bluuebunny/crossref_metadata_2025 huggingface dataset:
PERANCANGAN SISTEM PAKAR BERBASIS WEB UNTUK MENDETEKSI KERUSAKAN HANDPHONE DENGAN METODE FORWARD CHAINING
Authors: Hariyanto Eri , Pangaribuan Hotma
Published: December 2024

handphone or cell phones are electronic telecommunication devices that have capabilities and functions resembling computers. Almost all society own and use mobile phones for communication and business purposes, so that smartphones are a mandatory item for their users. Like other electronic goods, if used too often, cellphones are susceptible to damage due to various triggers such as exposure to liquids, falls, or improper use in everyday life. Not many people understand the types of cell phone damage. With the rise of irresponsible service agents who take advantage of people's ignorance in detecting damage to cellphones, a web-based expert system was designed to detect damage to damaged cellphones. With the creation of this system, ordinary people can also get an idea of ​​cell phone damage, often with the help of experts in the field. This system uses PHP as the backend, MYSQL as the database, and uses forward chaining.
Completing a molecular timetree of primates
Authors: Craig Jack M. , Hedges S. Blair , Kumar Sudhir
Published: December 2024

Primates, consisting of apes, monkeys, tarsiers, and lemurs, are among the most charismatic and well-studied animals on Earth, yet there is no taxonomically complete molecular timetree for the group. Combining the latest large-scale genomic primate phylogeny of 205 recognized species with the 400-species literature consensus tree available from TimeTree.org yields a phylogeny of just 405 primates, with 50 species still missing despite having molecular sequence data in the NCBI GenBank. In this study, we assemble a timetree of 455 primates, incorporating every species for which molecular data are available. We use a synthetic approach consisting of a literature review for published timetrees, de novo dating of untimed trees, and assembly of timetrees from novel alignments. The resulting near-complete molecular timetree of primates allows testing of two long-standing alternate hypotheses for the origins of primate biodiversity: whether species richness arises at a constant rate, in which case older clades have more species, or whether some clades exhibit faster rates of speciation than others, in which case, these fast clades would be more species-rich. Consistent with other large-scale macroevolutionary analyses, we found that the speciation rate is similar across the primate tree of life, albeit with some variation in smaller clades.
Quantitative assessment of urban surface deformation risks from tectonic and seismic activities using multitemporal microwave satellite remote sensing: a case study of Almaty city and its surroundings in Kazakhstan
Authors: Bayramov Emil , Sydyk Nurmakhambet , Nurakynov Serik , Yelisseyeva Alena , Neafie Jessica , Aliyeva Saida
Published: December 2024

The research goal of these studies was to monitor ground deformations for Almaty city during 2017–2023 and determine the spatial relationships with faults and tectonic plate boundaries. The small baseline subset interferometric synthetic aperture radar (SBAS-InSAR) was deployed for the interferometric measurements of ground deformations using Sentinel-1 radar satellite images. Distinct deformation patterns were observed from both sides of the tectonic plate boundary, indicating a standard faulting process. Identical deformation trends were observed from south to north, forming three transition zones from subsidence to uplift and subsidence again. The spatial relationship between faults and ground deformations was also observed in the transition zone with a densely built-up area subject to gradual surface declination with potential risks to infrastructure. Five incidents of building and bridge deformations with subsiding cumulative trends were observed in the same location. Most subsiding areas were in Zone 1, with maximum annual subsidence velocity and cumulative displacement of − 57 mm/y and – 399, respectively. In contrast, most uplifting areas were primarily in Zone 2, with maximum yearly uplift velocity and cumulative displacement of 40 mm/y and 254 mm, respectively, and mixed deformation patterns in Zone 3. These vertical movements in Almaty verify active tectonic plate activity that should be integrated into city risk assessment plans.
Effects of the Getting Ready for School intervention on children's school readiness skills
Authors: Marti-Castaner Maria , Merz Emily C. , Wiltshire Cynthia A. , Melvin Samantha A. , Henry Kimberly , Landers Cassie , Noble Kimberly G. , Duch Helena
Published: December 2024

Introduction

Skill-based curricula supplementing Head Start programming have shown great promise as early interventions improving school readiness of children from socioeconomically under-resourced families. The Getting Ready for School (GRS) intervention builds on such research by providing a supplemental skill-based curriculum targeting three core school readiness domains—language/literacy, math, and self-regulation—using learning activities aligned across the classroom and home contexts. The goal of this study was to examine the effects of the GRS intervention on school readiness skills in children in Head Start programs.

Methods

Participants were 3- to 4-year-olds (N = 463, 46% male, 81% Hispanic/Latine). Classrooms were non-randomly assigned to the GRS intervention (n = 20) or Head-Start-as-usual comparison group (n = 17). At pretest and posttest, children completed assessments of early language/literacy, math, and self-regulation. Multilevel modeling was used to examine the group-by-time interaction in prediction of children's school readiness skills.

Results

Significant group-by-time interactions were found for early language/literacy (vocabulary, print knowledge) and math skills. Children in the intervention group demonstrated significantly greater gains over time in these skills compared to children in the comparison group. At posttest, children in the intervention group had significantly higher vocabulary than children in the comparison group (effect size = 0.34). Intervention effects were not found for self-regulation.

Discussion

The GRS intervention may support early language/literacy and math skills in preschool children from socioeconomically under-resourced families. Future studies focused on a modified version of the intervention could demonstrate larger effect sizes and improvements in self-regulation.
Developing written communication skills in engineers in Spanish: is ChatGPT a tool or a hindrance?
Authors: Mirón-Mérida Vicente Antonio , García-García Rebeca María
Published: December 2024

As 2023 became a disruptive year, due to the accelerated appearance of AI tools such as ChatGPT, the educational systems started to change and adapt to the new approaches observed in students, teachers, and employers. Although AI is likely to be integrated into different industrial and academic processes, its indiscriminate use could hinder the development of soft skills, including oral and written communication. Hence, it is important to identify any AI-generated assignments to secure a successful learning process. For those reasons, in this work, the effectivity of three plagiarism checkers, namely Turnitin, Unicheck and GPTZero, was evaluated on an engineering-based written text generated in ChatGPT in the Spanish language. A comparison with the plagiarism rate obtained for an original piece was conducted with One-way ANOVA. In all the cases, based on the low plagiarism rates (Unicheck: 14.44%, Turnitin: 12.43%), no plagiarism was detected in the AI-generated texts. Likewise, the GPTZero platform detected low AI-Origin in the texts created in ChatGPT (1.04%). Both results denoted the low efficiency of these platforms for assignments in Spanish and the high risk of conducting plagiarism without implications. Additionally, different alternatives were proposed for either integrating ChatGPT in learning activities or replacing the use of AI to ensure the development of skills and competencies in the students.
Association between autonomy support, academic motivation, and life skills in pre-service physical education teachers and pre-service sport coaches
Authors: Ortiz-Rodríguez Verónica , Vergara-Torres Argenis P. , Ramírez-Nava Ruben , Tristán José , López-Walle Jeanette M.
Published: December 2024

This study aimed to analyze the relationships between the perception of the autonomy-support style created by the professor, the global academic intrinsic motivation and its three subtypes (to know, toward accomplishments, and to experience stimulation), and the life skills of future physical education (PE) teachers and sports coaches. The participants were 583 students (Mage = 20.77 years, SD = 2.94; 65% were men) belonging to a higher education program specialized in the training of PE teachers and sports coaches in Mexico. The results of the structural equation models showed that the perception of the autonomy-support style adopted by the professors was positively and significantly related to global academic intrinsic motivation and its three subtypes, and these were positively and significantly associated with each life skill. The mediation analyses confirmed the mediating role of global academic intrinsic motivation and subtypes between the perception of the autonomy-support style adopted by the professors and the student’s life skills. In conclusion, to promote the development of life skills in future PE teachers and sport coaches, it will not only be enough for their teachers to generate positive environments of autonomy-supportive styles, but they must also have intrinsic reasons to enhance these skills.
Everolimus in pituitary tumor: a review of preclinical and clinical evidence
Authors: Yao Zihong , Chen Hui
Published: December 2024

Although pituitary tumors (PTs) are mostly benign, some PTs are characterized by low surgical resection rates, high recurrence rates, and poor response to conventional treatments and profoundly affect patients’ quality of life. Everolimus (EVE) is the only FDA-approved mTOR inhibitor, which can be used for oral treatment. It effectively inhibits tumor cell proliferation and angiogenesis. It has been administered for various neuroendocrine tumors of the digestive tract, lungs, and pancreas. EVE not only suppresses the growth and proliferation of APT cells but also enhances their sensitivity to radiotherapy and chemotherapy. This review introduces the role of the PI3K/AKT/mTOR pathway in the development of APTs, comprehensively explores the current status of preclinical and clinical research of EVE in APTs, and discusses the blood-brain barrier permeability and safety of EVE.
Quantitative ultrasound imaging reveals distinct fracture-associated differences in tibial intracortical pore morphology and viscoelastic properties in aged individuals with and without diabetes mellitus – an exploratory study
Authors: Dehnen Carolin , Galindo Angela , Hoff Paula , Palme Oliver , Maurer Lukas , Raum Kay , Wiebe Edgar
Published: December 2024

Introduction

Diabetes mellitus (DM) is a chronic metabolic disorder that increases fragility fracture risk. Conventional DXA-based areal bone mineral density (aBMD) assessments often underestimate this risk. Cortical Backscatter (CortBS) ultrasound, a radiation-free technique, non-invasively analyzes cortical bone’s viscoelastic and microstructural properties. This study aimed to evaluate CortBS’s discriminative performance in DM patients compared to DXA and characterize changes in cortical bone microstructure in Type 1 and Type 2 DM (T1DM, T2DM) patients.

Methods

This in-vivo study included 89 DM patients (T1DM = 39, T2DM = 48) and 76 age- and sex-matched controls. DXA measured aBMD, while CortBS measurements were taken at the anteromedial tibia using a medical ultrasound scanner with custom software. Multivariate analysis of variance assessed the impact of DM type on CortBS and DXA measurement results. Partial least squares discriminant analyses with cross-validation were used to compare the discrimination performance for vertebral, non-vertebral, and any fragility fractures, adjusting for gender, age, and anthropometric parameters (weight, height, BMI).

Results

Fractures occurred in 8/23 T1DM, 17/18 T2DM, and 16/55 controls. DXA parameters were reduced in fracture patients, with significant diabetes impact. T2DM was associated with altered CortBS parameters, reduced scatterer density, and larger pores. CortBS outperformed DXA in discriminating fracture risk (0.61 ≤ AUC(DXA) ≤ 0.63, 0.68 ≤ AUC(CortBS) ≤ 0.69).

Conclusions

Both T1DM and T2DM showed altered bone metabolism, with T2DM linked to impaired tissue formation. CortBS provides insights into pathophysiological changes in diabetic bone and provided superior fracture risk assessment in DM patients compared to DXA.
Case report: Pheochromocytoma-induced pseudo-Cushing’s syndrome
Authors: Małgorzata Bobrowicz , Anna Nagórska , Anna Karpiłowska , Marek Rosłon , Joanna Hubska , Adrianna Gładka , Sadegh Toutounchi , Łukasz Koperski , Urszula Ambroziak
Published: December 2024

Non-neoplastic hypercortisolaemia, also known as pseudo-Cushing’s syndrome (PCS), is a physiological overactivation of the hypothalamic–pituitary–adrenal axis that can be triggered by conditions such as depression, eating disorders, extreme exercise, obesity, alcoholism, poorly controlled diabetes, chronic kidney disease, and cachexia. Here, we describe an unusual case of pheochromocytoma-induced PCS. A 66-year-old woman was referred to the hospital due to pronounced weakness, loss of appetite, apathy, weight loss, newly diagnosed diabetes mellitus, and poorly controlled hypertension. The biochemical evaluation suggested ACTH-dependent hypercortisolemia with severe hypokalemia, metabolic alkalosis, and hyperglycemia. Markedly elevated levels of metanephrines, along with imaging showing a heterogeneous adrenal lesion, provided evidence for pheochromocytoma. Considering the clinical features and the results of laboratory and imaging tests, there was a suspicion of hypercortisolemia due to ectopic ACTH secretion by a pheochromocytoma. The patient underwent adrenalectomy following pre-treatment with doxazosin and metyrapone, enteral feeding, protein supplementation, and insulin administration. Post-surgery, the patient did not require further antidiabetic medication, experienced gradual weight gain, improved well-being, and did not need glucocorticoid supplementation. Histopathological examination confirmed a pheochromocytoma; however, both anti-ACTH and anti-CRH stainings were negative, leading to a diagnosis of PCS. This case highlights the distinctive presentation of PCS caused by pheochromocytoma, as demonstrated through clinical, laboratory, and histopathological findings, and emphasizes the successful resolution achieved through adrenalectomy and supportive care.
Trained innate immunity as a potential link between preeclampsia and future cardiovascular disease
Authors: Carrasco-Wong Ivo , Sanchez Javiera M. , Gutierrez Jaime A. , Chiarello Delia I.
Published: December 2024

Preeclampsia (PE) is a complex pregnancy syndrome characterized by hypertension with or without proteinuria, affecting 2–6% of pregnancies globally. PE is characterized by excessive release of damage-associated molecular patterns (DAMPs) into the maternal circulation. This DAMP-rich milieu acts on innate immune cells, inducing a proinflammatory state characterized by elevated cytokines such as IL-1β and IL-18. This proinflammatory state in the mother and placenta results in the endothelial dysfunction strongly associated with cardiovascular disorders. While the immediate maternal and fetal risks of PE are well-documented, accumulating evidence indicates that PE also confers long-term cardiovascular risks to the mother, including hypertension, coronary heart disease, stroke, and heart failure. The underlying mechanisms connecting PE to these chronic cardiovascular conditions remain unclear. This article explores the potential role of trained innate immunity (TRIM) as a mechanistic link between PE and increased long-term cardiovascular risk. We propose that the persistent exposure to DAMPs during PE may epigenetically reprogram maternal innate immune cells and their progenitors, leading to TRIM. This reprogramming enhances the inflammatory response to subsequent stimuli, potentially contributing to endothelial dysfunction and chronic inflammation that predispose women to cardiovascular diseases later in life. Understanding the role of TRIM in PE could provide novel insights into the pathophysiology of PE-related cardiovascular complications and identify potential targets for therapeutic intervention. Further research is warranted to investigate the epigenetic and metabolic alterations in innate immune cells induced by PE and to determine how these changes may influence long-term maternal cardiovascular health.
The impact of productive services on the technological complexity of agricultural exports and the moderating role of environmental regulations
Authors: He Guoping , Zeng Zhihua
Published: December 2024

The integration of socialized services and green development are two major trends shaping modern agriculture. Similarly, the increasing technological complexity of exports has become a defining characteristic of contemporary agricultural trade. However, the relationship between agricultural services and the technological complexity of agricultural exports, as well as the potential influence of environmental regulations on this relationship, remains underexplored. This study utilizes provincial panel data from mainland China spanning 2007 to 2022 to investigate the impact of agricultural productive services on the technological complexity of agricultural exports. It also examines the mechanisms behind this impact and the moderating effects of different types of environmental regulations. The findings reveal that agricultural productive services significantly and robustly enhance the technological complexity of agricultural exports by fostering agricultural technological Advances and alleviating financial constraints. Furthermore, the study identifies varying moderating effects of environmental regulations. Command-and-control and voluntary public environmental regulations significantly amplify the positive impact of productive services on export complexity, whereas market-based environmental regulations show no significant effect. These findings suggest that promoting the development of agricultural services and optimizing environmental regulation policies are critical to enhancing the technological sophistication and sustainability of agricultural exports.
The introduction of coinage in Europe did not change pre-existing monetary patterns
Authors: Ialongo Nicola
Published: December 2024

Introduction

This paper investigates whether the introduction of coinage in Europe fundamentally changed pre-existing monetary circulation patterns. By analysing the statistical properties of bronze money before and after the advent of coinage (c. 1500–27 BCE), it challenges the prevailing assumption that coinage revolutionized the use and exchange of money. The research engages with longstanding academic debates between competing theories, which posit that money is either market-driven or state-imposed.

Methods

Using a combination of archaeological data and quantitative analysis, the study examines large datasets of pre-coinage money and early coinage, focusing on weight-based regulation and the log-normal distribution of mass values as key indicators of monetary behaviour.

Results

The findings reveal that pre-coinage bronze money, consisting of weighed metal fragments, circulated in a manner similar to early coinage. Both forms of money complied with weight-based systems and exhibited log-normal distribution patterns, reflecting structured economic behaviours. The analysis suggests that the introduction of coinage did not lead to a fundamental transformation in how money circulated but rather continued pre-existing patterns.

Discussion

These results challenge the assumption that state-issued coinage marked a watershed moment in the history of monetary economies. The paper proposes that the beginning of coinage introduced a minor technological improvement rather than a revolutionary change in monetary circulation, offering a new perspective on the continuity between pre-coinage and coinage-based economies in ancient Europe.
The immune mechanisms of acute exacerbations of idiopathic pulmonary fibrosis
Authors: Chen Tao , Sun Wei , Xu Zuo-jun
Published: December 2024

Acute exacerbations of idiopathic pulmonary fibrosis (AE-IPF) are the leading cause of mortality among patients with IPF. There is still a lack of effective treatments for AE-IPF, resulting in a hospitalization mortality rate as high as 70%–80%. To reveal the complicated mechanism of AE-IPF, more attention has been paid to its disturbed immune environment, as patients with IPF exhibit deficiencies in pathogen defense due to local immune dysregulation. During the development of AE-IPF, the classical stimulatory signals in adaptive immunity are inhibited, while the nonclassical immune reactions (Th17) are activated, attracting numerous neutrophils and monocytes to lung tissues. However, there is limited information about the specific changes in the immune response of AE-IPF. We summarized the immune mechanisms of AE-IPF in this review.
Lysate of Parabacteroides distasonis prevents severe forms of experimental autoimmune encephalomyelitis by modulating the priming of T cell response
Authors: Jiraskova Zakostelska Zuzana , Kraus Michal , Coufal Stepan , Prochazkova Petra , Slavickova Zaneta , Thon Tomas , Hrncir Tomas , Kreisinger Jakub , Kostovcikova Klara , Kleinova Pavlina , Lizrova Preiningerova Jana , Pavelcova Miluse , Ticha Veronika , Kovarova Ivana , Kubala Havrdova Eva , Tlaskalova-Hogenova Helena , Kverka Miloslav
Published: December 2024

The gut microbiota influences the reactivity of the immune system, and Parabacteroides distasonis has emerged as an anti-inflammatory commensal. Here, we investigated whether its lysate could prevent severe forms of neuroinflammation in experimental autoimmune encephalomyelitis (EAE) in mice and how this preventive strategy affects the gut microbiota and immune response. Lysate of anaerobically cultured P. distasonis (Pd lysate) was orally administered to C57BL/6 mice in four weekly doses. One week later, EAE was induced and disease severity was assessed three weeks after induction. Fecal microbiota changes in both vehicle- and Pd lysate-treated animals was analyzed by 16S V3–V4 amplicon sequencing and qPCR, antimicrobial peptide expression in the intestinal mucosa was measured by qPCR, and immune cell composition in the mesenteric and inguinal lymph nodes was measured by multicolor flow cytometry. Pd lysate significantly delayed the development of EAE and reduced its severity when administered prior to disease induction. EAE induction was the main factor in altering the gut microbiota, decreasing the abundance of lactobacilli and segmented filamentous bacteria. Pd lysate significantly increased the intestinal abundance of the genera Anaerostipes, Parabacteroides and Prevotella, and altered the expression of antimicrobial peptides in the intestinal mucosa. It significantly increased the frequency of regulatory T cells, induced an anti-inflammatory milieu in mesenteric lymph nodes, and reduced the activation of T cells at the priming site. Pd lysate prevents severe forms of EAE by triggering a T regulatory response and modulating T cell priming to autoantigens. Pd lysate could thus be a future modulator of neuroinflammation that increases the resistance to multiple sclerosis.
Enabling immune checkpoint blockade efficacy in T-lymphopenia by restoring CD8 T cell dynamics with IL-7 cytokine therapy
Authors: Kang Yeon-Woo , Choi Donghoon , Moon Dain , Lee Kun-Joo , Oh Youngsik , Yang Jaehyuk , Jeong Siheon , Park Uni , Im Sun-Kyoung , Yang Se Hwan , Lee Seung-Woo
Published: December 2024

Introduction

T-lymphopenia (TLP) is a frequently observed condition in cancer patients, often exacerbated by conventional chemo/radiotherapy, which impairs the efficacy of subsequent immune checkpoint blockade (ICB) therapy. This study aimed to understand the impact of TLP on ICB responsiveness and explore potential therapeutic strategies to enhance antitumor immunity.

Methods

To investigate ICB responsiveness depending on the severity of TLP, first, we established TLP mouse models that mimic clinically observed mild and severe TLP through thymectomy and anti-Thy1-induced peripheral T cell depletion. T cell-replete mice and T-lymphopenic mice were inoculated with palpable or advanced tumors to evaluate the antitumor efficacy of anti-PD-1 therapy according to the severity of TLP. Additionally, by utilizing established murine models, we analyzed matched blood, tumor-draining lymph nodes (TDLNs), and tumor samples by flow cytometry to investigate the mechanisms by which ICB responsiveness is impaired under T-lymphopenic conditions. Finally, to evaluate the combination effect of anti-PD-1 and recombinant IL-7 cytokine therapy (rhIL-7-hyFc) in T-lymphopenic conditions, we administered anti-PD-1, rhIL-7-hyFc, or both to advanced tumor-bearing T-lymphopenic mice and subsequently analyzed tumor growth and survival rates.

Results

Using mouse models mimicking clinical TLP, we observed that the antitumor efficacy of anti-PD-1 therapy was severely impaired in TLP, depending on the degree of TLP and the immunogenicity of the tumors. TLP mice showed a significant reduction in systemic CD8 T cells but stable intratumoral CD8 T cell numbers, suggesting maintained tumor infiltration despite systemic downregulation. Crucially, TLP led to a shift in the composition of tumor-infiltrating lymphocytes, with a decrease in PD-1+ tumor-reactive CD8 T cells and an increase in PD-1− bystander cells. This reduction in PD-1+ cells was linked to impaired clonal expansion in tumor-draining lymph nodes. To counteract these effects, we introduced recombinant IL-7 cytokine therapy (rhIL-7-hyFc), which effectively restored systemic T cell counts, enhanced PD-1+ CD8 T cell proliferation within tumors, and increased the population of stem-like progenitor cells. The combination of rhIL-7-hyFc and anti-PD-1 therapy resulted in significant tumor regression and improved mouse survival.

Discussion

Our findings highlight the critical role of IL-7 in reshaping the CD8 T cell landscape to improve ICB efficacy in TLP conditions, proposing a sequential therapeutic approach: conventional therapy to reduce tumor burden and enhance immunogenicity, followed by IL-7 therapy to restore and rejuvenate CD8 T cells, culminating in effective ICB treatment.
Optimizing immunogenicity and product presentation of a SARS-CoV-2 subunit vaccine composition: effects of delivery route, heterologous regimens with self-amplifying RNA vaccines, and lyophilization
Authors: Lykins William R. , Pollet Jeroen , White Jessica A. , Keegan Brian , Versteeg Leroy , Strych Ulrich , Chen Wen-Hsiang , Mohamath Raodoh , Ramer-Denisoff Gabi , Reed Sierra , Renshaw Christina , Beaver Samuel , Gerhardt Alana , Voigt Emily A. , Tomai Mark A. , Sitrin Robert , Choy Robert K. M. , Cassels Frederick J. , Hotez Peter J. , Bottazzi Maria Elena , Fox Christopher B.
Published: December 2024

Introduction

Dozens of vaccines have been approved or authorized internationally in response to the ongoing SARS-CoV-2 pandemic, covering a range of modalities and routes of delivery. For example, mucosal delivery of vaccines via the intranasal (i.n.) route has been shown to improve protective mucosal responses in comparison to intramuscular (i.m.) delivery. As we gain knowledge of the limitations of existing vaccines, it is of interest to understand if changes in product presentation or combinations of multiple vaccine modalities can further improve immunological outcomes.

Methods

We investigated a commercial-stage SARS-CoV-2 receptor binding domain (RBD) antigen adjuvanted with a clinical-stage TLR-7/8 agonist (3M-052) formulated on aluminum oxyhydroxide (Alum). In a murine immunogenicity model, we compared i.n. and i.m. dosing of the RBD-3M-052-Alum vaccine. We measured the magnitude of antibody responses in serum and lungs, the antibody-secreting cell populations in bone marrow, and antigen-specific cytokine-secreting splenocyte populations. Similarly, we compared different heterologous and homologous prime-boost regimens using the RBD-3M-052-Alum vaccine and a clinical-stage self-amplifying RNA (saRNA) vaccine formulated on a nanostructured lipid carrier (NLC) using the i.m. route alone. Finally, we developed a lyophilized presentation of the RBD-3M-052-Alum vaccine and compared it to the liquid presentation and a heterologous regimen including a previously characterized lyophilized form of the saRNA-NLC vaccine.

Results and discussion

We demonstrate that i.n. dosing of the RBD-3M-052-Alum vaccine increased IgA titers in the lung by more than 1.5 logs, but induced serum IgG titers 0.8 logs lower, in comparison to i.m. dosing of the same vaccine. We also show that the homologous prime-boost RBD-3M-052-Alum regimen led to the highest serum IgG and bronchial IgA titers, whereas the homologous saRNA-NLC regimen led to the highest splenocyte interferon-γ response. We found that priming with the saRNA-NLC vaccine and boosting with the RBD-3M-052-Alum vaccine led to the most desirable immune outcome of all regimens tested. Finally, we show that the lyophilized RBD-3M-052-Alum vaccine retained its immunological characteristics. Our results demonstrate that the route of delivery and the use of heterologous regimens each separately impacts the resulting immune profile, and confirm that multi-product vaccine regimens can be developed with stabilized presentations in mind.
Impact of steroid-sparing immunosuppressive agents on tumor outcome in the context of cancer immunotherapy with highlight on melanoma: a systematic literature review and meta-analysis
Authors: Strouse Jennifer , Chan Karmela Kimi , Baccile Rachel , He Gong , Louden Diana K. N. , Giurcanu Mihai , Singh Arohi , Rieth John , Abdel-Wahab Noha , Katsumoto Tamiko R. , Singh Namrata , Rouhani Sherin , Reid Pankti
Published: December 2024

Background

The impact of steroid-sparing immunosuppressive agents (SSIAs) for immune-related adverse events (irAEs) on tumor outcome is not well-known. This systematic review evaluates tumor outcomes for corticosteroid (CS) monotherapy versus CS with SSIA (CS-SSIA) for irAE treatment with a focus on melanoma.

Methods

Search was conducted through 1/5/23 using PubMed, Embase, Cochrane CENTRAL, and Web of Science. We included case series, retrospective/prospective observational studies and interventional clinical trials. Individual-level data was analyzed using KM curves and Cox regression for overall survival (OS) and progression free survival (PFS). Time to SSIA was treated as a time-varying exposure using landmark analysis (landmark timepoint=3 months after irAE) to account for immortal time bias. For group-level data, meta-analysis compared the use of SSIA to No SSIA for irAEs.

Results

Of twenty-two publications with individual-level data, 147 patients with any cancer (57 CS, 90 CS-SSIA) and 65 with melanoma (18 CS, 47 CS-SSIA) underwent landmark analysis. Twenty-two publications underwent group-level evaluation and four were included in the meta-analysis. CS-SSIA versus CS showed higher risk of all-cause mortality and progression (HR 2.75, 95%CI: 1.44-5.27, p<0.01 and HR 1.75, 95%CI: 1.07-2.85, p=0.03, respectively). Melanoma showed worse OS and PFS for CS-SSIA versus CS (HR 5.68, 95%CI: 1.31-24.67, p=0.02 and HR 2.68, 95%CI: 1.12-6.40, p=0.03, respectively). In the meta-analysis of group-level data (n=2558), we found worse OS and PFS for CS-SSIA versus No SSIA (HR 1.58, 95%CI: 1.25; 2.01, p<0.01 and 1.70, 95%CI: 1.25-2.33, p<0.01). Tumor necrosis factor-alpha inhibitors (TNFi) were the most common SSIA. In the melanoma cohort, TNFi had worse OS and PFS versus CS (HR 6.46, 95%CI: 1.43-29.19, p = 0.02 and HR 7.49, 95%CI: 2.29-24.48, p<0.01, respectively). TNFi versus Other SSIAs showed a trend toward worse OS and worse PFS (HR 6.96, 95%CI: 0.90-53.65, p=0.06 and HR 21.5, 95%CI: 2.63-175.8, p<0.01, respectively). Meta-analysis showed a concern for TNFi compared to Other SSIA (HR 1.56, 95%CI: 1.17-2.09, p<0.01 respectively).

Conclusions

While our results raise concern about the effects of CS-SSIA and TNFi for irAE therapy on tumor outcomes, prospective randomized controlled trials are needed to definitively assess the effect of SSIAs on tumor outcomes.
Angiogenesis and EMT regulators in the tumor microenvironment in lung cancer and immunotherapy
Authors: Yan Taotao , Shi Jiahai
Published: December 2024

Lung cancer remains the primary cause of cancer-related mortality, with factors such as postoperative tumor recurrence, metastasis, and therapeutic drug resistance exacerbating patient outcomes. Immunotherapy has emerged as a transformative approach, challenging conventional treatment paradigms for lung cancer. Consequently, advancing research in lung cancer immunotherapy is imperative. Recent studies indicate that numerous regulators within the tumor microenvironment (TME) drive tumor angiogenesis and epithelial-mesenchymal transition (EMT); these processes are interdependent, reciprocal, and collectively contribute to tumor progression. Tumor angiogenesis not only supplies adequate oxygen and nutrients for cellular proliferation but also establishes pathways facilitating tumor metastasis and creating hypoxic regions that foster drug resistance. Concurrently, EMT enhances metastatic potential and reinforces drug-resistance genes within tumor cells, creating a reciprocal relationship with angiogenesis. This interplay ultimately results in tumor invasion, metastasis, and therapeutic resistance. This paper reviews key regulators of angiogenesis and EMT, examining their impact on lung cancer immunotherapy and progression, and investigates whether newly identified regulators could influence lung cancer treatment, thus offering valuable insights for developing future therapeutic strategies.
Progress of cGAS-STING signaling pathway-based modulation of immune response by traditional Chinese medicine in clinical diseases
Authors: Zhi Hui , Fu Hui , Zhang Yunxin , Fan Ni , Zhao Chengcheng , Li Yunfei , Sun Yujiao , Li Yingpeng
Published: December 2024

The cGAS-STING signaling pathway is a critical component of the innate immune response, playing a significant role in various diseases. As a central element of this pathway, STING responds to both endogenous and exogenous DNA stimuli, triggering the production of interferons and pro-inflammatory cytokines to enhance immune defenses against tumors and pathogens. However, dysregulated activation of the STING pathway is implicated in the pathogenesis of multiple diseases, including autoinflammation, viral infections, and cancer. Traditional Chinese Medicines (TCMs), which have a long history of use, have been associated with positive effects in disease prevention and treatment. TCM formulations (e.g., Lingguizhugan Decoction, Yi-Shen-Xie-Zhuo formula) and active compounds (e.g., Glabridin, Ginsenoside Rd) can modulate the cGAS-STING signaling pathway, thereby influencing the progression of inflammatory, infectious, or oncological diseases. This review explores the mechanisms by which TCMs interact with the cGAS-STING pathway to regulate immunity, focusing on their roles in infectious diseases, malignancies, and autoimmune disorders.
Molecular cloning, expression and functional analysis of foxl2 from Chinese sturgeon (Acipenser sinensis) in relation to sex differentiation
Authors: Hu Yacheng , Tan Ruihua , Li Yang , Shu Tingting , Yang Gang , Chu Zhong , Wang Haoran , Liu Xueqing , Zhu Xin , Wang Binzhong , Guo Baifu , Wang Runqiu , Qu Huantao , Song Haoyong , Zhang Dezhi , Du Hejun , Li Zhiyuan , Chang Jianbo , Wang Dianchang , Xu Dan , Jiang Wei , Li Qingfei , Yang Yuanjin
Published: December 2024

Introduction

Our understanding of the regulatory mechanisms that govern the development of sexual characteristics in sturgeon, particularly the Chinese sturgeon (Acipenser sinensis), is limited. Foxl2, a member of the forkhead/HNF-3-related transcription factor family, is known for its role in precise gene regulation within specific tissues and its control over ovarian aromatase, a key enzyme in ovarian development and maturation. This study aimed to investigate the sexually dimorphic expression of foxl2 during the molecular and morphological sex differentiation stages in Chinese sturgeon.

Methods

We successfully isolated the full-length cDNAs of foxl2 in Chinese sturgeon. We then examined the expression profiles of this gene across various somatic tissues in both female and male specimens.

Results

Foxl2 was predominantly expressed in the ovulatory organs of two-year-old Chinese sturgeon, with significantly lower expression in other somatic tissues. We observed sexual dimorphism in foxl2 expression within gonads that had achieved morphological differentiation.

Discussion

The results suggest that foxl2 expression is intricately linked to the process of ovarian differentiation in Chinese sturgeon. Furthermore, we propose that the mRNA quantities of foxl2 could serve as an accurate biomarker for sex determination in sturgeon during their early growth stages.
Understanding the influence of plant genetic factors on rhizosphere microbiome assembly in Panax notoginseng
Authors: Shi Liping , Yang Mingming , Wei Guangfei , Wei Xiuye , Hong Fei , Ma Jiaxiang , Wu Zhe , Zheng Yuqing , Yang Miyi , Chen Shilin , Zhang Guozhuang , Dong Linlin
Published: December 2024

Introduction

Functional rhizosphere microbiomes (FRM) are critical for plant health and yield. However, the ecological succession of FRM and their links to plant genetic factors across the life cycle of perennial plants remain poorly understood.

Methods

This study profiled FRM, including plant-beneficial bacteria (PBB) and fungal plant pathogens (FPP), across different developmental stages of Panax notoginseng.

Results

The biodiversity of both PBB and FPP were significantly higher in rhizosphere compared with farmland soil, and exhibited different succession patterns with plant growth. The relative abundance of PBB, but not FPP, decreased after plant cultivation. There were significantly negative correlations between FPP and PBB, particularly the biocontrol subgroup (ρ = −0.56, p < 0.001). The antagonistic effects of biocontrol bacteria against fungal pathogens were further validated by in vitro assays. The fitting of neutral community model indicated that the deterministic assembly of PBB, especially the biocontrol subgroup, was the strongest at the 3rd-year root growth stage of P. notoginseng. Plant genes involved in protein export, biosynthesis of alkaloids and amino acids were identified as drivers of the deterministic assembly of biocontrol subcommunity by RNA-Seq analysis. Additionally, a total of 13 transcription factors potentially regulating the expression of these biosynthesis genes were identified through co-expression network. In summary, this study unveils the succession patterns of FRM throughout the life cycle of P. notoginseng and the underlying plant genetic mechanisms, providing valuable insights for developing new plant disease management strategies by manipulating microbes.
Inhibition of neuroinflammation by GIBH-130 (AD-16) reduces neurodegeneration, motor deficits, and proinflammatory cytokines in a hemiparkinsonian model
Authors: Bianchetti Maria E. , Ferreira Ana Flavia F. , Britto Luiz R. G.
Published: December 2024

Parkinson’s disease (PD) is a neurodegenerative condition characterized by the loss of dopaminergic neurons in the substantia nigra pars compacta (SNc) of the brain, manifesting itself with both motor and non-motor symptoms. A critical element of this pathology is neuroinflammation, which triggers a harmful neurotoxic cycle, exacerbating cell death within the central nervous system. AD-16 (also known as GIBH-130) is a recently identified compound capable of reducing the expression of pro-inflammatory cytokines while increasing the expression of anti-inflammatory cytokines in Alzheimer’s disease models. Here, for the first time, we sought to comprehend the potential impact of orally administered AD-16 in mitigating neurodegeneration and subsequent disease progression in PD. To accomplish this, 6- hydroxydopamine (6-OHDA) unilateral striatal injections were employed to induce a PD model in male C57BL/6 mice. Cylinder and apomorphine-induced rotation behavior tests were conducted to assess motor behavior and validate the PD model 3 days after the injection. AD-16 was administered via gavage daily between days 3 and 9 after surgery. On the last day of treatment, motor tests were performed again. All animals were euthanized on day 10 and immunohistochemistry techniques were performed to detect tyrosine hydroxylase (TH) and Iba-1 and thus label dopaminergic neurons and microglia in the SNc and striatum (CPu). These same regions were collected for ELISA assays to assess different cytokine concentrations. Our results revealed an enhancement in the motor function of the AD-16-treated animals, as well as reduced nigrostriatal neurodegeneration. In addition, AD-16 reduced the increase in microglia density and prevented the changes in its morphology observed in the PD animal models. Furthermore, AD-16 was able to avoid the increase of pro-inflammatory cytokines levels that were present in 6-OHDA-injected animals who received vehicle. Consequently, AD-16 emerges as a compound with significant potential for negative modulation of neurodegeneration and neuroinflammation suppression in the 6-OHDA animal model of Parkinson’s disease.
Brain-like hardware, do we need it?
Authors: Borghi Francesca , Nieus Thierry R. , Galli Davide E. , Milani Paolo
Published: December 2024

The brain’s ability to perform efficient and fault-tolerant data processing is strongly related to its peculiar interconnected adaptive architecture, based on redundant neural circuits interacting at different scales. By emulating the brain’s processing and learning mechanisms, computing technologies strive to achieve higher levels of energy efficiency and computational performance. Although efforts to address neuromorphic solutions through hardware based on top-down CMOS-based technologies have obtained interesting results in terms of energetic efficiency improvement, the replication of brain’s self-assembled and redundant architectures is not considered in the roadmaps of data processing electronics. The exploration of solutions based on self-assembled elemental blocks to mimic biological networks’ complexity is explored in the general frame of unconventional computing and it has not reached yet a maturity stage enabling a benchmark with standard electronic approaches in terms of performances, compatibility and scalability. Here we discuss some aspects related to advantages and disadvantages in the emulation of the brain for neuromorphic hardware. We also discuss possible directions in terms of hybrid hardware solutions where self-assembled substrates coexist and integrate with conventional electronics in view of neuromorphic architectures.
Mandarin-speaking children with different types of cochlear implant exhibit variations in the activation patterns of their central auditory processing
Authors: Mao Xiang , Zhang Ziyue , Yang Yijing , Wang Yue , Chen Yu , Wang Wei
Published: December 2024

Background

Cochlear implants (CIs) have the potential to facilitate auditory restoration in deaf children and contribute to the maturation of the auditory cortex. The type of CI may impact hearing rehabilitation in children with CI. We aimed to study central auditory processing activation patterns during speech perception in Mandarin-speaking pediatric CI recipients with different device characteristics.

Methods

We developed and implemented a multifeature paradigm for Mandarin pronunciation to capture mismatch negativity (MMN) responses in pediatric CI recipients, analyzed the cortical processing sources of MMN responses elicited by different stimuli, and identified significant differences in the frontal cerebral cortex activation between different types of CIs located in the corresponding brain regions according to the Anatomical Automatic Labeling (AAL) brain template. The clinical characteristics, aided hearing threshold (AHT), and speech perception accuracy (SPA) of these children were also recorded.

Results

This study involved 32 pediatric CI recipients, with 12 (37.5%) receiving unilateral implants, 10 (31.3%) receiving bilateral implants, and 10 (31.3%) receiving bimodal stimulation. The cortical areas involved in the MMN response to various Mandarin pronunciation stimuli showed the greatest activity in the prefrontal lobe. In children with bimodal stimulation, there was noticeable activation in prefrontal cortical areas. Children with unilateral and bilateral implants also showed activation of the prefrontal cortex, but the activation strength was relatively reduced. The activation of cortical areas did not consistently appear stronger in children with bilateral implants than in those with unilateral implants. Consonant and intensity stimuli showed greater activation, whereas duration and vowel stimuli showed weaker activation. Significant differences in frontal cerebral cortex activation between different types of CIs were predominantly observed in the superior frontal gyrus.

Conclusion

Bimodal stimulation should be considered whenever possible to maximize auditory benefits. For deaf children without any residual hearing, bilateral implantation is the best choice. Unilateral implantation is not as detrimental as previously thought for deaf children. Early cochlear implantation, comprehensive auditory training, and better adaptation to CI devices can efficiently compensate for unilateral hearing limitations.
Non-linear relationship between the first meal time of the day and gallstone incidence in American adults: a population-based cross-sectional study
Authors: Sun Tiange , Zhang Lidong , Lu Ying , Zhang Xianwen , Cui Jinhao , Yang Tongheng , Zhang Dan , Zheng Bowen , Zheng Shuguo
Published: December 2024

Background

Irregular meal time is associated with gallstones. The time–dose effect between meal time and gallstone formation remains unknown.

Objective

This study aimed to investigate the association between the first meal time (FMT) of the day and the prevalence of gallstones.

Methods

Based on data from the National Health and Nutrition Examination Survey from 2017 to March 2020, the associations between the FMT of the day and the prevalence of gallstones were analyzed via multivariable logistic regression, restricted cubic spline curves, subgroup analysis, and interaction tests.

Results

A total of 6,547 participants were included. The fully adjusted model indicated a positive correlation between the FMT of the day and the prevalence of gallstones (odds ratio [OR] = 1.05, 95% confidence interval [CI] = 1.02 ~ 1.08); this association was consistent across subgroups. The risk of developing gallstones was the greatest when the FMT was between 09:00 and 14:00 (OR [95% CI] = 1.49 [1.24 ~ 1.77]). There was a non-linear relationship between the FMT and gallstone incidence (P for non-linearity = 0.042), with an inflection point at 13.4 h. After the 13.4-h mark, the risk of developing gallstones did not increase further.

Conclusion

The FMT of the day is positively correlated with the prevalence of gallstones, and there is a non-linear relationship and threshold effect between the two. Skipping breakfast is associated with a greater risk of developing gallstones. This study provides new evidence for the dietary prevention of gallstones.