bluuebunny/crossref_metadata_2025 huggingface dataset:
Are Sports Champions Also Anti-Epidemic Heroes? Quantitative Research on the Influence of Sports Champions’ Demonstration Effect on the COVID-19 Epidemic in China
Authors: Huang Junpei , Lin Shanlang , Hu Xiaoli , Lin Ruofei
Published: February 2022

What kind of role do sports champions play in the COVID-19 epidemic? Do they contribute to the mitigation of the epidemic by some pathway? In this paper, we empirically explore the influence and mechanism of the demonstration effect of sports champions upon the COVID-19 epidemic using COVID-19-related dataset of prefecture-level cities in China from 1 January 2020 to 17 March 2020. The two-way fixed effect model of econometrics is applied to estimate the result, the instrumental variable approach is adopted to address potential endogeneity issues, and socio-economic factors including public health measures, residents’ self-protection awareness, effective distance from Wuhan are also taken into consideration. The results show that the demonstration effect of champions in major sporting events increases the participation in physical exercise, which in turn reduces the possibility of being infected with the epidemic. An increase of one gold medal results in a 0.93% increase in the sports population, then leads to a 3.58% decrease in the cumulative case growth rate (p < 0.01). Further, we find that the effect is greater in regions with developed economies and abundant sports resources. Interestingly, it is greater in regions with less attention to sports, which again confirms the role of the demonstration effect.
The Impact of Informal Social Support on Older Health: Evidence from China
Authors: Tang Daisheng , Wang Xinyuan , Liu Yahong , Bu Tao
Published: February 2022

Objectives: To explore the impact of informal social support (ISS) on older health. Methods: Multiple regression was used as the baseline regression, grouping regression was used to examine whether there were health effect differences among groups based on age and household registration, and insurance was selected to explore moderating effects of formal social support (FSS). Results: First, economic support, accompanied support, and number of intimate contacts had significantly positive effects on older health except for care support’s negative effects. Second, ISS had different health effects for different groups based on age and household registration. Third, FSS was a significant moderating for ISS. Conclusions: The government should emphasize and strengthen the supplementary role of ISS to FSS and promote the effective combination of the two, especially for the older who are high-age and rural, and further improve the role of care support.
Semantic Integration of Raster Data for Earth Observation on Territorial Units
Authors: Tran Ba-Huy , Aussenac-Gilles Nathalie , Comparot Catherine , Trojahn Cassia
Published: February 2022

Semantic technologies have proven their relevance in facilitating the interpretation of Earth Observation (EO) data through formats such as RDF and reusable models, especially for the representation of space and time. While rasters are the usual data format for the results of image processing algorithms, a recurrent problem is transferring the pixel values of these rasters into features that make sense of the areas of interest on the Earth, thus facilitating the interpretation of their content. This paper addresses this issue through a semantic data integration process based on spatial and temporal properties. We propose (i) a modular and generic semantic model for the homogeneous representation of data qualifying a geographical area of interest thanks to territorial units (land parcels, administrative units, forest areas, etc.) that we define as divisions of a larger territory according to a criteria in relation with human activities; and (ii) a semantic extraction, transformation and load (ETL) process that builds on the model and the data extracted from rasters and that maps aggregated data to the corresponding unit areas. We evaluate our approach in terms of the (i) adaptability of the proposed model and pipeline to accommodate different use cases (vineyard and urban expansion monitoring), (ii) added value of the generated datasets to assist in decision making, and (iii) scalability of the approach.
Salivary Glands after Prolonged Aluminum Exposure: Proteomic Approach Underlying Biochemical and Morphological Impairments in Rats
Authors: Souza-Monteiro Deiweson , Guerra Márcia Cristina dos Santos , Bittencourt Leonardo Oliveira , Aragão Walessa Alana Bragança , Dionizio Aline , Silveira Felipe Martins , Buzalaf Marília Afonso Rebelo , Martins Manoela Domingues , Crespo-Lopez Maria Elena , Lima Rafael Rodrigues
Published: February 2022

Aluminum (Al) is one of the most abundant elements on Earth, and its high extraction rate and industrial use make human exposure very common. As Al may be a human toxicant, it is important to investigate the effects of Al exposure, mainly at low doses and for prolonged periods, by simulating human exposure. This work aimed to study the effects of low-dose exposure to chloride aluminum (AlCl3) on the oxidative biochemistry, proteomic profile, and morphology of the major salivary glands. Wistar male rats were exposed to 8.3 mg/kg/day of AlCl3 via intragastric gavage for 60 days. Then, the parotid and submandibular glands were subjected to biochemical assays, proteomic evaluation, and histological analysis. Al caused oxidative imbalance in both salivary glands. Dysregulation of protein expression, mainly of those related to cytoarchitecture, energy metabolism and glandular function, was detected in both salivary glands. Al also promoted histological alterations, such as acinar atrophy and an increase in parenchymal tissue. Prolonged exposure to Al, even at low doses, was able to modulate molecular alterations associated with morphological impairments in the salivary glands of rats. From this perspective, prolonged Al exposure may be a risk to exposed populations and their oral health.
An RNA Polymerase III General Transcription Factor Engages in Cell Type-Specific Chromatin Looping
Authors: de Llobet Cucalon Lara , Di Vona Chiara , Morselli Marco , Vezzoli Marco , Montanini Barbara , Teichmann Martin , de la Luna Susana , Ferrari Roberto
Published: February 2022

Transcription factors (TFs) bind DNA in a sequence-specific manner and are generally cell type-specific factors and/or developmental master regulators. In contrast, general TFs (GTFs) are part of very large protein complexes and serve for RNA polymerases’ recruitment to promoter sequences, generally in a cell type-independent manner. Whereas, several TFs have been proven to serve as anchors for the 3D genome organization, the role of GTFs in genome architecture have not been carefully explored. Here, we used ChIP-seq and Hi-C data to depict the role of TFIIIC, one of the RNA polymerase III GTFs, in 3D genome organization. We find that TFIIIC genome occupancy mainly occurs at specific regions, which largely correspond to Alu elements; other characteristic classes of repetitive elements (REs) such as MIR, FLAM-C and ALR/alpha are also found depending on the cell’s developmental origin. The analysis also shows that TFIIIC-enriched regions are involved in cell type-specific DNA looping, which does not depend on colocalization with the master architectural protein CTCF. This work extends previous knowledge on the role of TFIIIC as a bona fide genome organizer whose action participates in cell type-dependent 3D genome looping via binding to REs.
Antibody-Drug Conjugate Targeting c-Kit for the Treatment of Small Cell Lung Cancer
Authors: Kim Kwang-Hyeok , Kim Jin-Ock , Park Jeong-Yang , Seo Min-Duk , Park Sang Gyu
Published: February 2022

Lung cancer is the leading cause of cancer-related deaths. Small cell lung cancer (SCLC) accounts for 15–25% of all lung cancers. It exhibits a rapid doubling time and a high degree of invasiveness. Additionally, overexpression of c-Kit occurs in 70% of SCLC patients. In this study, we evaluated an antibody-drug conjugate (ADC) that targets c-Kit, which is a potential therapeutic agent for SCLC. First, we generated and characterized 4C9, a fully human antibody that targets c-Kit and specifically binds to SCLC cells expressing c-Kit with a binding affinity of KD = 5.5 × 10−9 M. Then, we developed an ADC using DM1, a microtubule inhibitor, as a payload. 4C9-DM1 efficiently induced apoptosis in SCLC with an IC50 ranging from 158 pM to 4 nM. An in vivo assay using a xenograft mouse model revealed a tumor growth inhibition (TGI) rate of 45% (3 mg/kg) and 59% (5 mg/kg) for 4C9-DM1 alone. Combination treatment with 4C9-DM1 plus carboplatin/etoposide or lurbinectedin resulted in a TGI rate greater than 90% compared with the vehicle control. Taken together, these results indicate that 4C9-DM1 is a potential therapeutic agent for SCLC treatment.
Novel Biodegradable 3D-Printed Analgesics-Eluting-Nanofibers Incorporated Nuss Bars for Therapy of Pectus Excavatum
Authors: Liu Kuo-Sheng , Chen Wei-Hsun , Lee Chen-Hung , Su Yong-Fong , Liu Yen-Wei , Liu Shih-Jung
Published: February 2022

A novel hybrid biodegradable Nuss bar model was developed to surgically correct the pectus excavatum and reduce the associated pain during treatment. The scheme consisted of a three-dimensional (3D) printed biodegradable polylactide (PLA) Nuss bar as the surgical implant and electrospun polylactide–polyglycolide (PLGA) nanofibers loaded with lidocaine and ketorolac as the analgesic agents. The degradation rate and mechanical properties of the PLA Nuss bars were characterized after submersion in a buffered mixture for different time periods. In addition, the in vivo biocompatibility of the integrated PLA Nuss bars/analgesic-loaded PLGA nanofibers was assessed using a rabbit chest wall model. The outcomes of this work suggest that integration of PLA Nuss bar and PLGA/analgesic nanofibers could successfully enhance the results of pectus excavatum treatment in the animal model. The histological analysis also demonstrated good biocompatibility of the PLA Nuss bars with animal tissues. Eventually, the 3D printed biodegradable Nuss bars may have a potential role in pectus excavatum treatment in humans.
A Novel, Apparently Silent Variant in MFSD8 Causes Neuronal Ceroid Lipofuscinosis with Marked Intrafamilial Variability
Authors: Reith Milda , Zeltner Lena , Schäferhoff Karin , Witt Dennis , Zuleger Theresia , Haack Tobias B. , Bornemann Antje , Alber Michael , Ruf Susanne , Schoels Ludger , Stingl Katarina , Weisschuh Nicole
Published: February 2022

Variants in MFSD8 can cause neuronal ceroid lipofuscinoses (NCLs) as well as nonsyndromic retinopathy. The mutation spectrum includes mainly missense and stop variants, but splice sites and frameshift variants have also been reported. To date, apparently synonymous substitutions have not been shown to cause MFSD8-associated diseases. We report two closely related subjects from a consanguineous Turkish family who presented classical features of NCLs but demonstrated marked intrafamilial variability in age at the onset and severity of symptoms. In fact, the difference in the onset of first neurologic symptoms was 15 years and that of ophthalmologic symptoms was 12 years. One subject presented an intellectual disability and a considerable cerebellar ataxia syndrome, while the other subject showed no intellectual disability and only a mild atactic syndrome. The diagnostic genetic testing of both subjects based on genome sequencing prioritized a novel, apparently synonymous variant in MFSD8, which was found in homozygosity in both subjects. The variant was not located within an integral part of the splice site consensus sequences. However, the bioinformatic analyses suggested that the mutant allele is more likely to cause exon skipping due to an altered ratio of exonic splice enhancer and silencer motifs. Exon skipping was confirmed in vitro by minigene assays and in vivo by RNA analysis from patient lymphocytes. The mutant transcript is predicted to result in a frameshift and, if translated, in a truncated protein. Synonymous variants are often given a low priority in genetic diagnostics because of their expected lack of functional impact. This study highlights the importance of investigating the impact of synonymous variants on splicing.
Comparative Transcriptome Analysis of Two Sweet Sorghum Genotypes with Different Salt Tolerance Abilities to Reveal the Mechanism of Salt Tolerance
Authors: Chen Chengxuan , Shang Xiaoling , Sun Meiyu , Tang Sanyuan , Khan Aimal , Zhang Dan , Yan Hongdong , Jiang Yanxi , Yu Feifei , Wu Yaorong , Xie Qi
Published: February 2022

Sweet sorghum is a C4 crop that can be grown for silage forage, fiber, syrup and fuel production. It is generally considered a salt-tolerant plant. However, the salt tolerance ability varies among genotypes, and the mechanism is not well known. To further uncover the salt tolerance mechanism, we performed comparative transcriptome analysis with RNA samples in two sweet sorghum genotypes showing different salt tolerance abilities (salt-tolerant line RIO and salt-sensitive line SN005) upon salt treatment. These response processes mainly focused on secondary metabolism, hormone signaling and stress response. The expression pattern cluster analysis showed that RIO-specific response genes were significantly enriched in the categories related to secondary metabolic pathways. GO enrichment analysis indicated that RIO responded earlier than SN005 in the 2 h after treatment. In addition, we identified more transcription factors (TFs) in RIO than SN005 that were specifically expressed differently in the first 2 h of salt treatment, and the pattern of TF change was obviously different. These results indicate that an early response in secondary metabolism might be essential for salt tolerance in sweet sorghum. In conclusion, we found that an early response, especially in secondary metabolism and hormone signaling, might be essential for salt tolerance in sweet sorghum.
A Novel Role of Arrhythmia-Related Gene KCNQ1 Revealed by Multi-Omic Analysis: Theragnostic Value and Potential Mechanisms in Lung Adenocarcinoma
Authors: Chang Kai-Tun , Wu Hsing-Ju , Liu Chien-Wei , Li Chia-Ying , Lin Hung-Yu
Published: February 2022

The early diagnosis, prognostic prediction, and personalized therapy of lung adenocarcinoma (LUAD) remains a challenging issue. KCNQ1 (potassium voltage-gated channel subfamily Q Member 1) is implicated in long QT syndrome (LQTS) and cardiac arrhythmia, while its significance in LUAD remains unclear. In this study, we aimed to explore the significance of KCNQ1 in terms of clinical value, tumor immunity, underlying mechanisms, and a precision medicine approach by means of multi-omics analysis. The association of KCNQ1 with LUAD was first explored. Both altered variants and high expression of KCNQ1 in a TCGA-LUAD cohort indicated a favorable outcome. KCNQ1 levels had a negative correlation with tumor proliferation index Ki67 levels. siRNA-knockdown of KCNQ1 promoted the migration ability of lung cancer cells. KCNQ1 levels were decreased in LUAD tissue compared to normal tissue. A receiver operating characteristic (ROC) curve indicated good diagnostic efficiency of KCNQ1. High KCNQ1 is associated with an immunoactive profile of immune infiltration and immunomodulators and is involved in the inhibition of the cell cycle and DNA replication. Lapatinib was identified as a potent drug for LUAD in the context of low KCNQ1. This study unveiled the significance of KCNQ1 in diagnosis and prognosis and provided a corresponding precision medicine strategy for LUAD.
How Many Faces Does the Plant U-Box E3 Ligase Have?
Authors: Mao Xinguo , Yu Chunmei , Li Long , Wang Min , Yang Lili , Zhang Yining , Zhang Yanfei , Wang Jingyi , Li Chaonan , Reynolds Matthew Paul , Jing Ruilian
Published: February 2022

Ubiquitination is a major type of post-translational modification of proteins in eukaryotes. The plant U-Box (PUB) E3 ligase is the smallest family in the E3 ligase superfamily, but plays a variety of essential roles in plant growth, development and response to diverse environmental stresses. Hence, PUBs are potential gene resources for developing climate-resilient crops. However, there is a lack of review of the latest advances to fully understand the powerful gene family. To bridge the gap and facilitate its use in future crop breeding, we comprehensively summarize the recent progress of the PUB family, including gene evolution, classification, biological functions, and multifarious regulatory mechanisms in plants.
New and Emerging Targeted Therapies for Advanced Breast Cancer
Authors: Lau Kristie H. , Tan Alexandra M. , Shi Yihui
Published: February 2022

In the United States, breast cancer is among the most frequently diagnosed cancers in women. Breast cancer is classified into four major subtypes: human epidermal growth factor receptor 2 (HER2), Luminal-A, Luminal-B, and Basal-like or triple-negative, based on histopathological criteria including the expression of hormone receptors (estrogen receptor and/or progesterone receptor) and/or HER2. Primary breast cancer treatments can include surgery, radiation therapy, systemic chemotherapy, endocrine therapy, and/or targeted therapy. Endocrine therapy has been shown to be effective in hormone receptor-positive breast cancers and is a common choice for adjuvant therapy. However, due to the aggressive nature of triple-negative breast cancer, targeted therapy is becoming a noteworthy area of research in the search for non-endocrine-targets in breast cancer. In addition to HER2-targeted therapy, other emerging therapies include immunotherapy and targeted therapy against critical checkpoints and/or pathways in cell growth. This review summarizes novel targeted breast cancer treatments and explores the possible implications of combination therapy.
Cerebellar and Striatal Implications in Autism Spectrum Disorders: From Clinical Observations to Animal Models
Authors: Thabault Mathieu , Turpin Valentine , Maisterrena Alexandre , Jaber Mohamed , Egloff Matthieu , Galvan Laurie
Published: February 2022

Autism spectrum disorders (ASD) are complex conditions that stem from a combination of genetic, epigenetic and environmental influences during early pre- and postnatal childhood. The review focuses on the cerebellum and the striatum, two structures involved in motor, sensory, cognitive and social functions altered in ASD. We summarize clinical and fundamental studies highlighting the importance of these two structures in ASD. We further discuss the relation between cellular and molecular alterations with the observed behavior at the social, cognitive, motor and gait levels. Functional correlates regarding neuronal activity are also detailed wherever possible, and sexual dimorphism is explored pointing to the need to apprehend ASD in both sexes, as findings can be dramatically different at both quantitative and qualitative levels. The review focuses also on a set of three recent papers from our laboratory where we explored motor and gait function in various genetic and environmental ASD animal models. We report that motor and gait behaviors can constitute an early and quantitative window to the disease, as they often correlate with the severity of social impairments and loss of cerebellar Purkinje cells. The review ends with suggestions as to the main obstacles that need to be surpassed before an appropriate management of the disease can be proposed.
Methylxanthines Induce a Change in the AD/Neurodegeneration-Linked Lipid Profile in Neuroblastoma Cells
Authors: Janitschke Daniel , Lauer Anna Andrea , Bachmann Cornel Manuel , Winkler Jakob , Griebsch Lea Victoria , Pilz Sabrina Melanie , Theiss Elena Leoni , Grimm Heike Sabine , Hartmann Tobias , Grimm Marcus Otto Walter
Published: February 2022

Alzheimer’s disease (AD) is characterized by an increased plaque burden and tangle accumulation in the brain accompanied by extensive lipid alterations. Methylxanthines (MTXs) are alkaloids frequently consumed by dietary intake known to interfere with the molecular mechanisms leading to AD. Besides the fact that MTX consumption is associated with changes in triglycerides and cholesterol in serum and liver, little is known about the effect of MTXs on other lipid classes, which raises the question of whether MTX can alter lipids in a way that may be relevant in AD. Here we have analyzed naturally occurring MTXs caffeine, theobromine, theophylline, and the synthetic MTXs pentoxifylline and propentofylline also used as drugs in different neuroblastoma cell lines. Our results show that lipid alterations are not limited to triglycerides and cholesterol in the liver and serum, but also include changes in sphingomyelins, ceramides, phosphatidylcholine, and plasmalogens in neuroblastoma cells. These changes comprise alterations known to be beneficial, but also adverse effects regarding AD were observed. Our results give an additional perspective of the complex link between MTX and AD, and suggest combining MTX with a lipid-altering diet compensating the adverse effects of MTX rather than using MTX alone to prevent or treat AD.
Impact of Collagen Crosslinking on Dislocated Human Shoulder Capsules—Effect on Structural and Mechanical Properties
Authors: Cornette Pauline , Jaabar Ilhem Lilia , Dupres Vincent , Werthel Jean-David , Berenbaum Francis , Houard Xavier , Landoulsi Jessem , Nourissat Geoffroy
Published: February 2022

Classical treatments of shoulder instability are associated with recurrence. To determine whether the modification of the capsule properties may be an alternative procedure, the effect of crosslinking treatment on the structure and mechanical properties of diseased human shoulder capsules was investigated. Joint capsules harvested from patients during shoulder surgery (n = 5) were treated or not with UV and/or riboflavin (0.1%, 1.0% and 2.5%). The structure and the mechanical properties of the capsules were determined by atomic force microscopy. The effect of treatments on cell death was investigated. Collagen fibrils were well-aligned and adjacent to each other with a D-periodicity of 66.9 ± 3.2 nm and a diameter of 71.8 ± 15.4 nm in control untreated capsules. No effect of treatments was observed on the organization of the collagen fibrils nor on their intrinsic characteristics, including D-periodicity or their mean diameter. The treatments also did not induce cell death. In contrast, UV + 2.5% riboflavin induced capsule stiffness, as revealed by the increased Young’s modulus values (p < 0.0001 for each patient). Our results showed that the crosslinking procedure changed the biomechanics of diseased capsules, while keeping their structural organisation unchanged at the single fibril level. The UV/riboflavin crosslinking procedure may be a promising way to preserve the functions of collagen-based tissues and tune their elasticity for clinically relevant treatments.
Angiotensin Type-2 Receptors: Transducers of Natriuresis in the Renal Proximal Tubule
Authors: Carey Robert M. , Siragy Helmy M. , Gildea John J. , Keller Susanna R.
Published: February 2022

Angiotensin II (Ang II) type-2 receptors (AT2R) are expressed in the adult kidney, prominently in renal proximal tubule cells (RPTCs), and play an important role in opposing renal sodium (Na+) retention induced by Ang II stimulation of Ang II type-1 receptor (AT1R). Natriuresis induced by AT1R blockade is due at least in part to AT2R activation and whole body deletion of AT2Rs reduces the natriuretic response to increased blood pressure (BP). The major endogenous AT2R agonist mediating the natriuretic response is Ang III, the Ang II heptapeptide metabolite generated by aminopeptidase A, and the principal nephron site mediating inhibition of Na+ reabsorption by the AT2R is the renal proximal tubule (RPT). AT2Rs induce natriuresis via a bradykinin, nitric oxide and cyclic GMP (cGMP) signaling cascade. Recent studies demonstrated a key role for protein phosphatase 2A (PP2A) in the AT2R-mediated natriuretic response upstream of cGMP. By inducing natriuresis, AT2Rs lower BP in the Ang II-infusion model of hypertension. PP2A activation and the natriuretic response to AT2R stimulation are defective in spontaneously hypertensive rats, a model of primary hypertension in humans. AT2R agonists are candidates for proximal tubule natriuretic agents in Na+ and fluid retention disorders.
Fanconi Anemia Patients from an Indigenous Community in Mexico Carry a New Founder Pathogenic Variant in FANCG
Authors: Reyes Pedro , García-de Teresa Benilde , Juárez Ulises , Pérez-Villatoro Fernando , Fiesco-Roa Moisés O. , Rodríguez Alfredo , Molina Bertha , Villarreal-Molina María Teresa , Meléndez-Zajgla Jorge , Carnevale Alessandra , Torres Leda , Frias Sara
Published: February 2022

Fanconi anemia (FA) is a rare genetic disorder caused by pathogenic variants (PV) in at least 22 genes, which cooperate in the Fanconi anemia/Breast Cancer (FA/BRCA) pathway to maintain genome stability. PV in FANCA, FANCC, and FANCG account for most cases (~90%). This study evaluated the chromosomal, molecular, and physical phenotypic findings of a novel founder FANCG PV, identified in three patients with FA from the Mixe community of Oaxaca, Mexico. All patients presented chromosomal instability and a homozygous PV, FANCG: c.511-3_511-2delCA, identified by next-generation sequencing analysis. Bioinformatic predictions suggest that this deletion disrupts a splice acceptor site promoting the exon 5 skipping. Analysis of Cytoscan 750 K arrays for haplotyping and global ancestry supported the Mexican origin and founder effect of the variant, reaffirming the high frequency of founder PV in FANCG. The degree of bone marrow failure and physical findings (described through the acronyms VACTERL-H and PHENOS) were used to depict the phenotype of the patients. Despite having a similar frequency of chromosomal aberrations and genetic constitution, the phenotype showed a wide spectrum of severity. The identification of a founder PV could help for a systematic and accurate genetic screening of patients with FA suspicion in this population.
Cellular Senescence and Aging in Myotonic Dystrophy
Authors: Hasuike Yuhei , Mochizuki Hideki , Nakamori Masayuki
Published: February 2022

Myotonic dystrophy (DM) is a dominantly inherited multisystemic disorder affecting various organs, such as skeletal muscle, heart, the nervous system, and the eye. Myotonic dystrophy type 1 (DM1) and type 2 (DM2) are caused by expanded CTG and CCTG repeats, respectively. In both forms, the mutant transcripts containing expanded repeats aggregate as nuclear foci and sequester several RNA-binding proteins, resulting in alternative splicing dysregulation. Although certain alternative splicing events are linked to the clinical DM phenotypes, the molecular mechanisms underlying multiple DM symptoms remain unclear. Interestingly, multi-systemic DM manifestations, including muscle weakness, cognitive impairment, cataract, and frontal baldness, resemble premature aging. Furthermore, cellular senescence, a critical contributor to aging, is suggested to play a key role in DM cellular pathophysiology. In particular, several senescence inducers including telomere shortening, mitochondrial dysfunction, and oxidative stress and senescence biomarkers such as cell cycle inhibitors, senescence-associated secretory phenotype, chromatin reorganization, and microRNA have been implicated in DM pathogenesis. In this review, we focus on the clinical similarities between DM and aging, and summarize the involvement of cellular senescence in DM and the potential application of anti-aging DM therapies.
Thiacalixarenes with Sulfur Functionalities at Lower Rim: Heavy Metal Ion Binding in Solution and 2D-Confined Space
Authors: Muravev Anton , Yakupov Ayrat , Gerasimova Tatiana , Islamov Daut , Lazarenko Vladimir , Shokurov Alexander , Ovsyannikov Alexander , Dorovatovskii Pavel , Zubavichus Yan , Naumkin Alexander , Selektor Sofiya , Solovieva Svetlana , Antipin Igor
Published: February 2022

Sulfur-containing groups preorganized on macrocyclic scaffolds are well suited for liquid-phase complexation of soft metal ions; however, their binding potential was not extensively studied at the air–water interface, and the effect of thioether topology on metal ion binding mechanisms under various conditions was not considered. Herein, we report the interface receptor characteristics of topologically varied thiacalixarene thioethers (linear bis-(methylthio)ethoxy derivative L2, O2S2-thiacrown-ether L3, and O2S2-bridged thiacalixtube L4). The study was conducted in bulk liquid phase and Langmuir monolayers. For all compounds, the highest liquid-phase extraction selectivity was revealed for Ag+ and Hg2+ ions vs. other soft metal ions. In thioether L2 and thiacalixtube L4, metal ion binding was evidenced by a blue shift of the band at 303 nm (for Ag+ species) and the appearance of ligand-to-metal charge transfer bands at 330–340 nm (for Hg2+ species). Theoretical calculations for thioether L2 and its Ag and Hg complexes are consistent with experimental data of UV/Vis, nuclear magnetic resonance (NMR) spectroscopy, and single-crystal X-ray diffractometry of Ag–thioether L2 complexes and Hg–thiacalixtube L4 complex for the case of coordination around the metal center involving two alkyl sulfide groups (Hg2+) or sulfur atoms on the lower rim and bridging unit (Ag+). In thiacrown L3, Ag and Hg binding by alkyl sulfide groups was suggested from changes in NMR spectra upon the addition of corresponding salts. In spite of the low ability of the thioethers to form stable Langmuir monolayers on deionized water, one might argue that the monolayers significantly expand in the presence of Hg salts in the water subphase. Hg2+ ion uptake by the Langmuir–Blodgett (LB) films of ligand L3 was proved by X-ray photoelectron spectroscopy (XPS). Together, these results demonstrate the potential of sulfide groups on the calixarene platform as receptor unit towards Hg2+ ions, which could be useful in the development of Hg2+-selective water purification systems or thin-film sensor devices.
Diffracted X-ray Tracking Method for Measuring Intramolecular Dynamics of Membrane Proteins
Authors: Fujimura Shoko , Mio Kazuhiro , Ohkubo Tatsunari , Arai Tatsuya , Kuramochi Masahiro , Sekiguchi Hiroshi , Sasaki Yuji C.
Published: February 2022

Membrane proteins change their conformations in response to chemical and physical stimuli and transmit extracellular signals inside cells. Several approaches have been developed for solving the structures of proteins. However, few techniques can monitor real-time protein dynamics. The diffracted X-ray tracking method (DXT) is an X-ray-based single-molecule technique that monitors the internal motion of biomolecules in an aqueous solution. DXT analyzes trajectories of Laue spots generated from the attached gold nanocrystals with a two-dimensional axis by tilting (θ) and twisting (χ). Furthermore, high-intensity X-rays from synchrotron radiation facilities enable measurements with microsecond-timescale and picometer-spatial-scale intramolecular information. The technique has been applied to various membrane proteins due to its superior spatiotemporal resolution. In this review, we introduce basic principles of DXT, reviewing its recent and extended applications to membrane proteins and living cells, respectively.
Newborn Screening for X-Linked Adrenoleukodystrophy: Past, Present, and Future
Authors: Moser Ann B. , Seeger Elisa , Raymond Gerald V.
Published: February 2022

Newborn screening for X-linked adrenoleukodystrophy began in New York in 2013. Prior to this start, there was already significant information on the diagnosis and monitoring of asymptomatic individuals. Methods needed to be developed and validated for the use of dried blood spots. Following its institution in New York, its acceptance as a disorder on the Recommended Uniform Screening occurred. With it has come published recommendations on the surveillance and care of boys detected by newborn screening. There still remain challenges, but it is hoped that with periodic review, they may be overcome.
Early Hemodynamic Changes following Surgical Ablation of the Right Greater Splanchnic Nerve for the Treatment of Heart Failure with Preserved Ejection Fraction
Authors: Gajewski Piotr , Fudim Marat , Kittipibul Veraprapas , Engelman Zoar J. , Biegus Jan , Zymliński Robert , Ponikowski Piotr
Published: February 2022

Background: Permanent ablation of the right greater splanchnic nerve (GSN) has previously been demonstrated to improve quality of life and functional outcomes, as well as reduce abnormally high intracardiac filling pressures, in patients with heart failure with preserved ejection fraction (HFpEF) at 1, 3 and 12 months following the procedure. We hypothesize that hemodynamic changes that ensue from surgical right GSN ablation would be apparent as early as 24 h after the medical intervention. Methods and Results: This is a prespecified analysis of a single-arm, two-center, open-label study evaluating the effects of right GSN ablation via thoracoscopic surgery in HFpEF patients with pulmonary capillary wedge pressure (PCWP) ≥15 mmHg at rest or ≥25 mmHg with supine cycle ergometry. A total of seven patients (median age 67 years, 29% female) underwent GSN removal followed by invasive right heart catheterization within 24 h. GSN ablation resulted in a significant reduction in PCWP 24 h after the procedure compared to baseline for both 20 W exercise (baseline (28.0 ± 4.3 mmHg) to 24 h (19.6 ± 6.9 mmHg); p = 0.0124) and peak exercise (baseline (25.6 ± 2.4 mmHg) to 24 h (17.4 ± 5.9 mmHg); p = 0.0025). There were no significant changes in resting or leg-up hemodynamics. Conclusions: Permanent right GSN ablation leads to a reduction in intracardiac filling pressures during exercise, apparent as early as 24 h following the procedure.
Age-Related Macular Degeneration: New Insights in Diagnosis, Treatment, and Prevention
Authors: Mathis Thibaud , Kodjikian Laurent
Published: February 2022

Age-related macular degeneration (AMD) is an aging-related ocular disease that can be responsible for severe loss of visual acuity and loss of autonomy in patients [...]
Feasibility Trial to Evaluate Tendon Stiffness Obtained from Shear Wave Elastography Imaging as a Biomarker of Aromatase Inhibitor-Induced Arthralgias
Authors: Martinez Jessica A. , Taljanovic Mihra S. , Nuncio Zuniga Andres A. , Wertheim Betsy C. , Roe Denise J. , Ehsani Sima , Jiralerspong Sao , Segar Jennifer , Chalasani Pavani
Published: February 2022

Aromatase inhibitor-induced arthralgia (AIA) comprises significant, activity-limiting musculoskeletal symptoms, including joint pain, myalgia, and joint stiffness. We conducted a prospective feasibility study in postmenopausal women diagnosed with early-stage (0–3) hormone receptor positive (HR+) breast cancer who were candidates for treatment with adjuvant AI therapy (n = 16). Tendons of the hands and wrists and the median nerve were imaged using gray-scale and power Doppler ultrasound (US) and US SWE. Arthralgia symptoms were evaluated using the Breast Cancer Prevention Trial (BCPT) Symptom Checklist musculoskeletal subscale (MS) and the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain and stiffness subscales. At baseline, there were significant differences in the SW velocities of tendons between dominant and nondominant hands. Increased velocity in 2 of 6 tendons and the median nerve was associated with greater pain at baseline, whereas slower velocity of the extensor digitorum tendon (suggesting decreased stiffness) was associated with a higher WOMAC stiffness score. Increased SW velocity (suggestive of increased stiffness) at baseline in the abductor pollicis longus tendon was associated with a worsening of all three pain and stiffness measures by 6 months. Future studies should evaluate SWE scores related to AIA outcomes in a larger sample size.
Physiological Responses to Combat Sports in Metabolic Diseases: A Systematic Review
Authors: Eckstein Max Lennart , Schwarzinger Melanie , Haupt Sandra , Wachsmuth Nadine Bianca , Zimmer Rebecca Tanja , Sourij Harald , Zimmermann Paul , Zunner Beate Elisabeth Maria , Aberer Felix , Moser Othmar
Published: February 2022

The aim of this systematic review was to investigate how individuals with metabolic diseases respond to combat sports and if they are feasible, safe, and applicable. A systematic literature search was conducted in PubMed, from inception until 22 January 2021. Studies were included if combat sport exercise sessions were clearly defined and participants had the following types of metabolic disease: type 1 or 2 diabetes mellitus, metabolic syndrome, overweight, and obesity. Eleven studies, involving 472 participants of all age groups with type 1 diabetes mellitus, metabolic syndrome, overweight, or obesity were included in this systematic review. No studies involving combat sports and individuals with type 2 diabetes were found. Combat sports showed improved HbA1c levels over time in individuals with type 1 diabetes mellitus, which was not significantly different compared to the control group (p = 0.57). During the follow-up period, glycaemic variability decreased in those actively participating in combat sports. Fat-mass was higher in athletes performing combat sports with metabolic syndrome, compared to athletes without an increased cardiometabolic risk. In overweight/obese adolescents, combat sports showed improved parameters of physical fitness, cardio autonomic control, strength, and body composition compared to control groups. In all studies included in this systematic review, no adverse event associated with combat sports was reported. In conclusion, combat sports are safe and feasible in individuals with diabetes and/or obesity. For individuals with type 2 diabetes mellitus, no recommendations can be made, due to the lack of evidence in this cohort. Future studies investigating combat sports and metabolic diseases should aim for a structured exercise regimen and acknowledge the experience of the participants prior to starting an exercise intervention involving combat sports.
Heterogeneity of Genotype–Phenotype in Congenital Hypofibrinogenemia—A Review of Case Reports Associated with Bleeding and Thrombosis
Authors: Brunclikova Monika , Simurda Tomas , Zolkova Jana , Sterankova Miroslava , Skornova Ingrid , Dobrotova Miroslava , Kolkova Zuzana , Loderer Dusan , Grendar Marian , Hudecek Jan , Stasko Jan , Kubisz Peter
Published: February 2022

Congenital fibrinogen disorders are diseases associated with a bleeding tendency; however, there are also reports of thrombotic events. Fibrinogen plays a role in the pathogenesis of thrombosis due to altered plasma concentrations or modifications to fibrinogen’s structural properties, which affect clot permeability, resistance to lysis, and its stiffness. Several distinct types of genetic change and pathogenetic mechanism have been described in patients with bleeding and a thrombotic phenotype, including mutations affecting synthesis or processing in three fibrinogen genes. In this paper, we focused on familial hypofibrinogenemia, a rare inherited quantitative fibrinogen disorder characterized by decreased fibrinogen levels with a high phenotypic heterogeneity. To begin, we briefly review the basic information regarding fibrinogen’s structure, its function, and the clinical consequences of low fibrinogen levels. Thereafter, we introduce 15 case reports with various gene mutations derived from the fibrinogen mutation database GFHT (French Study Group on Hemostasis and Thrombosis), which are associated with congenital hypofibrinogenemia with both bleeding and thrombosis. Predicting clinical presentations based on genotype data is difficult. Genotype–phenotype correlations would be of help to better understand the pathologic properties of this rare disease and to provide a valuable tool for the identification of patients who are not only at risk of bleeding, but also at risk of a thrombotic event.
Severe Thrombocytopenia as a Manifestation of COVID-19 Infection
Authors: Mocan Mihaela , Chiorescu Roxana Mihaela , Tirnovan Andrada , Buksa Botond Sandor , Farcaș Anca Daniela
Published: February 2022

Clinical manifestations of COVID-19 infection can range from an asymptomatic clinical form to acute respiratory distress depending on the virus gateway, viral load, host immunity, and existing comorbidities. Some patients with COVID-19 infection can present hematological changes depending on the patient’s immune response and the severity of the infection. We present two different manifestations of thrombotic disorders related to COVID-19: one severe form of immune thrombocytopenia in a young woman with no comorbidities and a severe form of thrombocytopenia along with disseminated intravascular coagulation and acute urinary obstructive disease. Interestingly, both patients presented no signs of COVID-19 pneumonia. Failure to diagnose thrombocytopenia rapidly may lead to severe complications. Management with immunosuppressive corticosteroids in high doses should carefully balance the risk of bleeding versus deterioration due to infection.
The Burden of Vertebral Osteomyelitis—An Analysis of the Workforce before and after Treatment
Authors: Yagdiran Ayla , Bredow Jan , Weber Carolyn , Mousa Basha Ghaith , Eysel Peer , Fischer Julia , Jung Norma
Published: February 2022

Although vertebral osteomyelitis (VO) has a major impact on morbidity, functional status, and quality of life, data concerning the influence on the patient’s ability to work (ATW) are lacking. Therefore, the aim of this study was to analyze the work status after VO-treatment as well as risk factors associated with loss of the ATW. We conducted a post-hoc analysis of data from a prospective VO-registry (2008–2019) supplemented by workforce data. Primary endpoint was the work status after one year (T1). Univariate analysis comparing patients’ characteristics “at-work” versus “not-at-work” at T1 was performed. Of a total of 335 VO-patients, n = 52 (16%) were part of the workforce at time of diagnosis (T0), of which 22 (42%) failed to be part of the workforce at T1. A higher number of comorbidities and a body mass index (BMI) < 25 kg/m2 were associated with a reduced ATW. VO in working age patients is a debilitating condition and associated with reduced patients’ ATW. Patients engaged in heavy physical work mostly had a BMI < 25 kg/m2 and therefore were more severely affected and no longer able to keep their workforce. More support in retraining should be offered after successful treatment to maintain ATW and reduce the socio-economic burden.
Hearing Aid Effects and Satisfaction in Patients with Tinnitus
Authors: Lee Hyun , Kang Dae , Yeo Seung , Kim Sang
Published: February 2022

This study aimed to evaluate the effectiveness of and satisfaction with hearing aids as a treatment option for tinnitus with hearing loss. Methods: This retrospective study used the tinnitus handicap inventory (THI), the satisfaction with amplification in daily life (SADL) questionnaire, and a medical chart review. A total of 116 patients treated between August 2018 and December 2020 were included. All patients with tinnitus and hearing loss underwent the same counseling sessions. Sixty patients chose to have hearing aids fitted (aided group), whereas 56 patients chose not to (non-aided group). Both the groups had similar audiometric configurations, durations of tinnitus, and ages. Structured interviews were performed, with various measures evaluated using the visual analog scale (VAS) and the THI questionnaire, before and six months after fitting the hearing aids. The SADL questionnaire was administered 6 months after fitting the hearing aids. Results: The patients’ THI scores reduced 6 months after the counseling, but the improvement in the THI scores was only significant in the group that received hearing aids. There were significant differences between the VAS scores of the two groups, and the changes in the VAS scores in the groups were statistically different. Subjective satisfaction with a hearing aid increased with improvements to tinnitus-related discomfort. Conclusion: The study’s results indicated that patients with hearing loss and tinnitus can be treated with hearing aids and counseling.
Immunotherapeutic Approaches for the Treatment of HPV-Associated (Pre-)Cancer of the Cervix, Vulva and Penis
Authors: Rafael Tynisha S. , Rotman Jossie , Brouwer Oscar R. , van der Poel Henk G. , Mom Constantijne H. , Kenter Gemma G. , de Gruijl Tanja D. , Jordanova Ekaterina S.
Published: February 2022

Human papillomavirus (HPV) infection drives tumorigenesis in almost all cervical cancers and a fraction of vulvar and penile cancers. Due to increasing incidence and low vaccination rates, many will still have to face HPV-related morbidity and mortality in the upcoming years. Current treatment options (i.e., surgery and/or chemoradiation) for urogenital (pre-)malignancies can have profound psychosocial and psychosexual effects on patients. Moreover, in the setting of advanced disease, responses to current therapies remain poor and nondurable, highlighting the unmet need for novel therapies that prevent recurrent disease and improve clinical outcome. Immunotherapy can be a useful addition to the current therapeutic strategies in various settings of disease, offering relatively fewer adverse effects and potential improvement in survival. This review discusses immune evasion mechanisms accompanying HPV infection and HPV-related tumorigenesis and summarizes current immunotherapeutic approaches for the treatment of HPV-related (pre-)malignant lesions of the uterine cervix, vulva, and penis.
Severe Thrombotic Thrombocytopenic Purpura (TTP) with Organ Failure in Critically Ill Patients
Authors: Fodil Sofiane , Zafrani Lara
Published: February 2022

Thrombotic thrombocytopenic purpura (TTP) is a multiorgan disorder. Organ dysfunction occurs as a consequence of widespread microvascular thrombosis, especially in the heart, brain and kidney, causing transient or partial occlusion of vessels, resulting in organ ischemia. Intensive care unit (ICU) admission varies between 40% and 100% of patients with TTP, either because of severe organ failure or in order to initiate emergency plasma exchange (PEx). Severe neurologic manifestations and cardiac involvement have been associated with higher mortality. Acute kidney injury, although usually less severe than that in hemolytic and uremic syndrome, is common during TTP. Initial management in the ICU should always be considered in TTP patients. The current treatment of TTP in the acute phase is based on urgent PEx, combined with corticosteroid therapy, B-cell-targeted immunotherapy, rituximab and inhibition of the interaction between ultra-large Von Willebrand factor multimers and platelets, using caplacizumab, a monoclonal antibody. ICU management permits close monitoring and the rapid introduction of life-sustaining therapies. This review details the epidemiology of TTP in the ICU, organ failures of critically ill patients with TTP, and the initial management of TTP patients in the ICU.