bluuebunny/crossref_metadata_2025 huggingface dataset:
Mountain Hiking: Prolonged Eccentric Muscle Contraction during Simulated Downhill Walking Perturbs Sensorimotor Control Loops Needed for Safe Dynamic Foot–Ground Interactions
Authors: Werner Inge , Valero-Cuevas Francisco J. , Federolf Peter
Published: April 2023

Safe mountain hiking requires precise control of dynamic foot–ground interactions. In addition to vision and vestibular afferents, limb proprioception, sensorimotor control loops, and reflex responses are used to adapt to the specific nature of the ground contact. Diminished leg dexterity and balance during downhill walking is usually attributed to fatigue. We investigated the supplementary hypothesis that the eccentric contractions inherent to downhill walking can also disrupt muscle proprioception, as well as the sensorimotor control loops and reflex responses that depend on it. In this study, we measured leg dexterity (LD), anterior–posterior (AP) and medio–lateral (ML) bipedal balance, and maximal voluntary leg extension strength in young and healthy participants before and after 30 min of simulated downhill walking at a natural pace on a treadmill at a 20° decline. Post–pre comparisons of LD (p < 0.001) and AP balance (p = 0.001) revealed significant reductions in dynamic foot–ground interactions after eccentric exercise without an accompanying reduction in leg extension strength. We conclude that eccentric contractions during downhill walking can disrupt the control of dynamic foot–ground interactions independently of fatigue. We speculate that mountaineering safety could be improved by increasing conscious attention to compensate for unadjusted proprioception weighting, especially in the descent.
Salt-Specific Suppression of the Cold Denaturation of Thermophilic Multidomain Initiation Factor 2
Authors: Džupponová Veronika , Tomášková Nataša , Antošová Andrea , Sedlák Erik , Žoldák Gabriel
Published: April 2023

Thermophilic proteins and enzymes are attractive for use in industrial applications due to their resistance against heat and denaturants. Here, we report on a thermophilic protein that is stable at high temperatures (Ttrs, hot 67 °C) but undergoes significant unfolding at room temperature due to cold denaturation. Little is known about the cold denaturation of thermophilic proteins, although it can significantly limit their applications. We investigated the cold denaturation of thermophilic multidomain protein translation initiation factor 2 (IF2) from Thermus thermophilus. IF2 is a GTPase that binds to ribosomal subunits and initiator fMet-tRNAfMet during the initiation of protein biosynthesis. In the presence of 9 M urea, measurements in the far-UV region by circular dichroism were used to capture details about the secondary structure of full-length IF2 protein and its domains during cold and hot denaturation. Cold denaturation can be suppressed by salt, depending on the type, due to the decreased heat capacity. Thermodynamic analysis and mathematical modeling of the denaturation process showed that salts reduce the cooperativity of denaturation of the IF2 domains, which might be associated with the high frustration between domains. This characteristic of high interdomain frustration may be the key to satisfying numerous diverse contacts with ribosomal subunits, translation factors, and tRNA.
Partners in Postmortem Interval Estimation: X-ray Diffraction and Fourier Transform Spectroscopy
Authors: Rubio Leticia , Suárez Juan , Martin-de-las-Heras Stella , Zapico Sara C.
Published: April 2023

The postmortem interval (PMI) is difficult to estimate in later stages of decomposition. There is therefore a need to develop reliable methodologies to estimate late PMI. This study aims to assess whether there is a correlation between changes in the mineral composition of human teeth and the estimation of PMI. X-ray diffraction (XRD) and attenuated total reflection Fourier transform infrared (ATR-FTIR) spectroscopy techniques were performed to address this challenge. Forty healthy human teeth obtained from odontological clinics were stored at different times (0, 10, 25, 50 years; N = 10/group). XRD and ATR-FTIR parameters related to the structure and composition of teeth were studied. Our results showed that the crystallinity index, crystal size index, mineral-to-organic matrix ratio (M/M) and carbonate/phosphate ratio (C/P) had the strongest association with PMI. For larger PMIs, there was a significant increase in crystallinity, crystal size and M/M ratio, while the C/P ratio showed a specific decrease with increasing PMI. According to our results, the parameters of crystallinity, crystal size, M/M ratio and C/P ratio can be considered highly accurate in determining a PMI of 10 years of data; crystallinity and mineral maturity can be considered useful in determining a PMI of 25 years; and crystallinity and mineral maturity can be considered highly accurate in determining a PMI of 50 years. A particular XRD index was identified as the most suitable parameter to estimate PMI: crystallinity. The joint use of XRD and ATR-FTIR analyses could be a promising alternative for dating human teeth.
Neuroprotective Effects of Lactobacillus plantarum PS128 in a Mouse Model of Parkinson’s Disease: The Role of Gut Microbiota and MicroRNAs
Authors: Lee Yan Zhang , Cheng Shih-Hsuan , Chang Min-Yu , Lin Yu-Fen , Wu Chien-Chen , Tsai Ying-Chieh
Published: April 2023

Parkinson’s disease (PD) is a neurodegenerative disease characterized by motor deficits and marked neuroinflammation in various brain regions. The pathophysiology of PD is complex and mounting evidence has suggested an association with the dysregulation of microRNAs (miRNAs) and gut dysbiosis. Using a rotenone-induced PD mouse model, we observed that administration of Lactobacillus plantarum PS128 (PS128) significantly improved motor deficits in PD-like mice, accompanied by an increased level of dopamine, reduced dopaminergic neuron loss, reduced microglial activation, reduced levels of inflammatory factors, and enhanced expression of neurotrophic factor in the brain. Notably, the inflammation-related expression of miR-155-5p was significantly upregulated in the proximal colon, midbrain, and striatum of PD-like mice. PS128 reduced the level of miR-155-5p, whereas it increased the expression of suppressor of cytokine signaling 1 (SOCS1), a direct target of miR-155-5p and a critical inhibitor of the inflammatory response in the brain. Alteration of the fecal microbiota in PD-like mice was partially restored by PS128 administration. Among them, Bifidobacterium, Ruminiclostridium_6, Bacteroides, and Alistipes were statistically correlated with the improvement of rotenone-induced motor deficits and the expression of miR-155-5p and SOCS1. Our findings suggested that PS128 ameliorates motor deficits and exerts neuroprotective effects by regulating the gut microbiota and miR-155-5p/SOCS1 pathway in rotenone-induced PD-like mice.
Ca2+-Activated K+ Channels in Progenitor Cells of Musculoskeletal Tissues: A Narrative Review
Authors: Takács Roland , Kovács Patrik , Ebeid Rana Abdelsattar , Almássy János , Fodor János , Ducza László , Barrett-Jolley Richard , Lewis Rebecca , Matta Csaba
Published: April 2023

Musculoskeletal disorders represent one of the main causes of disability worldwide, and their prevalence is predicted to increase in the coming decades. Stem cell therapy may be a promising option for the treatment of some of the musculoskeletal diseases. Although significant progress has been made in musculoskeletal stem cell research, osteoarthritis, the most-common musculoskeletal disorder, still lacks curative treatment. To fine-tune stem-cell-based therapy, it is necessary to focus on the underlying biological mechanisms. Ion channels and the bioelectric signals they generate control the proliferation, differentiation, and migration of musculoskeletal progenitor cells. Calcium- and voltage-activated potassium (KCa) channels are key players in cell physiology in cells of the musculoskeletal system. This review article focused on the big conductance (BK) KCa channels. The regulatory function of BK channels requires interactions with diverse sets of proteins that have different functions in tissue-resident stem cells. In this narrative review article, we discuss the main ion channels of musculoskeletal stem cells, with a focus on calcium-dependent potassium channels, especially on the large conductance BK channel. We review their expression and function in progenitor cell proliferation, differentiation, and migration and highlight gaps in current knowledge on their involvement in musculoskeletal diseases.
The Cannabinoids, CBDA and THCA, Rescue Memory Deficits and Reduce Amyloid-Beta and Tau Pathology in an Alzheimer’s Disease-like Mouse Model
Authors: Kim Juyong , Choi Pilju , Park Young-Tae , Kim Taejung , Ham Jungyeob , Kim Jin-Chul
Published: April 2023

Most studies related to hemp are focused on Cannabidiol (CBD) and Tetrahydrocannabinol (THC); however, up to 120 types of phytocannabinoids are present in hemp. Hemp leaves contain large amounts of Cannabidiolic acid (CBDA) and Tetrahydrocannabinolic acid (THCA), which are acidic variants of CBD and THC and account for the largest proportion of CBDA. In recent studies, CBDA exhibited anti-hyperalgesia and anti-inflammatory effects. THCA also showed anti-inflammatory and neuroprotective effects that may be beneficial for treating neurodegenerative diseases. CBDA and THCA can penetrate the blood–brain barrier (BBB) and affect the central nervous system. The purpose of this study was to determine whether CBDA and THCA ameliorate Alzheimer’s disease (AD)-like features in vitro and in vivo. The effect of CBDA and THCA was evaluated in the Aβ1–42-treated mouse model. We observed that Aβ1–42-treated mice had more hippocampal Aβ and p-tau levels, pathological markers of AD, and loss of cognitive function compared with PBS-treated mice. However, CBDA- and THCA-treated mice showed decreased hippocampal Aβ and p-tau and superior cognitive function compared with Aβ1–42-treated mice. In addition, CBDA and THCA lowered Aβ and p-tau levels, alleviated calcium dyshomeostasis, and exhibited neuroprotective effects in primary neurons. Our results suggest that CBDA and THCA have anti-AD effects and mitigate memory loss and resilience to increased hippocampal Ca2+, Aβ, and p-tau levels. Together, CBDA and THCA may be useful therapeutic agents for treating AD.
Effect of Cytomegalovirus Reactivation on Inflammatory Status and Mortality of Older COVID-19 Patients
Authors: Giacconi Robertina , Cardelli Maurizio , Piacenza Francesco , Pierpaoli Elisa , Farnocchia Elisabetta , Di Rosa MirKo , Bonfigli Anna Rita , Casoli Tiziana , Marchegiani Francesca , Marcheselli Fiorella , Recchioni Rina , Stripoli Pierpaolo , Galeazzi Roberta , Cherubini Antonio , Fedecostante Massimiliano , Sarzani Riccardo , Di Pentima Chiara , Giordano Piero , Antonicelli Roberto , Provinciali Mauro , Lattanzio Fabrizia
Published: April 2023

Herpesviridae reactivation such as cytomegalovirus (CMV) has been described in severe COVID-19 (COronaVIrusDisease-2019). This study aimed to understand if CMV reactivation in older COVID-19 patients is associated with increased inflammation and in-hospital mortality. In an observational single-center cohort study, 156 geriatric COVID-19 patients were screened for CMV reactivation by RT-PCR. Participants underwent a comprehensive clinical investigation that included medical history, functional evaluation, laboratory tests and cytokine assays (TNF-α, IFN-α, IL-6, IL-10) at hospital admission. In 19 (12.2%) of 156 COVID-19 patients, CMV reactivation was detected. Multivariate Cox regression models showed that in-hospital mortality significantly increased among CMV positive patients younger than 87 years (HR: 9.94, 95% CI: 1.66–59.50). Other factors associated with in-hospital mortality were C-reactive protein (HR: 1.17, 95% CI: 1.05–1.30), neutrophil count (HR: 1.20, 95% CI: 1.01–1.42) and clinical frailty scale (HR:1.54, 95% CI: 1.04–2.28). In patients older than 87 years, neutrophil count (HR: 1.13, 95% CI: 1.05–1.21) and age (HR: 1.15, 95% CI: 1.01–1.31) were independently associated with in-hospital mortality. CMV reactivation was also correlated with increased IFN-α and TNF-α serum levels, but not with IL-6 and IL-10 serum changes. In conclusion, CMV reactivation was an independent risk factor for in-hospital mortality in COVID-19 patients younger than 87 years old, but not in nonagenarians.
A Basic Review on Estrogen Receptor Signaling Pathways in Breast Cancer
Authors: Clusan Léa , Ferrière François , Flouriot Gilles , Pakdel Farzad
Published: April 2023

Breast cancer is the most common cancer and the deadliest among women worldwide. Estrogen signaling is closely associated with hormone-dependent breast cancer (estrogen and progesterone receptor positive), which accounts for two-thirds of tumors. Hormone therapy using antiestrogens is the gold standard, but resistance to these treatments invariably occurs through various biological mechanisms, such as changes in estrogen receptor activity, mutations in the ESR1 gene, aberrant activation of the PI3K pathway or cell cycle dysregulations. All these factors have led to the development of new therapies, such as selective estrogen receptor degraders (SERDs), or combination therapies with cyclin-dependent kinases (CDK) 4/6 or PI3K inhibitors. Therefore, understanding the estrogen pathway is essential for the treatment and new drug development of hormone-dependent cancers. This mini-review summarizes current literature on the signalization, mechanisms of action and clinical implications of estrogen receptors in breast cancer.
POLD1 as a Prognostic Biomarker Correlated with Cell Proliferation and Immune Infiltration in Clear Cell Renal Cell Carcinoma
Authors: Tian Junjie , Cheng Cheng , Gao Jianguo , Fu Guanghou , Xu Zhijie , Chen Xiaoyi , Wu Yunfei , Jin Baiye
Published: April 2023

DNA polymerase delta 1 catalytic subunit (POLD1) plays a vital role in genomic copy with high fidelity and DNA damage repair processes. However, the prognostic value of POLD1 and its relationship with tumor immunity in clear cell renal cell carcinoma (ccRCC) remains to be further explored. Transcriptional data sets and clinical information were obtained from the TCGA, ICGC, and GEO databases. Differentially expressed genes (DEGs) were derived from the comparison between the low and high POLD1 expression groups in the TCGA–KIRC cohort. KEGG and gene ontology (GO) analyses were performed for those DEGs to explore the potential influence of POLD1 on the biological behaviors of ccRCC. The prognostic clinical value and mutational characteristics of patients were described and analyzed according to the POLD1 expression levels. TIMER and TISIDB databases were utilized to comprehensively investigate the potential relevance between the POLD1 levels and the status of the immune cells, as well as the tumor infiltration of immune cells. In addition, RT-qPCR, Western blot, immunohistochemistry and several functional and animal experiments were performed for clinical, in vitro and in vivo validation. POLD1 was highly expressed in a variety of tumors including ccRCC, and further verified in a validation cohort of 60 ccRCC samples and in vitro cell line experiments. POLD1 expression levels in the ccRCC samples were associated with various clinical characteristics including pathologic tumor stage and histologic grade. ccRCC patients with high POLD1 expression have poor clinical outcomes and exhibit a higher rate of somatic mutations than those with low POLD1 expression. Cox regression analysis also showed that POLD1 could act as a potential independent prognostic biomarker. The DEGs associated with POLD1 were significantly enriched in the immunity-related pathways. Moreover, further immune infiltration analysis indicated that high POLD1 expression was associated with high NK CD56bright cells, Treg cells, and myeloid-derived suppressor cells’ (MDSCs) infiltration scores, as well as their marker gene sets of immune cell status. Meanwhile, POLD1 exhibited resistance to various drugs when highly expressed. Finally, the knockdown of POLD1 inhibited the proliferation and migration, and promoted the apoptosis of ccRCC cells in vitro and in vivo, as well as influenced the activation of oncogenic signaling. Our current study demonstrated that POLD1 is a potential prognostic biomarker for ccRCC patients. It might create a tumor immunosuppressive microenvironment and inhibit the susceptibility to ferroptosis leading to a poor prognosis.
A Method and Formula for the Quantitative Analysis of the Total Bioactivity of Natural Products
Authors: Mathew Shintu , Raju Ritesh , Zhou Xian , Bodkin Francis , Govindaraghavan Suresh , Münch Gerald
Published: April 2023

Identification of bioactive natural products from plants starts with the screening of extracts for a desired bioactivity such as antimicrobial, antifungal, anti-cancer, anti-inflammatory, or neuroprotective. When the bioactivity shows sufficient potency, the plant material is subjected to bio-activity-guided fractionation, which involves, e.g., sequential extraction followed by chromatographic separation, including HPLC. The bioactive compounds are then structurally identified by high-resolution mass spectrometry and nuclear magnetic resonance (NMR). One of the questions that come up during the purification process is how much of the bioactivity originally present in the crude extract is preserved during the purification process. If this is the case, it is interesting to investigate if the loss of total bioactivity is caused by the loss of material during purification or by the degradation or evaporation of potent compounds. A further possibility would be the loss of synergy between compounds present in the mixture, which disappears when the compounds are separated. In this publication, a novel formula is introduced that allows researchers to calculate total bioactivity in biological samples using experimental data from our research into the discovery of anti-inflammatory compounds from Backhousia myrtifolia (Grey Myrtle). The results presented show that a raw ethanolic extract retains slightly more bioactivity than the sum of all sequential extracts per gram of starting material and that—despite a large loss of material during HPLC purification—the total bioactivity in all purified fractions is retained, which is indicative of rather an additive than a synergistic principle.
Design, Synthesis and Biological Evaluation of 6-(Imidazo[1,2-a]pyridin-6-yl)quinazoline Derivatives as Anticancer Agents via PI3Kα Inhibition
Authors: Li Mei , Wang Daoping , Li Qing , Luo Fang , Zhong Ting , Wu Hongshan , Xiong Liang , Yuan Meitao , Su Mingzhi , Fan Yanhua
Published: April 2023

Aberrant expression of the phosphatidylinositol 3-kinase (PI3K) signalling pathway is often associated with tumourigenesis, progression and poor prognosis. Hence, PI3K inhibitors have attracted significant interest for the treatment of cancer. In this study, a series of new 6-(imidazo[1,2-a]pyridin-6-yl)quinazoline derivatives were designed, synthesized and characterized by 1H NMR, 13C NMR and HRMS spectra analyses. In the in vitro anticancer assay, most of the synthetic compounds showed submicromolar inhibitory activity against various tumour cell lines, among which 13k is the most potent compound with IC50 values ranging from 0.09 μΜ to 0.43 μΜ against all the tested cell lines. Moreover, 13k induced cell cycle arrest at G2/M phase and cell apoptosis of HCC827 cells by inhibition of PI3Kα with an IC50 value of 1.94 nM. These results suggested that compound 13k might serve as a lead compound for the development of PI3Kα inhibitor.
RanBP1: A Potential Therapeutic Target for Cancer Stem Cells in Lung Cancer and Glioma
Authors: Kahm Yeon-Jee , Kim In-Gyu , Kim Rae-Kwon
Published: April 2023

Cancer stem cells (CSCs) are known to be one of the factors that make cancer treatment difficult. Many researchers are thus conducting research to efficiently destroy CSCs. Therefore, we sought to suggest a new target that can efficiently suppress CSCs. In this study, we observed a high expression of Ran-binding protein 1 (RanBP1) in lung cancer stem cells (LCSCs) and glioma stem cells (GSCs). Upregulated RanBP1 expression is strongly associated with the expression of CSC marker proteins and CSC regulators. In addition, an elevated RanBP1 expression is strongly associated with a poor patient prognosis. CSCs have the ability to resist radiation, and RanBP1 regulates this ability. RanBP1 also affects the metastasis-associated epithelial–mesenchymal transition (EMT) phenomenon. EMT marker proteins and regulatory proteins are affected by RanBP1 expression, and cell motility was regulated according to RanBP1 expression. The cancer microenvironment influences cancer growth, metastasis, and cancer treatment. RanBP1 can modulate the cancer microenvironment by regulating the cytokine IL-18. Secreted IL-18 acts on cancer cells and promotes cancer malignancy. Our results reveal, for the first time, that RanBP1 is an important regulator in LCSCs and GSCs, suggesting that it holds potential for use as a potential therapeutic target.
Computer-Assisted Design of Peptide-Based Radiotracers
Authors: Patamia Vincenzo , Zagni Chiara , Brullo Ilaria , Saccullo Erika , Coco Alessandro , Floresta Giuseppe , Rescifina Antonio
Published: April 2023

In medical imaging, techniques such as magnetic resonance imaging, contrast-enhanced computerized tomography, positron emission tomography (PET), and single-photon emission computed tomography (SPECT) are extensively available and routinely used for disease diagnosis. PET probes with peptide-based targeting are typically composed of small peptides especially developed to have high affinity and specificity for a range of cellular and tissue targets. These probes’ key benefits include being less expensive than traditional antibody-based PET tracers and having an effective chemical modification process that allows them to be radiolabeled with almost any radionuclide, making them highly appealing for clinical usage. Currently, as with every pharmaceutical design, the use of in silico strategies is steadily growing in this field, even though it is not part of the standard toolkit used during radiopharmaceutical design. This review describes the recent applications of computational design approaches in the design of novel peptide-based radiopharmaceuticals.
Inclisiran—A Revolutionary Addition to a Cholesterol-Lowering Therapy
Authors: Dec Adrianna , Niemiec Aleksandra , Wojciechowska Eliza , Maligłówka Mateusz , Bułdak Łukasz , Bołdys Aleksandra , Okopień Bogusław
Published: April 2023

Hypercholesterolemia plays a crucial role in the development of atherosclerosis, but it remains an undertreated and underdiagnosed disease. Taking into consideration the high prevalence of lipid disorders, long duration of the asymptomatic course of the disease, life-threatening complications resulting from inaccurate therapy, and stringent treatment goals concerning LDL cholesterol level in the prevention of cardiovascular events, novel lipid-lowering therapies have been introduced in the last few years. In this article, a drug belonging to the group of small interfering RNA (siRNA) called inclisiran is described. It is a novel molecule that increases the number of LDL receptors (LDLRs) on the surface of hepatic cells by preventing the formation of proprotein convertase subtilisin/kexin type 9 (PCSK9) responsible for the degradation of LDLRs. With great potential for lowering plasma LDL cholesterol level, high liver specificity, comfortable dosing regimen, and good tolerance without significant adverse effects, it could play an important part in future hypolipemic therapies.
Smell Dysfunction in Patients with Primary Sjögren’s Syndrome: Impact on Quality of Life
Authors: Al-Ezzi Minan Y. , Khan Khalid S. , Tappuni Anwar R.
Published: April 2023

Objectives: Patients with primary Sjögren’s syndrome (pSS) often report smell and taste disturbances. However, the correlation between smell impairment and mucosal dryness is not well understood. The objectives of this study were to investigate the following: (1) the prevalence of smell hypofunction in patients with SS; (2) the impact of smell hypofunction on their quality of life (QoL); (3) whether the patients’ smell is correlated with xerostomia; and (4) whether the patients’ smell is affected by taste hypofunction, disease duration, age, smoking or self-reported neuropathy. Methodology: An ethically approved cross-sectional study was conducted on 65 female patients with SS and 62 sex-matched healthy controls. Their smell was assessed using the University of Pennsylvania Smell Identification Test. Their taste acuity was assessed using the Taste Strips Test. A visual analogue scale was used for the self-assessment of smell and taste functions. Xerostomia was assessed by the salivary flow rate, clinical oral dryness score and the Xerostomia Inventory. The patients’ QoL and mental health well-being were assessed using validated questionnaires. Results: In the SS group, the patients’ smell function was impaired in 27/65 patients compared with the controls (15/62, p < 0.05), and it did not correlate with the severity of xerostomia, taste acuity (r = 0.05, p = 0.6) or self-reported nasal dryness (r = −0.02, p = 0.7). In the patients’ group, smell hypofunction was not correlated with disease duration (β = 0.1, 95% CI = −0.07–0.1) or smoking (β = −0.02, 95% CI = −8–7). Age was not correlated with the smell function in the patients’ group (β = −0.1, p = 0.5) but was correlated significantly with smell in the healthy participants’ group (β = −0.3, p = 0.02). Neuropathy affected 81.2% of the patients’ group. Their QoL and mental health well-being were not affected by smell hypofunction. Conclusion: Smell hypofunction appears to be a clinical manifestation in patients with SS, but it does not seem to be associated with the severity of mucosal dryness or with taste disturbance.
Secondary IgA Nephropathy and IgA-Associated Nephropathy: A Systematic Review of Case Reports
Authors: Tota Maciej , Baron Vanessa , Musial Katie , Derrough Bouchra , Konieczny Andrzej , Krajewska Magdalena , Turkmen Kultigin , Kusztal Mariusz
Published: April 2023

Primary (pIgAN), secondary IgA nephropathy (sIgAN), and IgA-associated nephropathy can be distinguished. While pIgAN has been thoroughly studied, information about the etiology of sIgAN remains scarce. As concerns sIgAN, several studies suggest that different etiologic factors play a role and ultimately lead to a pathophysiologic process similar to that of pIgAN. In this article, we review a vast number of cases in order to determine the novel putative underlying diseases of sIgAN. Moreover, updates on the common pathophysiology of primary disorders and sIgAN are presented. We identified liver, gastrointestinal, oncological, dermatological, autoimmune, and respiratory diseases, as well as infectious, iatrogenic, and environmental factors, as triggers of sIgAN. As novel biological therapies for listed underlying diseases emerge, we suggest implementing drug-induced sIgAN as a new significant category. Clinicians should acknowledge the possibility of sIgAN progression in patients treated with TNF-α inhibitors, IL-12/IL-23-inhibitors, immune checkpoint inhibitors, CTLA-4, oral anticoagulants, thioureylene derivatives, and anti-vascular endothelial growth factor drugs.
Electrical Storm Has Worse Prognosis Compared to Sustained Ventricular Tachycardia after VT Ablation
Authors: Mueller Julian , Chakarov Ivaylo , Halbfass Philipp , Nentwich Karin , Ene Elena , Berkovitz Artur , Sonne Kai , Barth Sebastian , Waechter Christian , Schupp Tobias , Behnes Michael , Akin Ibrahim , Deneke Thomas
Published: April 2023

Background: Electrical storm (ES) represents a serious heart rhythm disorder. This study investigates the impact of ES on acute ablation success and long-term outcomes after VT ablation compared to non-ES patients. Methods: In this large single-centre study, patients presenting with ES and undergoing VT ablation from June 2018 to April 2021 were compared to patients undergoing VT ablation due to ventricular tachyarrhythmias but without ES. The primary prognostic outcome was VT recurrence, and secondary endpoints were rehospitalization rates and cardiovascular mortality, all after a median follow-up of 22 months. Results: A total of 311 patients underwent a first VT ablation due to ventricular tachyarrhythmias and were included (63 ± 14 years; 86% male). Of these, 108 presented with ES. In the ES cohort, dilated cardiomyopathy as underlying heart disease was significantly higher (p = 0.008). Major complications were equal across both groups (all p > 0.05). Ablation of the clinical VT was achieved in 94% of all patients (p > 0.05). Noninducibility of any VT was achieved in 91% without ES and in 76% with ES (p = 0.001). Patients with ES revealed increased VT recurrence rates during follow-up (65% vs. 40%; log rank p = 0.001; HR 1.841, 95% CI 1.289–2.628; p = 0.001). Furthermore, ES patients suffered from increased rehospitalization rates (73% vs. 48%; log rank p = 0.001; HR 1.948, 95% CI 1.415–2.682; p = 0.001) and cardiovascular mortality (18% vs. 9%; log rank p = 0.045; HR 1.948, 95% CI 1.004–3.780; p = 0.049). After multivariable adjustment, ES was a strong independent predictor of VT recurrence and rehospitalization rates, but not for mortality. In a propensity score-matched cohort, patients with ES still had a higher risk of VT recurrences and rehospitalizations compared to non-ES patients. Conclusions: VT ablation in patients with ES is challenging and these patients reveal the highest risk for recurrent VTs, rehospitalization and cardiovascular mortality. These patients need close follow-ups and optimal guideline-directed therapy.
Assessment of Impact of Human Leukocyte Antigen-Type and Cytokine-Type Responses on Outcomes after Targeted Therapy Currently Used to Treat Chronic Lymphocytic Leukemia
Authors: Andreescu Mihaela , Berbec Nicoleta , Tanase Alina
Published: April 2023

Tumor growth and metastasis are reliant on intricate interactions between the host immune system and various counter-regulatory immune escape mechanisms employed by the tumor. Tumors can resist immune surveillance by modifying the expression of human leukocyte antigen (HLA) molecules, which results in the impaired presentation of tumor-associated antigens, subsequently evading detection and destruction by the immune system. The management of chronic lymphocytic leukemia (CLL) is based on symptom severity and includes various types of targeted therapies, including rituximab, obinutuzumab, ibrutinib, acalabrutinib, zanubrutinib, idelalisib, and venetoclax. These therapies rely on the recognition of specific peptides presented by HLAs on the surface of tumor cells by T cells, leading to an immune response. HLA class I molecules are found in most human cell types and interact with T-cell receptors (TCRs) to activate T cells, which play a vital role in inducing adaptive immune responses. However, tumor cells may evade T-cell attack by downregulating HLA expression, limiting the efficacy of HLA-dependent immunotherapy. The prognosis of CLL largely depends on the presence or absence of genetic abnormalities, such as del(17p), TP53 point mutations, and IGHV somatic hypermutation status. These oral targeted therapies alone or in combination with anti-CD20 antibodies have replaced chemoimmunotherapy as the primary treatment for CLL. In this review, we summarize the current clinical evidence on the impact of HLA- and cytokine-type responses on outcomes after targeted therapies currently used to treat CLL.
Comparison of Outcomes of Active Surveillance in Intermediate-Risk Versus Low-Risk Localised Prostate Cancer Patients: A Systematic Review and Meta-Analysis
Authors: Mukherjee Subhabrata , Papadopoulos Dimitrios , Norris Joseph M. , Wani Mudassir , Madaan Sanjeev
Published: April 2023

Currently, there is no clear consensus regarding the role of active surveillance (AS) in the management of intermediate-risk prostate cancer (IRPC) patients. We aim to analyse data from the available literature on the outcomes of AS in the management of IRPC patients and compare them with low-risk prostate cancer (LRPC) patients. A comprehensive literature search was performed, and relevant data were extracted. Our primary outcome was treatment-free survival, and secondary outcomes were metastasis-free survival, cancer-specific survival, and overall survival. The DerSimonian–Laird random-effects method was used for the meta-analysis. Out of 712 studies identified following an initial search, 25 studies were included in the systematic review. We found that both IRPC and LRPC patients had nearly similar 5, 10, and 15 year treatment-free survival rate, 5 and 10 year metastasis-free survival rate, and 5 year overall survival rate. However, cancer-specific survival rates at 5, 10, and 15 years were significantly lower in IRPC compared to LRPC group. Furthermore, IRPC patients had significantly inferior long-term overall survival rate (10 and 15 year) and metastasis-free survival rate (15 year) compared to LRPC patients. Both the clinicians and the patients can consider this information during the informed decision-making process before choosing AS.
Role of Epithelial-to-Mesenchymal Transition of Retinal Pigment Epithelial Cells in Glaucoma Cupping
Authors: O’Driscoll Eabha , Hughes Emily , Irnaten Mustapha , Kuehn Markus , Wallace Deborah , O’Brien Colm
Published: April 2023

Optic nerve head (ONH) cupping is a clinical feature of glaucoma associated with extracellular matrix (ECM) remodelling and lamina cribrosa (LC) fibrosis. Peripapillary atrophy (PPA) occurs commonly in glaucoma, and is characterised by the loss of retinal pigment epithelium (RPE) adjacent to the ONH. Under pro-fibrotic conditions, epithelial cells throughout the body can differentiate into fibroblast-like cells through epithelial-to-mesenchymal transition (EMT) and contribute to ECM fibrosis. This is investigated here in the context of glaucoma and PPA. Human-donor ONH sections were assessed for the presence of the RPE cell-specific marker RPE65 using immunofluorescence. We examined the EMT response of ARPE-19 cells to the following glaucoma-related stimuli: cyclic mechanical stretch, mechanical stiffness, transforming growth factor beta (TGFβ), and tumour necrosis factor alpha (TNFα). The gene expression was measured using the PCR of the epithelial tight junction marker zona occludens 1 (ZO-1) and the mesenchymal markers alpha smooth muscle actin (αSMA) and vimentin. A scratch assay was used to assess the ARPE-19 migration. Significant RPE-65 staining was demonstrated in the glaucomatous ONH. The cyclic stretching and substrate stiffness of the ARPE-19 cells caused a significant decrease in ZO-1 (p = 0.04), and an increase in αSMA (p = 0.04). The scratch assays demonstrated increased migration of ARPE19 in the presence of TNFα (p = 0.02). Furthermore, ARPE-19 cells undergo an EMT-like transition (gain of αSMA, loss of ZO-1 and increased migration) in response to glaucomatous stimuli. This suggests that during PPA, RPE cells have the potential to migrate into the ONH and differentiate into fibroblast-like cells, contributing to glaucomatous ONH cupping.
Determinants of Lipid Parameters in Patients without Diagnosed Cardiovascular Disease—Results of the Polish Arm of the EUROASPIRE V Survey
Authors: Ratajczak Jakub , Kubica Aldona , Michalski Piotr , Pietrzykowski Łukasz , Białczyk Aleksandra , Kosobucka-Ozdoba Agata , Bergmann Katarzyna , Buczkowski Krzysztof , Krintus Magdalena , Jankowski Piotr , Kubica Jacek
Published: April 2023

To assess the determinants of lipid parameters in primary care patients without diagnosed cardiovascular disease (CVD), a cross-sectional study was conducted during 2018–2019 with a total of 200 patients. The following lipid parameters were measured: total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), triglycerides (TG), small, dense LDL (sdLDL-C), and lipoprotein (a) (Lp(a)). Predictors of elevated and adequately controlled lipid parameters were assessed with logistic regression analysis. Older age was related to higher risk of TC ≥ 6.2 mmol/L [OR 1.03 (95% CI 1.0–1.05)], sdLDL-C ≥ 1.0 mmol/L [OR 1.05 (95% CI 1.0–1.1)], and decreased risk of Lp(a) ≥ 50 mg/dL [OR 0.97 (95% CI 0.94–0.99)]. Patients with diabetes mellitus (DM) had increased probability of TG ≥ 2.25 mmol/L [OR 3.77 (95% CI 1.34–10.6)] and Lp(a) ≥ 50 mg/dL [OR 2.97 (1.34–6.10)] as well as adequate control of TG and Lp(a). Higher material status was related to lower risk of TC ≥ 6.2 mmol/L [OR 0.19 (95% CI 0.04–0.82)] and LDL-C ≥ 3.6 mmol/L [OR 0.33 (95% CI 0.12–0.92)]. High BMI was related to increased [OR 1.14 (95% CI 1.02–1.29)], and female gender [OR 0.33 (95% CI 0.12–0.96)] and hypertension [OR 0.29 (95% CI 0.1–0.87)] to decreased risk of TG ≥ 2.25 mmol/L [OR 1.14 (95% CI 1.02–1.29)]. Taking lipid-lowering drugs (LLD) was associated with LDL-C < 2.6 mmol/L [OR 2.1 (95% CI 1.05–4.19)] and Lp(a) < 30 mg/dL [OR 0.48 (95% CI 0.25–0.93)]. Physical activity was related to LDL-C < 2.6 mmol/L [OR 2.02 (95% CI 1.02–3.98)]. Higher abdominal circumference was associated with decreased risk of TG < 1.7 mmol/L [OR 0.96 (95% CI 0.93–0.99)]. Elevated lipid parameters were related to age, gender, material status, BMI, history of DM, and hypertension. Adequate control was associated with age, education, physical activity, LLD, history of DM, and abdominal circumference.
Preserving Ambulation in a Gene Therapy-Treated Girl Affected by Metachromatic Leukodystrophy: A Case Report
Authors: Faccioli Silvia , Sassi Silvia , Pandarese Daniela , Borghi Corrado , Montemaggiori Valentina , Sarzana Marina , Scarparo Stefano , Butera Carla , Calbi Valeria , Aiuti Alessandro , Fumagalli Francesca
Published: April 2023

(1) Background: Atidarsagene autotemcel is a hematopoietic stem and progenitor cell gene therapy (HSPC-GT) approved to treat early-onset metachromatic leukodystrophy (MLD). The purpose of this case report is to describe the long-term management of residual gait impairment of a child with late infantile MLD treated with HSPC-GT. (2) Methods: Assessment included Gross Motor Function Measure-88, nerve conduction study, body mass index (BMI), Modified Tardieu Scale, passive range of motion, modified Medical Research Council scale, and gait analysis. Interventions included orthoses, a walker, orthopedic surgery, physiotherapy, and botulinum. (3) Results: Orthoses and a walker were fundamental to maintaining ambulation. Orthopedic surgery positively influenced gait by reducing equinovarus. Nonetheless, unilateral recurrence of varo-supination was observed, attributable to spasticity and muscle imbalance. Botulinum improved foot alignment but induced transient overall weakness. A significant increase in BMI occurred. Finally, a shift to bilateral valgopronation was observed, more easily managed with orthoses. (4) Conclusions: HSPC-GT preserved survival and locomotor abilities. Rehabilitation was then considered fundamental as a complementary treatment. Muscle imbalance and increased BMI contributed to gait deterioration in the growing phase. Caution is recommended when considering botulinum in similar subjects, as the risk of inducing overall weakness can outweigh the benefits of spasticity reduction.
Forest Transition and Fuzzy Environments in Neoliberal Mexico
Authors: Simmons Cynthia , Astier Marta , Walker Robert , Navia-Antezana Jaime Fernando , Gao Yan , Galván-Miyoshi Yankuic , Klooster Dan
Published: April 2023

Although deforestation remains a continuing threat to both the natural world and its resident human populations, a countervailing land cover dynamic has been observed in many nations. This process of landscape turnaround, the so-called forest transition, holds the potential of regenerating ecosystem services by sparing land from agricultural activities and abandoning it to forest succession. Here, we present a case study of a long-term process of forest transition that is ongoing in the Patzcuaro watershed of the state of Michoacán, Mexico. The research to be discussed comprises a remote sensing analysis designed to (1) capture the land cover impacts of a multidecadal process of trade liberalization (1996–2018); (2) ascertain the role that land tenure plays in land use dynamics affecting forest cover, and (3) resolve forest cover types into native forest, secondary vegetation, and “commodity” covers of fruit trees, in this case, avocado. Mexico presents a useful case for addressing these three design elements. Our analysis, undertaken for both private property and collective modes of resource management in five communities, reveals a forest transition annualized at 20 ha-yr−1, or a gain of eight percent for the period. This translates into a relative rate of forest transition of 0.39%-yr−1 which is three times faster than what is occurring in the temperate biome on a national scale (0.07%-yr−1). Most of the forest transition is occurring on private holdings and stems from field abandonment as farming systems intensify production with avocado plantations and cow–calf operations. As this study demonstrates, forest transitions are not occurring ubiquitously across nations but instead are highly localized occurrences driven by a myriad of distal and proximate factors involving disparate sets of stakeholders. Consequently, policy makers who are keen to expand forest transitions to fulfill their national climate action commitments under the Paris Agreement must first promote research into the complexity of landscapes and drivers of land change at regional and local scales.
Dermatology Publications on COVID-19 during the First Pandemic Year: Creativity or Opportunism?
Authors: Amerio Paolo , Giuliani Federica , Coppola Marco , Lobefaro Fabio , Gualdi Giulio
Published: April 2023

Introduction: Dermatologists had to face several challenges during the COVID-19 pandemic. In this scenario, a large amount of data has been produced and published. Objectives: We present a literature analysis of publications on COVID-19 in the dermatology field in the first year of the pandemic. Methods: The research was carried out by searching the PubMed database using keywords related to “COVID-19” combined with the keyword “Dermatology” in the “affiliation” search field and collecting articles published from February 2020 to December 2020. Results: A total of 816 publications from 57 countries were retrieved. Overall, publications increased notably along the timespan considered in this study and appeared to be closely linked to pandemic progression in different countries. In addition, article types (i.e., commentaries, case reports, original research) appeared to be strictly influenced by the pandemic’s progression. However, the number and category of these publications may raise questions regarding the scientific relevance of the messages reported. Conclusions: Our analysis provides a descriptive quantitative analysis and suggests that publications do not always respond to real scientific needs but are sometimes linked to a need/opportunity for publication.
A Study of Oribatid Mites as Potential Intermediate Hosts of Anoplocephalid Tapeworms of Tatra chamois and Tatra marmots from the Tatra Mountains, Central Europe, and Report of a New Intermediate Host for Andrya cuniculi, the Parasite of Leporidae
Authors: Jászayová Alexandra , Režnarová Jana , Chovancová Gabriela , Kostygov Alexei Yu , Yurchenko Vyacheslav , Antolová Daniela , Zwijacz-Kozica Tomasz , Csanády Alexander , Hurníková Zuzana
Published: April 2023

Tatra chamois (Rupicapra rupicapra tatrica (Blahout 1972)) and Tatra marmot (Marmota marmota latirostris (Kratochvíl 1961)) are significant endemic subspecies of the subalpine and alpine ranges of the Tatra Mountains in Central Europe. In four studied localities in the range of their typical biotopes in Slovakia and Poland, we investigated intestinal parasites of Tatra chamois and Tatra marmots, with an emphasis on anoplocephalid tapeworms. We also studied the occurrence, species diversity, and abundance of oribatid mites as intermediate hosts thereof, and the prevalence of cysticercoid larval stages of anoplocephalid tapeworms in collected oribatids using morphological and molecular methods. Coprological analyses revealed the average positivity of Moniezia spp. in chamois faeces at 23.5% and Ctenotaenia marmotae in marmot samples at 71.1%, with significant differences between the localities under study. Morphological analyses determined the presence of cysticercoids in five oribatid species: Ceratozetes gracilis, Edwardzetes edwardsi, Scheloribates laevigatus, Trichoribates novus, and Tectocepheus velatus sarekensis. This is the first record of T. v. sarekensis as an intermediate host of anoplocephalid tapeworms, as well as the first report of Andrya cuniculi occurrence in the territory of the Tatra Mountains, confirmed also by molecular methods.
Thematic Exordium for Special Issue “Density Functional Theory Application on Chemical Calculation”
Authors: Chachkov Denis V. , Mikhailov Oleg V.
Published: April 2023

The history of quantum chemistry dates back to 1926, when the German physicist Erwin Schrödinger, in his classical works [...]
Mechanical Performance and Chloride Penetration of Calcium Sulfoaluminate Concrete in Marine Tidal Zone
Authors: Tang Xudong , Zhan Shulin , Xu Qiang , He Kui
Published: April 2023

The enhancement of the durability of sulfoaluminate cement (CSA) in marine environments is of great importance. To this end, an investigation was carried out involving the placement of CSA concrete in the tidal zone of Zhairuoshan Island, Zhoushan, China, and subjected to a 20-month marine tidal exposure test. The comparison was made with ordinary Portland cement (OPC) concrete to evaluate the effectiveness of the former. The test findings indicate that the compressive strength of both types of concrete is reduced by seawater dry-wet cycling, and the porosity of the surface concrete is increased. However, the compressive strength of CSA concrete is observed to be more stable under long-term drying–wetting cycles. When the ettringite in the CSA surface concrete is decomposed due to carbonization and alkalinity reduction, its products will react with Ca2+ and SO42− in seawater to regenerate ettringite to fill in the concrete pores, making the concrete strength more stable and hindering chlorine penetration. Furthermore, CSA concrete exhibits a higher capillary absorption capacity than OPC concrete, which results in chloride accumulation on its surface. However, the diffusion capacity of chloride in CSA concrete is significantly lower than that in OPC concrete.
Hydrothermal Synthesis of CaAl-LDH Intercalating with Eugenol and Its Corrosion Protection Performances for Reinforcing Bar
Authors: Liu Ang , Gu Haohua , Geng Yongjuan , Wang Pan , Gao Song , Li Shaochun
Published: April 2023

Layered double hydroxides (LDHs) intercalating with a corrosion inhibitor for slowing down the corrosion of a reinforcing bar has attracted considerable attention. However, achieving high-loading capacity of organic inhibitor in LDH with high efficiency and long-term protection characteristics remains an important challenge. In this work, the CaAl-LDH intercalating with eugenol (EG) was synthesized via a continuous hydrothermal method. The prepared LDHs were characterized by SEM, XRD, UV-vis absorption spectra and TGA. Additionally, the corrosion protection performances of LDH-EG for steel bar were studied in detail via the electrochemical method. The results show that the loading amount of EG in LDHs was about 30% and about 80% EG could be released from LDH-EG within 4 h in SCPs containing 3.5% NaCl. The electrochemical test results show that the Rct value (105~106 Ω · cm2) of steel-mortar incorporated with LDH-EG has increased by 3–4 orders of magnitude compared to the specimen without LDHs (102~103 Ω · cm2) after 16 dry–wet cycles corrosion test. The significantly improved protection capability is mainly derived from two aspects: one is the filling effect of LDH, which can fill the pores of mortar and improve the impermeability; another reason is that the intercalated EG can slowly diffuse out of the inner structure of LDHs in a controllable way and result in a relatively long-term effect of corrosion inhibition.