bluuebunny/crossref_metadata_2025 huggingface dataset:
Connectivity Patterns of Deep Brain Stimulation Targets in Patients with Gilles de la Tourette Syndrome
Authors: Heiden Petra , Hoevels Mauritius , Bayram Dilruba , Baldermann Juan , Schüller Thomas , Huys Daniel , Visser-Vandewalle Veerle , Andrade Pablo
Published: January 2021

Since 1999, several targets for deep brain stimulation (DBS) in Gilles de la Tourette syndrome (GTS) have emerged showing similar success rates. Studies using different tractography techniques have identified connectivity profiles associated with a better outcome for individual targets. However, GTS patients might need individualized therapy. The objective of this study is to analyze the connectivity profile of different DBS targets for GTS. We identified standard target coordinates for the centromedian nucleus/nucleus ventro-oralis internus (CM/Voi), the CM/parafascicular (CM-Pf) complex, the anteromedial globus pallidus internus (amGPi), the posteroventral GPi (pvGPi), the ventral anterior/ventrolateral thalamus (VA/VL), and the nucleus accumbens/anterior limb of the internal capsule (Nacc/ALIC). Probabilistic tractography was performed from the targets to different limbic and motor areas based on patient-specific imaging and a normative connectome (HCP). Our analysis showed significant differences between the connectivity profiles of standard DBS targets (p < 0.05). Among all targets, the pvGPi showed the strongest connection to the sensorimotor cortex, while the amGPi showed the strongest connection to the prefrontal cortex in patient-specific imaging. Differences were observed between the connectivity profiles when using probabilistic tractography based on patient data and HCP. Our findings showed that the connectivity profiles of different DBS targets to major motor and limbic areas differ significantly. In the future, these differences may be considered when planning DBS for GTS patients employing an individualized approach. There were compelling differences in connectivity profiles when using different tractography techniques.
Current Melanoma Treatments: Where Do We Stand?
Authors: Moreira Alvaro , Heinzerling Lucie , Bhardwaj Nina , Friedlander Philip
Published: January 2021

Groundbreaking research in immunology and cancer biology in the last few decades has led to the discovery and development of novel therapeutics, such as immune checkpoint inhibitors and targeted therapies, which have revolutionized the clinical care of patients with metastatic melanoma. Updated data from the largest clinical trials continue to support the use of these treatment modalities, both in the metastatic and in adjuvant settings, with studies showing the predicted plateau effect on survival curves. However, with growing evidence that neoadjuvant therapy is also associated with high rates of recurrence-free survival, the question about whether patients should receive adjuvant or neoadjuvant treatment raises new questions about therapeutic options. Finally, management after resistance and intervention with novel immunotherapies are newer challenges, particularly in the field of non-cutaneous melanoma.
Promoterless Transposon Mutagenesis Drives Solid Cancers via Tumor Suppressor Inactivation
Authors: Aiderus Aziz , Contreras-Sandoval Ana M. , Meshey Amanda L. , Newberg Justin Y. , Ward Jerrold M. , Swing Deborah A. , Copeland Neal G. , Jenkins Nancy A. , Mann Karen M. , Mann Michael B.
Published: January 2021

A central challenge in cancer genomics is the systematic identification of single and cooperating tumor suppressor gene mutations driving cellular transformation and tumor progression in the absence of oncogenic driver mutation(s). Multiple in vitro and in vivo gene inactivation screens have enhanced our understanding of the tumor suppressor gene landscape in various cancers. However, these studies are limited to single or combination gene effects, specific organs, or require sensitizing mutations. In this study, we developed and utilized a Sleeping Beauty transposon mutagenesis system that functions only as a gene trap to exclusively inactivate tumor suppressor genes. Using whole body transposon mobilization in wild type mice, we observed that cumulative gene inactivation can drive tumorigenesis of solid cancers. We provide a quantitative landscape of the tumor suppressor genes inactivated in these cancers and show that, despite the absence of oncogenic drivers, these genes converge on key biological pathways and processes associated with cancer hallmarks.
Alterations of NK Cell Phenotype in the Disease Course of Multiple Myeloma
Authors: Pazina Tatiana , MacFarlane Alexander W. , Bernabei Luca , Dulaimi Essel , Kotcher Rebecca , Yam Clinton , Bezman Natalie A. , Robbins Michael D. , Ross Eric A. , Campbell Kerry S. , Cohen Adam D.
Published: January 2021

Accumulating evidence demonstrates important roles for natural killer (NK) cells in controlling multiple myeloma (MM). A prospective flow cytometry-based analysis of NK cells in the blood and bone marrow (BM) of MM patient subgroups was performed (smoldering (SMM), newly diagnosed (ND), relapsed/refractory, (RR) and post-stem cell transplantation (pSCT)). Assessments included the biomarker expression and function of NK cells, correlations between the expression of receptors on NK cells with their ligands on myeloma cells, and comparisons between MM patient subgroups and healthy controls. The most striking differences from healthy controls were found in RR and pSCT patients, in which NK cells were less mature and expressed reduced levels of the activating receptors DNAM-1, NKG2D, and CD16. These differences were more pronounced in the BM than in blood, including upregulation of the therapeutic targets TIM3, TIGIT, ICOS, and GITR. Their expression suggests NK cells became exhausted upon chronic encounters with the tumor. A high expression of SLAMF7 on blood NK cells correlated with shorter progression-free survival. This correlation was particularly evident in ND patients, including on mature CD56dim NK cells in the BM. Thus, our NK cell analysis identified possible therapeutic targets in MM and a biomarker with prognostic potential for disease progression.
The Impact of Multidisciplinary Team Meetings on Patient Management in Oncologic Thoracic Surgery: A Single-Center Experience
Authors: Petrella Francesco , Radice Davide , Guarize Juliana , Piperno Gaia , Rampinelli Cristiano , de Marinis Filippo , Spaggiari Lorenzo
Published: January 2021

Background: the aim of this paper is to quantify multidisciplinary team meeting (MDT) impact on the decisional clinical pathway of thoracic cancer patients, assessing the modification rate of the initial out-patient evaluation. Methods: the impact of MDT was classified as follows: confirmation: same conclusions as out-patient hypothesis; modification: change of out-patient hypothesis; implementation: definition of a clear clinical track/conclusion for patients that did not receive any clinical hypothesis; further exams required: the findings that emerged in the MDT meeting require further exams. Results: one thousand consecutive patients evaluated at MDT meetings were enrolled. Clinical settings of patients were: early stage lung cancer (17.4%); locally advanced lung cancer (27.4%); stage IV lung cancer (9.8%); mesothelioma (1%); metastases to the lung from other primary tumors (4%); histologically proven or suspected recurrence from previous lung cancer (15%); solitary pulmonary nodule (19.2%); mediastinal tumors (3.4%); other settings (2.8%). Conclusions: MDT meetings impact patient management in oncologic thoracic surgery by modifying the out-patient clinical hypothesis in 10.6% of cases; the clinical settings with the highest decisional modification rates are “solitary pulmonary nodule” and “proven or suspected recurrence” with modification rates of 14.6% and 13.3%, respectively.
Adenosinergic Pathway: A Hope in the Immunotherapy of Glioblastoma
Authors: Jin Ketao , Mao Chunsen , Chen Lin , Wang Lude , Liu Yuyao , Yuan Jianlie
Published: January 2021

Brain tumors comprise different types of malignancies, most of which are originated from glial cells. Glioblastoma multiforme (GBM) is the most aggressive type of brain tumor with a poor response to conventional therapies and dismal survival rates (15 months) despite multimodal therapies. The development of immunotherapeutic strategies seems to be necessary to enhance the overall survival of GBM patients. So far, the immunotherapies applied in GBM had promising results in the primary phases of clinical trials but failed to continue their beneficial effects in later phases. GBM-microenvironment (GME) is a heterogenic and rigorously immunosuppressive milieu wrapping by an impenetrable blood-brain barrier. Hence, in-depth knowledge about the dominant immunosuppressive mechanisms in the GME could foster GBM immunotherapy. Recently, the adenosinergic pathway (AP) is found to be a major player in the suppression of antitumor immune responses in the GME. Tumor cells evolve to metabolize pro-inflammatory ATP to anti-inflammatory adenosine. Adenosine can suppress immune responses through the signaling of adenosine receptors on immune cells. The preclinical results targeting AP in GBM showed promising results in reinvigorating antitumor responses, overriding chemoresistance, and increasing survival. We reviewed the current GBM immunotherapies and elaborated on the role of AP in the immunopathogenesis, treatment, and even prognosis of GBM. We suggest that future clinical studies should consider this pathway in their combination therapies along with other immunotherapeutic approaches.
Chemotherapy-Induced Upregulation of Somatostatin Receptor-2 Increases the Uptake and Efficacy of 177Lu-DOTA-Octreotate in Neuroendocrine Tumor Cells
Authors: Shah Rashmi G. , Merlin Marine A. , Adant Samuel , Zine-Eddine Fayçal , Beauregard Jean-Mathieu , Shah Girish M.
Published: January 2021

The peptide receptor radionuclide therapy (PRRT) with 177Lu-DOTA-octreotate (LuTate) is recommended for different types of neuroendocrine tumors (NETs) which overexpress somatostatin receptors (SSTR). A combination with chemotherapy improves objective response to LuTate in NET patients and here we characterized chemotherapy-induced upregulation of SSTR2 receptors as a cause for this improved response to LuTate. The NET cell lines with low (BON-1) or relatively high (NCI-H727) SSTR2-expression levels, and non-NET cancer and normal cells were treated with chemotherapeutic drugs and assessed for upregulation of SSTR2. We report that an exposure to low or high doses of drugs, such as temozolomide for 24 h or 5 day results in upregulation of SSTR2 between 3–7 days, increased LuTate uptake and decreased rate of cell proliferation. This effect is at the level of SSTR2-mRNA and is more pronounced in low SSTR2 expressing BON-1 than in high SSTR2 expressing NCI-H727 or non-NET cancer or normal cells. Thus, a properly timed pre-treatment with low-dose chemotherapy could not only improve therapeutic efficacy of LuTate in NET patients who are presently eligible for PRRT, but also allow PRRT to be administered to patients with low SSTR-expressing NETs, who would otherwise not respond to this modality because of insufficient radiation delivery.
The Presence of an In Situ Component on Pre-Treatment Biopsy Is Not Associated with Response to Neoadjuvant Chemotherapy for Breast Cancer
Authors: Labrosse Julie , Morel Charlotte , Lam Thanh , Laas Enora , Feron Jean-Guillaume , Coussy Florence , Lae Marick , Reyal Fabien , Hamy Anne-Sophie
Published: January 2021

A ductal in situ (DCIS) component is often associated with invasive breast carcinoma (BC), and its effect on response to treatment is unknown. We assessed the predictive value of the DCIS component for pathologic complete response (pCR) after neoadjuvant chemotherapy (NAC). We analyzed a cohort of 1148 T1–3NxM0 breast cancer (BC) patients treated by NAC at Institut Curie between 2002 and 2012. The presence of a DCIS component was retrospectively recorded from both the pre-NAC biopsy pathological report and surgical specimens. We included 1148 BC patients treated by NAC for whom pre- and post-NAC data concerning the in situ component were available. DCIS was present before NAC in 19.6% of the population. Overall, 283 patients (19.4%) achieved pCR after NAC. There was no significant association between the presence of DCIS on pre-NAC biopsy and pCR. In a multivariate analysis including subtype, tumor size, grade, mitotic index, and Ki67 index, only BC subtype (luminal/TNBC/HER2-positive) and Ki67 were significantly associated with pCR. The presence of a DCIS component on pre-NAC biopsy is not associated with pCR and does not seem to be a critical factor for predicting response to NAC.
ADCC against MICA/B Is Mediated against Differentiated Oral and Pancreatic and Not Stem-Like/Poorly Differentiated Tumors by the NK Cells; Loss in Cancer Patients due to Down-Modulation of CD16 Receptor
Authors: Kaur Kawaljit , Safaie Tahmineh , Ko Meng-Wei , Wang Yuhao , Jewett Anahid
Published: January 2021

Tumor cells are known to upregulate major histocompatibility complex-class I chain related proteins A and B (MICA/B) expression under stress conditions or due to radiation exposure. However, it is not clear whether there are specific stages of cellular maturation in which these ligands are upregulated or whether the natural killer (NK) cells differentially target these tumors in direct cytotoxicity or antibody-dependent cell cytotoxicity (ADCC). We used freshly isolated primary and osteoclast (OCs)-expanded NK cells to determine the degree of direct cytotoxicity or of ADCC using anti-MICA/B monoclonal antibodies (mAbs) against oral stem-like/poorly-differentiated oral squamous cancer stem cells (OSCSCs) and Mia PaCa-2 (MP2) pancreatic tumors as well as their well-differentiated counterparts: namely, oral squamous carcinoma cells (OSCCs) and pancreatic PL12 tumors. By using phenotypic and functional analysis, we demonstrated that OSCSCs and MP2 tumors were primary targets of direct cytotoxicity by freshly isolated NK cells and not by ADCC mediated by anti-MICA/B mAbs, which was likely due to the lower surface expression of MICA/B. However, the inverse was seen when their MICA/B-expressing differentiated counterparts, OSCCs and PL12 tumors, were used in direct cytotoxicity and ADCC, in which there was lower direct cytotoxicity but higher ADCC mediated by the NK cells. Differentiation of the OSCSCs and MP2 tumors by NK cell-supernatants abolished the direct killing of these tumors by the NK cells while enhancing NK cell-mediated ADCC due to the increased expression of MICA/B on the surface of these tumors. We further report that both direct killing and ADCC against MICA/B expressing tumors were significantly diminished by cancer patients’ NK cells. Surprisingly, OC-expanded NK cells, unlike primary interleukin-2 (IL-2) activated NK cells, were found to kill OSCCs and PL12 tumors, and under these conditions, we did not observe significant ADCC using anti-MICA/B mAbs, even though the tumors expressed a higher surface expression of MICA/B. In addition, differentiated tumor cells also expressed higher levels of surface epidermal growth factor receptor (EGFR) and programmed death-ligand 1(PDL1) and were more susceptible to NK cell-mediated ADCC in the presence of anti-EGFR and anti-PDL1 mAbs compared to their stem-like/poorly differentiated counterparts. Overall, these results suggested the possibility of CD16 receptors mediating both direct cytotoxicity and ADCC, resulting in the competitive use of these receptors in either direct killing or ADCC, depending on the differentiation status of tumor cells and the stage of maturation and activation of NK cells.
Image Contrast, Image Pre-Processing, and T1 Mapping Affect MRI Radiomic Feature Repeatability in Patients with Colorectal Cancer Liver Metastases
Authors: McHugh Damien J. , Porta Nuria , Little Ross A. , Cheung Susan , Watson Yvonne , Parker Geoff J. M. , Jayson Gordon C. , O’Connor James P. B.
Published: January 2021

Imaging biomarkers require technical, biological, and clinical validation to be translated into robust tools in research or clinical settings. This study contributes to the technical validation of radiomic features from magnetic resonance imaging (MRI) by evaluating the repeatability of features from four MR sequences: pre-contrast T1- and T2-weighted images, pre-contrast quantitative T1 maps (qT1), and contrast-enhanced T1-weighted images. Fifty-one patients with colorectal cancer liver metastases were scanned twice, up to 7 days apart. Repeatability was quantified using the intraclass correlation coefficient (ICC) and repeatability coefficient (RC), and the impact of non-Gaussian feature distributions and image normalisation was evaluated. Most radiomic features had non-Gaussian distributions, but Box–Cox transformations enabled ICCs and RCs to be calculated appropriately for an average of 97% of features across sequences. ICCs ranged from 0.30 to 0.99, with volume and other shape features tending to be most repeatable; volume ICC > 0.98 for all sequences. 19% of features from non-normalised images exhibited significantly different ICCs in pair-wise sequence comparisons. Normalisation tended to increase ICCs for pre-contrast T1- and T2-weighted images, and decrease ICCs for qT1 maps. RCs tended to vary more between sequences than ICCs, showing that evaluations of feature performance depend on the chosen metric. This work suggests that feature-specific repeatability, from specific combinations of MR sequence and pre-processing steps, should be evaluated to select robust radiomic features as biomarkers in specific studies. In addition, as different repeatability metrics can provide different insights into a specific feature, consideration of the appropriate metric should be taken in a study-specific context.
Patterns and Relevance of Langerhans Islet Invasion in Pancreatic Cancer
Authors: Goess Ruediger , Mutgan Ayse , Çalışan Umut , Erdoğan Yusuf , Ren Lei , Jäger Carsten , Safak Okan , Stupakov Pavel , Istvanffy Rouzanna , Friess Helmut , Ceyhan Güralp , Demir Ihsan
Published: January 2021

Background: Pancreatic cancer‐associated diabetes mellitus (PC‐DM) is present in most patients with pancreatic cancer, but its pathogenesis remains poorly understood. Therefore, we aimed to characterize tumor infiltration in Langerhans islets in pancreatic cancer and determine its clinical relevance. Methods: Langerhans islet invasion was systematically analyzed in 68 patients with pancreatic ductal adenocarcinoma (PDAC) using histopathological examination and 3D in vitro migration assays were performed to assess chemoattraction of pancreatic cancer cells to islet cells. Results: Langerhans islet invasion was present in all patients. We found four different patterns of islet invasion: (Type I) peri‐insular invasion with tumor cells directly touching the boundary, but not penetrating the islet; (Type II) endo‐insular invasion with tumor cells inside the round islet; (Type III) distorted islet structure with complete loss of the round islet morphology; and (Type IV) adjacent cancer and islet cells with solitary islet cells encountered adjacent to cancer cells. Pancreatic cancer cells did not exhibit any chemoattraction to islet cells in 3D assays in vitro. Further, there was no clinical correlation of islet invasion using the novel Islet Invasion Severity Score (IISS), which includes all invasion patterns with the occurrence of diabetes mellitus. However, Type IV islet invasion was related to worsened overall survival in our cohort. Conclusions: We systematically analyzed, for the first time, islet invasion in human pancreatic cancer. Four different main patterns of islet invasion were identified. Diabetes mellitus was not related to islet invasion. However, more research on this prevailing feature of pancreatic cancer is needed to better understand underlying principles.
1D Zn(II) Coordination Polymers as Effective Heterogeneous Catalysts in Microwave-Assisted Single-Pot Deacetalization-Knoevenagel Tandem Reactions in Solvent-Free Conditions
Authors: Paul Anup , Karmakar Anirban , Guedes da Silva M. Fátima C. , Pombeiro Armando J. L.
Published: January 2021

The new 1D CPs [Zn(L1)(H2O)4]n.nH2O (1) and [Zn(L2)(H2O)2]n (2) [L1 = 1,1′-(ethane-1,2-diyl)bis(6-oxo-1,6-dihydropyridine-3-carboxylic acid); L2 = 1,1′-(propane-1,3-diyl)bis(6-oxo-1,6-dihydropyridine-3-carboxylic acid)] were prepared from flexible dicarboxylate pro-ligands (H2L1 and H2L2). Both CPs 1 and 2 were characterized by elemental, FTIR, and powder X-ray diffraction analysis. Their geometry and the structural features were unveiled by single-crystal X-ray diffraction analysis. The underlying topology of the CPs was illustrated by the topological analysis of the H-bonded structure of CP 1, which revealed a 3,4,6-connected trinodal net. On the other hand, topological analysis on the hydrogen-bonded network of CP 2 showed a 2,3,3,4,6,7-connected hexanodal net. The thermal stability of the CPs was investigated by thermogravimetric analysis. CPs 1 and 2 act as heterogeneous catalysts in one-pot tandem deacetalization–Knoevenagel condensation reactions under environmentally mild conditions. CPs 1 exhibits a yield of ca. 91% in a microwave-assisted solvent-free medium, whereas a slightly lower yield was obtained for CP 2 (87%) under the same experimental protocol. The recyclability of catalyst 1 was also assessed. To our knowledge, these are the first Zn(II)-based CPs to be applied as heterogeneous catalysts for the above tandem reactions under environmentally friendly conditions.
Low Temperature Deposition of TiO2 Thin Films through Atmospheric Pressure Plasma Jet Processing
Authors: Gosavi Suresh , Tabei Rena , Roy Nitish , Latthe Sanjay S. , Hunge Yuvaraj M. , Suzuki Norihiro , Kondo Takeshi , Yuasa Makoto , Teshima Katsuya , Fujishima Akira , Terashima Chiaki
Published: January 2021

Titanium dioxide (TiO2) has been widely used as a catalyst material in different applications such as photocatalysis, solar cells, supercapacitor, and hydrogen production, due to its better chemical stability, high redox potential, wide band gap, and eco-friendly nature. In this work TiO2 thin films have been deposited onto both glass and silicon substrates by the atmospheric pressure plasma jet (APPJ) technique. The structure and morphological properties of TiO2 thin films are studied using different characterization techniques like X-ray diffraction (XRD), X-ray photoelectron spectroscopy (XPS), Raman spectroscopy, and field emission scanning electron microscopy. XRD study reveals the bronze-phase of TiO2. The XPS study shows the presence of Ti, O, C, and N elements. The FE-SEM study shows the substrate surface is well covered with a nearly round shaped grain of different size. The optical study shows that all the deposited TiO2 thin films exhibit strong absorption in the ultraviolet region. The oleic acid photocatalytic decomposition study demonstrates that the water contact angle decreased from 80.22 to 27.20° under ultraviolet illumination using a TiO2 photocatalyst.
microRNAs Mediated Regulation of the Ribosomal Proteins and its Consequences on the Global Translation of Proteins
Authors: Reza Abu Musa Md Talimur , Yuan Yu-Guo
Published: January 2021

Ribosomal proteins (RPs) are mostly derived from the energy-consuming enzyme families such as ATP-dependent RNA helicases, AAA-ATPases, GTPases and kinases, and are important structural components of the ribosome, which is a supramolecular ribonucleoprotein complex, composed of Ribosomal RNA (rRNA) and RPs, coordinates the translation and synthesis of proteins with the help of transfer RNA (tRNA) and other factors. Not all RPs are indispensable; in other words, the ribosome could be functional and could continue the translation of proteins instead of lacking in some of the RPs. However, the lack of many RPs could result in severe defects in the biogenesis of ribosomes, which could directly influence the overall translation processes and global expression of the proteins leading to the emergence of different diseases including cancer. While microRNAs (miRNAs) are small non-coding RNAs and one of the potent regulators of the post-transcriptional gene expression, miRNAs regulate gene expression by targeting the 3′ untranslated region and/or coding region of the messenger RNAs (mRNAs), and by interacting with the 5′ untranslated region, and eventually finetune the expression of approximately one-third of all mammalian genes. Herein, we highlighted the significance of miRNAs mediated regulation of RPs coding mRNAs in the global protein translation.
Cytokine-Mediated Crosstalk between Immune Cells and Epithelial Cells in the Gut
Authors: Mahapatro Mousumi , Erkert Lena , Becker Christoph
Published: January 2021

Cytokines are small proteins that are secreted by a vast majority of cell types in the gut. They not only establish cell-to-cell interactions and facilitate cellular signaling, but also regulate both innate and adaptive immune responses, thereby playing a central role in genetic, inflammatory, and infectious diseases of the gut. Both, immune cells and gut epithelial cells, play important roles in intestinal disease development. The epithelium is located in between the mucosal immune system and the gut microbiome. It not only establishes an efficient barrier against gut microbes, but it also signals information from the gut lumen and its composition to the immune cell compartment. Communication across the epithelial cell layer also occurs in the other direction. Intestinal epithelial cells respond to immune cell cytokines and their response influences and shapes the microbial community within the gut lumen. Thus, the epithelium should be seen as a translator or a moderator between the microbiota and the mucosal immune system. Proper communication across the epithelium seems to be a key to gut homeostasis. Indeed, current genome-wide association studies for intestinal disorders have identified several disease susceptibility loci, which map cytokine signatures and their related signaling genes. A thorough understanding of this tightly regulated cytokine signaling network is crucial. The main objective of this review was to shed light on how cytokines can orchestrate epithelial functions such as proliferation, cell death, permeability, microbe interaction, and barrier maintenance, thereby safeguarding host health. In addition, cytokine-mediated therapy for inflammation and cancer are discussed.
Synbiotics Alleviate the Gut Indole Load and Dysbiosis in Chronic Kidney Disease
Authors: Yang Chih-Yu , Chen Ting-Wen , Lu Wan-Lun , Liang Shih-Shin , Huang Hsien-Da , Tseng Ching-Ping , Tarng Der-Cherng
Published: January 2021

Chronic kidney disease (CKD) has long been known to cause significant digestive tract pathology. Of note, indoxyl sulfate is a gut microbe-derived uremic toxin that accumulates in CKD patients. Nevertheless, the relationship between gut microbiota, fecal indole content, and blood indoxyl sulfate level remains unknown. In our study, we established an adenine-induced CKD rat model, which recapitulates human CKD-related gut dysbiosis. Synbiotic treatment in CKD rats showed a significant reduction in both the indole-producing bacterium Clostridium and fecal indole amount. Furthermore, gut microbiota diversity was reduced in CKD rats but was restored after synbiotic treatment. Intriguingly, in our end-stage kidney disease (ESKD) patients, the abundance of indole-producing bacteria, Bacteroides, Prevotella, and Clostridium, is similar to that of healthy controls. Consistently, the fecal indole tends to be higher in the ESKD patients, but the difference did not achieve statistical significance. However, the blood level of indoxyl sulfate was significantly higher than that of healthy controls, implicating that under an equivalent indole production rate, the impaired renal excretion contributes to the accumulation of this notorious uremic toxin. On the other hand, we did identify two short-chain fatty acid-producing bacteria, Faecalibacterium and Roseburia, were reduced in ESKD patients as compared to the healthy controls. This may contribute to gut dysbiosis. We also identified that three genera Fusobacterium, Shewanella, and Erwinia, in the ESKD patients but not in the healthy controls. Building up gut symbiosis to treat CKD is a novel concept, but once proved effective, it will provide an additional treatment strategy for CKD patients.
A Comprehensive Study of the Retinal Phenotype of Rpe65-Deficient Dogs
Authors: Annear Matthew J , Mowat Freya M , Occelli Laurence M , Smith Alexander J , Curran Paul G , Bainbridge James W , Ali Robin R , Petersen-Jones Simon M
Published: January 2021

The Rpe65-deficient dog has been important for development of translational therapies of Leber congenital amaurosis type 2 (LCA2). The purpose of this study was to provide a comprehensive report of the natural history of retinal changes in this dog model. Rpe65-deficient dogs from 2 months to 10 years of age were assessed by fundus imaging, electroretinography (ERG) and vision testing (VT). Changes in retinal layer thickness were assessed by optical coherence tomography and on plastic retinal sections. ERG showed marked loss of retinal sensitivity, with amplitudes declining with age. Retinal thinning initially developed in the area centralis, with a slower thinning of the outer retina in other areas starting with the inferior retina. VT showed that dogs of all ages performed well in bright light, while at lower light levels they were blind. Retinal pigment epithelial (RPE) inclusions developed and in younger dogs and increased in size with age. The loss of photoreceptors was mirrored by a decline in ERG amplitudes. The slow degeneration meant that sufficient photoreceptors, albeit very desensitized, remained to allow for residual bright light vision in older dogs. This study shows the natural history of the Rpe65-deficient dog model of LCA2.
Special Issue on “Ubiquitin and Autophagy”
Authors: Nazarko Taras Y.
Published: January 2021

The Special Issue of Cells on “Ubiquitin and Autophagy” is a tribute to the multifaceted role of ubiquitin and autophagic ubiquitin-like (UBL) proteins in the autophagy-related (ATG) pathways [...]
Role of Synovial Exosomes in Osteoclast Differentiation in Inflammatory Arthritis
Authors: Song Ji Eun , Kim Ji Soo , Shin Ji Hye , Moon Ki Won , Park Jin Kyun , Park Kyong Soo , Lee Eun Young
Published: January 2021

This study aimed to investigate the characteristics of exosomes isolated from synovial fluid and their role in osteoclast differentiation in different types of inflammatory arthritis. Exosomes isolated from synovial fluid of rheumatoid arthritis (RA), ankylosing spondylitis (AS), gout, and osteoarthritis (OA) patients were co-incubated with CD14+ mononuclear cells from healthy donors without macrophage colony-stimulating factor (M-CSF) and receptor activator of nuclear factor kappa-B ligand (RANKL). Osteoclast differentiation was evaluated via tartrate-resistant acid phosphatase (TRAP) staining and activity and F-actin ring formation. RANKL expression on synovial exosomes was assessed using flow cytometry and an enzyme-linked immunosorbent assay (ELISA). Synovial exosomes were the lowest in OA patients; these induced osteoclastogenesis in the absence of M-CSF and RANKL. Osteoclastogenesis was significantly higher with more exosomes in RA (p = 0.030) than in OA patients, but not in AS or gout patients. On treating macrophages with a specified number of synovial exosomes from RA/AS patients, exosomes induced greater osteoclastogenesis in RA than in AS patients. Synovial exosomal RANKL levels were significantly higher in RA (p = 0.035) than in AS patients. Synovial exosome numbers vary with the type of inflammatory arthritis. Synovial exosomes from RA patients may bear the disease-specific “synovial signature of osteoclastogenesis.”
Hedgehog Signaling, a Critical Pathway Governing the Development and Progression of Hepatocellular Carcinoma
Authors: Ding Jia , Li Hui-Yan , Zhang Li , Zhou Yuan , Wu Jian
Published: January 2021

Hedgehog (Hh) signaling is a classic morphogen in controlling embryonic development and tissue repairing. Aberrant activation of Hh signaling has been well documented in liver cancer, including hepatoblastoma, hepatocellular carcinoma (HCC) and cholangiocarcinoma. The present review aims to update the current understanding on how abnormal Hh signaling molecules modulate initiation, progression, drug resistance and metastasis of HCC. The latest relevant literature was reviewed with our recent findings to provide an overview regarding the molecular interplay and clinical relevance of the Hh signaling in HCC management. Hh signaling molecules are involved in the transformation of pre-carcinogenic lesions to malignant features in chronic liver injury, such as nonalcoholic steatohepatitis. Activation of GLI target genes, such as ABCC1 and TAP1, is responsible for drug resistance in hepatoma cells, with a CD133−/EpCAM− surface molecular profile, and GLI1 and truncated GLI1 account for the metastatic feature of the hepatoma cells, with upregulation of matrix metalloproteinases. A novel bioassay for the Sonic Hh ligand in tissue specimens may assist HCC diagnosis with negative α-fetoprotein and predict early microvascular invasion. In-depth exploration of the Hh signaling deepens our understanding of its molecular modulation in HCC initiation, drug sensitivity and metastasis, and guides precise management of HCC on an individual basis.
Mitochondrial Cyclosporine A-Independent Palmitate/Ca2+-Induced Permeability Transition Pore (PA-mPT Pore) and Its Role in Mitochondrial Function and Protection against Calcium Overload and Glutamate Toxicity
Authors: Mironova Galina D. , Pavlov Evgeny V.
Published: January 2021

A sharp increase in the permeability of the mitochondrial inner membrane known as mitochondrial permeability transition (or mPT) occurs in mitochondria under the conditions of Ca2+ and ROS stress. Permeability transition can proceed through several mechanisms. The most common mechanism of mPT is based on the opening of a cyclosporine A (CSA)-sensitive protein channel in the inner membrane. In addition to the CSA-sensitive pathway, mPT can occur through the transient opening of lipid pores, emerging in the process of formation of palmitate/Ca2+ complexes. This pathway is independent of CSA and likely plays a protective role against Ca2+ and ROS toxicity. The review considers molecular mechanisms of formation and regulation of the palmitate/Ca2+-induced pores, which we designate as PA-mPT to distinguish it from the classical CSA-sensitive mPT. In the paper, we discuss conditions of its opening in the biological membranes, as well as its role in the physiological and pathophysiological processes. Additionally, we summarize data that indicate the involvement of PA-mPT in the protection of mitochondria against calcium overload and glutamate-induced degradation in neurons.
Effect of Microbial Short-Chain Fatty Acids on CYP3A4-Mediated Metabolic Activation of Human Pluripotent Stem Cell-Derived Liver Organoids
Authors: Mun Seon Ju , Lee Jaeseo , Chung Kyung-Sook , Son Mi-Young , Son Myung Jin
Published: January 2021

The early and accurate prediction of the hepatotoxicity of new drug targets during nonclinical drug development is important to avoid postmarketing drug withdrawals and late-stage failures. We previously established long-term expandable and functional human-induced pluripotent stem cell (iPSC)-derived liver organoids as an alternative source for primary human hepatocytes. However, PSC-derived organoids are known to present immature fetal characteristics. Here, we treated these liver organoids with microbial short-chain fatty acids (SCFAs) to improve metabolic maturation based on microenvironmental changes in the liver during postnatal development. The effects of the three main SCFA components (acetate, propionate, and butyrate) and their mixture on liver organoids were determined. Propionate (1 µM) significantly promoted the CYP3A4/CYP3A7 expression ratio, and acetate (1 µM), propionate (1 µM), and butyrate (1 µM) combination treatment, compared to no treatment (control), substantially increased CYP3A4 activity and albumin secretion, as well as gene expression. More importantly, mixed SCFA treatment accurately revealed troglitazone-induced hepatotoxicity, which was redeemed on a potent CYP3A4 inhibitor ketoconazole treatment. Overall, we determined, for the first time, that SCFA mixture treatment might contribute to the accurate evaluation of the CYP3A4-dependent drug toxicity by improving metabolic activation, including CYP3A4 expression, of liver organoids.
Mono(ADP-ribosyl)ation Enzymes and NAD+ Metabolism: A Focus on Diseases and Therapeutic Perspectives
Authors: Poltronieri Palmiro , Celetti Angela , Palazzo Luca
Published: January 2021

Mono(ADP-ribose) transferases and mono(ADP-ribosyl)ating sirtuins use NAD+ to perform the mono(ADP-ribosyl)ation, a simple form of post-translational modification of proteins and, in some cases, of nucleic acids. The availability of NAD+ is a limiting step and an essential requisite for NAD+ consuming enzymes. The synthesis and degradation of NAD+, as well as the transport of its key intermediates among cell compartments, play a vital role in the maintenance of optimal NAD+ levels, which are essential for the regulation of NAD+-utilizing enzymes. In this review, we provide an overview of the current knowledge of NAD+ metabolism, highlighting the functional liaison with mono(ADP-ribosyl)ating enzymes, such as the well-known ARTD10 (also named PARP10), SIRT6, and SIRT7. To this aim, we discuss the link of these enzymes with NAD+ metabolism and chronic diseases, such as cancer, degenerative disorders and aging.
Mass Spring Models of Amorphous Solids
Authors: Kot Maciej
Published: January 2021

In this paper we analyse static properties of mass spring models (MSMs) with the focus of modelling non crystalline materials, and explore basic improvements, which can be made to MSMs with disordered point placement. Presented techniques address the problem of high variance of MSM properties which occur due to randomised nature of point distribution. The focus is placed on tuning spring parameters in a way which would compensate for local non-uniformity of point and spring density. We demonstrate that a simple force balancing algorithm can improve properties of the MSM on a global scale, while a more detailed stress distribution analysis is needed to achieve local scale improvements. Considered MSMs are three dimensional.
Performance Evaluation of Road Pavement Green Concrete: An Application of Advance Decision-Making Approach before Life Cycle Assessment
Authors: Alhazmi Hatem , Shah Syyed Adnan Raheel , Basheer Muhammad Aamir
Published: January 2021

Rigid pavement structures are one of the costly components of the infrastructure development process. It consumes a huge quantity of ingredients necessary for concrete development. Hence, a newly introduced concept of circular economy in combination with waste management was introduced to solve this problem. In this study, three waste products (rice husk ash (RHA), wood sawdust (WSD), and processes waste tea (PWT)) was utilized to develop the concrete for rigid pavement structures by replacing the sand, i.e., a filler material at different percentages. During the testing procedure of compressive (CS), tensile (TS), and flexural strength (FS) properties, RHA and WSD at 5% replacement were found to be a good replacement of sand to develop required concrete. This study will help in the production of eco-friendly rigid pavement structures and a pathway of life cycle assessment in the future.
Mucilages from Different Plant Species Affect the Characteristics of Bio-Mortars for Restoration
Authors: Alisi Chiara , Bacchetta Loretta , Bojorquez Emanuel , Falconieri Mauro , Gagliardi Serena , Insaurralde Mirta , Martinez Maria Fernanda Falcon , Orozco Alejandro Meza , Persia Franca , Sprocati Anna Rosa , Procacci Silvia , Tatì Angelo
Published: January 2021

The need for compatible materials for the preservation of cultural heritage has resulted in the revival of lime-based mortar technology and other applications. This work investigates the cohesion and integrity of lime mortars added with fresh mucilage extracted from five plants and evaluates their bioreceptivity for long-term durability. Specimens of lime mortars added with 2.5% of fresh mucilage extracted from Aloe vera, Cylindropuntia californica, Opuntia engelmannii, Opuntia ficus-indica and Salvia hispanica mucilages were analyzed for color change (colorimetry), cohesion (ultrasound measurements), integrity (X-rays) and bioreceptivity (microbiological tests).The internal structure of the specimens added with Cacti mucilages shows better compactness, and no color change was noticed in the bio-mortars also after aging. The bioreceptivity response of mortars inoculated with bacteria, fungi and a photosynthetic biofilm was quite different. Specimens added with Aloe and Cylindropuntia mucilages showed a higher extent of bioreceptivity than the control; the specimens of bio-mortars added with Opuntia engelmannii, Opuntia ficus-indica and Salvia hispanica mucilages did not appear, up to threemonths after the contamination, any microbial growth. These results indicate that the addition of mucilage improves the mortar qualities, but the choice of the plant mucilage must be carefully evaluated since it can be responsible for changes in the bioreceptivity of the mortar.
Different Approaches to Low-Wettable Materials for Freezing Environments: Design, Performance and Durability
Authors: Boveri Giulio , Corozzi Alessandro , Veronesi Federico , Raimondo Mariarosa
Published: January 2021

Ice nucleation and accretion leads to multiple problems such as freezing of the streets which can cause traffic collisions or people injuries, and collapse of high voltage power lines leading to black-out and icing of aircraft components, causing major aeronautic accidents. The most widespread strategies for the removal of accumulated ice layers result in most cases being expensive, time-consuming and hazardous for the environment. In this work we present the design of hydrophobic hybrid inorganic-organic coatings via Lotus leaf-like and slippery liquid infused porous surfaces (SLIPS) approaches with reduced, lasting wetting performance in cold environments. Static and dynamic wetting behavior was evaluated at room and sub-zero temperatures. The main target was the selection of the most suitable design approaches and formulations of coatings to be applied on metals or alloys when the contact time between the droplet and the material surface has to be minimized. In the temperature range from −10 to 0 °C, we report evidence of a stable hydrophobicity and a low water contact angle hysteresis (below 15°) of all the SLIPS developed. The surfaces’ ability to keep their wetting performance unchanged during the freeze/and frost/thaw durability cycles stood out as a key issue for further development at larger scale.
Volatile Iridium and Platinum MOCVD Precursors: Chemistry, Thermal Properties, Materials and Prospects for Their Application in Medicine
Authors: Karakovskaya Ksenya I. , Dorovskikh Svetlana I. , Vikulova Evgeniia S. , Ilyin Igor Yu. , Zherikova Kseniya V. , Basova Tamara V. , Morozova Natalya B.
Published: January 2021

Interest in iridium and platinum has been steadily encouraged due to such unique properties as exceptional chemical inertia and corrosion resistance, high biological compatibility, and mechanical strength, which are the basis for their application in medical practice. Metal-organic chemical vapor deposition (MOCVD) is a promising method to fabricate Ir and Pt nanomaterials, multilayers, and heterostructures. Its advantages include precise control of the material composition and microstructure in deposition processes at relatively low temperatures onto non-planar substrates. The development of MOCVD processes is inextricably linked with the development of the chemistry of volatile precursors, viz., specially designed coordination and organometallic compounds. This review describes the synthesis methods of various iridium and platinum precursors, their thermal properties, and examples of the use of MOCVD, including formation of films for medical application and bimetallics. Although metal acetylacetonates are currently the most widely used precursors, the recently developed heteroligand Ir(I) and Pt(IV) complexes appear to be more promising in both synthetic and thermochemical aspects. Their main advantage is their ability to control thermal properties by modifying several types of ligands, making them tunable to deposit films onto different types of materials and to select a combination of compatible compounds for obtaining the bimetallic materials.
Research Progresses on Ceramic Materials of Thermal Barrier Coatings on Gas Turbine
Authors: Wu Shuo , Zhao Yuantao , Li Wenge , Liu Weilai , Wu Yanpeng , Liu Fukang
Published: January 2021

Thermal barrier coatings (TBCs) play a vitally important role in protecting the hot parts of a gas turbine from high temperature and corrosion effectively. More and more attention has been paid to the performance modification of ZrO2-based ceramics and seeking for new ceramic materials to meet requirements of gas turbine TBCs. The working principle, merits, and demerits of main technologies for coating preparation are elaborated in this paper, and the properties of new ceramic materials are reviewed. It is found that the thermal conductivity, thermal stability, mechanical properties, and other performances of traditional ZrO2-based ceramics could be improved effectively by doping modification. The emphases for new ceramic materials research were put on pyrochlores, magnetoplumbites, rare-earth tantalates, etc. Rare-earth tantalates with great potentials as new top ceramic materials were described in detail. In the end, the development directions of advanced top ceramic coatings, combining doping modification with preparation technology to regulate and control structure property of high-performance ceramic material, were put forward.
Long Term Evaluation of Biodegradation and Biocompatibility In-Vivo the Mg-0.5Ca-xZr Alloys in Rats
Authors: Sindilar Eusebiu-Viorel , Munteanu Corneliu , Pasca Sorin Aurelian , Mihai Iuliana , Henea Madalina Elena , Istrate Bogdan
Published: January 2021

Biodegradable alloys in Mg have the advantages of traditional metallic materials and those of biodegradable polymers with superior strength, lower density and ideal rigidity for fixing bone fractures. The biocompatibility and biodegradability of the five concentrations of Mg-0.5Ca-xZr alloys used were assessed using clinical and laboratory examinations that followed over time: tissue reaction, histological and imaging (RX, CT and SEM) evolution at 1, 2, 4 and 8 weeks after implant. The main purpose of this study was to investigate in vivo the long-term effect of Mg-0.5Ca-xZr alloys in rats. The results confirmed that Mg-0.5Ca-xZr alloys are biocompatible and biodegradable and are recommended to be used as possible materials for new orthopedics devices.