bluuebunny/crossref_metadata_2025 huggingface dataset:
Could Macroscopic Dark Matter (Macros) Give Rise to Mini-Lightning Flashes out of a Blue Sky without Clouds?
Authors: Cooray Vernon , Cooray Gerald , Rubinstein Marcos , Rachidi Farhad
Published: September 2021

A recent study pointed out that macroscopic dark matter (macros) traversing through the Earth’s atmosphere can give rise to hot and ionized channels similar to those associated with lightning leaders. The authors of the study investigated the possibility that when such channels created by macros pass through a thundercloud, lightning leaders may be locked in by these ionized channels, creating lightning discharges with perfectly straight channels. They suggested the possibility of detecting such channels as a means of detecting the passage of macros through the atmosphere. In this paper, we show that such macros crossing the atmosphere under fair weather conditions could also give rise to mini-lightning flashes with current amplitudes in the order of a few hundred Amperes. These mini-lightning flashes would generate a thunder signature similar to or stronger than those of long laboratory sparks and they could also be detected by optical means. As in the case of thunderstorm-assisted macro lightning, these mini-lightning flashes are also associated with straight channels. Moreover, since the frequency of mini-lightning flashes is about thirty times greater than the macro-generated lightning flashes assisted by thunderstorms, they could be used as a means to look for the paths of macroscopic dark matter crossing the atmosphere.
On Solvability Conditions for a Certain Conjugation Problem
Authors: Vasilyev Vladimir , Eberlein Nikolai
Published: September 2021

We study a certain conjugation problem for a pair of elliptic pseudo-differential equations with homogeneous symbols inside and outside of a plane sector. The solution is sought in corresponding Sobolev–Slobodetskii spaces. Using the wave factorization concept for elliptic symbols, we derive a general solution of the conjugation problem. Adding some complementary conditions, we obtain a system of linear integral equations. If the symbols are homogeneous, then we can apply the Mellin transform to such a system to reduce it to a system of linear algebraic equations with respect to unknown functions.
Galectins in Endothelial Cell Biology and Angiogenesis: The Basics
Authors: Thijssen Victor L.
Published: September 2021

Angiogenesis, the growth of new blood vessels out of existing vessels, is a complex and tightly regulated process. It is executed by the cells that cover the inner surface of the vasculature, i.e., the endothelial cells. During angiogenesis, these cells adopt different phenotypes, which allows them to proliferate and migrate, and to form tube-like structures that eventually result in the generation of a functional neovasculature. Multiple internal and external cues control these processes and the galectin protein family was found to be indispensable for proper execution of angiogenesis. Over the last three decades, several members of this glycan-binding protein family have been linked to endothelial cell functioning and to different steps of the angiogenesis cascade. This review provides a basic overview of our current knowledge regarding galectins in angiogenesis. It covers the main findings with regard to the endothelial expression of galectins and highlights their role in endothelial cell function and biology.
Mechanosensitivity in Pulmonary Circulation: Pathophysiological Relevance of Stretch-Activated Channels in Pulmonary Hypertension
Authors: Barbeau Solène , Gilbert Guillaume , Cardouat Guillaume , Baudrimont Isabelle , Freund-Michel Véronique , Guibert Christelle , Marthan Roger , Vacher Pierre , Quignard Jean-François , Ducret Thomas
Published: September 2021

A variety of cell types in pulmonary arteries (endothelial cells, fibroblasts, and smooth muscle cells) are continuously exposed to mechanical stimulations such as shear stress and pulsatile blood pressure, which are altered under conditions of pulmonary hypertension (PH). Most functions of such vascular cells (e.g., contraction, migration, proliferation, production of extracellular matrix proteins, etc.) depend on a key event, i.e., the increase in intracellular calcium concentration ([Ca2+]i) which results from an influx of extracellular Ca2+ and/or a release of intracellular stored Ca2+. Calcium entry from the extracellular space is a major step in the elevation of [Ca2+]i, involving a variety of plasmalemmal Ca2+ channels including the superfamily of stretch-activated channels (SAC). A common characteristic of SAC is that their gating depends on membrane stretch. In general, SAC are non-selective Ca2+-permeable cation channels, including proteins of the TRP (Transient Receptor Potential) and Piezo channel superfamily. As membrane mechano-transducers, SAC convert physical forces into biological signals and hence into a cell response. Consequently, SAC play a major role in pulmonary arterial calcium homeostasis and, thus, appear as potential novel drug targets for a better management of PH.
The HMGB Protein KlIxr1, a DNA Binding Regulator of Kluyveromyces lactis Gene Expression Involved in Oxidative Metabolism, Growth, and dNTP Synthesis
Authors: Rico-Díaz Agustín , Barreiro-Alonso Aída , Rey-Souto Cora , Becerra Manuel , Lamas-Maceiras Mónica , Cerdán M. Esperanza , Vizoso-Vázquez Ángel
Published: September 2021

In the traditional fermentative model yeast Saccharomyces cerevisiae, ScIxr1 is an HMGB (High Mobility Group box B) protein that has been considered as an important regulator of gene transcription in response to external changes like oxygen, carbon source, or nutrient availability. Kluyveromyces lactis is also a useful eukaryotic model, more similar to many human cells due to its respiratory metabolism. We cloned and functionally characterized by different methodologies KlIXR1, which encodes a protein with only 34.4% amino acid sequence similarity to ScIxr1. Our data indicate that both proteins share common functions, including their involvement in the response to hypoxia or oxidative stress induced by hydrogen peroxide or metal treatments, as well as in the control of key regulators for maintenance of the dNTP (deoxyribonucleotide triphosphate) pool and ribosome synthesis. KlIxr1 is able to bind specific regulatory DNA sequences in the promoter of its target genes, which are well conserved between S. cerevisiae and K. lactis. Oppositely, we found important differences between ScIrx1 and KlIxr1 affecting cellular responses to cisplatin or cycloheximide in these yeasts, which could be dependent on specific and non-conserved domains present in these two proteins.
A Set of 17 microRNAs Common for Brain and Cerebrospinal Fluid Differentiates Primary Central Nervous System Lymphoma from Non-Malignant Brain Tumors
Authors: Sromek Maria , Rymkiewicz Grzegorz , Paziewska Agnieszka , Szafron Lukasz Michal , Kulecka Maria , Zajdel Michalina , Kulinczak Mariusz , Dabrowska Michalina , Balabas Aneta , Bystydzienski Zbigniew , Chechlinska Magdalena , Siwicki Jan Konrad
Published: September 2021

The diagnosis of primary central nervous system (CNS) lymphoma, which is predominantly of the diffuse large B-cell lymphoma type (CNS DLBCL), is challenging. MicroRNAs (miRs) are gene expression-regulating non-coding RNAs that are potential biomarkers. We aimed to distinguish miR expression patterns differentiating CNS DLBCL and non-malignant CNS diseases with tumor presentation (n-ML). Next generation sequencing-based miR profiling of cerebrospinal fluids (CSFs) and brain tumors was performed. Sample source-specific (CSF vs. brain tumor) miR patterns were revealed. Even so, a set of 17 miRs differentiating CNS DLBCL from n-ML, no matter if assessed in CSF or in a tumor, was identified. Along with the results of pathway analyses, this suggests their pathogenic role in CNS DLBCL. A combination of just four of those miRs (miR-16-5p, miR-21-5p, miR-92a-3p, and miR-423-5p), assessed in CSFs, discriminated CNS DLBCL from n-ML samples with 100% specificity and 67.0% sensitivity. Analyses of paired CSF-tumor samples from patients with CNS DLBCL showed significantly lower CSF levels of miR-26a, and higher CSF levels of miR-15a-5p, miR-15b-5p, miR-19a-3p, miR-106b-3p, miR-221-3p, and miR-423-5p. Noteworthy, the same miRs belonged to the abovementioned set differentiating CNS DLBCL from non-malignant CNS diseases. Our results not only add to the basic knowledge, but also hold significant translational potential.
B Cells and Autoantibodies in AIRE Deficiency
Authors: Wolff Anette S. B. , Braun Sarah , Husebye Eystein S. , Oftedal Bergithe E.
Published: September 2021

Autoimmune polyendocrine syndrome type 1 (APS-1) is a rare but severe monogenetic autoimmune endocrine disease caused by failure of the Autoimmune Regulator (AIRE). AIRE regulates the negative selection of T cells in the thymus, and the main pathogenic mechanisms are believed to be T cell-mediated, but little is known about the role of B cells. Here, we give an overview of the role of B cells in thymic and peripheral tolerance in APS-1 patients and different AIRE-deficient mouse models. We also look closely into which autoantibodies have been described for this disorder, and their implications. Based on what is known about B cell therapy in other autoimmune disorders, we outline the potential of B cell therapies in APS-1 and highlight the unresolved research questions to be answered.
Targeting Cancer Cells Overexpressing Folate Receptors with New Terpolymer-Based Nanocapsules: Toward a Novel Targeted DNA Delivery System for Cancer Therapy
Authors: Bellotti Elena , Cascone Maria Grazia , Barbani Niccoletta , Rossin Daniela , Rastaldo Raffaella , Giachino Claudia , Cristallini Caterina
Published: September 2021

Chemotherapeutics represent the standard treatment for a wide range of cancers. However, these agents also affect healthy cells, thus leading to severe off-target effects. Given the non-selectivity of the commonly used drugs, any increase in the selective tumor tissue uptake would represent a significant improvement in cancer therapy. Recently, the use of gene therapy to completely remove the lesion and avoid the toxicity of chemotherapeutics has become a tendency in oncotherapy. Ideally, the genetic material must be safely transferred from the site of administration to the target cells, without involving healthy tissues. This can be achieved by encapsulating genes into non-viral carriers and modifying their surface with ligands with high selectivity and affinity for a relevant receptor on the target cells. Hence, in this work we evaluate the use of terpolymer-based nanocapsules for the targeted delivery of DNA toward cancer cells. The surface of the nanocapsules is decorated with folic acid to actively target the folate receptors overexpressed on a variety of cancer cells. The nanocapsules demonstrate a good ability of encapsulating and releasing DNA. Moreover, the presence of the targeting moieties on the surface of the nanocapsules favors cell uptake, opening up the possibility of more effective therapies.
Targeting TIGIT for Immunotherapy of Cancer: Update on Clinical Development
Authors: Rotte Anand , Sahasranaman Srikumar , Budha Nageshwar
Published: September 2021

Immune checkpoint blockers have dramatically improved the chances of survival in patients with metastatic cancer, but only a subset of the patients respond to treatment. Search for novel targets that can improve the responder rates and overcome the limitations of adverse events commonly seen with combination therapies, like PD-1 plus CTLA-4 blockade and PD-1/PD-L1 plus chemotherapy, led to the development of monoclonal antibodies blocking T-cell immunoglobulin and ITIM domain (TIGIT), a inhibitory checkpoint receptor expressed on activated T cells and NK cells. The strategy showed potential in pre-clinical and early clinical studies, and 5 molecules are now in advanced stages of evaluation (phase II and above). This review aims to provide an overview of clinical development of anti-TIGIT antibodies and describes the factors considered and thought process during early clinical development. Critical aspects that can decide the fate of clinical programs, such as origin of the antibody, Ig isotype, FCγR binding, and the dose as well as dosing schedule, are discussed along with the summary of available efficacy and safety data from clinical studies and the challenges in the development of anti-TIGIT antibodies, such as identifying patients who can benefit from therapy and getting payer coverage.
The Impact of Monoclonal Antibodies on Airway Smooth Muscle Contractility in Asthma: A Systematic Review
Authors: Calzetta Luigino , Aiello Marina , Frizzelli Annalisa , Bertorelli Giuseppina , Ritondo Beatrice Ludovica , Rogliani Paola , Chetta Alfredo
Published: September 2021

Airway hyperresponsiveness (AHR) represents a central pathophysiological hallmark of asthma, with airway smooth muscle (ASM) being the effector tissue implicated in the onset of AHR. ASM also exerts pro-inflammatory and immunomodulatory actions, by secreting a wide range of cytokines and chemokines. In asthma pathogenesis, the overexpression of several type 2 inflammatory mediators including IgE, IL-4, IL-5, IL-13, and TSLP has been associated with ASM hyperreactivity, all of which can be targeted by humanized monoclonal antibodies (mAbs). Therefore, the aim of this review was to systematically assess evidence across the literature on mAbs for the treatment of asthma with respect to their impact on the ASM contractile tone. Omalizumab, mepolizumab, benralizumab, dupilumab, and tezepelumab were found to be effective in modulating the contractility of the ASM and preventing the AHR, but no available studies concerning the impact of reslizumab on the ASM were identified from the literature search. Omalizumab, dupilumab, and tezepelumab can directly modulate the ASM in asthma, by specifically blocking the interaction between IgE, IL-4, and TSLP, and their receptors are located on the surface of ASM cells. Conversely, mepolizumab and benralizumab have prevalently indirect impacts against AHR by targeting eosinophils and other immunomodulatory effector cells promoting inflammatory processes. AHR has been suggested as the main treatable trait towards precision medicine in patients suffering from eosinophilic asthma, therefore, well-designed head-to-head trials are needed to compare the efficacy of those mAbs that directly target ASM contractility specifically against the AHR in severe asthma, namely omalizumab, dupilumab, and tezepelumab.
Chimeric Antigen Receptor T cell Therapy and the Immunosuppressive Tumor Microenvironment in Pediatric Sarcoma
Authors: Terry Rachael L. , Meyran Deborah , Fleuren Emmy D. G. , Mayoh Chelsea , Zhu Joe , Omer Natacha , Ziegler David S. , Haber Michelle , Darcy Phillip K. , Trapani Joseph A. , Neeson Paul J. , Ekert Paul G.
Published: September 2021

Sarcomas are a diverse group of bone and soft tissue tumors that account for over 10% of childhood cancers. Outcomes are particularly poor for children with refractory, relapsed, or metastatic disease. Chimeric antigen receptor T (CAR T) cells are an exciting form of adoptive cell therapy that potentially offers new hope for these children. In early trials, promising outcomes have been achieved in some pediatric patients with sarcoma. However, many children do not derive benefit despite significant expression of the targeted tumor antigen. The success of CAR T cell therapy in sarcomas and other solid tumors is limited by the immunosuppressive tumor microenvironment (TME). In this review, we provide an update of the CAR T cell therapies that are currently being tested in pediatric sarcoma clinical trials, including those targeting tumors that express HER2, NY-ESO, GD2, EGFR, GPC3, B7-H3, and MAGE-A4. We also outline promising new CAR T cells that are in pre-clinical development. Finally, we discuss strategies that are being used to overcome tumor-mediated immunosuppression in solid tumors; these strategies have the potential to improve clinical outcomes of CAR T cell therapy for children with sarcoma.
Current Landscape of Non-Small Cell Lung Cancer: Epidemiology, Histological Classification, Targeted Therapies, and Immunotherapy
Authors: Rodak Olga , Peris-Díaz Manuel David , Olbromski Mateusz , Podhorska-Okołów Marzenna , Dzięgiel Piotr
Published: September 2021

Non-small cell lung cancer (NSCLC) is a subtype of the most frequently diagnosed cancer in the world. Its epidemiology depends not only on tobacco exposition but also air quality. While the global trends in NSCLC incidence have started to decline, we can observe region-dependent differences related to the education and the economic level of the patients. Due to an increasing understanding of NSCLC biology, new diagnostic and therapeutic strategies have been developed, such as the reorganization of histopathological classification or tumor genotyping. Precision medicine is focused on the recognition of a genetic mutation in lung cancer cells called “driver mutation” to provide a variety of specific inhibitors of improperly functioning proteins. A rapidly growing group of approved drugs for targeted therapy in NSCLC currently allows the following mutated proteins to be treated: EGFR family (ERBB-1, ERBB-2), ALK, ROS1, MET, RET, NTRK, and RAF. Nevertheless, one of the most frequent NSCLC molecular sub-types remains without successful treatment: the K-Ras protein. In this review, we discuss the current NSCLC landscape treatment focusing on targeted therapy and immunotherapy, including first- and second-line monotherapies, immune checkpoint inhibitors with chemotherapy treatment, and approved predictive biomarkers.
Carfilzomib, Lenalidomide, and Dexamethasone Followed by Salvage Autologous Stem Cell Transplant with or without Maintenance for Relapsed or Refractory Multiple Myeloma
Authors: Baertsch Marc-Andrea , Fougereau Mathilde , Hielscher Thomas , Sauer Sandra , Breitkreutz Iris , Jordan Karin , Müller-Tidow Carsten , Goldschmidt Hartmut , Raab Marc-Steffen , Hillengass Jens , Giesen Nicola
Published: September 2021

Salvage high-dose chemotherapy and autologous stem cell transplantation (HDCT/ASCT) is a treatment option for relapsed and/or refractory multiple myeloma (RRMM). No data are available on salvage HDCT/ASCT following re-induction treatment with state-of-the-art triplet regimens. We retrospectively report on 44 patients receiving salvage HDCT/ASCT following re-induction with carfilzomib/lenalidomide/dexamethasone (KRd). All patients received frontline HDCT/ASCT with median time to progression (TTP1) of 2.9 (1.2–13.5) years, enabling paired comparison of frontline and salvage HDCT/ASCT. After re-induction and before salvage transplant, 25/44 patients (57%) attained ≥ very good partial response (VGPR), which increased to 34/44 (77%) at best response after salvage HDCT/ASCT. Median progression-free survival (PFS) was 23.3 months from salvage HDCT/ASCT. Patients with ≥ VGPR at the time of salvage HDCT/ASCT and those receiving maintenance treatment post salvage HDCT/ASCT had significantly superior PFS (hazard ratio (HR) 0.19, p = 0.001 and HR 0.20, p = 0.009). In patients achieving at least an equal depth of response before salvage HDCT/ASCT as before frontline HDCT/ASCT, PFS after salvage HDCT/ASCT was comparable to the frontline situation (p = 0.3). This is the first report of state-of-the-art triplet re-induction and salvage HDCT/ASCT for RRMM after frontline transplantation. Deep remissions achieved with KRd translate into prolonged PFS following salvage HDCT/ASCT and are enhanced by maintenance treatment.
Virtual Monoenergetic Images of Dual-Energy CT—Impact on Repeatability, Reproducibility, and Classification in Radiomics
Authors: Euler André , Laqua Fabian Christopher , Cester Davide , Lohaus Niklas , Sartoretti Thomas , Pinto dos Santos Daniel , Alkadhi Hatem , Baessler Bettina
Published: September 2021

The purpose of this study was to (i) evaluate the test–retest repeatability and reproducibility of radiomic features in virtual monoenergetic images (VMI) from dual-energy CT (DECT) depending on VMI energy (40, 50, 75, 120, 190 keV), radiation dose (5 and 15 mGy), and DECT approach (dual-source and split-filter DECT) in a phantom (ex vivo), and (ii) to assess the impact of VMI energy and feature repeatability on machine-learning-based classification in vivo in 72 patients with 72 hypodense liver lesions. Feature repeatability and reproducibility were determined by concordance–correlation–coefficient (CCC) and dynamic range (DR) ≥0.9. Test–retest repeatability was high within the same VMI energies and scan conditions (percentage of repeatable features ranging from 74% for SFDE mode at 40 keV and 15 mGy to 86% for DSDE at 190 keV and 15 mGy), while reproducibility varied substantially across different VMI energies and DECTs (percentage of reproducible features ranging from 32.8% for SFDE at 5 mGy comparing 40 with 190 keV to 99.2% for DSDE at 15 mGy comparing 40 with 50 keV). No major differences were observed between the two radiation doses (<10%) in all pair-wise comparisons. In vivo, machine learning classification using penalized regression and random forests resulted in the best discrimination of hemangiomas and metastases at low-energy VMI (40 keV), and for cysts at high-energy VMI (120 keV). Feature selection based on feature repeatability did not improve classification performance. Our results demonstrate the high repeatability of radiomics features when keeping scan and reconstruction conditions constant. Reproducibility diminished when using different VMI energies or DECT approaches. The choice of optimal VMI energy improved lesion classification in vivo and should hence be adapted to the specific task.
Spectrum of Germline Pathogenic Variants in BRCA1/2 Genes in the Apulian Southern Italy Population: Geographic Distribution and Evidence for Targeted Genetic Testing
Authors: Patruno Margherita , De Summa Simona , Resta Nicoletta , Caputo Mariapia , Costanzo Silvia , Digennaro Maria , Pilato Brunella , Bagnulo Rosanna , Pantaleo Antonino , Simone Cristiano , Natalicchio Maria Iole , De Matteis Elisabetta , Tarantino Paolo , Tommasi Stefania , Paradiso Angelo
Published: September 2021

BRCA1/2-associated hereditary breast and ovarian cancer is the most common form of hereditary breast and ovarian cancer and occurs in all ethnicities and racial populations. Different BRCA1/BRCA2 pathogenic variants (PVs) have been reported with a wide variety among populations. In this study, we retrospectively analyzed prevalence and geographic distribution of pathogenic germline BRCA1/2 variants in families from Apulia in southern Italy and evaluated the genotype–phenotype correlations. Data were collected from Oncogenetic Services present in Apulian hospitals and a shared database was built containing Apulian native probands (n = 2026) that had undergone genetic testing from 2004 to 2019. PVs were detected in 499 of 2026 (24.6%) probands and 68.5% of them (342 of 499) were in the BRCA1 gene. We found 65 different PVs in BRCA1 and 46 in BRCA2. There were 10 most recurrent PVs and their geographical distribution appears to be significantly specific for each province. We have assumed that these PVs are related to the historical and geopolitical changes that occurred in Apulia over time and/or to a “founder effect”. Broader knowledge of BRCA1/2 prevalence and recurring PVs in specific geographic areas could help establish more flexible genetic testing strategies that may enhance our ability to detect high-risk subjects.
Mesoporous Carbon Production by Nanocasting Technique Using Boehmite as a Template
Authors: Ortega-Franqueza María , Ivanova Svetlana , Domínguez María Isabel , Centeno Miguel Ángel
Published: September 2021

A series of mesoporous carbonaceous materials were synthesized by the nanocasting technique using boehmite as a template and glucose as a carbon precursor. After pyrolysis and template removal, the resulting material is a mesoporous carbon that can be additionally doped with N, B and K during prepyrolysis impregnation. In addition, the influence of doping on the morphology, crystallinity and stability of the synthesized carbons was studied using X-ray diffraction, nitrogen physisorption, thermogravimetry, Raman and IR spectroscopy and transmission electron microscopy. While the nanocasting process is effective for the formation of mesopores, KOH and urea do not modify the textural properties of carbon. The use of H3PO4 as a dopant, however, led to the formation of an AlPO4 compound and resulted in a solid with a lower specific surface area and higher microporosity. All doped solids present higher thermal stability as a positive effect of the introduction of heteroatoms to the carbon skeleton. The phosphorus-doped sample has better oxidation resistance, with a combustion temperature 120–150 °C higher than those observed for the other materials.
Cell Sources for Cartilage Repair—Biological and Clinical Perspective
Authors: Urlić Inga , Ivković Alan
Published: September 2021

Cell-based therapy represents a promising treatment strategy for cartilage defects. Alone or in combination with scaffolds/biological signals, these strategies open many new avenues for cartilage tissue engineering. However, the choice of the optimal cell source is not that straightforward. Currently, various types of differentiated cells (articular and nasal chondrocytes) and stem cells (mesenchymal stem cells, induced pluripotent stem cells) are being researched to objectively assess their merits and disadvantages with respect to the ability to repair damaged articular cartilage. In this paper, we focus on the different cell types used in cartilage treatment, first from a biological scientist’s perspective and then from a clinician’s standpoint. We compare and analyze the advantages and disadvantages of these cell types and offer a potential outlook for future research and clinical application.
Autophagy Dysregulation in Diabetic Kidney Disease: From Pathophysiology to Pharmacological Interventions
Authors: Gonzalez Claudio D. , Carro Negueruela María Paula , Nicora Santamarina Catalina , Resnik Roxana , Vaccaro Maria I.
Published: September 2021

Diabetic kidney disease (DKD) is a frequent, potentially devastating complication of diabetes mellitus. Several factors are involved in its pathophysiology. At a cellular level, diabetic kidney disease is associated with many structural and functional alterations. Autophagy is a cellular mechanism that transports intracytoplasmic components to lysosomes to preserve cellular function and homeostasis. Autophagy integrity is essential for cell homeostasis, its alteration can drive to cell damage or death. Diabetic kidney disease is associated with profound autophagy dysregulation. Autophagy rate and flux alterations were described in several models of diabetic kidney disease. Some of them are closely linked with disease progression and severity. Some antidiabetic agents have shown significant effects on autophagy. A few of them have also demonstrated to modify disease progression and improved outcomes in affected patients. Other drugs also target autophagy and are being explored for clinical use in patients with diabetic kidney disease. The modulation of autophagy could be relevant for the pharmacological treatment and prevention of this disease in the future. Therefore, this is an evolving area that requires further experimental and clinical research. Here we discuss the relationship between autophagy and Diabetic kidney disease and the potential value of autophagy modulation as a target for pharmacological intervention.
Response to Cysteamine in Osteoclasts Obtained from Patients with Nephropathic Cystinosis: A Genotype/Phenotype Correlation
Authors: Quinaux Thomas , Bertholet-Thomas Aurélia , Servais Aude , Boyer Olivia , Vrillon Isabelle , Hogan Julien , Lemoine Sandrine , Gaillard Ségolène , Alioli Candide , Vasseur Sophie , Acquaviva Cécile , Peyruchaud Olivier , Machuca-Gayet Irma , Bacchetta Justine
Published: September 2021

Bone complications of cystinosis have been recently described. The main objectives of this paper were to determine in vitro the impact of CTNS mutations and cysteamine therapy on human osteoclasts and to carry out a genotype-phenotype analysis related to osteoclastic differentiation. Human osteoclasts were differentiated from peripheral blood mononuclear cells (PBMCs) and were treated with increasing doses of cysteamine (0, 50, 200 µM) and then assessed for osteoclastic differentiation. Results are presented as median (min-max). A total of 17 patients (mainly pediatric) were included, at a median age of 14 (2–61) years, and a eGFR of 64 (23–149) mL/min/1.73 m2. Most patients (71%) were under conservative kidney management (CKM). The others were kidney transplant recipients. Three functional groups were distinguished for CTNS mutations: cystinosin variant with residual cystin efflux activity (RA, residual activity), inactive cystinosin variant (IP, inactive protein), and absent protein (AP). PBMCs from patients with residual cystinosin activity generate significantly less osteoclasts than those obtained from patients of the other groups. In all groups, cysteamine exerts an inhibitory effect on osteoclastic differentiation at high doses. This study highlights a link between genotype and osteoclastic differentiation, as well as a significant impact of cysteamine therapy on this process in humans.
Interleukin-26 Has Synergistic Catabolic Effects with Palmitate in Human Articular Chondrocytes via the TLR4-ERK1/2-c-Jun Signaling Pathway
Authors: Chen Yi-Ting , Wang Chih-Chien , Cheng Chia-Pi , Liu Feng-Cheng , Lee Chian-Her , Lee Herng-Sheng , Peng Yi-Jen
Published: September 2021

The inflammatory cytokine interleukin-26 (IL-26) is highly expressed in the serum and synovial fluid of patients with inflammatory arthritis. The effect of IL-26 on human articular chondrocytes (HACs) remains unclear. Obesity is associated with disability of patients with rheumatoid arthritis and disease activity in those with ankylosing spondylitis. The saturated free fatty acid palmitate with IL-1β can synergistically induce catabolic effects in HACs. The aim of this study was to evaluate the effects of IL-26 and palmitate in HACs. In this study, palmitate markedly synergizes the IL-26-induced proinflammatory effects and matrix protease, including COX-2, IL-6, and MMP-1, in HACs via the toll-like receptor 4 (TLR4)-ERK1/2-c-Jun signal transduction pathway. The synergistic catabolic effects of palmitate and IL-26 were attenuated by inhibitors of TLR4 (TAK242), ERK1/2 (U0126), or c-Jun (SP600125) in HACs and cartilage matrix. In addition, metformin, a potential inhibitor of TLR4, also decreased expression of COX-2 and IL-6 induced by co-incubation with IL-26 and palmitate. IL-26 and palmitate synergistically induced expression of inflammatory and catabolic mediators, resulting in articular cartilage matrix breakdown. The present study also revealed a possible mechanism and therapeutic targets against articular cartilage degradation by increased saturated fatty acids in patients with inflammatory arthritis.
Predicting Water Availability in Water Bodies under the Influence of Precipitation and Water Management Actions Using VAR/VECM/LSTM
Authors: Kaur Harleen , Alam Mohammad Afshar , Mariyam Saleha , Alankar Bhavya , Chauhan Ritu , Adnan Rana Muhammad , Kisi Ozgur
Published: September 2021

Recently, awareness about the significance of water management has risen as population growth and global warming increase, and economic activities and land use continue to stress our water resources. In addition, global water sustenance efforts are crippled by capital-intensive water treatments and water reclamation projects. In this paper, a study of water bodies to predict the amount of water in each water body using identifiable unique features and to assess the behavior of these features on others in the event of shock was undertaken. A comparative study, using a parametric model, was conducted among Vector Autoregression (VAR), the Vector Error Correction Model (VECM), and the Long Short-Term Memory (LSTM) model for determining the change in water level and water flow of water bodies. Besides, orthogonalized impulse responses (OIR) and forecast error variance decompositions (FEVD) explaining the evolution of water levels and flow rates, the study shows the significance of VAR/VECM models over LSTM. It was found that on some water bodies, the VAR model gave reliable results. In contrast, water bodies such as water springs gave mixed results of VAR/VECM.
Preparation and Application of Polyurethane Coating Material Based on Epoxycyclohexane-Tetrahydrofuran in Paper Conservation
Authors: Liu Juan , Jin Shan-Shan , Qi Ying-Ping , Shen Yong-Feng , Li Hua
Published: September 2021

Paper cultural heritages are valuable historical records and also abound in cultural resources. Due to its organic property, paper is susceptible to aging, destruction by environmental pollution and human factors. At present, many countries in the world are facing the problem of paper conservation. Coating reinforcement is one of the methods for paper conservation, in which the choice of reinforcing resin is key. A transparent polyurethane, based on epoxycyclohexane (CHO)-tetrahydrofuran (THF) copolyether, was adopted in this study. The ring-opening polymerization for generating the CHO-THF copolyether took place by the reactants CHO and THF, in the catalysis of boron trifluoride diethyl etherate, initiation of glycerol. Characterizations of the synthetic copolyether were conducted by infrared (IR) spectroscopy and proton nuclear magnetic resonance (1HNMR) spectroscopy. The transparent polyurethane was then produced by the CHO-THF copolyether and hexamethylene diisocyanate (HDI) trimer. The influences of different concentrations of polyurethane solution upon the paper tensile strength, elongation, folding endurance, tearing strength, gloss, and brightness were studied. These findings suggest that 10% polyurethane solution is optimal, not only for greatly improving the paper performance, but also for keeping with the principle of “repair as old”. The applied results demonstrate that the polyurethane based on the CHO-THF copolyether has the characteristics of copolyether along with polyurethane, displaying good mechanical properties in paper reinforcement.
Growth and Characterization of Ce-Doped Luag Single Crystal Fibers from Transparent Ceramics by Laser-Heated Pedestal Method
Authors: Dai Yun , Zhang Zhonghan , Wang Xibin , Lu Zhuowei , Kou Huamin , Su Liangbi , Wu Anhua
Published: September 2021

Scintillation single crystal fibers (SCFs) have great potential applications in the new generation of high-energy ray and particle detectors due to their morphological advantages. In this work; Ce:LuAG SCFs with a diameter of 1 mm were grown along the direction of [111] by laser-heated pedestal growth (LHPG) method using a transparent ceramic as the source rod; and a doping concentration was 0.1 at%, 0.3 at%, 1 at%, respectively. The effects of growth rate and annealing in air on the scintillation and optical properties of SCF are discussed in detail. The results of analyzing the absorption spectra; radioluminescence (RL) spectra; pulse-height spectra and fluorescence lifetime of SCFs show that the SCF maintains excellent scintillation performance while having a fiber structure. Therefore; Ce:LuAG SCF is a potential candidate material for detector.
Activity of the Gamma Secretase Inhibitor AL101 in Desmoid Tumors: A Case Report of 2 Adult Cases
Authors: Chan David , Kaplan Jason , Gordon Gary , Desai Jayesh
Published: September 2021

Desmoid tumors (aggressive fibromatosis) are soft tissue mesenchymal tumors that can be locally invasive and life-threatening. Depending on the location, these tumors are often unresectable or tend to recur after surgery. To date, there are no approved systemic therapies for desmoid tumors. These tumors typically harbor mutations in the β-catenin oncogene CTNNB1 or the tumor suppressor gene adenomatous polyposis coli, resulting in constitutive activation of the WNT pathway. The Notch pathway is part of the underlying cause for desmoid tumor development, possibly due to crosstalk with the WNT pathway, providing a rationale for Notch inhibition as a therapeutic strategy. The gamma secretase activation of the Notch receptor can be targeted with investigational gamma secretase inhibitors. In this case report, we follow the course of 2 patients with desmoid tumors treated with the highly potent, parenterally administered investigational gamma secretase inhibitor AL101, resulting in long-lasting responses. Case 1 reports on a patient with a mesenteric desmoid tumor who participated in a phase 1 trial and then transitioned into a compassionate use program; Case 2 reports on a patient with recurrent pelvic tumors receiving AL101 through a compassionate use program. After tumor progression on other systemic therapies, Cases 1 and 2 had confirmed partial responses (41% and 60% maximal tumor size decrease from baseline) recorded after 1.0 and 1.6 years of treatment with AL101, with a duration of response of 8.6+ and 2.6+ years, respectively. Also, in a phase 1 study of AL102, a potent orally administered gamma secretase inhibitor that shares structural features with AL101, a patient with a desmoid tumor was noted to have tumor shrinkage. Formal clinical testing of AL102 for the treatment of patients with desmoid tumors that are not amenable to surgery or are refractory to/recurrent from other prior therapies is currently underway.
Trade-Off Relationships of Leaf Functional Traits of Lycium ruthenicum in Response to Soil Properties in the Lower Reaches of Heihe River, Northwest China
Authors: Li Shanjia , Gou Wei , Wang Hui , White James F. , Wu Guoqiang , Su Peixi
Published: September 2021

Soil properties affect plant growth and cause variation in leaf functional traits. Lycium ruthenicum Murray is one of the desert dominant shrubs and halophytes in the lower reaches of Heihe River, Northwest China. We analyzed the trade-off relationships of 14 leaf functional traits of eight L. ruthenicum populations growing at varying distances from the river and discussed the effects that soil properties have on leaf functional traits. The results showed that: Lower leaf nitrogen (N) content indicated that L.ruthenicum was located at the slow investment–return axis of the species resource utilization graph. Compared with non-saline and very slightly saline habitats, populations of slightly saline habitats showed a higher carbon to nitrogen ratio (C:N). Redundancy analysis (RDA) revealed a relatively strong relationship between leaf functional traits and soil properties, the first RDA axis accounted for 70.99 and 71.09% of the variation in 0–40 and 40–80 cm of soil properties. Relative importance analysis found that in the 0–40 cm soil layer, leaf traits variations were mainly influenced by soil moisture (SWC), HCO3− and CO32− ions content, while leaf traits variations in the 40–80 cm soil layer were mainly influenced by HCO3− and SO42−. L.ruthenicum has a foliar resource acquisition method and a resource conservation trade-off with a flexible life history strategy in habitats with drought and salinity stress. In the shallow soil layers, water affects leaf traits variation greater than salt, and in both shallow and deep soil layers, HCO3− plays a dominant role on leaf traits. This study provides insights into the adversity adaptation strategies of desert plants and the conservation and restoration of arid-saline ecosystems.
C-Reactive Protein for the Early Assessment of Non-Malarial Febrile Patients: A Retrospective Diagnostic Study
Authors: Bertoli Giulia , Mazzi Cristina , Ronzoni Niccolò , Silva Ronaldo , Spinicci Michele , Pozzi Marco , Sponga Pietro , Aiello Andrea , Ursini Tamara , Bartoloni Alessandro , Olliaro Piero , Bisoffi Zeno , Buonfrate Dora
Published: September 2021

Biomarkers, especially CRP, have demonstrated their relevance to differentiate viral from bacterial infection, even though a reliable threshold is far to being found. In low- and middle-income countries, affordable and user-friendly rapid diagnostic tests based on biomarkers can be widely adopted to help health workers in the management of non-malarial fever. The primary objective of this study is to assess the best CRP cut-off to distinguish viral from bacterial infections. Other biomarkers were evaluated for the same purpose, alone or in combination with CRP. We retrospectively collected data from two referral hospital departments for infectious and tropical diseases in Italy. Areas under the ROC curve (AUC) were calculated and then compared using the DeLong test. Overall, we included 1193 febrile cases (viral 20.74% vs. bacterial 79.25%). We also collected malaria (n = 202) and intestinal parasite (n = 186) cases to establish their impact on biomarkers. CRP had the best accuracy in differentiating viral from bacterial infections. The best performance of CRP was a cut-off of 11 mg/L. All other biomarkers studied had significantly lower accuracy. Median CRP values were within the normal ranges in parasitic infections, while they were higher in malaria. None of the combinations of CRP with other biomarkers significantly increased the accuracy of CRP alone.
The Impact of Phototherapy on the Accuracy of Transcutaneous Bilirubin Measurements in Neonates: Optimal Measurement Site and Timing
Authors: Ho Shau-Ru , Lin Yu-Chen , Chen Chi-Nien
Published: September 2021

Transcutaneous bilirubinometer devices are widely applied to assess neonatal hyperbilirubinemia. However, the optimal skin site and timing of transcutaneous bilirubin (TCB) measurements for the strongest correlation with total serum bilirubin (TSB) levels after phototherapy are still unclear. We conducted a retrospective observational study evaluating the correlation of TCB and TSB levels in neonates postphototherapy. The TCB measurements on the forehead and mid-sternum at 0 and 30 min postphototherapy were assessed by using a JM-103 bilirubinometer. Paired TCB and TSB measurements were assessed by Pearson correlation and Bland–Altman plots. We analyzed 40 neonates with 96 TSB and 384 TCB measurements. The TSB level correlated moderately with the forehead TCB level at 30 min postphototherapy (r = 0.65) and less strongly with the midsternum TCB level at 0 min postphototherapy (r = 0.52). The forehead at 30 min after cessation of phototherapy was the best time point and location of TCB measurement for the assessment of neonatal jaundice status. The reliability of TCB measurements varied across skin sites and durations after phototherapy. The effectiveness of TCB measurement to assess neonatal hyperbilirubinemia is much better on covered skin areas (foreheads) 30 min postphototherapy. The appropriate application of transcutaneous bilirubinometers could aid in clinical practice and avoid unnecessary management.
Patient-Reported Outcomes and Preferences for Colon Capsule Endoscopy and Colonoscopy: A Systematic Review with Meta-Analysis
Authors: Deding Ulrik , Cortegoso Valdivia Pablo , Koulaouzidis Anastasios , Baatrup Gunnar , Toth Ervin , Spada Cristiano , Fernández-Urién Ignacio , Pennazio Marco , Bjørsum-Meyer Thomas
Published: September 2021

Colon capsule endoscopy as an alternative to colonoscopy for the diagnosis of colonic disease may serve as a less invasive and more tolerable investigation for patients. Our aim was to examine patient-reported outcomes for colon capsule endoscopy compared to conventional optical colonoscopy including preference of investigation modality, tolerability and adverse events. A systematic literature search was conducted in Web of Science, PubMed and Embase. Search results were thoroughly screened for in- and exclusion criteria. Included studies underwent assessment of transparency and completeness, after which, data for meta-analysis were extracted. Pooled estimates of patient preference were calculated and heterogeneity was examined including univariate meta-regressions. Patient-reported tolerability and adverse events were reviewed. Out of fourteen included studies, twelve had investigated patient-reported outcomes in patients who had undergone both investigations, whereas in two the patients were randomized between investigations. Pooled patient preferences were estimated to be 52% (CI 95%: 41–63%) for colon capsule endoscopy and 45% (CI 95%: 33–57%) for conventional colonoscopy: not indicating a significant difference. Procedural adverse events were rarely reported by patients for either investigation. The tolerability was high for both colon capsule endoscopy and conventional colonoscopy. Patient preferences for conventional colonoscopy and colon capsule endoscopy were not significantly different. Procedural adverse events were rare and the tolerability for colon capsule endoscopy was consistently reported higher or equal to that of conventional colonoscopy.
The Importance of the Novel Postpartum Uterine Ultrasonographic Scale in Numerical Assessments of Uterine Involution Regarding Perinatal Maternal and Fetal Outcomes
Authors: Covali Roxana , Socolov Demetra , Carauleanu Alexandru , Pavaleanu Ioana , Akad Mona , Boiculese Lucian Vasile , Socolov Razvan Vladimir
Published: September 2021

Background: Uterine involution assessments are critical for the prevention of postpartum hemorrhage. Various methods have been used worldwide. Methods: The PUUS (Postpartum Uterine Ultrasonographic Scale) method evaluates, by transabdominal ultrasonography, the length of the endometrium of the uterine cavity occupied by blood or debris, from grade 0 (no blood) to grade 4 (over three-quarters of the endometrial length occupied by blood/debris). A total of 131 consecutive patients admitted for delivery in the Elena Doamna Obstetrics and Gynecology University Hospital in Iasi, Romania, were prospectively evaluated using the PUUS method. The mean age was 27.72 years old, and they were examined during the first 24–48 h after vaginal delivery, or in the first 48–72 h after cesarean delivery. For patients with a PUUS grade greater than 1, re-examination was preformed daily in the following days, until the PUUS grade decreased to 1 or 0. Results: By standardizing uterine involution in a numerical fashion, we precisely demonstrate that uterine involution varied with the method of delivery (vaginal/cesarean) and with the number of vials of oxytocin received intrapartum, but not with the number of vials of ergometrine maleate received, and not with the origin of the parturient (rural/urban).
Object or Background: An Interpretable Deep Learning Model for COVID-19 Detection from CT-Scan Images
Authors: Singh Gurmail , Yow Kin-Choong
Published: September 2021

The new strains of the pandemic COVID-19 are still looming. It is important to develop multiple approaches for timely and accurate detection of COVID-19 and its variants. Deep learning techniques are well proved for their efficiency in providing solutions to many social and economic problems. However, the transparency of the reasoning process of a deep learning model related to a high stake decision is a necessity. In this work, we propose an interpretable deep learning model Ps-ProtoPNet to detect COVID-19 from the medical images. Ps-ProtoPNet classifies the images by recognizing the objects rather than their background in the images. We demonstrate our model on the dataset of the chest CT-scan images. The highest accuracy that our model achieves is 99.29%.