressed alopecia genes (NKG2DL, IL2-Rβ, JAK1, and STAT1) in CD8+ T cells. Notably, E40 was effected more in-tensely in these biochemical categories than those of GE2000. Consequently, E40 and GE2000 ef-fectively prevented DT stress. Additionally, two materials activated mechanisms for hair for-mation through the biological activities of three categories.

Receptor-interacting protein kinase 1 (RIPK1) plays a crucial role in controlling inflammation and cell death. Its function is tightly controlled through post-translational modifications, enabling its dynamic switch between promoting cell survival and triggering cell death. Phosphorylation of RIPK1 at various sites serves as a critical mechanism for regulating its activity, exerting either activating or inhibitory effects. Perturbations in RIPK1 phosphorylation status have profound implications for the development of severe inflammatory diseases in humans. This review explores the intricate regulation of RIPK1 phosphorylation and dephosphorylation and highlights the potential of targeting RIPK1 phosphorylation as a promising therapeutic strategy for mitigating human diseases.

Magnetogenetics emerges as a transformative approach for modulating cellular signaling pathways through the strategic application of magnetic fields and nanoparticles. This technique leverages the unique properties of magnetic nanoparticles (MNPs) to induce mechanical or thermal stimuli within cells, facilitating the activation of mechano- and thermosensitive proteins without the need for traditional ligand-receptor interactions. Unlike traditional modalities that often require invasive interventions and lack precision in targeting specific cellular functions, magnetogenetics offers a non-invasive alternative with the capacity for deep tissue penetration and the potential for targeting a broad spectrum of cellular processes. This review underscores magnetogenetics' broad applicability, from steering stem cell differentiation to manipulating neuronal activity and immune responses, highlighting its potential in regenerative medicine, neuroscience, and cancer therapy. Furthermore, the review explores the challenges and future directions of magnetogenetics, including the development of genetically programmed magnetic nanoparticles and the integration of magnetic field-sensitive cells for in vivo applications. Magnetogenetics stands at the forefront of cellular manipulation technologies, offering novel insights into cellular signaling and opening new avenues for therapeutic interventions.

GCTs are developmental tumors and likely to reflect ontogenetic and teratogenetic determinants. The objective was to identify syndromes with or without congenital anomalies and non-syndromic defects as potential risk factors. Patients with extracranial GCTs (eGCTs) registered in MAKEI 96/MAHO 98 between 1996 and 2017 were used. According to Teilum's holistic concept malignant and benign teratomas were registered. We used a case control study design with Orphanet as a reference group for syndromic defects and the Mainz birth registry (EUROCAT) for congenital anomalies at birth. Co-occurring genetic syndromes and/or congenital anomalies were assessed accordingly. Odds ratios and 95% confidence intervals were calculated and p-values for Fisher’s exact test with Bonferroni correction if needed. A strong association was confirmed for Swyer (OR 338.6, 95% CI 43.7-2623.6) and Currarino syndrome (OR 34.2, 95% CI 13.2-88.6). We additionally found 17 isolated cases of eGCT with a wide range of syndromes, however not significantly associated following Bonferroni correction. All these cases pertained to girls. Regarding non-syndromic defects, no association with eGCTs could be identified. In our study we confirmed a strong association for Swyer and Currarino syndromes with additional congenital anomalies.

Protein Kinase C delta (PKCδ) has emerged as a key protective molecule against systemic lupus erythematosus (SLE or lupus), an autoimmune disease characterized by anti-double stranded (ds) DNA IgGs. Although PKCδ deficient mice and lupus patients with mutated PRKCD genes clearly demonstrate the requirement of PKCδ for preventing lupus autoimmunity, this critical tolerance mechanism remains poorly understood. We recently reported that PKCδ selectively deletes anti-dsDNA B cells in the germinal center (GC), disclosing a key B cell tolerance mechanism that prevents lupus autoimmunity. PKCδ’s tolerance function is activated by sphingomyelin synthase 2 (SMS2), a lipid enzyme whose expression is generally reduced in B cells from lupus patients. Moreover, pharmacologic strengthening of the SMS2/PKCδ tolerance pathway alleviated lupus pathogenesis in mice. Here, we review relevant publications in order to provide mechanistic insights into PKCδ’s tolerance activity, and discuss the potential significance of therapeutically targeting PKCδ’s tolerance activity in the GC for selectively inhibiting lupus autoimmunity.

The blood count is crucial for assessing bone marrow's cell production and differentiation during infections, gauging disease severity, and monitoring therapeutic responses. The profile of blood count in chronic form of paracoccidioidomycosis (PCM) has been insufficiently explored. To better understand the changes in hematological cells in different stages of the PCM chronic form, we evaluated the blood count, including immature blood cells in automated equipment, before and during the treatment follow-up of 62 chronic PCM patients. Predominantly male (96.8%) with an average age of 54.3 (SD 6.9) years, participants exhibited pre-treatment conditions such as anemia (45.2%), monocytosis (38.7%), and leukocytosis (17.7%) which became less frequent after clinical cure. Anemia was more prevalent in severe cases. Notably, hemoglobin and reticulocyte hemoglobin content increased, while leukocytes, monocytes, neutrophils, immature granulocytes, and platelets decreased. Chronic PCM induced manageable hematological abnormalities, mainly in the red blood series. Monocytosis, indicating monocytes' role in PCM's immune response, was frequent. Post-treatment, especially after achieving clinical cure, significant improvements were observed in various hematological indices, including immature granulocytes and reticulocyte hemoglobin content, underscoring the impact of infection on these parameters.