bluuebunny/crossref_metadata_2025 huggingface dataset:
Expanding the Molecular Spectrum of ANKRD11 Gene Defects in 33 Patients with a Clinical Presentation of KBG Syndrome
Authors: Bestetti Ilaria , Crippa Milena , Sironi Alessandra , Tumiatti Francesca , Masciadri Maura , Smeland Marie Falkenberg , Naik Swati , Murch Oliver , Bonati Maria Teresa , Spano Alice , Cattaneo Elisa , Mariani Milena , Gotta Fabio , Crosti Francesca , Cavalli Pietro , Pantaleoni Chiara , Natacci Federica , Bedeschi Maria Francesca , Milani Donatella , Maitz Silvia , Selicorni Angelo , Spaccini Luigina , Peron Angela , Russo Silvia , Larizza Lidia , Low Karen , Finelli Palma
Published: May 2022

KBG syndrome (KBGS) is a neurodevelopmental disorder caused by the Ankyrin Repeat Domain 11 (ANKRD11) haploinsufficiency. Here, we report the molecular investigations performed on a cohort of 33 individuals with KBGS clinical suspicion. By using a multi-testing genomic approach, including gene sequencing, Chromosome Microarray Analysis (CMA), and RT-qPCR gene expression assay, we searched for pathogenic alterations in ANKRD11. A molecular diagnosis was obtained in 22 out of 33 patients (67%). ANKRD11 sequencing disclosed pathogenic or likely pathogenic variants in 18 out of 33 patients. CMA identified one full and one terminal ANKRD11 pathogenic deletions, and one partial duplication and one intronic microdeletion, with both possibly being pathogenic. The pathogenic effect was established by RT-qPCR, which confirmed ANKRD11 haploinsufficiency only for the three deletions. Moreover, RT-qPCR applied to six molecularly unsolved KBGS patients identified gene downregulation in a clinically typical patient with previous negative tests, and further molecular investigations revealed a cryptic deletion involving the gene promoter. In conclusion, ANKRD11 pathogenic variants could also involve the regulatory regions of the gene. Moreover, the application of a multi-test approach along with the innovative use of RT-qPCR improved the diagnostic yield in KBGS suspected patients.
Molecular Mechanism of Induction of Bone Growth by the C-Type Natriuretic Peptide
Authors: Rintz Estera , Węgrzyn Grzegorz , Fujii Toshihito , Tomatsu Shunji
Published: May 2022

The skeletal development process in the body occurs through sequential cellular and molecular processes called endochondral ossification. Endochondral ossification occurs in the growth plate where chondrocytes differentiate from resting, proliferative, hypertrophic to calcified zones. Natriuretic peptides (NPTs) are peptide hormones with multiple functions, including regulation of blood pressure, water-mineral balance, and many metabolic processes. NPTs secreted from the heart activate different tissues and organs, working in a paracrine or autocrine manner. One of the natriuretic peptides, C-type natriuretic peptide-, induces bone growth through several mechanisms. This review will summarize the knowledge, including the newest discoveries, of the mechanism of CNP activation in bone growth.
The Expression of Connexin 37, 40, 43, 45 and Pannexin 1 in the Early Human Retina and Choroid Development and Tumorigenesis
Authors: Žužul Matea , Lozić Mirela , Filipović Natalija , Čanović Samir , Didović Pavičić Ana , Petričević Joško , Kunac Nenad , Šoljić Violeta , Saraga-Babić Mirna , Konjevoda Suzana , Vukojevic Katarina
Published: May 2022

The expression pattern of Connexins (Cx) 37, 40, 43, 45 and Pannexin 1 (Pnx1) was analyzed immunohistochemically, as well as semi-quantitatively and quantitatively in histological sections of developing 8th- to 12th-week human eyes and postnatal healthy eye, in retinoblastoma and different uveal melanomas. Expressions of both Cx37 and Cx43 increased during development but diminished in the postnatal period, being higher in the retina than in the choroid. Cx37 was highly expressed in the choroid of retinoblastoma, and Cx43 in epitheloid melanoma, while they were both increasingly expressed in mixoid melanoma. In contrast, mild retinal Cx40 expression during development increased to strong in postnatal period, while it was significantly higher in the choroid of mixoid melanoma. Cx45 showed significantly higher expression in the developing retina compared to other samples, while it became low postnatally and in all types of melanoma. Pnx1 was increasingly expressed in developing choroid but became lower in the postnatal eye. It was strongly expressed in epithelial and spindle melanoma, and particularly in retinoblastoma. Our results indicate importance of Cx37 and Cx40 expression in normal and pathological vascularization, and Cx43 expression in inflammatory response. Whereas Cx45 is involved in early stages of eye development, Pnx1might influence cell metabolism. Additionally, Cx43 might be a potential biomarker of tumor prognosis.
Non-Aziridination Approaches to 3-Arylaziridine-2-carboxylic Acid Derivatives and 3-Aryl-(aziridin-2-yl)ketones
Authors: Strumfs Boriss , Velikijs Kirils , Uljanovs Romans , Sinkarevs Stanislavs , Strumfa Ilze
Published: May 2022

Highly functionalized aziridines, including compounds with aromatic moieties, are attractive substrates both in synthetic and medical areas of chemistry. There is a broad and interesting set of synthetic methods for reaching these compounds. Aziridination represents the most explored tool, but there are several other more specific, less well-known, but highly promising approaches. Therefore, the current review focuses on recently described or updated ways to obtain 3-arylated aziridines via different non-aziridination-based synthetic methods, reported mainly since 2000. The presented methods belong to two main directions of synthesis, namely, cyclization of open-chain substrates and rearrangement of other heterocycles. Cyclization of open-chain substrates includes the classic Gabriel-Cromwell type cyclization of halogenated substrates with amines, base-promoted cyclization of activated aminoalcohols (or its analogues), and the oxidative cyclization of β-dicarbonyls. Rearrangements of other heterocycles are presented as the Baldwin rearrangement of 4-isoxazolines, the cycloaddition of 1.3-dipoles or dienes to 2H-azirines, and the addition of C- and N-nucleophiles to the double bond of azirines.
Comprehensive Flow-Cytometric Quality Assessment of Ram Sperm Intended for Gene Banking Using Standard and Novel Fertility Biomarkers
Authors: Vašíček Jaromír , Baláži Andrej , Svoradová Andrea , Vozaf Jakub , Dujíčková Linda , Makarevich Alexander V. , Bauer Miroslav , Chrenek Peter
Published: May 2022

Flow cytometry becomes a common method for analysis of spermatozoa quality. Standard sperm characteristics such as viability, acrosome and chromatin integrity, oxidative damage (ROS) etc. can be easily assess in any animal semen samples. Moreover, several fertility-related markers were observed in humans and some other mammals. However, these fertility biomarkers have not been previously studied in ram. The aim of this study was to optimize the flow-cytometric analysis of these standard and novel markers in ram semen. Ram semen samples from Slovak native sheep breeds were analyzed using CASA system for motility and concentration and were subsequently stained with several fluorescent dyes or specific antibodies to evaluate sperm viability (SYBR-14), apoptosis (Annexin V, YO-PRO-1, FLICA, Caspases 3/7), acrosome status (PNA, LCA, GAPDHS), capacitation (merocyanine 540, FLUO-4 AM), mitochondrial activity (MitoTracker Green, rhodamine 123, JC-1), ROS (CM-H2DCFDA, DHE, MitoSOX Red, BODIPY), chromatin (acridine orange), leukocyte content, ubiquitination and aggresome formation, and overexpression of negative biomarkers (MKRN1, SPTRX-3, PAWP, H3K4me2). Analyzed semen samples were divided into two groups according to viability as indicators of semen quality: Group 1 (viability over 60%) and Group 2 (viability under 60%). Significant (p < 0.05) differences were found between these groups in sperm motility and concentration, apoptosis, acrosome integrity (only PNA), mitochondrial activity, ROS production (except for DHE), leukocyte and aggresome content, and high PAWP expression. In conclusion, several standard and novel fluorescent probes have been confirmed to be suitable for multiplex ram semen analysis by flow cytometry as well as several antibodies have been validated for the specific detection of ubiquitin, PAWP and H3K4me2 in ram spermatozoa.
The Progression of N6-methyladenosine Study and Its Role in Neuropsychiatric Disorders
Authors: Lei Chunguang , Wang Qingzhong
Published: May 2022

Epitranscriptomic modifications can affect every aspect of RNA biology, including stability, transport, splicing, and translation, participate in global intracellular mRNA metabolism, and regulate gene expression and a variety of biological processes. N6-methyladenosine (m6A) as the most prevalent modification contributes to normal embryonic brain development and memory formation. However, changes in the level of m6A modification and the expression of its related proteins cause abnormal nervous system functions, including brain tissue development retardation, axon regeneration disorders, memory changes, and neural stem cell renewal and differentiation disorders. Recent studies have revealed that m6A modification and its related proteins play key roles in the development of various neuropsychiatric disorders, such as depression, Alzheimer’s disease, and Parkinson’s disease. In this review, we summarize the research progresses of the m6A modification regulation mechanism in the central nervous system and discuss the effects of gene expression regulation mediated by m6A modification on the biological functions of the neuropsychiatric disorders, thereby providing some insight into new research targets and treatment directions for human diseases.
Ribonomics Approaches to Identify RBPome in Plants and Other Eukaryotes: Current Progress and Future Prospects
Authors: Haroon Muhammad , Afzal Rabail , Zafar Muhammad Mubashar , Zhang Hongwei , Li Lin
Published: May 2022

RNA-binding proteins (RBPs) form complex interactions with RNA to regulate the cell’s activities including cell development and disease resistance. RNA-binding proteome (RBPome) aims to profile and characterize the RNAs and proteins that interact with each other to carry out biological functions. Generally, RNA-centric and protein-centric ribonomic approaches have been successfully developed to profile RBPome in different organisms including plants and animals. Further, more and more novel methods that were firstly devised and applied in mammalians have shown great potential to unravel RBPome in plants such as RNA-interactome capture (RIC) and orthogonal organic phase separation (OOPS). Despise the development of various robust and state-of-the-art ribonomics techniques, genome-wide RBP identifications and characterizations in plants are relatively fewer than those in other eukaryotes, indicating that ribonomics techniques have great opportunities in unraveling and characterizing the RNA–protein interactions in plant species. Here, we review all the available approaches for analyzing RBPs in living organisms. Additionally, we summarize the transcriptome-wide approaches to characterize both the coding and non-coding RBPs in plants and the promising use of RBPome for booming agriculture.
Roles and Applications of Red Blood Cell-Derived Extracellular Vesicles in Health and Diseases
Authors: Yang Lan , Huang Shiqi , Zhang Zhirong , Liu Zhenmi , Zhang Ling
Published: May 2022

Red blood cell-derived extracellular vesicles (RBCEVs) are vesicles naturally produced by red blood cells and play multiple roles such as acting as cell-to-cell communication messengers in both normal physiological and diseased states. RBCEVs are highly promising delivery vehicles for therapeutic agents such as biomolecules and nucleic acids as they are easy to source, safe, and versatile. RBCEVs autonomously target the liver and pass the blood–brain barrier into the brain, which is highly valuable for the treatment of liver and brain diseases. RBCEVs can be modified by various functional units, including various functional molecules and nanoparticles, to improve their active targeting capabilities for tumors or other sites. Moreover, the RBCEV level is significantly shifted in many diseased states; hence, they can also serve as important biomarkers for disease diagnoses. It is clear that RBCEVs have considerable potential in multiple medical applications. In this review, we briefly introduce the biological roles of RBCEVs, presented interesting advances in RBCEV applications, and discuss several challenges that need to be addressed for their clinical translation.
Optimization of Photothermal Therapy Treatment Effect under Various Laser Irradiation Conditions
Authors: Kim Donghyuk , Kim Hyunjung
Published: May 2022

The photothermal effect refers to a phenomenon in which light energy is converted into heat energy, and in the medical field, therapeutics based on this phenomenon are used for anticancer treatment. A new treatment technique called photothermal therapy kills tumor tissue through a temperature increase and has the advantages of no bleeding and fast recovery. In this study, the results of photothermal therapy for squamous cell carcinoma in the skin layer were analyzed numerically for different laser profiles, intensities, and radii and various concentrations of gold nanoparticles (AuNPs). According to the heat-transfer theory, the temperature distribution in the tissue was calculated for the conditions under which photothermal therapy was performed, and the therapeutic effect was quantitatively confirmed through three apoptotic variables. In addition, the laser intensity and the volume fraction of AuNPs were optimized, and the results provide useful criteria for optimizing the treatment effects in photothermal therapy.
Effects of Bile Acid Modulation by Dietary Fat, Cholecystectomy, and Bile Acid Sequestrant on Energy, Glucose, and Lipid Metabolism and Gut Microbiota in Mice
Authors: Park Sunmin , Zhang Ting , Yue Yu , Wu Xuangao
Published: May 2022

Bile acid metabolism, involved with the digestion and absorption of nutrients in the gut, is linked to the gut microbiota community, greatly impacting the host’s metabolism. We examined the hypothesis that the modulation of bile acid metabolism by dietary fat contents, gallbladder removal (GBX; cholecystectomy), and bile acid sequestrant (BAS; cholestyramine) treatment could alter energy, glucose, and lipid metabolism through the changes in the gut microbiota. Mice were randomly assigned to the following six groups: (1) Sham GBX surgery (Sham) + low fat/high carbohydrate diet (LFD), (2) Sham + high fat diet (HFD), (3) Sham + HFD + BAS, (4) GBX + LFD, (5) GBX + HFD, and (6) GBX + HFD + BAS. BAS groups received 2% cholestyramine. After an 8-week intervention, energy, glucose, and lipid metabolism, and the gut microbiota community were measured. HFD groups exhibited higher body weight gain than LFD, and GBX increased the weight gain comped to Sham groups regardless of BAS in HFD (p < 0.05). Homeostatic model assessment for insulin resistance (HOMA-IR) was higher in HFD than LFD, and GBX increased it regardless of BAS. Serum lipid profiles were worsened in GBX + HFD compared to Sham + LFD, whereas BAS alleviated them, except for serum HDL cholesterol. Hepatic tumor-necrosis-factor-α (TNF-α) mRNA expression and lipid peroxide contents increased with GBX and BAS treatment compared to Sham and no BAS treatment (p < 0.05). Hepatic mRNA expression of sterol regulatory element-binding transcription factor 1c (SREBP1c) and peroxisome proliferator-activated receptor gamma (PPAR-γ) exhibited the same trend as that of tumor necrosis factor-α (TNF-α). The α-diversity of gut bacteria decreased in GBX + HFD and increased in GBX + HFD + BAS. Akkermentia, Dehalobacterium, SMB53, and Megamonas were high in the Sham + LFD, and Veillonella and Streptococcus were rich in the Sham + HFD, while Oscillospira and Olsenella were high in Sham + HFD + BAS (p < 0.05). GBX + LFD increased Lactobacillus and Sutterella while GBX + HFD + BAS elevated Clostridium, Alistipes, Blautia, Eubacterium, and Coprobacillus (p < 0.05). In conclusion, the modulation of bile acid metabolism influences energy, glucose, and lipid metabolisms, and it might be linked to changes in the gut microbiota by bile acid metabolism modulation.
Chemical Probes and Activity-Based Protein Profiling for Cancer Research
Authors: Al Mazid Mohammad Faysal , Park Seung Bin , Cheekatla Subba Rao , Murale Dhiraj P. , Shin Kyung Ho , Lee Jun-Seok
Published: May 2022

Chemical probes can be used to understand the complex biological nature of diseases. Due to the diversity of cancer types and dynamic regulatory pathways involved in the disease, there is a need to identify signaling pathways and associated proteins or enzymes that are traceable or detectable in tests for cancer diagnosis and treatment. Currently, fluorogenic chemical probes are widely used to detect cancer-associated proteins and their binding partners. These probes are also applicable in photodynamic therapy to determine drug efficacy and monitor regulating factors. In this review, we discuss the synthesis of chemical probes for different cancer types from 2016 to the present time and their application in monitoring the activity of transferases, hydrolases, deacetylases, oxidoreductases, and immune cells. Moreover, we elaborate on their potential roles in photodynamic therapy.
Creative Narration as a Design Technique
Authors: Manias Dimosthenis , Mavrommati Irene
Published: May 2022

Creative narration is a structured ideation technique based on storytelling. It has the potential to enhance the initial design process of ideation in terms of collaboration and creativity. People from various disciplines, following specific steps, collaborate to create a story. Afterward, inspired by their stories, they create products and services. In this paper, two case studies are presented and compared, where the technique of creative narration was used in the contexts of two creative workshops. An initial assessment of this process, highlighting the strong and weak points of the technique, is discussed in this paper.
Critical Success Factors Evaluation by Multi-Criteria Decision-Making: A Strategic Information System Planning and Strategy-As-Practice Perspective
Authors: Kim Sehoon
Published: May 2022

Strategic information system planning (SISP) is a central process that enables organizations to identify the strategic alignment of their IT portfolio to achieve their business needs and objectives. The extant SISP literature has focused on theoretical and processual aspects and has left methodological ambiguity about how SISP is practiced. This paper contributes to the current knowledge by providing a mixed-methods SISP framework labeled CSF-MCDM for company-wide strategic alignment. The paper conducts a methodological synthesis, embracing an expert-based qualitative approach based on a PEST-SWOT and causal layered analysis to draw the critical success factors of a next-generation business system for an automotive company in South Korea. The derived CSF dimensions and sub-criteria are evaluated by the multi-criteria decision-making model, engaging a strategy-as-practice lens to SISP to enable an integrative analysis of IS strategy formulation, planning, and implementation. The findings reveal the relative strategic priorities of dimensions, the following core activities, and the global priorities for resource distribution planning for IS strategy of the firm. This paper argues that bringing replicability with SISP and diversifying methodological approaches within the organization is substantial. This paper also suggests that future researchers validate the suggested framework for scientific replicability and expand the SISP research stream within the entire IS/IT ecosystem.
Mechanistic Studies of Oxygen-Atom Transfer (OAT) in the Homogeneous Conversion of N2O by Ru Pincer Complexes
Authors: Liang Guangchao , Zhang Min , Webster Charles Edwin
Published: May 2022

As the overall turnover-limiting step (TOLS) in the homogeneous conversion of N2O, the oxygen-atom transfer (OAT) from an N2O to an Ru-H complex to generate an N2 and Ru-OH complex has been comprehensively investigated by density functional theory (DFT) computations. Theoretical results show that the proton transfer from Ru-H to the terminal N of endo N2O is most favorable pathway, and the generation of N2 via OAT is accomplished by a three-step mechanism [N2O-insertion into the Ru-H bond (TS-1-2, 24.1 kcal mol−1), change of geometry of the formed (Z)-O-bound oxyldiazene intermediate (TS-2-3, 5.5 kcal mol−1), and generation of N2 from the proton transfer (TS-3-4, 26.6 kcal mol−1)]. The Gibbs free energy of activation (ΔG‡) of 29.0 kcal mol−1 for the overall turnover-limiting step (TOLS) is determined. With the participation of potentially existing traces of water in the THF solvent serving as a proton shuttle, the Gibbs free energy of activation in the generation of N2 (TS-3-4-OH2) decreases to 15.1 kcal mol−1 from 26.6 kcal mol−1 (TS-3-4). To explore the structure–activity relationship in the conversion of N2O to N2, the catalytic activities of a series of Ru-H complexes (C1–C10) are investigated. The excellent linear relationships (R2 > 0.91) between the computed hydricities (ΔGH−) and ΔG‡ of TS-3-4, between the computed hydricities (ΔGH−) and the ΔG‡ of TOLS, were obtained. The utilization of hydricity as a potential parameter to predict the activity is consistent with other reports, and the current results suggest a more electron-donating ligand could lead to a more active Ru-H catalyst.
Exercising with a Single Ventricle: Limitations and Therapies
Authors: Haley Jessica Erin , Davis Christopher
Published: May 2022

Treatment for Hypoplastic Left Heart Syndrome (HLHS) and other single ventricle conditions requires a series of surgical interventions for long-term survival, typically culminating in the Fontan procedure. The result is an abnormal circulatory physiology with an absence of a sub-pulmonary ventricle. Exercise capacity in the Fontan circulation is often limited and is due to multiple factors, both central and peripheral. Multiple interventions, both pharmacologic and nonpharmacologic, have been studied to attempt to overcome these inherent limitations. This review will focus on the physiology of the exercising Fontan patient and on the interventions aimed at the enhancement of exercise capacity studied thus far.
Risk of Severe Infection among Rheumatoid Arthritis Patients on Biological DMARDs: A Population-Based Cohort Study
Authors: Bellan Mattia , Scotti Lorenza , Ferrante Daniela , Calzaducca Elisa , Manfredi Giulia Francesca , Sainaghi Pier Paolo , Barone-Adesi Francesco
Published: May 2022

Biological disease-modifying anti-rheumatic drugs (bDMARDs) are widely used for the management of rheumatoid arthritis, although their benefits are counterweight by an increased risk of infections. In the present study, we used administrative data to compare the risk of severe infections among different classes of bDMARDs. A retrospective cohort study was conducted using Administrative Health Databases of the Piedmont Region, Italy. Relevant data were obtained from: (1) the inhabitants registry, (2) hospital discharge records, and (3) the co-payment exemption registry and (4) drug claims registry. Fine and Gray competing risk models were fitted to evaluate the association between the use of different types of bDMARDs and occurrence of severe infection accounting for treatment interruption as competing risk. A total of 1780 new users of bDMARDs were identified. Among them, 50 hospitalizations for infection occurred during the study period. The use of Tocilizumab was associated with an increased risk of infection, compared to tumor necrosis factor (TNF) inhibitor drugs (sub-distribution hazard ratios-sHR: 2.510; 95% CI: 1.279–4.926), whereas no difference in the risk of severe infection was found for abatacept (sHR: 0.584; 95% CI: 0.234–1.457). bDMARDs treatment is generally safe in clinical practice with slight but important differences among classes. The increased risk of infection associated with tocilizumab use should be taken into account when balancing the risk and benefits of starting a treatment with this drug.
Clinical Outcomes following Biologically Enhanced Demineralized Bone Matrix Augmentation of Complex Rotator Cuff Repair
Authors: Wellington Ian J. , Muench Lukas N. , Hawthorne Benjamin C. , Uyeki Colin L. , Antonacci Christopher L. , McCarthy Mary Beth , Connors John P. , Kia Cameron , Mazzocca Augustus D. , Berthold Daniel P.
Published: May 2022

Complex rotator cuff tears provide a significant challenge for treating surgeons, given their high failure rate following repair and the associated morbidity. The purpose of this study is to evaluate the clinical outcomes of patients who underwent biologically enhanced demineralized bone matrix augmentation of rotator cuff repairs. Twenty patients with complex rotator cuff tears underwent arthroscopic rotator cuff repair by a single surgeon with demineralized bone matrix (DBM) augmentation that was biologically enhanced with platelet-rich plasma and concentrated bone marrow aspirate. Post-operative MRI was used to determine surgical success. Patient reported outcome measures and range of motion data were collected pre-operatively and at the final post-operative visit for each patient. Ten patients (50%) with DBM augmentation of their arthroscopic rotator cuff repair were deemed non-failures. The failure group had less improvement of visual analogue pain scale (p = 0.017), Simple Shoulder Test (p = 0.032), Single Assessment Numerical Evaluation (p = 0.006) and abduction (p = 0.046). There was no difference between the groups for change in American Shoulder and Elbow Society score (p = 0.096), Constant-Murley score (p = 0.086), forward elevation (p = 0.191) or external rotation (p = 0.333). The present study found that 50% of patients who underwent biologically enhanced DBM augmentation of their rotator cuff repair demonstrated MRI-determined failure of supraspinatus healing.
The Non-Concordance of Self-Reported and Performance-Based Measures of Vestibular Dysfunction in Military and Civilian Populations Following TBI
Authors: Wood Nicholas I. , Hentig James , Hager Madison , Hill-Pearson Candace , Hershaw Jamie N. , Souvignier Alicia R. , Bobula Selena A.
Published: May 2022

As a predominately young, physically active, and generally healthy population, service members (SMs) with vestibular dysfunction (VD) following a TBI may not be accurately represented by the current civilian reference ranges on assessments of VD. This study enrolled SMs who were referred for vestibular rehabilitation following a mild/moderate TBI. The participants self-reported VD using the Activities-specific Balance Confidence (ABC) scale and the Dizziness Handicap Inventory (DHI) followed by evaluation of vestibular performance using computerized dynamic posturography sensory organizational test (CDP–SOT). Retrospective analysis of these outcomes comparing the study sample of SMs to the reported civilian samples revealed SMs self-reported lower VD with significantly higher balance confidence (ABC: 77.11 ± 14.61, p < 0.05) and lower dizziness (DHI: 37.75 ± 11.74, p < 0.05) than civilians. However, the SMs underperformed in performance-based evaluations compared to civilians with significantly lower CDP–SOT composite and ratio scores (COMP: 68.46 ± 13.46, p < 0.05; VIS: 81.36 ± 14.03, p < 0.01; VEST: 55.63 ± 22.28, p < 0.05; SOM: 90.46 ± 10.17, p < 0.05). Correlational analyses identified significant relationships between the ABC and CDP–SOT composite (r = 0.380, p < 0.01) and ratio scores (VIS: r = 0.266, p < 0.05; VEST: r = 0.352, p < 0.01). These results highlight the importance of recognizing and understanding nuances in assessing VD in SMs to ensure they have access to adequate care and rehabilitation prior to returning to duty.
Changing Medical Paradigm on Inflammatory Eye Disease: Technology and Its Implications for P4 Medicine
Authors: Inomata Takenori , Sung Jaemyoung
Published: May 2022

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Differential Diagnosis between Takotsubo Syndrome and Acute Coronary Syndrome—A Prospective Analysis of Novel Cardiovascular Biomarkers for a More Selective Triage
Authors: Topf Albert , Mirna Moritz , Paar Vera , Motloch Lukas J. , Bacher Nina , Franz Marcus , Hoppe Uta C. , Kretzschmar Daniel , Lichtenauer Michael
Published: May 2022

Introduction: Takotsubo syndrome (TTS) is clinically indistinguishable from an ACS. Despite the implementation of clinical scoring systems and novel biomarkers, coronary angiography currently remains necessary for differential diagnosis. Methods: 93 patients with chest pain and the suspicion of TTS were enrolled in two study centers. Fetuin-A, IGFBP-2, Galectin-3, and TNF α were determined in serum samples, collected within 24 h after the onset of symptoms. Serum levels of biomarkers were analyzed for the differential diagnostic value between TTS and ACS. Results: Compared to TTS, patients with ACS had significantly lower serum levels of Fetuin-A and IGFBP-2. The cut-off value of Fetuin-A for the identification of TTS compared to ACS was 55.74 μg/mL (sensitivity: 100.0%, specificity: 82.6%, PPV: 63.2%, NPV: 100.0%). An optimal cut-off value for IGFBP-2 for the differential diagnosis between TTS and ACS was determined as 171.77 ng/mL (sensitivity: 76.0%, specificity: 82.6%, PPV: 76.4%, NPV 72.7%). Conclusion: Fetuin-A and IGFBP-2 might facilitate the triage between TTS and ACS and could be therefore of great benefit for the guidance of treatment.
Dickkopf Homolog 3 (DKK3) as a Prognostic Marker in Lupus Nephritis: A Prospective Monocentric Experience
Authors: Sciascia Savino , Barinotti Alice , Radin Massimo , Cecchi Irene , Menegatti Elisa , Terzolo Edoardo , Rossi Daniela , Baldovino Simone , Fenoglio Roberta , Roccatello Dario
Published: May 2022

Background: The gold standard for diagnosis of lupus nephritis (LN) is still represented by renal biopsy, and serological prognostic biomarkers are still lacking. Dickkopf homolog-3 (DKK3) has been suggested as a marker of tissue fibrosis in different conditions; however, its role in autoimmune diseases needs to be elucidated. Here, we investigated the prognostic role of DKK3 in systemic lupus erythematosus (SLE) patients with and without LN, assessing its changes in relation to kidney function, flares, and interstitial fibrosis. Methods: Overall, 132 SLE patients (57 with LN) were included and prospectively followed up for at least 36 months. DKK3 was measured in serum at baseline. Biopsies were evaluated for glomerular involvement, interstitial fibrosis, and tubular atrophy. Results: Patients with biopsy-proven LN had significantly higher levels of DKK3 than those without (median [min–max]: 215 ng/mL [81–341] vs. 21.1 ng/mL [1–69], p < 0.01). DKK3 levels were associated with prevalent chronic kidney diseases (OR: 4.31 [C.I. 2.01–6.61] per DKK3 doubling, p < 0.01), higher chronicity index at biopsy (1.75 [1.51–2.77] per DKK3 doubling, p < 0.01), and flares rate (OR: 1.45 [C.I. 1.1–5.71] per DKK3 doubling, p < 0.044). Conclusions: While kidney biopsy still represents the gold standard for diagnostic and prognostic assessment in LN, DKK3 could represent an additional prognostic tool to monitor SLE patients and guide therapeutic choices.
High-Throughput Sequencing of Complementarity Determining Region 3 in the Heavy Chain of B-Cell Receptor in Renal Transplant Recipients: A Preliminary Report
Authors: Wu Tsai-Hung , Liao Hsien-Tzung , Li Tzu-Hao , Tsai Hung-Cheng , Lin Niang-Cheng , Chen Cheng-Yen , Tsai Shih-Feng , Huang Tzu-Hao , Tsai Chang-Youh , Yu Chia-Li
Published: May 2022

Background: Graft failure resulting from rejection or any other adverse event usually originates from an aberrant and/or exaggerated immune response and is often catastrophic in renal transplantation. So, it is essential to monitor patients’ immune status for detecting a rejection/graft failure early on. Methods: We monitored the sequence change of complementary determining region 3 (CDR3) in B-cell receptor (BCR) immunoglobulin heavy-chain (IGH) immune repertoire (iR) in 14 renal transplant patients using next-generation sequencing (NGS), correlating its diversity to various clinical events occurring after transplantation. BCR-IGH-CDR3 in peripheral blood mononuclear cells was sequenced along the post-transplantation course by NGS using the iRweb server. Results: Datasets covering VDJ regions of BCR-IGH-CDR3 indicated clonal diversity (D50) variations along the post-transplant course. Furthermore, principal component analysis showed the clustering of these sequence variations. A total of 544 shared sequences were identified before transplantation. D50 remained low in three patients receiving rituximab. Among them, one’s D50 resumed after 3 m, indicating graft tolerance. The D50 rapidly increased after grafting and decreased thereafter in four patients without rejection, decreased in two patients with T-cell-mediated rejection (TCMR) and exhibited a sharp down-sliding after 3 m in two patients receiving donations after cardiac death (DCD). In another two patients with TCMR, D50 was low just before individual episodes, but either became persistently low or returned to a plateau, depending on the failure or success of the immunosuppressive treatments. Shared CDR3 clonal expansions correlated to D50 changes. Agglomerative hierarchical clustering showed a commonly shared CDR3 sequence and at least two different clusters in five patients. Conclusions: Clonal diversity in BCR-IGH-CDR3 varied depending on clinical courses of 14 renal transplant patients, including B-cell suppression therapy, TCMR, DCD, and graft tolerance. Adverse events on renal graft failure might lead to different clustering of BCR iR. However, these preliminary data need further verification in further studies for the possible applications of iR changes as genetic expression biomarkers or laboratory parameters to detect renal graft failure/rejection earlier.
Implementation of EHMRG Risk Model in an Italian Population of Elderly Patients with Acute Heart Failure
Authors: Falsetti Lorenzo , Zaccone Vincenzo , Guerrieri Emanuele , Perrotta Giulio , Diblasi Ilaria , Giuliani Luca , Palma Linda Elena Gialluca , Viticchi Giovanna , Fioranelli Agnese , Moroncini Gianluca , Pansoni Adolfo , Luccarini Marinella , Martino Marianna , Scalpelli Caterina , Burattini Maurizio , Tarquinio Nicola
Published: May 2022

Acute heart failure (AHF) is a cardiac emergency with an increasing incidence, especially among elderly patients. The Emergency Heart failure Mortality Risk Grade (EHMRG) has been validated to assess the 7-days AHF mortality risk, suggesting the management of patients admitted to an emergency department (ED). EHMRG has never been implemented in Italian ED nor among elderly patients. We aimed to assess EHMRG score accuracy in predicting in-hospital death in a retrospective cohort of elderly subjects admitted for AHF from the ED to an Internal Medicine Department. We enrolled, in a 24-months timeframe, all the patients admitted to an Internal Medicine Department from ED for AHF. We calculated the EHMRG score, subdividing patients into six categories, and assessing in-hospital mortality and length of stay. We evaluated EHMRG accuracy with ROC curve analysis and survival with Kaplan–Meier and Cox models. We collected 439 subjects, with 45 in-hospital deaths (10.3%), observing a significant increase of in-hospital death along with EHMRG class, from 0% (class 1) to 7.7% (class 5b; p < 0.0001). EHMRG was fairly accurate in the whole cohort (AUC: 0.75; 95%CI: 0.68–0.83; p < 0.0001), with the best cutoff observed at >103 (Se: 71.1%; Sp: 72.8%; LR+: 2.62; LR-: 0.40; PPV: 23.0%; NPV: 95.7%), but performed better considering the events in the first seven days of admission (AUC: 0.83; 95%; CI: 0.75–0.91; p < 0.0001). In light of our observations, EHMRG can be useful also for the Italian emergency system to predict the risk of short-term mortality for AHF among elderly patients. EHMRG performance was better in the first seven days but remained acceptable when considering the whole period of hospitalization.
Global Impact of the COVID-19 Pandemic on Orthopedics and the Implications of Telemedicine: A Systematic Review of the Literature
Authors: Hsu Chia-Hao , Huang Hsuan-Ti , Chen Chung-Hwan , Fu Yin-Chih , Chou Pei-Hsi , Hsu Nin-Chieh
Published: May 2022

This study aimed to systematically review the literature on the impact of the coronavirus disease (COVID-19) pandemic on the orthopedics field by focusing on multiple aspects, including orthopedic training and application, performance, work loading, change of practice, research work, and other psychological factors. Published articles were searched using the PubMed database. Articles were selected in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Of 58 studies published between 1 January 2020 and 1 October 2021, 57 peer-reviewed original articles were included. Nearly 90% of students experienced an impact of the pandemic on application. The impact on training stemmed from redeployment rates of 20.9–23.1%. The rate of emergency or outpatient visits decreased from 18% to 58.6%. The rates of all surgeries or emergency surgeries decreased by 15.6–49.4%, while the rates of elective surgeries decreased by 43.5–100%. The rate of work loading ranged from 33% to 66%. Approximately 50–100% of surgeons had a change of practice. A total of 40.5% of orthopedic surgeons experienced mild psychological pressure. Approximately 64% had stopped research participant recruitment. Most of the included studies were conducted in Europe, followed by Asia and North America. It is suggested orthopedic surgeons prepare more sufficient, flexible, and reservable staffing measures, proper preventive strategies and surgical scheduling algorithms, and set up dedicated venues and equipment for routine telemedicine with staff training for virtual teaching or consultations in case of future impacts on orthopedics.
Paravalvular Leakages after Surgical Aortic-Valve Replacement and after Transcatheter Aortic-Valve Implantation: Strategies to Increase the Success Rate of Percutaneous Closure
Authors: Freixa Xavier , Gabani Rami , Cepas-Guillén Pedro , Flores-Umanzor Eduardo , Estévez-Loureiro Rodrigo , Onorato Eustaquio
Published: May 2022

Moderate to severe paravalvular-leak (PVL) regurgitation after surgical aortic-valve replacement or after transcatheter valve implantation represents a well-known complication associated with symptoms related to heart failure, hemolysis, or both in patients with multiple comorbidities and with poor prognostic outcomes. The transcatheter closure of aortic paravalvular leaks (APVLs) is currently considered a valid alternative to cardiac surgery. Nevertheless, careful patient selection, optimal cardiac imaging for intraprocedural guidance, and expert operators are key for success. Although technically demanding, particularly in APVLs after transcatheter valve implantation, catheter-based closure is an effective, less invasive, and often the only option for high-risk patients with symptomatic PVL regurgitation.
Efficacy and Safety of Different Courses of Tongxinluo Capsule as Adjuvant Therapy for Coronary Heart Disease after Percutaneous Coronary Intervention: A Systematic Review and Meta-Analysis of Randomized Controlled Trials
Authors: Hui Jiaqi , Yuan Rong , Li Pengqi , Xin Qiqi , Miao Yu , Shen Xiaoxu , Xu Fengqin , Cong Weihong
Published: May 2022

Tongxinluo capsule (TXLC) is a widely used traditional Chinese medicine for coronary heart disease (CHD). However, the efficacy and safety of different courses of TXLC for CHD after percutaneous coronary intervention (PCI) have not been systematically evaluated yet. The Cochrane Library, PubMed, Embase, China National Knowledge Infrastructure, Wanfang Database, and Chinese Scientific Journal Database were searched from the inception to 26 August 2021. A meta-analysis was performed using a fixed- or random-effects model. The risk of adverse cardiovascular events, mortality, or adverse effects was evaluated by risk ratio (RR) with 95% confidence interval (CI). Thirty-four studies involving 3652 patients were finally included. After the 6-month treatment, compared with conventional treatment alone, TXLC combined with conventional treatment achieved better efficacy in lowering the risk of angiographic restenosis (RR = 0.37, 95% CI = 0.28–0.48, p < 0.001), myocardial infarction (RR = 0.38, 95% CI = 0.25–0.60, p < 0.001), heart failure (RR = 0.32, 95% CI = 0.18–0.56, p < 0.001), angina (RR = 0.26, 95% CI = 0.17–0.38, p < 0.001), revascularization (RR = 0.20, 95% CI = 0.09–0.46, p < 0.001), all-cause mortality (RR = 0.24, 95% CI = 0.10–0.58, p = 0.001), and mortality due to any cardiovascular event (RR = 0.27, 95% CI = 0.09–0.80, p = 0.018). After the 12-month treatment, TXLC reduced the recurrence risk of angina (RR = 0.40, 95% CI = 0.20–0.80, p = 0.009). However, there was no difference in any outcomes after the 3-month treatment. Besides, no difference was found in the incidence of adverse effects after the 3-month and 6-month treatments (3 months: RR = 0.73, 95% CI = 0.35–1.56, p = 0.418; 6 months: RR = 1.71, 95% CI = 0.74–3.93, p = 0.209). The certainty of evidence ranged from very low to moderate due to the risk of bias, inconsistency, and imprecision. TXLC showed beneficial effects on reducing the adverse cardiovascular events without compromising safety for CHD patients after PCI on the 6-month course. However, due to the unavoidable risk of bias, more high-quality and long-term studies are still needed to further evaluate the efficacy and safety of TXLC in many countries, not only in China.
Management of Green Mold Disease in White Button Mushroom (Agaricus bisporus) and Its Yield Improvement
Authors: Altaf Suhail , Jan Shaheen Kousar , Ahanger Shafat Ahmad , Basu Umer , Rather Roaf Ahmad , Wani Owais Ali , Rasool Farahnaz , Mushtaq Muntazir , Yassin Mohamed Taha , Mostafa Ashraf Abdel-Fattah , Elgorban Abdallah M. , El-Haroun Ehab , El-Sabrout Ahmed M. , Casini Ryan , Elansary Hosam O.
Published: May 2022

Mycoparasites cause serious losses in profitable mushroom farms worldwide. The negative impact of green mold (Trichoderma harzianum) reduces cropping surface and damages basidiomes, limiting production and harvest quality. The goal of the current study was to evaluate new generation fungicides, to devise suitable management strategies against the green mold disease under prevailing agro-climatic conditions. Six non-systemic and five systemic fungitoxicants were evaluated for their efficacy against pathogen, T. harzianum, and host, Agaricus bisporus, under in vitro conditions. Among non-systemic fungicides, chlorothalonil and prochloraz manganese with mean mycelium inhibition of 76.87 and 93.40 percent, respectively, were highly inhibitory against the pathogen. The least inhibition percentage of 7.16 of A. bisporus was exhibited by chlorothalonil. Under in vivo conditions, use of captan 50 WP resulted in a maximum yield of button mushroom of 14.96 kg/qt. So far, systemic fungicides were concerned, carbendazim proved extremely inhibitory to the pathogen (89.22%), with least inhibitory effect on host mycelium (1.56%). However, application of non-systemic fungitoxicants further revealed that fungicide prochloraz manganese 50 WP at 0.1–0.2 percent or chlorothalonil 50 WP at 0.2 percent, exhibited maximum disease control of 89.06–96.30 percent. Moreover, the results of systemic fungitoxicants showed that carbendazim 50 WP or thiophanate methyl 70 WP at 0.1 percent reduced disease to 2.29–3.69 percent, hence exhibiting the disease control of 80.11–87.66 percent. Under in vivo conditions, fungicide myclobutanil at 0.1 percent concentration produced the maximum button mushroom production of 12.87 kg/q.
Photoinactivation of Yeast and Biofilm Communities of Candida albicans Mediated by ZnTnHex-2-PyP4+ Porphyrin
Authors: Souza Sueden O. , Raposo Bruno L. , Sarmento-Neto José F. , Rebouças Júlio S. , Macêdo Danielle P. C. , Figueiredo Regina C. B. Q. , Santos Beate S. , Freitas Anderson Z. , Cabral Filho Paulo E. , Ribeiro Martha S. , Fontes Adriana
Published: May 2022

Candida albicans is the main cause of superficial candidiasis. While the antifungals available are defied by biofilm formation and resistance emergence, antimicrobial photodynamic inactivation (aPDI) arises as an alternative antifungal therapy. The tetracationic metalloporphyrin Zn(II) meso-tetrakis(N-n-hexylpyridinium-2-yl)porphyrin (ZnTnHex-2-PyP4+) has high photoefficiency and improved cellular interactions. We investigated the ZnTnHex-2-PyP4+ as a photosensitizer (PS) to photoinactivate yeasts and biofilms of C. albicans strains (ATCC 10231 and ATCC 90028) using a blue light-emitting diode. The photoinactivation of yeasts was evaluated by quantifying the colony forming units. The aPDI of ATCC 90028 biofilms was assessed by the MTT assay, propidium iodide (PI) labeling, and scanning electron microscopy. Mammalian cytotoxicity was investigated in Vero cells using MTT assay. The aPDI (4.3 J/cm2) promoted eradication of yeasts at 0.8 and 1.5 µM of PS for ATCC 10231 and ATCC 90028, respectively. At 0.8 µM and same light dose, aPDI-treated biofilms showed intense PI labeling, about 89% decrease in the cell viability, and structural alterations with reduced hyphae. No considerable toxicity was observed in mammalian cells. Our results introduce the ZnTnHex-2-PyP4+ as a promising PS to photoinactivate both yeasts and biofilms of C. albicans, stimulating studies with other Candida species and resistant isolates.
Fun30 and Rtt109 Mediate Epigenetic Regulation of the DNA Damage Response Pathway in C. albicans
Authors: Maurya Prashant Kumar , Garai Pramita , Goel Kaveri , Bhatt Himanshu , Dutta Anindita , Goyal Aarti , Dewasthale Sakshi , Gupta Meghna , Haokip Dominic Thangminlen , Barik Sanju , Muthuswami Rohini
Published: May 2022

Fun30, an ATP-dependent chromatin remodeler from S. cerevisiae, is known to mediate both regulation of gene expression as well as DNA damage response/repair. The Fun30 from C. albicans has not yet been elucidated. We show that C. albicans Fun30 is functionally homologous to both S. cerevisiae Fun30 and human SMARCAD1. Further, C. albicans Fun30 can mediate double-strand break end resection as well as regulate gene expression. This protein regulates transcription of RTT109, TEL1, MEC1, and SNF2-genes that encode for proteins involved in DNA damage response and repair pathways. The regulation mediated by C. albicans Fun30 is dependent on its ATPase activity. The expression of FUN30, in turn, is regulated by histone H3K56 acetylation catalyzed by Rtt109 and encoded by RTT109. The RTT109Hz/FUN30Hz mutant strain shows sensitivity to oxidative stress and resistance to MMS as compared to the wild-type strain. Quantitative PCR showed that the sensitivity to oxidative stress results from downregulation of MEC1, RAD9, MRC1, and RAD5 expression; ChIP experiments showed that Fun30 but not H3K56ac regulates the expression of these genes in response to oxidative stress. In contrast, upon treatment with MMS, the expression of RAD9 is upregulated, which is modulated by both Fun30 and H3K56 acetylation. Thus, Fun30 and H3K56 acetylation mediate the response to genotoxic agents in C. albicans by regulating the expression of DNA damage response and repair pathway genes.