bluuebunny/crossref_metadata_2025 huggingface dataset:
Illness Experiences of Brazilian People Who Were Hospitalized Due to COVID-19 and Faced Long COVID Repercussions in Their Daily Life: A Constructivist Grounded Theory Study
Authors: Marques Francielle Renata Danielli Martins , Laranjeira Carlos , Carreira Lígia , Gallo Adriana Martins , Baccon Wanessa Cristina , Paiano Marcelle , Baldissera Vanessa Denardi Antoniassi , Salci Maria Aparecida
Published: December 2023

Long COVID is a multisystem condition that has multiple consequences for the physical, mental, and social health of COVID-19 survivors. The impact of the long COVID condition remains unclear, particularly among middle-aged and older adults, who are at greater risk than younger people of persisting symptoms associated with COVID-19. Therefore, we aimed to understand the experiences of middle-aged and older people who had been hospitalized for COVID-19 and the repercussions of long-term COVID symptoms in their daily lives. A qualitative study was carried out, adopting the framework of the constructivist grounded theory (CGT) proposed by Kathy Charmaz. Fifty-six middle-aged and older adult participants from the southern region of Brazil were recruited. Data were gathered from semi-structured telephone interviews. Concomitantly a comparative analysis was performed to identify categories and codes using the MaxQDA® software (version 2022). Three subcategories were identified: (1) experiencing COVID-19 in the acute phase; (2) oscillating between ‘good days’ and ‘bad days’ in long COVID; and (3) (re)constructing identity. These concepts interact with each other and converge upon the central category of this study: recasting oneself to the uniqueness of the illness experience of long COVID. Our findings provided insights related to the disruption in the lives of long COVID-19 sufferers who still live with persistent symptoms of the disease, including physical, social, family, emotional and spiritual repercussions. Likewise, this study may aid in developing friendly and welcoming social environments, lowering stigma and prejudice towards patients with long COVID, and fostering prompt and suitable policy support and mental health care for these individuals.
Influence of Early Freezing on the Pore Structure Characteristics of Concrete and Its Correlation with Mechanical Properties
Authors: Wang Chun-Hong , Hao Bin-Bin , Liu Shi-Wei , Yuan Le-Zhong
Published: December 2023

Early freezing of concrete is common in the construction of water conservancy projects in northern China. Early freezing damage induces the deterioration of the mechanical properties of concrete structures, which seriously affects the safety, stability, and service life of engineering structures. Through a laboratory uniaxial compression test and a computed tomography (CT) test, the influence law of freezing time and freezing temperature on the mechanical properties of concrete is analyzed herein. The three-dimensional pore structure of concrete at different freezing times is reconstructed. The pore distribution and pore structure characteristic parameters of concrete at different freezing times are studied. The correlation between mechanical properties and the pore structure of early frozen concrete is determined. The results show that with the delay of freezing time, the porosity of concrete test blocks increases first and then decreases. The average pore surface area primarily decreases and then increases. The average pore diameter increases with the trend of a quadratic parabola. The average pore form factor primarily decreases, then increases, and then decreases. The average pore surface area has the best correlation with the compressive strength and elastic modulus of early frozen concrete. The outcomes suggest that the average pore surface area should be preferred when constructing the mesoscopic damage index of early frozen concrete. Relevant results provide support for revealing the macro and micro damage mechanisms of early frozen concrete.
Investigating the Mechanical Deterioration Effect of Hard Sandstone Induced by Layer Structure under Uniaxial Compression
Authors: Cheng Yun , Song Zhanping , Wu Fahong , Zhu Xiaoping , Yuan Wei
Published: December 2023

The deterioration of the surrounding rock at the tunnel bottom is a damage mechanics issue that occurs under disturbance load. To investigate the anisotropic characteristics of mechanical behavior and the AE response mechanism of layered sandstone, uniaxial compression tests and acoustic emission (AE) monitoring were conducted. The results show that the layer structure causes remarkable anisotropic characteristics in the wave velocities. The strain characteristics and mechanical parameters of layered sandstone exhibit obvious deterioration effects. The local strain and overall strain show a synergistic feature, with the local strain path being more complex and the deformation response being extremely sensitive. The peak stress and elastic modulus both exhibit V-type distribution rules, slowly decreasing first, then rapidly decreasing, and finally increasing rapidly, with the boundary points of the layer angle being 45° and 67.50°. The peak stress and elastic modulus show a nonlinear exponential correlation with the layer angle, and the sandstone belongs to the intermediate anisotropy level. The rupture pattern shows significant anisotropic characteristics, with the failure modes including tension failure, including tension failure I and tension failure Ⅱ, shear failure, and tension–shear composite failure. The fractal dimension shows a negative correlation with the layer deterioration effect. The AE activity exhibits a phased response characteristic to the aging deformation of layer structure. The more obvious the layer deterioration effect is, the longer the AE delay is. The AE intensity of tensile failure sandstone is generally greater than that of oblique shear failure.
Effects of Embedded Expanded Polystyrene Boards on the Hysteretic Behavior of Innovative Precast Braced Concrete Shear Walls
Authors: Tang Yachao , Li Hongnan
Published: December 2023

An innovative type of precast braced concrete shear (PBCS) wall has been tested and verified to have comparable shear resistances relative to conventional cast-in-place reinforced concrete (RC) shear walls. The triangular or rectangular embedded expanded polystyrene (EPS) boards in PBCS wall panels can not only considerably reduce concrete use but also reduce the structural weight. To understand the functions of EPS boards in more depth, this paper investigates the effects of the thickness ratio of different shapes of EPS on the hysteretic behaviors of PBCS walls with various shear span ratios (SSRs). The finite element (FE) models of PBCS walls based on the multi-layer shell element are developed and verified to be sufficiently accurate in comparison with the experimental results. The analysis results indicate that the bearing capacity, lateral stiffness and ductility of PBCS walls show a downward trend with the increase in the thickness ratio of EPS boards. The rectangular EPS board has a more pronounced effect on weight reduction as well as concrete use reduction compared to the triangular EPS board under the same thickness ratio. The formulations regarding the bearing capacity are developed and show good agreement with the numerical results. The thickness ratio limit for PBCS walls to satisfy the ductility requirement is addressed. This investigation not only provides insight into the cyclic behavior of PBCS walls with varied thickness ratios but also demonstrates the potential applicability of PBCS walls in precast concrete (PC) structures for both thermal insulation and earthquake resistance purposes.
First-in-Human Dose-Escalation Study of the Novel Oral Depsipeptide Class I-Targeting HDAC Inhibitor Bocodepsin (OKI-179) in Patients with Advanced Solid Tumors
Authors: Schreiber Anna R. , Kagihara Jodi A. , Corr Bradley R. , Davis S. Lindsey , Lieu Christopher , Kim Sunnie S. , Jimeno Antonio , Camidge D. Ross , Williams Jud , Heim Amy M. , Martin Anne , DeMattei John A. , Holay Nisha , Triplett Todd A. , Eckhardt S. Gail , Litwiler Kevin , Winkler James , Piscopio Anthony D. , Diamond Jennifer R.
Published: December 2023

(1) Background: Histone deacetylases (HDACs) play a critical role in epigenetic signaling in cancer; however, available HDAC inhibitors have limited therapeutic windows and suboptimal pharmacokinetics (PK). This first-in-human phase I dose escalation study evaluated the safety, PK, pharmacodynamics (PDx), and efficacy of the oral Class I-targeting HDAC inhibitor bocodepsin (OKI-179). (2) Patients and Methods: Patients (n = 34) with advanced solid tumors were treated with OKI-179 orally once daily in three schedules: 4 days on 3 days off (4:3), 5 days on 2 days off (5:2), or continuous in 21-day cycles until disease progression or unacceptable toxicity. Single-patient escalation cohorts followed a standard 3 + 3 design. (3) Results: The mean duration of treatment was 81.2 (range 11–447) days. The most frequent adverse events in all patients were nausea (70.6%), fatigue (47.1%), and thrombocytopenia (41.2%). The maximum tolerated dose (MTD) of OKI-179 was 450 mg with 4:3 and 200 mg with continuous dosing. Dose-limiting toxicities included decreased platelet count and nausea. Prolonged disease control was observed, including two patients with platinum-resistant ovarian cancer. Systemic exposure to the active metabolite exceeded the preclinical efficacy threshold at doses lower than the MTD and was temporally associated with increased histone acetylation in circulating T cells. (4) Conclusions: OKI-179 has a manageable safety profile at the recommended phase 2 dose (RP2D) of 300 mg daily on a 4:3 schedule with prophylactic oral antiemetics. OKI-179 is currently being investigated with the MEK inhibitor binimetinib in patients with NRAS-mutated melanoma in the phase 2 Nautilus trial.
The Diagnostic Yield and Implications of Targeted Founder Pathogenic Variant Testing in an Israeli Cohort
Authors: Abu Shtaya Aasem , Kedar Inbal , Mattar Samar , Mahamid Ahmad , Basel-Salmon Lina , Farage Barhom Sarit , Naftaly Nathan Sofia , Magal Nurit , Azulay Noy , Levy Zalcberg Michal , Chen-Shtoyerman Rakefet , Segol Ori , Seri Mor , Reznick Levi Gili , Shkedi-Rafid Shiri , Vinkler Chana , Netzer Iris , Hagari Bechar Ofir , Chamma Liat , Liberman Sari , Goldberg Yael
Published: December 2023

Founder pathogenic variants (PVs) are prevalent in Israel. This study investigated the current practice of offering cancer patients two-step genetic testing, starting with targeted testing for recurring founder PVs, followed, if negative, by next-generation sequencing. A total of 2128 subjects with cancer or a positive family history underwent oncogenetic testing with a panel of 51 recurring PVs at a tertiary medical center in March 2020–January 2023. Those with a known familial PV (n = 370) were excluded from the analysis. Among the remainder, 128/1758 (7%) were heterozygous for at least one variant, and 44 (34%) carried a PV of medium-high penetrance (MHPV). Cancer was diagnosed in 1519/1758 patients (86%). The diagnostic yield of founder MHPV testing was 2% in cancer patients and 4% in healthy individuals with a positive family history. It was higher in Ashkenazi Jews than non-Ashkenazi Jews and Arabs, but not over 10% for any type of cancer, and it was significantly higher in younger (<40 years) than older (>50 years) individuals (7% vs. 1%). Eighty-four of the heterozygotes (66%), mostly Ashkenazi Jews, harbored a low-penetrance variant (LPV) not associated with the diagnosed cancer, usually APC c.3902T>A. These findings question the advantage of two-step testing. LPVs should not be included in targeted testing because this can lead to an overestimation of the yield, and their detection does not preclude further comprehensive testing.
COVID-19 in Patients with Melanoma: A Single-Institution Study
Authors: Anastasopoulou Amalia , Diamantopoulos Panagiotis T. , Kouzis Panagiotis , Saridaki Maria , Sideris Konstantinos , Samarkos Michael , Gogas Helen
Published: December 2023

We conducted a single-center, non-interventional retrospective study of melanoma patients with COVID-19 (1 March 2020 until 17 March 2023). The cohort was further divided into three groups according to the periods of SARS-CoV-2 variant dominance in Greece. We recorded demographics, comorbidities, vaccination data, cancer diagnosis/stage, types of systemic melanoma treatments, date of COVID-19 diagnosis and survival. We identified 121 patients. The vast majority (87.6%) had advanced disease (stages III or IV). A total of 80.1% of the patients were receiving immune checkpoint inhibitor-based therapies, 92.5% had asymptomatic/mild COVID-19 and 7.4% had moderate/severe/critical disease, while 83.5% contracted COVID-19 during the third period of the pandemic. Sixteen patients (13.2%) were hospitalized for COVID-19 with a median length of stay of 12 days (range: 1–55 days). Advanced age, heart failure, number of comorbidities (≤1 vs. >1), vaccination status and the time period of the infection correlated with more severe COVID-19, whereas only heart failure and time period were independently correlated with severity. The 30-day mortality rate after COVID-19 was 4.2%. With a median follow-up of 340 days post-COVID-19, 17.4% of patients were deceased. In this cohort of melanoma patients with COVID-19, the 30-day mortality rate was low. There was no association between melanoma stage, treatment receipt and type of treatment with COVID-19 severity.
Progress in Glioma Stem Cell Research
Authors: Ramar Vanajothi , Guo Shanchun , Hudson BreAnna , Liu Mingli
Published: December 2023

Glioblastoma multiforme (GBM) represents a diverse spectrum of primary tumors notorious for their resistance to established therapeutic modalities. Despite aggressive interventions like surgery, radiation, and chemotherapy, these tumors, due to factors such as the blood–brain barrier, tumor heterogeneity, glioma stem cells (GSCs), drug efflux pumps, and DNA damage repair mechanisms, persist beyond complete isolation, resulting in dismal outcomes for glioma patients. Presently, the standard initial approach comprises surgical excision followed by concurrent chemotherapy, where temozolomide (TMZ) serves as the foremost option in managing GBM patients. Subsequent adjuvant chemotherapy follows this regimen. Emerging therapeutic approaches encompass immunotherapy, including checkpoint inhibitors, and targeted treatments, such as bevacizumab, aiming to exploit vulnerabilities within GBM cells. Nevertheless, there exists a pressing imperative to devise innovative strategies for both diagnosing and treating GBM. This review emphasizes the current knowledge of GSC biology, molecular mechanisms, and associations with various signals and/or pathways, such as the epidermal growth factor receptor, PI3K/AKT/mTOR, HGFR/c-MET, NF-κB, Wnt, Notch, and STAT3 pathways. Metabolic reprogramming in GSCs has also been reported with the prominent activation of the glycolytic pathway, comprising aldehyde dehydrogenase family genes. We also discuss potential therapeutic approaches to GSC targets and currently used inhibitors, as well as their mode of action on GSC targets.
ERK3 Increases Snail Protein Stability by Inhibiting FBXO11-Mediated Snail Ubiquitination
Authors: Kim Seon-Hee , Ryu Ki-Jun , Hong Keun-Seok , Kim Hyemin , Han Hyeontak , Kim Minju , Kim Taeyoung , Ok Dong Woo , Yang Jung Wook , Hwangbo Cheol , Kim Kwang Dong , Yoo Jiyun
Published: December 2023

Snail is a key regulator of the epithelial-mesenchymal transition (EMT), the key step in the tumorigenesis and metastasis of tumors. Although induction of Snail transcription precedes the induction of EMT, the post-translational regulation of Snail is also important in determining Snail protein levels, stability, and its ability to induce EMT. Several kinases are known to enhance the stability of the Snail protein by preventing its ubiquitination; however, the precise molecular mechanisms by which these kinases prevent Snail ubiquitination remain unclear. Here, we identified ERK3 as a novel kinase that interacts with Snail and enhances its protein stability. Although ERK3 could not directly phosphorylate Snail, Erk3 increased Snail protein stability by inhibiting the binding of FBXO11, an E3 ubiquitin ligase that can induce Snail ubiquitination and degradation, to Snail. Importantly, functional studies and analysis of clinical samples indicated the crucial role of ERK3 in the regulation of Snail protein stability in pancreatic cancer. Therefore, we conclude that ERK3 is a key regulator for enhancing Snail protein stability in pancreatic cancer cells by inhibiting the interaction between Snail and FBXO11.
Chemotherapy and Radiotherapy Long-Term Adverse Effects on Oral Health of Childhood Cancer Survivors: A Systematic Review and Meta-Analysis
Authors: Pombo Lopes Joana , Rodrigues Inês , Machado Vanessa , Botelho João , Bandeira Lopes Luísa
Published: December 2023

The survival rate for pediatric cancer has increased over the past few decades, short- and long-term complications have been detected and studied, and oral complications have emerged as an important topic of research. Here, we aimed to highlight the importance of oral manifestations that may only become apparent years or even decades after cancer treatment. This systematic review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis. We searched articles using PubMed via the MEDLINE, Web of Science, and LILACS databases until October 2023. Overall, 35 observational studies were included, and the results estimated a pooled prevalence of the following dental anomalies: discoloration, 53%; crown-root malformations and agenesis, 36%; enamel hypoplasia, 32%; root development alterations, 29%; unerupted teeth, 24%; microdontia, 16%; hypodontia, 13%; and macrodontia, 7%. Most childhood cancer survivors have at least one dental sequela. Childhood cancer survivors presented a higher risk of having dental alterations than control counterparts. Additional analyses reveal possible sex-based differences that should be explored in future studies. These results collectively highlight the importance of oral healthcare and the prevention of disease in childhood cancer survivors.
Robotic-Assisted Ivor Lewis Esophagectomy Is Safe and Cost Equivalent Compared to Minimally Invasive Esophagectomy in a Tertiary Referral Center
Authors: Knitter Sebastian , Maurer Max M. , Winter Axel , Dobrindt Eva M. , Seika Philippa , Ritschl Paul V. , Raakow Jonas , Pratschke Johann , Denecke Christian
Published: December 2023

In recent decades, robotic-assisted minimally invasive esophagectomy (RAMIE) has been increasingly adopted for patients with esophageal cancer (EC) or cancer of the gastroesophageal junction (GEJ). However, concerns regarding its costs compared to conventional minimally invasive esophagectomy (MIE) have emerged. This study examined outcomes and costs of RAMIE versus total MIE in 128 patients who underwent Ivor Lewis esophagectomy for EC/GEJ at our department between 2017 and 2021. Surgical costs were higher for RAMIE (EUR 12,370 vs. EUR 10,059, p < 0.001). Yet, median daily (EUR 2023 vs. EUR 1818, p = 0.246) and total costs (EUR 30,510 vs. EUR 29,180, p = 0.460) were comparable. RAMIE showed a lower incidence of postoperative pneumonia (8% vs. 25%, p = 0.029) and a trend towards shorter hospital stays (15 vs. 17 days, p = 0.205), which may have equalized total costs. Factors independently associated with higher costs included readmission to the intensive care unit (hazard ratio [HR] = 7.0), length of stay (HR = 13.5), anastomotic leak (HR = 17.0), and postoperative pneumonia (HR = 5.4). In conclusion, RAMIE does not impose an additional financial burden. This suggests that RAMIE may be considered as a valid alternative approach for esophagectomy. Attention to typical cost factors can enhance postoperative care across surgical methods.
Gene-Specific Discriminative Echocardiogram Findings in Hypertrophic Cardiomyopathy Determined Using Artificial Intelligence: A Pilot Study
Authors: Glavaški Mila , Ilić Aleksandra , Velicki Lazar
Published: December 2023

Hypertrophic cardiomyopathy (HCM) is among the most common forms of cardiomyopathies, with a prevalence of 1:200 to 1:500 people. HCM is caused by variants in genes encoding cardiac sarcomeric proteins, of which a majority reside in MYH7, MYBPC3, and TNNT2. Up to 40% of the HCM cases do not have any known HCM variant. Genotype–phenotype associations in HCM remain incompletely understood. This study involved two visits of 46 adult patients with a confirmed diagnosis of HCM. In total, 174 genes were analyzed on the Next-Generation Sequencing platform, and transthoracic echocardiography was performed. Gene-specific discriminative echocardiogram findings were identified using the computer vision library Fast AI. This was accomplished with the generation of deep learning models for the classification of ultrasonic images based on the underlying genotype and a later analysis of the most decisive image regions. Gene-specific echocardiogram findings were identified: for variants in the MYH7 gene (vs. variant not detected), the most discriminative structures were the septum, left ventricular outflow tract (LVOT) segment, anterior wall, apex, right ventricle, and mitral apparatus; for variants in MYBPC3 gene (vs. variant not detected) these were the septum, left ventricle, and left ventricle/chamber; while for variants in the TNNT2 gene (vs. variant not detected), the most discriminative structures were the septum and right ventricle.
Upgrading Epoxy Supports for Enzyme Immobilization by Affinity Function Doping—A Case Study with Phenylalanine Ammonia-Lyase from Petroselinum crispum
Authors: Alács Bálint , Zrinyi Anna , Hornyánszky Gábor , Poppe László , Bell Evelin
Published: December 2023

This article provides a method to upgrade epoxy-functionalized carriers for covalent enzyme immobilization to selective carriers suitable for covalent immobilization of metal affinity-tagged enzymes without the need of preliminary enzyme purification. Affinity function doping of the epoxy-functionalized surface introduces an advanced possibility to avoid the costly and time-consuming downstream processes required for efficient immobilization on non-selective epoxy carriers. Our approach is based on the partial functionalization of surface epoxides via a proper diamine-derived linker and an ethylenediaminetetraacetic dianhydride-based chelator charged with cobalt ions. The solid macroporous carriers, doped with metal affinity functions, have both coordinative binding ability (rapid anchoring the metal affinity-tagged enzymes to the surface) and subsequent covalent bond-forming ability (preferred binding of the tagged enzyme to the surface after proper washing by the residual epoxide functions), enabling a single operation for the enrichment and immobilization of a recombinant phenylalanine ammonia-lyase from parsley fused to a polyhistidine affinity tag. The immobilized PcPAL was applied in the ammonia elimination of racemic phenylalanine, 4-chlorophenylalanine, and 4-bromophenylalanine to produce the corresponding d-phenylalanines, in addition to the formation of (E)-cinnamates, as well as in ammonia addition reactions to (E)-cinnamates, yielding the corresponding enantiopure l-phenylalanines.
Mining, Identification, and Characterization of Three Xylanases from the Microbiota of T. fuciformis with Its Companion Strains
Authors: Lin Yanhuan , Li Changle , Wei Chenxin , Lin Hui , Zhang Liaoyuan
Published: December 2023

Microbial xylanase has wide application in bioenergy, animal feed, environmental protection, the pulp and paper industry, and agricultural development. In this study, three xylanases from the microbiota of T. fuciformis with its companion strains were identified by metagenomics sequencing. The three enzymes were subjected to cloning and expression in E. coli or P. pastoris, purification, and characterization for their properties. The results showed that AsXyn1, from Annulohypoxylon stygium, among the three enzymes possessed high thermostability at 40 °C and broad pH tolerance in the range of 2.0–10.0, exhibiting its application potential. Furthermore, it was found that post-translational modification (such as glycosylation) of AsXyn1 enzyme modulated its activity, kinetic parameters, and thermostability. These results and findings provided a hint for enzyme modification and design in future.
The Cysteine Protease Legumain Is Upregulated by Vitamin D and Is a Regulator of Vitamin D Metabolism in Mice
Authors: Forbord Karl Martin , Okla Meshail , Lunde Ngoc Nguyen , Bosnjak-Olsen Tatjana , Arnekleiv Guro , Hesselson Daniel , Johansen Harald Thidemann , Tang Jonathan C. Y. , Kassem Moustapha , Solberg Rigmor , Jafari Abbas
Published: December 2023

Legumain is a lysosomal cysteine protease that has been implicated in an increasing amount of physiological and pathophysiological processes. However, the upstream mechanisms regulating the expression and function of legumain are not well understood. Here, we provide in vitro and in vivo data showing that vitamin D3 (VD3) enhances legumain expression and function. In turn, legumain alters VD3 bioavailability, possibly through proteolytic cleavage of vitamin D binding protein (VDBP). Active VD3 (1,25(OH)2D3) increased legumain expression, activity, and secretion in osteogenic cultures of human bone marrow stromal cells. Upregulation of legumain was also observed in vivo, evidenced by increased legumain mRNA in the liver and spleen, as well as increased legumain activity in kidneys from wild-type mice treated with 25(OH)D3 (50 µg/kg, subcutaneously) for 8 days compared to a control. In addition, the serum level of legumain was also increased. We further showed that active legumain cleaved purified VDBP (55 kDa) in vitro, forming a 45 kDa fragment. In vivo, no VDBP cleavage was found in kidneys or liver from legumain-deficient mice (Lgmn−/−), whereas VDBP was cleaved in wild-type control mice (Lgmn+/+). Finally, legumain deficiency resulted in increased plasma levels of 25(OH)D3 and total VD3 and altered expression of key renal enzymes involved in VD3 metabolism (CYP24A1 and CYP27B1). In conclusion, a regulatory interplay between VD3 and legumain is suggested.
Super-Resolution Analysis of the Origins of the Elementary Events of ER Calcium Release in Dorsal Root Ganglion Neurons
Authors: Hurley Miriam E. , Shah Shihab S. , Sheard Thomas M. D. , Kirton Hannah M. , Steele Derek S. , Gamper Nikita , Jayasinghe Izzy
Published: December 2023

Coordinated events of calcium (Ca2+) released from the endoplasmic reticulum (ER) are key second messengers in excitable cells. In pain-sensing dorsal root ganglion (DRG) neurons, these events can be observed as Ca2+ sparks, produced by a combination of ryanodine receptors (RyR) and inositol 1,4,5-triphosphate receptors (IP3R1). These microscopic signals offer the neuronal cells with a possible means of modulating the subplasmalemmal Ca2+ handling, initiating vesicular exocytosis. With super-resolution dSTORM and expansion microscopies, we visualised the nanoscale distributions of both RyR and IP3R1 that featured loosely organised clusters in the subplasmalemmal regions of cultured rat DRG somata. We adapted a novel correlative microscopy protocol to examine the nanoscale patterns of RyR and IP3R1 in the locality of each Ca2+ spark. We found that most subplasmalemmal sparks correlated with relatively small groups of RyR whilst larger sparks were often associated with larger groups of IP3R1. These data also showed spontaneous Ca2+ sparks in <30% of the subplasmalemmal cell area but consisted of both these channel species at a 3.8–5 times higher density than in nonactive regions of the cell. Taken together, these observations reveal distinct patterns and length scales of RyR and IP3R1 co-clustering at contact sites between the ER and the surface plasmalemma that encode the positions and the quantity of Ca2+ released at each Ca2+ spark.
Understanding Bartonella-Associated Infective Endocarditis: Examining Heart Valve and Vegetation Appearance and the Role of Neutrophilic Leukocytes
Authors: Meidrops Kristians , Groma Valerija , Goldins Niks Ricards , Apine Lauma , Skuja Sandra , Svirskis Simons , Gudra Dita , Fridmanis Davids , Stradins Peteris
Published: December 2023

Background. The endocardium and cardiac valves undergo severe impact during infective endocarditis (IE), and the formation of vegetation places IE patients at a heightened risk of embolic complications and mortality. The relevant literature indicates that 50% of IE cases exhibit structurally normal cardiac valves, with no preceding history of heart valve disease. Gram-positive cocci emerge as the predominant causative microorganisms in IE, while Gram-negative Bartonella spp., persisting in the endothelium, follow pathogenic pathways distinct from those of typical IE-causing agents. Employing clinical as well as advanced microbiological and molecular assays facilitated the identification of causative pathogens, and various morphological methods were applied to evaluate heart valve damage, shedding light on the role of neutrophilic leukocytes in host defense. In this research, the immunohistochemical analysis of neutrophilic leukocyte activation markers such as myeloperoxidase, neutrophil elastase, calprotectin, and histone H3, was performed. A distinct difference in the expression patterns of these markers was observed when comparing Bartonella spp.-caused and non-Bartonella spp.-caused IE. The markers exhibited significantly higher expression in non-Bartonella spp.-caused IE compared to Bartonella spp.-caused IE, and they were more prevalent in vegetation than in the valvular leaflets. Notably, the expression of these markers in all IE cases significantly differed from that in control samples. Furthermore, we advocated the use of 16S rRNA Next-Generation Sequencing on excised heart valves as an effective diagnostic tool for IE, particularly in cases where blood cultures yielded negative results. The compelling results achieved in this study regarding the enigmatic nature of Bartonella spp. IE’s pathophysiology contribute significantly to our understanding of the peculiarities of inflammation and immune responses.
Obesity and Body Composition in Relation to Liver and Kidney Ultrasound Elastography in Paediatric Patients with Either Hypertension or Chronic Kidney Disease
Authors: Marčun Varda Nataša , Golob Jančič Sonja , Močnik Mirjam
Published: December 2023

(1) Background: Ultrasound elastography is a novel ultrasound technique for evaluating tissue elasticity. One of the key factors influencing the measurement in children is excess weight. This study aimed to evaluate the effect of body composition, namely, fat mass, on liver and kidney ultrasound elastography in paediatric patients. (2) Methods: 114 participants, in whom bioimpedance, along with liver and kidney ultrasound elastography, were performed, were included (37 patients with chronic kidney disease, 46 patients with hypertension, and 31 healthy subjects). (3) Results: Bioimpedance analysis showed a significant correlation between liver elastography parameters and the phase angle (p = 0.002), fat-free mass (p = 0.001), body cell mass (p = 0.001), total body water (p = 0.001), extracellular water (p = 0.006), and, to lesser extent, fat mass (p = 0.041). On the contrary, kidney elastography parameters strongly correlated only with fat mass (p < 0.001 for both kidneys). (4) Conclusions: Liver and kidney stiffness increased in overweight participants and showed significant correlation with fat mass, particularly in the case of kidney elastography.
Analysis of Somatic Mutations in the TCGA-LIHC Whole Exome Sequence to Identify the Neoantigen for Immunotherapy in Hepatocellular Carcinoma
Authors: Pulakuntla Swetha , Syed Khajamohiddin , Reddy Vaddi Damodara
Published: December 2023

There are numerous clinically proven methods for treating cancer worldwide. Immunotherapy has been used to treat cancer with significant success in the current studies. The purpose of this work is to identify somatically altered target gene neoantigens and investigate liver cancer-related immune cell interaction and functional changes for potential immunotherapy in future clinical trials. Clinical patient data from the Cancer Genome Atlas (TCGA) database were used in this investigation. The R maf utility package was used to perform somatic analysis. The 17-mer peptide neoantigens were extracted using an in-house Python software called Peptide.py. Additionally, the epitope analysis was conducted using NetMHCpan4.1 program. Neopeptide immunogenicity was assessed using DeepCNN-Ineo, and tumor immune interaction, association with immune cells, correlation, and survival analysis were assessed using the TIMER web server. Based on somatic mutation analysis, we have identified the top 10 driver genes (TP53, TNN, CTNNB1, MUC16, ALB, PCLO, MUC4, ABCA13, APOB, and RYR2). From the superfamily of 20 HLA (Human leukocyte antigens) allele epitopes, we discovered 5653 neopeptides. Based on T cell receptor face hydrophobic analysis, these neopeptides were subjected to immunogenicity investigation. A mutation linked to tumor growth may have an impact on immune cells. According to this study’s correlation and survival analysis, all driver genes may function as immune targets for liver cancer. These genes are recognized to be immune targets. In the future, immune checkpoint inhibitors may be developed to prolong patient survival times and prevent hepatocellular carcinoma (HCC) through immunotherapy.
Thymoquinone: A Promising Therapeutic Agent for the Treatment of Colorectal Cancer
Authors: Kurowska Natalia , Madej Marcel , Strzalka-Mrozik Barbara
Published: December 2023

Colorectal cancer (CRC) is one of the most commonly diagnosed cancers and is responsible for approximately one million deaths each year. The current standard of care is surgical resection of the lesion and chemotherapy with 5-fluorouracil (5-FU). However, of concern is the increasing incidence in an increasingly younger patient population and the ability of CRC cells to develop resistance to 5-FU. In this review, we discuss the effects of thymoquinone (TQ), one of the main bioactive components of Nigella sativa seeds, on CRC, with a particular focus on the use of TQ in combination therapy with other chemotherapeutic agents. TQ exhibits anti-CRC activity by inducing a proapoptotic effect and inhibiting proliferation, primarily through its effect on the regulation of signaling pathways crucial for tumor progression and oxidative stress. TQ can be used synergistically with chemotherapeutic agents to enhance their anticancer effects and to influence the expression of signaling pathways and other genes important in cancer development. These data appear to be most relevant for co-treatment with 5-FU. We believe that TQ is a suitable candidate for consideration in the chemoprevention and adjuvant therapy for CRC, but further studies, including clinical trials, are needed to confirm its safety and efficacy in the treatment of cancer.
Geomorphic Response of the Georgia Bight Coastal Zone to Accelerating Sea Level Rise, Southeastern USA
Authors: Parkinson Randall W. , Wdowinski Shimon
Published: December 2023

Synthesis of geologic and chronologic data generated from Holocene sedimentary sequences recovered along the inner continental shelf, shoreface, and modern coastal zone of the Georgia Bight reveal a synchronous sequence of paleoenvironmental events that occurred in response to rate of sea level rise tipping points. During the early Holocene (11.7–8.2 cal kyr BP), the paleoshoreline was overstepped and submerged by rapidly rising seas that averaged ~5 mm yr−1. Rates of rise during the middle Holocene (8.2–4.2 cal kyr BP) averaged ~2 mm yr−1 and this deceleration resulted in the formation of coastal environments and sedimentary sequences that were subsequently reworked as the shoreface continued its landward and upward migration. The modern coastal zone emerged commensurate with the late Holocene (4.2–0 cal kyr BP), when the rate of sea level rise averaged <1 mm yr−1. Analysis of water level data collected at six NOAA tide gauge stations located along the Georgia Bight coast indicates the rate of relative sea level rise has increased from a historical average of 3.6 ± 0.2 mm yr−1 (<1972 to 2022) to 6.6 ± 0.8 (1993 to 2022) and during the 21st century it has averaged 9.8 ± 0.3 mm yr−1 (2003 to 2022). The current rate of sea level rise is nearly double the early Holocene rate of rise. Based upon a novel application of the principle of uniformitarianism (i.e., the past is the key to the future), the likely geomorphic trajectory of the Georgia Bight coastal zone under conditions of 21st century accelerating sea level rise will be one of increasing instability (e.g., coastal erosion) and flooding (e.g., overwash, breaching). Evidence of an emerging instability within the coastal zone has been previously reported throughout the region and supports the trajectory of geomorphic change proposed herein. This will ultimately result in the submergence of existing landscapes and replacement by estuarine and marine environments, which may hasten in pace and scale given the current rate of sea level rise is expected to continue accelerating throughout this century. These findings have not been previously reported and should be considered by coastal practitioners responsible for conceptualizing risk, as well as the formulation and implementation of adaptation action plans designed to mitigate threats to the built and natural environment induced by climate change.
Enhanced Electrochemical Performance of LaMnO3 Nanoparticles by Ca/Sr Doping
Authors: Zheng Junhan , Zhao Hongquan , Guo Xu , Jin Xiaoyun , Wang Lei , Dong Songtao , Chen Jian
Published: December 2023

In this paper, the sol-gel method was used to synthesize powders of LaMnO3 (LMO), La0.85Ca0.15MnO3 (LCM), and La0.85Sr0.15MnO3 (LSM). The effect of substituting Ca and Sr at the A-site on the perovskite crystal structure and electrochemical capabilities of LMO was investigated. LCM retained its orthogonal structure in comparison to the parent LMO components, whereas LSM transitioned to a rhombic structure. At 0.5 A/g, the specific capacitance of LCM and LSM electrodes is 185.5 F/g and 248 F/g, respectively. The specific capacitance of LCM was three times greater than that of the LMO electrode. Among the three samples (LMO, 22.25 m2 g−1; LSM, 31.56 m2 g−1), the LCM sample exhibited the highest specific surface area of 38.79 m2 g−1. The charge transfer resistances of the LMO, LCM, and LSM are 0.48 Ω, 0.36 Ω, and 0.38 Ω, respectively. The LCM electrode exhibits the greatest capacitance performance due to its more refined morphology, increased concentration of oxygen vacancy, and more complete utilization of the perovskite bulk structure. The above results demonstrate that Ca or Sr substitution of A-site compounds has great potential for supercapacitor applications.
Measurement of Dilational Modulus of an Adsorbed BSA Film Using Pendant Bubble Tensiometry: From a Clean Interface to Saturation
Authors: Hussain Siam , Rivas Johann Eduardo Maradiaga , Tseng Wen-Chi , Tsay Ruey-Yug , Noskov Boris , Loglio Giuseppe , Lin Shi-Yow
Published: December 2023

Two open issues on the measurement of the dilational modulus (E) for an adsorbed protein film during the adsorption process have been unacknowledged: how E varies during the adsorption and the length of time needed to attain a stable E value. A new approach for detecting the E variation from a clean air–water interface to saturated film and estimating the time needed to reach a saturated state was proposed. A pendant bubble tensiometer was utilized for measuring the relaxations of surface tension (ST) and surface area (SA), and the E was evaluated from the relaxation data of minute distinct perturbances. The data showed a clear variation in E during the BSA adsorption: E sharply decreased to a minimum at the early stage of BSA adsorption; then, it rose from this minimum and oscillated for a while before reaching an E corresponding to a saturated BSA film after a significant duration. The adsorbed BSA film took ~35 h to reach its saturated state, which was much longer than the reported lifetime of the adsorbed film in the literature. A rapid surface perturbation (forced bubble expansion/compression) could change the E, causing a significant drop in E followed by a slow increase to the original stable value.
The Establishment and Verification of a Nomogram Model for Predicting the Overall Survival of Medullary Thyroid Carcinoma: An Analysis Based on the SEER Database
Authors: Wang Wankun , Wang Xujin , Che Gang , Qiao Jincheng , Chen Zhendong , Liu Jian
Published: December 2023

(1) Background: This study aimed to establish a nomogram model for predicting the overall survival (OS) of medullary thyroid carcinoma (MTC) patients based on the Surveillance, Epidemiology, and End Results (SEER) database. (2) Methods: Patients with MTC in the SEER database from 2004 to 2015 were included and divided into a modeling group and an internal validation group. We also selected MTC patients from our center from 2007 to 2019 to establish an external validation group. Univariate and multivariate Cox regression analyses were used to screen for significant independent variables and to establish a nomogram model. Kaplan–Meier (K-M) curves were plotted to evaluate the influence of the predictors. The C-indexes, areas under the curves (AUCs), and calibration curves were plotted to validate the predictive effect of the model. (3) Results: A total of 1981 MTC patients from the SEER database and 85 MTC patients from our center were included. The univariate and multivariate Cox regression analyses showed that age, tumor size, N stage, and M stage were significant factors, and a nomogram model was established. The C-index of the modeling group was 0.792, and the AUCs were 0.811, 0.825, and 0.824. The C-index of the internal validation group was 0.793, and the AUCs were 0.847, 0.846, and 0.796. The C-index of the external validation group was 0.871, and the AUCs were 0.911 and 0.827. The calibration curves indicated that the prediction ability was reliable. (4) Conclusions: A nomogram model based on age, tumor size, N stage, and M stage was able to predict the OS of MTC patients.
Novel Therapeutics in Ovarian Cancer: Expanding the Toolbox
Authors: Moufarrij Sara , O’Cearbhaill Roisin E.
Published: December 2023

Despite high response rates to initial therapy, most patients with ovarian cancer will ultimately recur and go on to develop resistance to standard treatments. Novel therapies have been developed to overcome drug resistance and alter the tumor immune microenvironment by targeting oncogenic pathways, activating the innate immune response, and enhancing drug delivery. In this review, we discuss the current and future roles of chemotherapy, targeted agents such as poly (ADP-ribose) polymerase (PARP) inhibitors, bevacizumab, and mirvetuximab in the treatment of ovarian cancer. We explore the emerging role of therapeutic targets, including DNA repair pathway inhibitors and novel antibody–drug conjugates. Furthermore, we delve into the role of immunotherapeutic agents such as interleukins as well as immune-promoting agents such as oncolytic viruses and cancer vaccines. Innovative combination therapies using these agents have led to a rapidly evolving treatment landscape and promising results for patients with recurrent ovarian cancer.
Comparison of Robotic and Open Lobectomy for Lung Cancer in Marginal Pulmonary Function Patients: A Single-Centre Retrospective Study
Authors: Zirafa Carmelina Cristina , Manfredini Beatrice , Romano Gaetano , Sicolo Elisa , Castaldi Andrea , Bagalà Elena , Morganti Riccardo , Cariello Claudia , Davini Federico , Melfi Franca
Published: December 2023

Background: The treatment of non-small-cell lung cancer (NSCLC) patients with reduced respiratory function represents a challenge for thoracic surgeons. Minimally invasive surgery seems to be beneficial for these patients because it reduces tissue trauma and its impact on respiratory mechanics. Application of the robotic technique, the use of CO2 insufflation and longer surgical time are factors that could influence the outcomes of marginal pulmonary function patients. The objective of this study was to evaluate the impact of the robotic technique on the postoperative outcomes of patients with poor lung function. Methods: We retrospectively collected and analyzed data from consecutive marginal respiratory function patients who underwent robotic or open lobectomy for NSCLC. Data regarding clinical, operative and postoperative details were compared between the open and robotic approaches. Results: The outcomes of 100 patients with reduced respiratory function were evaluated, of whom 59 underwent open lobectomies and 41 underwent robotic lobectomies. Robotic lobectomy was characterized by a longer operative time, a reduced hospital stay and a lower incidence of postoperative complications (22% vs. 33.9%), when compared to the open approach. Conclusion: Robotic lobectomy is a safe and feasible procedure for patients with marginal pulmonary function.
Potential of Machine Learning for Predicting Sleep Disorders: A Comprehensive Analysis of Regression and Classification Models
Authors: Alazaidah Raed , Samara Ghassan , Aljaidi Mohammad , Haj Qasem Mais , Alsarhan Ayoub , Alshammari Mohammed
Published: December 2023

Sleep disorder is a disease that can be categorized as both an emotional and physical problem. It imposes several difficulties and problems, such as distress during the day, sleep-wake disorders, anxiety, and several other problems. Hence, the main objective of this research was to utilize the strong capabilities of machine learning in the prediction of sleep disorders. In specific, this research aimed to meet three main objectives. These objectives were to identify the best regression model, the best classification model, and the best learning strategy that highly suited sleep disorder datasets. Considering two related datasets and several evaluation metrics that were related to the tasks of regression and classification, the results revealed the superiority of the MultilayerPerceptron, SMOreg, and KStar regression models compared with the other twenty three regression models. Furthermore, IBK, RandomForest, and RandomizableFilteredClassifier showed superior performance compared with other classification models that belonged to several learning strategies. Finally, the Function learning strategy showed the best predictive performance among the six considered strategies in both datasets and with respect to the most evaluation metrics.