bluuebunny/crossref_metadata_2025 huggingface dataset:
An Inverse Problem for the Subdiffusion Equation with a Non-Local in Time Condition
Authors: Ashurov Ravshan , Shakarova Marjona , Umarov Sabir
Published: June 2024

An inverse problem of determining the right-hand side of the abstract subdiffusion equation with a fractional Caputo derivative is considered in a Hilbert space H. For the forward problem, instead of the Cauchy condition, the non-local in time condition u(0)=u(T) is taken. The right-hand side of the equation has the form g(t)f with a given function g(t) and an unknown element f∈H. If the function g(t) preserves its sign, then under a over-determined condition u(t0)=ψ, t0∈(0,T), it is proved that the solution of the inverse problem exists and is unique. An example is given showing the violation of the uniqueness of the solution for some sign-changing functions g(t). For such functions g(t), under certain conditions on this function, one can achieve the well-posedness of the problem by choosing properly t0. Moreover, we show that for some g(t), for the existence of a solution to the inverse problem, certain orthogonality conditions must be satisfied, but in this case there is no uniqueness. To the best knowledge of authors, the inverse problem with the non-local condition u(0)=u(T) has been considered for the first time. Moreover, all the results obtained are new not only for the subdiffusion equation, but also for the classical diffusion equation.
Design of the Novel Fractional Order Hybrid Whale Optimizer for Thermal Wind Power Generation Systems with Integration of Chaos Infused Wind Power
Authors: Wadood Abdul , Sattar Khan Babar , Albalawi Hani , Alatwi Aadel Mohammed
Published: June 2024

This article introduces a novel optimization approach known as fractional order whale optimization algorithm (FWOA). The proposed optimizer incorporates the idea of fractional calculus (FC) into the mathematical structure of the conventional whale optimization algorithm (WOA). To validate the efficiency of the proposed FWOA, it is applied to address the challenges associated with the economic load dispatch (ELD) problem, which is a nonconvex, nonlinear, and non-smooth optimization problem. The objectives associated with ELD such as fuel cost and wind power generation cost minimization are achieved by taking into consideration different practical constraints like valve point loading effect (VPLE), transmission line losses, generator constraints, and stochastically variation of renewable energy sources (RES) integration. RES, particularly wind energy, has garnered more attention in recent times due to a range of environmental and economic factors. Stochastic wind (SW) power is also included in the ELD problem formulation. The incomplete gamma function (IGF) quantifies the influence of wind power. To assess its efficacy, the suggested approach is applied to a range of power systems including 3 generating units, 13 generating units and 40 generating units, consisting of 37 thermal units and 3 wind power units. To further strengthen the performance of the optimizer, the FWOA is hybridized with the interior point algorithm (IPA) to further refine the outcomes of the FWOA. The FWOA and IPA are used to address the problem of ELD while including the unpredictable nature of wind power. The simulation results of the suggested technique are compared with the most advanced heuristic optimization methods available, and it has been observed that the proposed optimizer obtained a superior and refined solution when compared to other state of the art optimization techniques. Furthermore, the efficacy of the suggested strategy in enhancing the solution of the ELD issue is validated through statistical analysis in terms of minimum fitness value.
Mapping of Supra-Glacial Debris Cover in the Greater Caucasus: A Semi-Automated Multi-Sensor Approach
Authors: Tielidze Levan G. , Iacob George , Holobâcă Iulian Horia
Published: June 2024

Supra-glacial debris cover is important for the control of surface ice melt and glacier retreat in mountain regions. Despite the progress in techniques based on various satellite imagery, the mapping of debris-covered glacier boundaries over large regions remains a challenging task. Previous studies of the debris-covered glaciers in the Greater Caucasus have only focused on limited areas. In this study, using the Sentinel 1–2 imagery (2020), DebCovG-carto toolbox, and existing glacier inventory (2020), we produced the first detailed assessment of supra-glacial debris cover for individual glaciers in the entire Greater Caucasus. Our study shows that in 2020, 10.3 ± 5.6% of the glacier surface in this mountain region was covered by debris. A comparison of sub-regions such as the Elbrus Massif and other individual glaciers from the central Greater Caucasus shows an increasing trend of supra-glacial debris cover from 2014 to 2020. The total area of supra-glacial debris cover expanded from ~4.6% to ~5.8% for Elbrus and from ~9.5% to ~13.9% for the glaciers of the central Greater Caucasus during the same period. Supra-glacial debris cover also expanded upward on these glaciers between 2014 and 2020. A recent increase in rock-ice avalanche activity in combination with increased air temperature and decreased precipitation in the Greater Caucasus may be responsible for this upward migration and expanded area of supra-glacial debris cover. This study provides valuable insights into the spatial distribution, temporal evolution, and factors influencing supra-glacial debris cover in the Greater Caucasus. The findings contribute to our understanding of glacier dynamics and highlight the importance of continuous monitoring and assessment of supra-glacial debris cover in the context of climate change and glacier retreat. We recommend using the DebCovG-carto toolbox for regional assessment of supra-glacial debris coverage in other mountain regions as well.
Brassinolide Alleviates Chilling Injury of Sweet Cherry (Prunus avium L. cv. Tieton) during Cold Storage
Authors: Zhu Yixing , Zhang Shuang , Niu Chenyu , Chen Haobin , Zhu Fangyu , Farouk Amr , Lu Jiancai , Chen Cunkun , Ban Zhaojun , Huang Jun
Published: June 2024

Brassinolide (BR) is a natural plant hormone that enhances stress resistance, preserving the freshness and quality of postharvest fruits. This study investigated the effects of exogenous BR on chilling injury, physiological characteristics, and antioxidant capacity in sweet cherries (Prunus avium L. cv. Tieton) during cold storage. Cherries were treated with distilled water (Control, CK), 2 μmol·L−1 BR (CL1), and 10 μmol·L−1 BR (CL2) for 30 min, then stored at 2 ± 1 °C for 28 d. Sampling occurred every 7 d to assess BR’s impact. BR treatment significantly reduced the chilling injury index (28 d values: CK 39.56%, CL1 14.22%, CL2 21.33%) and weight loss index (28 d values: CK 4.07%, CL1 1.00%, CL2 1.77%), and delayed the decline in fruit firmness and quality. Additionally, BR increased the sugar acid ratio, vitamin C, total phenolic, and flavonoid contents while reducing superoxide anion (O2−) and hydrogen peroxide (H2O2) accumulation. Notably, BR significantly lowered polyphenol oxidase (PPO) and peroxidase (POD) activities, with CL1 showing superior efficacy. The findings indicate that BR application can potentially reduce postharvest chilling injury in sweet cherries and maintain their quality after harvest, providing a theoretical basis for its application in sweet cherry storage and preservation.
Evaluation of Resilience and Mental Health in the “Post-Pandemic Era” among University Students: Protocol for a Mixed-Methods Study
Authors: Magorokosho Natasja Kudzai , Heraclides Alexandros , Papaleontiou-Louca Eleonora , Prodromou Maria
Published: June 2024

Background: The mental well-being of university students has been a growing concern in Public Health and has been exacerbated by the COVID-19 pandemic. The pandemic (including the post-pandemic era) introduced and exacerbated a variety of potential stressors for vulnerable individuals and communities, resulting in an increase in mental health issues among university students. Resilience, as a process, is the ability of a system to adapt and grow in the face of adversity. This is a crucial aspect to consider when examining the coping of university students in critical situations such as COVID-19. Objective: This study aims to assess the association between resilience and mental health outcomes among university students in Cyprus during the post-COVID-19 pandemic era. Methods: A parallel embedded mixed methods research design will be utilized to assess resilience, measured by the Conner–Davidson Resilience Scale (CD-RISC), the COVID-19 Impact Scale (CIS) and mental health outcomes measured by the Symptom Checklist 90-Revised (SCL 90-R), during the COVID-19 post-pandemic era (January 2022–July 2024) among university students in the Republic of Cyprus. The study will be conducted in two stages: a pilot study followed by the main study. Quantitative data will be collected through a web-based survey, while qualitative data will be obtained through in-person focus groups designed to capture participants’ experiences. Participants will be recruited using a proportional quota sampling approach to achieve representativeness based on predefined demographics. The study protocol has been approved by the Cyprus Bioethics Committee (approval no: EEC/EP/2023/31). Discussion: This study is expected to broaden our understanding of the intricate interactions between the COVID-19 pandemic’s impact, resilience, and mental health outcomes. The focus on university students’ psychological wellbeing is consistent with the call by the WHO to focus on mental health (World Health Organization, 2019).
Climate Change and Psychiatry: The Correlation between the Mean Monthly Temperature and Admissions to an Acute Inpatient Unit
Authors: Rizzo Pesci Nicola , Teobaldi Elena , Maina Giuseppe , Rosso Gianluca
Published: June 2024

Background: Psychiatric disorders are large contributors to the global disease burden, but research on the impact of climate change on them is limited. Our aim is to investigate the correlation between temperature and exacerbations of psychiatric disorders to help inform clinical management and future public health policies. Methods: Temperature records for the summer months from 2013 to 2022 were obtained from the meteorological station of the Department of Physics of Turin University. Data on patients admitted to the acute psychiatric unit were extracted from registries of San Luigi Gonzaga University Hospital (Turin, Italy). Regression analyses were used to investigate the correlation between temperature and number of admissions and to test for confounding variables. Results: A total of 1600 admissions were recorded. The monthly temperature and number of admissions were directly correlated (p = 0.0020). The correlation was significant for the subgroup of admissions due to Bipolar Disorders (p = 0.0011), but not for schizophrenia or major depressive disorder. After multiple regression analyses, the effect of temperature remained significant (p = 0.0406). Conclusions: These results confirm the impact of meteorological factors on mental disorders, particularly on BD. This can contribute to personalised follow-up and efficient resource allocation and poses grounds for studies into etiopathological mechanisms and therapeutic implications.
How Can Transitional Housing Be Improved? Insights from Residents’ Experiences and Perceptions in New York City
Authors: Jouzi Zeynab , San Diego Lauren , Lewis Neil A. , Leak Tashara M.
Published: June 2024

Homelessness, affecting over half a million Americans, significantly elevates the risks of mental and physical health issues, consequently diminishing life expectancy when compared with the general population. Homelessness is a critical public health issue, and efforts are needed to address lack of housing as a social determinant of health. Transitional housing (TH) programs emerge as vital interventions, offering a place to stay with various support services to facilitate the transition to permanent residency. Nearly half of the unhoused population in the country and over 90% in New York live in TH or shelters. Despite the high utilization rates of TH, engagement with support services and opportunities for improvement remain poorly understood. This study aimed to fill this gap by examining the factors influencing support service usage and opportunities for enhancement through semi-structured interviews with TH residents in New York City to capture their lived experiences and perspectives. Analysis of the interviews (n = 20) revealed five main factors affecting service engagement that aligned with constructs of the socioecological model: intrapersonal (self-efficacy, chronic health conditions, mental health), interpersonal (parenthood and well-being of children with special needs, individual staff interactions, and communication), institutional (bureaucratic challenges, administrative burden, and living facilities), community (social isolation and educational opportunity), and policy (challenge meeting basic needs and undocumented status). Recommendations for bridging service gaps primarily arose at the institutional and community levels, offering critical insights for administrators to tailor services more effectively to TH residents’ needs, thus contributing to the broader goal of advancing health equity among the unhoused.
A Review of Data Mining Strategies by Data Type, with a Focus on Construction Processes and Health and Safety Management
Authors: Pireddu Antonella , Bedini Angelico , Lombardi Mara , Ciribini Angelo L. C. , Berardi Davide
Published: June 2024

Increasingly, information technology facilitates the storage and management of data useful for risk analysis and event prediction. Studies on data extraction related to occupational health and safety are increasingly available; however, due to its variability, the construction sector warrants special attention. This review is conducted under the research programs of the National Institute for Occupational Accident Insurance (Inail). Objectives: The research question focuses on identifying which data mining (DM) methods, among supervised, unsupervised, and others, are most appropriate for certain investigation objectives, types, and sources of data, as defined by the authors. Methods: Scopus and ProQuest were the main sources from which we extracted studies in the field of construction, published between 2014 and 2023. The eligibility criteria applied in the selection of studies were based on the Preferred Reporting Items for Systematic Review and Meta-Analyses (PRISMA). For exploratory purposes, we applied hierarchical clustering, while for in-depth analysis, we used principal component analysis (PCA) and meta-analysis. Results: The search strategy based on the PRISMA eligibility criteria provided us with 63 out of 2234 potential articles, 206 observations, 89 methodologies, 4 survey purposes, 3 data sources, 7 data types, and 3 resource types. Cluster analysis and PCA organized the information included in the paper dataset into two dimensions and labels: “supervised methods, institutional dataset, and predictive and classificatory purposes” (correlation 0.97–8.18 × 10−1; p-value 7.67 × 10−55–1.28 × 10−22) and the second, Dim2 “not-supervised methods; project, simulation, literature, text data; monitoring, decision-making processes; machinery and environment” (corr. 0.84–0.47; p-value 5.79 × 10−25–-3.59 × 10−6). We answered the research question regarding which method, among supervised, unsupervised, or other, is most suitable for application to data in the construction industry. Conclusions: The meta-analysis provided an overall estimate of the better effectiveness of supervised methods (Odds Ratio = 0.71, Confidence Interval 0.53–0.96) compared to not-supervised methods.
Transporter Proteins as Therapeutic Drug Targets—With a Focus on SGLT2 Inhibitors
Authors: Komaniecka Nina , Maroszek Sonia , Drozdzik Maria , Oswald Stefan , Drozdzik Marek
Published: June 2024

Membrane transporters interact not only with endogenous substrates but are also engaged in the transport of xenobiotics, including drugs. While the coordinated function of uptake (solute carrier family—SLC and SLCO) and efflux (ATP-binding cassette family—ABC, multidrug and toxic compound extrusion family—MATE) transporter system allows vectorial drug transport, efflux carriers alone achieve barrier functions. The modulation of transport functions was proved to be effective in the treatment strategies of various pathological states. Sodium–glucose cotransporter-2 (SGLT2) inhibitors are the drugs most widely applied in clinical practice, especially in the treatment of diabetes mellitus and heart failure. Sodium taurocholate co-transporting polypeptide (NTCP) serves as virus particles (HBV/HDV) carrier, and inhibition of its function is applied in the treatment of hepatitis B and hepatitis D by myrcludex B. Inherited cholestatic diseases, such as Alagille syndrome (ALGS) and progressive familial intrahepatic cholestasis (PFIC) can be treated by odevixibat and maralixibat, which inhibit activity of apical sodium-dependent bile salt transporter (ASBT). Probenecid can be considered to increase uric acid excretion in the urine mainly via the inhibition of urate transporter 1 (URAT1), and due to pharmacokinetic interactions involving organic anion transporters 1 and 3 (OAT1 and OAT3), it modifies renal excretion of penicillins or ciprofloxacin as well as nephrotoxicity of cidofovir. This review discusses clinically approved drugs that affect membrane/drug transporter function.
Natural Guardians: Natural Compounds as Radioprotectors in Cancer Therapy
Authors: Stasiłowicz-Krzemień Anna , Gościniak Anna , Formanowicz Dorota , Cielecka-Piontek Judyta
Published: June 2024

Cancer remains a significant global health challenge, with millions of deaths attributed to it annually. Radiotherapy, a cornerstone in cancer treatment, aims to destroy cancer cells while minimizing harm to healthy tissues. However, the harmful effects of irradiation on normal cells present a formidable obstacle. To mitigate these effects, researchers have explored using radioprotectors and mitigators, including natural compounds derived from secondary plant metabolites. This review outlines the diverse classes of natural compounds, elucidating their roles as protectants of healthy cells. Furthermore, the review highlights the potential of these compounds as radioprotective agents capable of enhancing the body’s resilience to radiation therapy. By integrating natural radioprotectors into cancer treatment regimens, clinicians may improve therapeutic outcomes while minimizing the adverse effects on healthy tissues. Ongoing research in this area holds promise for developing complementary strategies to optimize radiotherapy efficacy and enhance patient quality of life.
Benefits of NGS in Advanced Lung Adenocarcinoma Vary by Populations and Timing of Examination
Authors: Lee Po-Hsin , Ou Wei-Fan , Huang Yen-Hsiang , Hsu Kuo-Hsuan , Tseng Jeng-Sen , Chang Gee-Chen , Yang Tsung-Ying
Published: June 2024

Despite the widespread application of next-generation sequencing (NGS) in advanced lung adenocarcinoma, its impact on survival and the optimal timing for the examination remain uncertain. This cohort study included advanced lung adenocarcinoma patients who underwent NGS testing. We categorized patients into four groups: Group 1: treatment-naïve, upfront NGS; Group 2: Treatment-naïve, exclusionary EGFR/ALK/ROS1; Group 3: post-treatment, no known EGFR/ALK/ROS1; Group 4: known driver mutation and post-TKI treatment. A total of 424 patients were included. There were 128, 126, 90, and 80 patients in Groups 1, 2, 3, and 4, respectively. In Groups 1, 2, 3, and 4, targetable mutations were identified in 76.6%, 49.2%, 41.1%, and 33.3% of the patients, respectively (p < 0.001). Mutation-targeted treatments were applied in 68.0%, 15.1%, 27.8%, and 22.5% of the patients, respectively (p < 0.001). In the overall population, patients receiving mutation-targeted treatments exhibited significantly longer overall survival (OS) (aHR 0.54 [95% CI 0.37–0.79], p = 0.001). The most profound benefit was seen in the Group 1 patients (not reached vs. 40.4 months, p = 0.028). The median OS of patients with mutation-targeted treatments was also significantly longer among Group 2 patients. The median post-NGS survival of patients receiving mutation-targeted treatments was numerically longer in Group 3 and Group 4 patients. In conclusion, mutation-targeted therapy is associated with a favorable outcome. However, the opportunities of NGS-directed treatment and the survival benefits of mutation-targeted treatment were various among different populations.
Synthesis and Characterization of Vanadium Nitride/Carbon Nanocomposites
Authors: Morales Helia Magali , Vieyra Horacio , Sanchez David A. , Fletes Elizabeth M. , Odlyzko Michael , Lodge Timothy P. , Padilla-Gainza Victoria , Alcoutlabi Mataz , Parsons Jason G.
Published: June 2024

The present work focuses on the synthesis of a vanadium nitride (VN)/carbon nanocomposite material via the thermal decomposition of vanadyl phthalocyanine (VOPC). The morphology and chemical structure of the synthesized compounds were characterized using scanning electron microscopy (SEM), transmission electron microscopy (TEM), energy dispersive spectroscopy (EDS), Fourier transformed infrared spectroscopy (FTIR), X-ray diffraction (XRD), and X-ray photoemission spectroscopy (XPS). The successful syntheses of the VOPC and non-metalated phthalocyanine (H2PC) precursors were confirmed using FTIR and XRD. The VN particles present a needle-like morphology in the VN synthesized by the sol-gel method. The morphology of the VN/C composite material exhibited small clusters of VN particles. The XRD analysis of the thermally decomposed VOPC indicated a mixture of amorphous carbon and VN nanoparticles (VN(TD)) with a cubic structure in the space group FM-3M consistent with that of VN. The XPS results confirmed the presence of V(III)-N bonds in the resultant material, indicating the formation of a VN/C nanocomposite. The VN/C nanocomposite synthesized through thermal decomposition exhibited a high carbon content and a cluster-like distribution of VN particles. The VN/C nanocomposite was used as an anode material in LIBs, which delivered a specific capacity of 307 mAh g−1 after 100 cycles and an excellent Coulombic efficiency of 99.8 at the 100th cycle.
Combined Application of Cold Physical Plasma and Chemotherapeutics against Chondrosarcoma Cells
Authors: Nitsch Andreas , Qarqash Sara , Schulze Frank , Nonnenmacher Lars , Bekeschus Sander , Tzvetkov Mladen V. , Wassilew Georgi I. , Haralambiev Lyubomir
Published: June 2024

Chondrosarcoma (CS) is a rare malignant bone sarcoma that primarily affects cartilage cells in the femur and pelvis. While most subtypes exhibit slow growth with a very good prognosis, some aggressive subtypes have a poorer overall survival. CS is known for its resistance to chemotherapy and radiotherapy, leaving surgery as the sole effective therapeutic option. Cold physical plasma (CPP) has been explored in vitro as a potential therapy, demonstrating positive anti-tumor effects on CS cells. This study investigated the synergistic effects of combining CPP with cytostatics on CS cells. The chemotherapeutic agents cisplatin, doxorubicin, and vincristine were applied to two CS cell lines (CAL-78 and SW1353). After determining their IC20 and IC50, they were combined with CPP in both cell lines to assess their impact on the cell proliferation, viability, metabolism, and apoptosis. This combined approach significantly reduced the cell proliferation and viability while increasing the apoptosis signals compared to cytostatic therapy alone. The combination of CPP and chemotherapeutic drugs shows promise in targeting chemoresistant CS cells, potentially improving the prognosis for patients in clinical settings.
A Review of the Molecular Determinants of Therapeutic Response in Non-Small Cell Lung Cancer Brain Metastases
Authors: Boldig Catherine , Boldig Kimberly , Mokhtari Sepideh , Etame Arnold B.
Published: June 2024

Lung cancer is a leading cause of cancer-related morbidity and mortality worldwide. Metastases in the brain are a common hallmark of advanced stages of the disease, contributing to a dismal prognosis. Lung cancer can be broadly classified as either small cell lung cancer (SCLC) or non-small cell lung cancer (NSCLC). NSCLC represents the most predominant histology subtype of lung cancer, accounting for the majority of lung cancer cases. Recent advances in molecular genetics, coupled with innovations in small molecule drug discovery strategies, have facilitated both the molecular classification and precision targeting of NSCLC based on oncogenic driver mutations. Furthermore, these precision-based strategies have demonstrable efficacy across the blood–brain barrier, leading to positive outcomes in patients with brain metastases. This review provides an overview of the clinical features of lung cancer brain metastases, as well as the molecular mechanisms that drive NSCLC oncogenesis. We also explore how precision medicine-based strategies can be leveraged to improve NSCLC brain metastases.
The Total Denervation of the Ischemic Kidney Induces Differential Responses in Sodium Transporters’ Expression in the Contralateral Kidney in Goldblatt Rats
Authors: Shimoura Caroline G. , Oliveira Tales L. , Lincevicius Gisele S. , Crajoinas Renato O. , Oliveira-Sales Elizabeth B. , Varela Vanessa A. , Gomes Guiomar N. , Bergamaschi Cassia T. , Campos Ruy R.
Published: June 2024

The Goldblatt model of hypertension (2K-1C) in rats is characterized by renal sympathetic nerve activity (rSNA). We investigated the effects of unilateral renal denervation of the clipped kidney (DNX) on sodium transporters of the unclipped kidneys and the cardiovascular, autonomic, and renal functions in 2K-1C and control (CTR) rats. The mean arterial pressure (MAP) and rSNA were evaluated in experimental groups. Kidney function and NHE3, NCC, ENaCβ, and ENaCγ protein expressions were assessed. The glomerular filtration rate (GRF) and renal plasma flow were not changed by DNX, but the urinary (CTR: 0.0042 ± 0.001; 2K-1C: 0.014 ± 0.003; DNX: 0.005 ± 0.0013 mL/min/g renal tissue) and filtration fractions (CTR: 0.29 ± 0.02; 2K-1C: 0.51 ± 0.06; DNX: 0.28 ± 0.04 mL/min/g renal tissue) were normalized. The Na+/H+ exchanger (NHE3) was reduced in 2K-1C, and DNX normalized NHE3 (CTR: 100 ± 6; 2K-1C: 44 ± 14, DNX: 84 ± 13%). Conversely, the Na+/Cl− cotransporter (NCC) was increased in 2K-1C and was reduced by DNX (CTR: 94 ± 6; 2K-1C: 144 ± 8; DNX: 60 ± 15%). In conclusion, DNX in Goldblatt rats reduced blood pressure and proteinuria independently of GRF with a distinct regulation of NHE3 and NCC in unclipped kidneys.
The Human Neonatal Skin Fibroblast, an Available Cell Source for Tissue Production and Transplantation, Exhibits Low Risk of Immunogenicity In Vitro
Authors: Magne Brice , Ferland Karel , Savard Étienne , Barbier Martin A. , Morissette Amélie , Larouche Danielle , Beaudoin-Cloutier Chanel , Germain Lucie
Published: June 2024

The immunogenicity of allogeneic skin fibroblasts in transplantation has been controversial. Whether this controversy comes from a natural heterogeneity among fibroblast subsets or species-specific differences between human and mouse remains to be addressed. In this study, we sought to investigate whether fibroblasts derived from either adult or neonatal human skin tissues could induce different immune responses toward phagocytosis and T cell activation using in vitro co-culture models. Our results indicate that both phagocytosis and T cell proliferation are reduced in the presence of neonatal skin fibroblasts compared to adult skin fibroblasts. We also show that neonatal skin fibroblasts secrete paracrine factors that are responsible for reduced T cell proliferation. In addition, we show that neonatal skin fibroblasts express less class II human leukocyte antigen (HLA) molecules than adult skin fibroblasts after interferon gamma priming, which might also contribute to reduced T cell proliferation. In conclusion, this study supports the use of allogeneic neonatal skin fibroblasts as a readily available cell source for tissue production and transplantation to treat patients with severe injuries.
Current and Emerging Treatment Paradigms in Colorectal Cancer: Integrating Hallmarks of Cancer
Authors: Salva de Torres Clara , Baraibar Iosune , Saoudi González Nadia , Ros Javier , Salva Francesc , Rodríguez-Castells Marta , Alcaraz Adriana , García Ariadna , Tabernero Josep , Élez Elena
Published: June 2024

The treatment of unresectable metastatic colorectal cancer has evolved over the last two decades, as knowledge of cancer biology has broadened and new targets have emerged. ‘The Hallmarks of Cancer’ illustrate the crucial capabilities acquired by cells to become malignant and represent the evolution of knowledge of tumor biology. This review integrates these novel targets and therapies into selected hallmarks: sustaining proliferative signaling, inducing vasculature, avoiding immune destruction, genome instability and mutation, reprogramming cellular metabolism, and resisting cell death. The different strategies and combinations under study are based on treatments with anti-EGFR, anti-VEGF, and anti-HER2 agents, KRAS G12C inhibitors, BRAF and MEK inhibitors, and immune checkpoint inhibitors. However, new approaches are emerging, including vaccines, WEE1 inhibitors, and PARP inhibitors, among others. The further deciphering of cancer biology will unravel new targets, develop novel therapies, and improve patients’ outcomes.
GmANKTM21 Positively Regulates Drought Tolerance and Enhanced Stomatal Response through the MAPK Signaling Pathway in Soybean
Authors: Zhao Yue , Wang Sinan , Ma Xiaofei , He Yu , Zhou Jingwen , Jiao Shuang , Xun Jianing , Kong Xiaoyu , Wu Xiaoxia , Bai Xi
Published: June 2024

Drought stress is one of the significant abiotic stresses that limit soybean (Glycine max [L.] Merr.) growth and production. Ankyrin repeat (ANK) proteins, being highly conserved, occupy a pivotal role in diverse biological processes. ANK genes were classified into nine subfamilies according to conserved domains in the soybean genome. However, the function of ANK-TM subfamily proteins (Ankyrin repeat proteins with a transmembrane domain) in the abiotic-stress response to soybean remains poorly understood. In this study, we first demonstrated the subcellular localization of GmANKTM21 in the cell membrane and nucleus. Drought stress-induced mRNA levels of GmANKTM21, which encodes proteins belonging to the ANK-TM subfamily, Transgenic 35S:GmANKTM21 soybean improved drought tolerance at the germination and seedling stages, with higher stomatal closure in soybean, lower water loss, lower malondialdehyde (MDA) content, and less reactive oxygen species (ROS) production compared with the wild-type soybean (Dongnong50). RNA-sequencing (RNA-seq) and RT-qPCR analysis of differentially expressed transcripts in overexpression of GmANKTM21 further identified potential downstream genes, including GmSPK2, GmSPK4, and GmCYP707A1, which showed higher expression in transgenic soybean, than those in wild-type soybean and KEGG enrichment analysis showed that MAPK signaling pathways were mostly enriched in GmANKTM21 overexpressing soybean plants under drought stress conditions. Therefore, we demonstrate that GmANKTM21 plays an important role in tolerance to drought stress in soybeans.
The White Clover TrMYB33-TrSAMS1 Module Contributes to Drought Tolerance by Modulation of Spermidine Biosynthesis via an ABA-Dependent Pathway
Authors: Zhang Youzhi , Qin Xiaofang , He Zhirui , Zhang Yan , Li Zhou , Nie Gang , Zhao Junming , Feng Guangyan , Peng Yan
Published: June 2024

Spermidine is well known to accumulate in plants exposed to drought, but the regulatory network associated with its biosynthesis and accumulation and the underlying molecular mechanisms remain unclear. Here, we demonstrated that the Trifolium repens TrMYB33 relayed the ABA signal to modulate drought-induced spermidine production by directly regulating the expression of TrSAMS1, which encodes an S-adenosylmethionine synthase. This gene was identified by transcriptome and expression analysis in T. repens. TrSAMS1 overexpression and its pTRV-VIGS-mediated silencing demonstrated that TrSAMS1 is a positive regulator of spermidine synthesis and drought tolerance. TrMYB33 was identified as an interacting candidate through yeast one-hybrid library screening with the TrSAMS1 promoter region as the bait. TrMYB33 was confirmed to bind directly to the predicted TAACCACTAACCA (the TAACCA MYB binding site is repeated twice in tandem) within the TrSAMS1 promoter and to act as a transcriptional activator. Additionally, TrMYB33 contributed to drought tolerance by regulating TrSAMS1 expression and modulating spermidine synthesis. Additionally, we found that spermidine accumulation under drought stress depended on ABA and that TrMYB33 coordinated ABA-mediated upregulation of TrSAMS1 and spermidine accumulation. This study elucidated the role of a T. repens MYB33 homolog in modulating spermidine biosynthesis. The further exploitation and functional characterization of the TrMYB33–TrSAMS1 regulatory module can enhance our understanding of the molecular mechanisms responsible for spermidine accumulation during drought stress.
Systemic Pharmacotherapeutic Treatment of the ACTA1-MCM/FLExDUX4 Preclinical Mouse Model of FSHD
Authors: Lu-Nguyen Ngoc , Snowden Stuart , Popplewell Linda , Malerba Alberto
Published: June 2024

Aberrant expression of the double homeobox 4 (DUX4) gene in skeletal muscle predominantly drives the pathogenesis of facioscapulohumeral muscular dystrophy (FSHD). We recently demonstrated that berberine, an herbal extract known for its ability to stabilize guanine–quadruplex structures, effectively downregulates DUX4 expression in FSHD patient-derived myoblasts and in mice overexpressing exogenous DUX4 after viral vector-based treatment. Here, we sought to confirm berberine’s inhibitory efficacy on DUX4 in the widely used FSHD-like transgenic mouse model, ACTA1-MCM/FLExDUX4, where DUX4 is induced at pathogenic levels using tamoxifen. Animals repeatedly treated with berberine via intraperitoneal injections for 4 weeks exhibited significant reductions in both mRNA and protein levels of DUX4, and in mRNA expression of murine DUX4-related genes. This inhibition translated into improved forelimb muscle strength and positive alterations in important FSHD-relevant cellular pathways, although its impact on muscle mass and histopathology was less pronounced. Collectively, our data confirm the efficacy of berberine in downregulating DUX4 expression in the most relevant FSHD mouse model. However, further optimization of dosing regimens and new studies to enhance the bioavailability of berberine in skeletal muscle are warranted to fully leverage its therapeutic potential for FSHD treatment.
PEGylated Micro/Nanoparticles Based on Biodegradable Poly(Ester Amides): Preparation and Study of the Core–Shell Structure by Synchrotron Radiation-Based FTIR Microspectroscopy and Electron Microscopy
Authors: Makharadze Davit , Kantaria Temur , Yousef Ibraheem , del Valle Luis J. , Katsarava Ramaz , Puiggalí Jordi
Published: June 2024

Surface modification of drug-loaded particles with polyethylene glycol (PEG) chains is a powerful tool that promotes better transport of therapeutic agents, provides stability, and avoids their detection by the immune system. In this study, we used a new approach to synthesize a biodegradable poly(ester amide) (PEA) and PEGylating surfactant. These were employed to fabricate micro/nanoparticles with a core–shell structure. Nanoparticle (NP)-protein interactions and self-assembling were subsequently studied by synchrotron radiation-based FTIR microspectroscopy (SR-FTIRM) and transmission electron microscopy (TEM) techniques. The core–shell structure was identified using IR absorption bands of characteristic chemical groups. Specifically, the stretching absorption band of the secondary amino group (3300 cm−1) allowed us to identify the poly(ester amide) core, while the band at 1105 cm−1 (C-O-C vibration) was useful to demonstrate the shell structure based on PEG chains. By integration of absorption bands, a 2D intensity map of the particle was built to show a core–shell structure, which was further supported by TEM images.
Pexidartinib and Immune Checkpoint Inhibitors Combine to Activate Tumor Immunity in a Murine Colorectal Cancer Model by Depleting M2 Macrophages Differentiated by Cancer-Associated Fibroblasts
Authors: Shimizu Daisuke , Yuge Ryo , Kitadai Yuki , Ariyoshi Misa , Miyamoto Ryo , Hiyama Yuichi , Takigawa Hidehiko , Urabe Yuji , Oka Shiro
Published: June 2024

Tumor-associated macrophages (TAMs) and cancer-associated fibroblasts (CAFs) are known to play supportive roles in tumor development and progression, but their interactions in colorectal cancer (CRC) remain unclear. Here, we investigated the effects of colon-cancer-derived CAFs on TAM differentiation, migration, and tumor immunity, both in vitro and in vivo. When co-cultured with monocytes, CAFs attracted monocytes and induced their differentiation into M2 macrophages. Immunohistology of surgically resected human CRC specimens and orthotopically transplanted mouse tumors revealed a correlation between numbers of CAFs and numbers of M2 macrophages. In a mouse model of CRC orthotopic transplantation, treatment with an inhibitor of the colony-stimulating factor-1 receptor (PLX3397) depleted M2 macrophages and increased CD8-positive T cells infiltrating the tumor nest. While this treatment had a minor effect on tumor growth, combining PLX3397 with anti-PD-1 antibody significantly reduced tumor growth. RNA-seq following combination therapy showed activation of tumor immunity. In summary, CAFs are involved in the induction and mobilization of M2 macrophage differentiation in the CRC tumor immune microenvironment, and the combination of cancer immunotherapy and PLX3397 may represent a novel therapeutic option for CRC.
Pentagalloyl Glucose (PGG) Exhibits Anti-Cancer Activity against Aggressive Prostate Cancer by Modulating the ROR1 Mediated AKT-GSK3β Pathway
Authors: Sivaganesh Vignesh , Ta Tram M. , Peethambaran Bela
Published: June 2024

Androgen-receptor-negative, androgen-independent (ARneg-AI) prostate cancer aggressively proliferates and metastasizes, which makes treatment difficult. Hence, it is necessary to continue exploring cancer-associated markers, such as oncofetal Receptor Tyrosine Kinase like Orphan Receptor 1 (ROR1), which may serve as a form of targeted prostate cancer therapy. In this study, we identify that Penta-O-galloyl-β-D-glucose (PGG), a plant-derived gallotannin small molecule inhibitor, modulates ROR1-mediated oncogenic signaling and mitigates prostate cancer phenotypes. Results indicate that ROR1 protein levels were elevated in the highly aggressive ARneg-AI PC3 cancer cell line. PGG was selectively cytotoxic to PC3 cells and induced apoptosis of PC3 (IC50 of 31.64 µM) in comparison to normal prostate epithelial RWPE-1 cells (IC50 of 74.55 µM). PGG was found to suppress ROR1 and downstream oncogenic pathways in PC3 cells. These molecular phenomena were corroborated by reduced migration, invasion, and cell cycle progression of PC3 cells. PGG minimally and moderately affected RWPE-1 and ARneg-AI DU145, respectively, which may be due to these cells having lower levels of ROR1 expression in comparison to PC3 cells. Additionally, PGG acted synergistically with the standard chemotherapeutic agent docetaxel to lower the IC50 of both compounds about five-fold (combination index = 0.402) in PC3 cells. These results suggest that ROR1 is a key oncogenic driver and a promising target in aggressive prostate cancers that lack a targetable androgen receptor. Furthermore, PGG may be a selective and potent anti-cancer agent capable of treating ROR1-expressing prostate cancers.
The Role of Aging and Senescence in Immune Checkpoint Inhibitor Response and Toxicity
Authors: Jain Sidharth S. , Burton Sojo Giselle , Sun Harry , Friedland Benjamin N. , McNamara Megan E. , Schmidt Marcel O. , Wellstein Anton
Published: June 2024

Cellular senescence accumulates with age and has been shown to impact numerous physiological and pathological processes, including immune function. The role of cellular senescence in cancer is multifaceted, but the impact on immune checkpoint inhibitor response and toxicity has not been fully evaluated. In this review, we evaluate the impact of cellular senescence in various biological compartments, including the tumor, the tumor microenvironment, and the immune system, on immune checkpoint inhibitor efficacy and toxicity. We provide an overview of the impact of cellular senescence in normal and pathological contexts and examine recent studies that have connected aging and cellular senescence to immune checkpoint inhibitor treatment in both the pre-clinical and clinical contexts. Overall, senescence plays a multi-faceted, context-specific role and has been shown to modulate immune-related adverse event incidence as well as immune checkpoint inhibitor response.
Single-Cell RNA Sequencing Reveals the Spatial Heterogeneity and Functional Alteration of Endothelial Cells in Chronic Hepatitis B Infection
Authors: Shi Jingqi , Li Qingyu , Li Jian , Zhou Jianglin , Zhang Xiaochang , Wang Shengqi , Guo Liang
Published: June 2024

Chronic Hepatitis B virus (CHB) infection is a global health challenge, causing damage ranging from hepatitis to cirrhosis and hepatocellular carcinoma. In our study, single-cell RNA sequencing (scRNA-seq) analysis was performed in livers from mice models with chronic inflammation induced by CHB infection and we found that endothelial cells (ECs) exhibited the largest number of differentially expressed genes (DEGs) among all ten cell types. NF-κB signaling was activated in ECs to induce cell dysfunction and subsequent hepatic inflammation, which might be mediated by the interaction of macrophage-derived and cholangiocyte-derived VISFATIN/Nampt signaling. Moreover, we divided ECs into three subclusters, including periportal ECs (EC_Z1), midzonal ECs (EC_Z2), and pericentral ECs (EC_Z3) according to hepatic zonation. Functional analysis suggested that pericentral ECs and midzonal ECs, instead of periportal ECs, were more vulnerable to HBV infection, as the VISFATIN/Nampt- NF-κB axis was mainly altered in these two subpopulations. Interestingly, pericentral ECs showed increasing communication with macrophages and cholangiocytes via the Nampt-Insr and Nampt-Itga5/Itgb1 axis upon CHB infection, which contribute to angiogenesis and vascular capillarization. Additionally, ECs, especially pericentral ECs, showed a close connection with nature killer (NK) cells and T cells via the Cxcl6-Cxcr6 axis, which is involved in shaping the microenvironment in CHB mice livers. Thus, our study described the heterogeneity and functional alterations of three subclusters in ECs. We revealed the potential role of VISFATIN/Nampt signaling in modulating ECs characteristics and related hepatic inflammation, and EC-derived chemokine Cxcl16 in shaping NK and T cell recruitment, providing key insights into the multifunctionality of ECs in CHB-associated pathologies.
The Role of Tubulin Polymerization-Promoting Protein2 (TPPP2) in Spermatogenesis: A Narrative Review
Authors: Orosz Ferenc
Published: June 2024

Tubulin polymerization-promoting protein2 (TPPP2) is one of the three paralogs of mammalian TPPP proteins. Its possible role in spermatogenesis is described in this narrative review. TPPP2 is expressed specifically in the male reproductive system, mainly in testes and sperm, and also in the epididymis. In testes, TPPP2 is exclusively expressed in elongating spermatids; in the epididymis, it is located in the middle piece of the sperm tail. TPPP2 is involved in spermiogenesis, in steps which are determinative for the formation and morphology of spermatids. The inhibition of TPPP2 decreases sperm motility (the curvilinear velocity of sperms), probably due to influencing mitochondrial energy production since TPPP2 knockout mice possess an impaired mitochondrial structure. There are data on the role of TPPP2 in various mammalian species: human, mouse, swine, and various ruminants; there is a significant homology among TPPP2s from different species. Experiments with Tppp2−/−-mice show that the absence of TPPP2 results in decreased sperm count and serious dysfunction of sperm, including decreased motility; however, the in vitro capacitation and acrosome reaction are not influenced. The symptoms show that Tppp2−/−-mice may be considered as a model for oligoasthenozoospermia.
SAHA/5-AZA Enhances Acetylation and Degradation of mutp53, Upregulates p21 and Downregulates c-Myc and BRCA-1 in Pancreatic Cancer Cells
Authors: Di Crosta Michele , Ragone Francesca Chiara , Benedetti Rossella , D’Orazi Gabriella , Gilardini Montani Maria Saveria , Cirone Mara
Published: June 2024

Epigenetic changes are common in cancer and include aberrant DNA methylation and histone modifications, including both acetylation or methylation. DNA methylation in the promoter regions and histone deacetylation are usually accompanied by gene silencing, and may lead to the suppression of tumor suppressors in cancer cells. An interaction between epigenetic pathways has been reported that could be exploited to more efficiently target aggressive cancer cells, particularly those against which current treatments usually fail, such as pancreatic cancer. In this study, we explored the possibility to combine the DNA demethylating agent 5-AZA with HDAC inhibitor SAHA to treat pancreatic cancer cell lines, focusing on the acetylation of mutp53 and the consequences on its stability, as well as on the interaction of this protein with c-myc and BRCA-1, key molecules in cancer survival. The results obtained suggest that SAHA/5-AZA combination was more effective than single treatments to promote the degradation of mutp53, to upregulate p21 and downregulate c-Myc and BRCA-1, thus increasing DNA damage and cytotoxicity in pancreatic cancer cells.
Mild Systemic Inflammation Increases Erythrocyte Fragility
Authors: Stuart Charlotte M. , Jacob Carmen , Varatharaj Aravinthan , Howard Sarah , Chouhan Joe K. , Teeling Jessica L. , Galea Ian
Published: June 2024

There is growing evidence that inflammation impairs erythrocyte structure and function. We assessed the impact of mild systemic inflammation on erythrocyte fragility in three different settings. In order to investigate causation, erythrocyte osmotic fragility was measured in mice challenged with a live attenuated bacterial strain to induce low-grade systemic inflammation; a significant increase in erythrocyte osmotic fragility was observed. To gather evidence that systemic inflammation is associated with erythrocyte fragility in humans, two observational studies were conducted. First, using a retrospective study design, the relationship between reticulocyte-based surrogate markers of haemolysis and high-sensitivity C-reactive protein was investigated in 9292 healthy participants of the UK Biobank project. Secondly, we prospectively assessed the relationship between systemic inflammation (measured by the urinary neopterin/creatinine ratio) and erythrocyte osmotic fragility in a mixed population (n = 54) of healthy volunteers and individuals with long-term medical conditions. Both human studies were in keeping with a relationship between inflammation and erythrocyte fragility. Taken together, we conclude that mild systemic inflammation increases erythrocyte fragility and may contribute to haemolysis. Further research is needed to assess the molecular underpinnings of this pathway and the clinical implications in inflammatory conditions.