bluuebunny/crossref_metadata_2025 huggingface dataset:
46,XX Differences of Sex Development outside congenital adrenal hyperplasia: pathogenesis, clinical aspects, puberty, sex hormone replacement therapy and fertility outcomes
Authors: Stancampiano Marianna Rita , Meroni Silvia Laura Carla , Bucolo Carmen , Russo Gianni
Published: May 2024

The term ‘differences of sex development’ (DSD) refers to a group of congenital conditions that are associated with atypical development of chromosomal, gonadal, and/or anatomical sex. DSD in individuals with a 46,XX karyotype can occur due to fetal or postnatal exposure to elevated amount of androgens or maldevelopment of internal genitalia. Clinical phenotype could be quite variable and for this reason these conditions could be diagnosed at birth, in newborns with atypical genitalia, but also even later in life, due to progressive virilization during adolescence, or pubertal delay. Understand the physiological development and the molecular bases of gonadal and adrenal structures is crucial to determine the diagnosis and best management and treatment for these patients. The most common cause of DSD in 46,XX newborns is congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency, determining primary adrenal insufficiency and androgen excess. In this review we will focus on the other rare causes of 46,XX DSD, outside CAH, summarizing the most relevant data on genetic, clinical aspects, puberty and fertility outcomes of these rare diseases.
Station-network cooperative planning method of urban integrated energy system based on energy flow model
Authors: Fu Xin , Yu Shunjiang , He Qibo , Wang Long , Niu Chengeng , Yang Li
Published: May 2024

Coordinated siting and sizing for energy stations and supply networks in urban integrated energy system (UIES) is significant for economic improvement and carbon emissions reduction. A station-network cooperative planning method of UIES based on energy flow model is proposed. First, an operation model of heat network based on energy flow theory is proposed, which solves the problem that the temperature mixing equation in the traditional operation model cannot be applied to heat network planning. On this basis, a bi-level model for station-network cooperative planning of UIES is constructed, in which the upper level optimizes the siting and sizing of the energy station and the topology of the supply network, and the lower level optimizes the operation of the UIES and feeds back the operation cost of the UIES to the upper level. Finally, a solution method of cooperative planning based on the Karush-Kuhn-Tucher condition is proposed, to transform the bi-level nonlinear optimization model into a single-level linear optimization model for efficient solution. Case studies on the 55-node and 77-road urban topology show that the proposed method can perform an effective planning on energy supply network topology and rationally configure the capacity of various devices in the energy station.
Multi-dimensional potential assessment of grid-connected mega-scale floating PV power plants across heterogeneous climatic zones
Authors: Mumtaz Amna , Abbas Kazmi Syed Ali , Altamimi Abdullah , Khan Zafar A. , Alyami Saeed
Published: May 2024

Floating Photovoltaic (FPV) systems are gradually becoming more desirable due to a multitude of reasons, encompassing proximity to urban water reservoirs (facilitating city access) and their technical advantages. Climate change potentially presents risks of drought and FPV can potentially benefit by providing clean energy as well as saving water from evaporation. However, detailed studies are required to comprehensively evaluate the potential of FPV considering not only the technical parameters but evaluating the climatic effects as well. This paper presents an integrated multi-dimensional framework for the analysis of 2.5 MW grid-connected FPV systems over different climatic zones. In the first layer, a techno-economic and performance evaluation is carried out by fine-tuning different inputs of systems to make it ideal for proposed analyses under actual FPV conditions. Similarly, in the second layer environmental along with forest absorbing carbon analyses are performed. While socio analysis observed in the third fold is based on various SDGs and their indicators. Results reveal that the Dam with cold in winter and hot in summer climate conditions observed a most feasible site with a Levelized cost of energy (LCOE) of $0.047/kWh and a Net present value (NPV) of million $1.7705, respectively. In contrast, a Dam with mild cold climate conditions proves the least feasible site with LCOE of $0.057/kWh and NPV of million $1.0256, respectively. Similarly, the former Dam saved 20.50% higher CO2 emissions as compared to the latter, as well as required hectares of forest absorbing carbon. A comparative analysis observes a capacity factor of 22% and a performance ratio (PR) of 5%–10% higher as compared to solar photovoltaic (SPV) for dams with extreme weather.
Genetic variants in DBC1, SIRT1, UCP2 and ADRB2 as potential biomarkers for severe obesity and metabolic complications
Authors: da Fonseca Ana Carolina Proença , Assis Izadora Sthephanie da Silva , Salum Kaio Cezar Rodrigues , Palhinha Lohanna , Abreu Gabriella de Medeiros , Zembrzuski Verônica Marques , Campos Junior Mario , Nogueira-Neto José Firmino , Cambraia Amanda , Souza Junior Mauro Lucio Ferreira , Maya-Monteiro Clarissa Menezes , Cabello Pedro Hernán , Bozza Patrícia Torres , Carneiro João Regis Ivar
Published: May 2024

Introduction

Obesity is a multifactorial disease associated with the development of many comorbidities. This disease is associated with several metabolic alterations; however, it has been shown that some individuals with obesity do not exhibit metabolic syndrome. Adipose tissue neutralizes the detrimental effects of circulating fatty acids, ectopic deposition, and inflammation, among others, through its esterification into neutral lipids that are stored in the adipocyte. However, when the adipocyte is overloaded, i.e., its expansion capacity is exceeded, this protection is lost, resulting in fatty acid toxicity with ectopic fat accumulation in peripheral tissues and inflammation. In this line, this study aimed to investigate whether polymorphisms in genes that control adipose tissue fat storage capacity are potential biomarkers for severe obesity susceptibility and also metabolic complications.

Methods

This study enrolled 305 individuals with severe obesity (cases, BMI≥35 kg/m2) and 196 individuals with normal weight (controls, 18.5≤BMI≤24.9 kg/m2). Demographic, anthropometric, biochemical, and blood pressure variables were collected from the participants. Plasma levels of leptin, resistin, MCP1, and PAI1 were measured by Bio-Plex 200 Multiplexing Analyzer System. Genomic DNA was extracted and variants in DBC1 (rs17060940), SIRT1 (rs7895833 and rs1467568), UCP2 (rs660339), PPARG (rs1801282) and ADRB2 (rs1042713 and rs1042714) genes were genotyped by PCR allelic discrimination using TaqMan® assays.

Results

Our findings indicated that SIRT1 rs7895833 polymorphism was a risk factor for severe obesity development in the overdominant model. SIRT1 rs1467568 and UCP2 rs660339 were associated with anthropometric traits. SIRT1 rs1467568 G allele was related to lower medians of body adipose index and hip circumference, while the UCP2 rs660339 AA genotype was associate with increased body mass index. Additionally, DBC1 rs17060940 influenced glycated hemoglobin. Regarding metabolic alterations, 27% of individuals with obesity presented balanced metabolic status in our cohort. Furthermore, SIRT1 rs1467568 AG genotype increased 2.5 times the risk of developing metabolic alterations. No statistically significant results were observed with Peroxisome Proliferator-Activated Receptor Gama and ADRB2 polymorphisms.

Discussion/Conclusion

This study revealed that SIRT1 rs7895833 and rs1467568 are potential biomarkers for severe obesity susceptibility and the development of unbalanced metabolic status in obesity, respectively. UCP2 rs660339 and DBC1 rs17060940 also showed a significant role in obesity related-traits.
Clinical outcomes of immune checkpoint inhibitor combined with other targeted or immunological therapy regimens for the treatment of advanced bile tract cancer: a systematic review and meta-analysis
Authors: Zhou Jianpeng , Li Jia , Fan Zhongqi , Lv Guoyue , Wang Guangyi
Published: May 2024

Background and aims

A single immune checkpoint inhibitor (ICI) regimen has limited value in treating advanced bile tract cancer (BTC); therefore, ICI combination therapy is often applied. This meta-analysis aimed to evaluate the effectiveness and safety of ICI combination therapy for advanced BTC.

Methods

The study protocol was registered on PROSPERO (CRD42023452422). Data on the median progression-free survival (PFS), median overall survival (OS), objective response rate (ORR), disease control rate (DCR), and grade ≥3 adverse events (AEs) reported in relevant studies were pooled and analyzed to determine the efficacy and safety of ICI combination therapy.

Results

In total, 15 studies with 665 patients were included in this meta-analysis. The overall ORR and DCR were 34.6% and 77.6%, respectively. The overall median PFS and OS were 6.06 months [95% confidence interval (CI): 4.91–7.21] and 12.11 months (95% CI: 10.66–13.55), respectively. Patients receiving ICI combination therapy in addition to other therapies had a considerably prolonged median PFS and OS (z=9.69, p<0.001 and z=16.17, p<0.001). Patients treated as first-line treatment had a substantially longer median PFS and OS compared to patients treated as non-first-line treatment (z=11.19, p<0.001 and z=49.17, p<0.001). The overall pooled grade ≥3 AEs rate was 38.2% (95% CI: 0.268–0.497) and was not influenced by whether ICI therapy was combined with other treatments or not or the treatment line.

Conclusion

Advanced BTC patients may benefit from ICI combination treatment without additional AEs. However, concurrent chemotherapy or radiotherapy is still needed to achieve better outcomes.

Systematic review registration

https://www.crd.york.ac.uk/prospero/, identifier CRD42023452422.
Immunocytes interact directly with cancer cells in the tumor microenvironment: one coin with two sides and future perspectives
Authors: Ye Zhiyi , Cheng Pu , Huang Qi , Hu Jingjing , Huang Liming , Hu Guoming
Published: May 2024

The tumor microenvironment is closely linked to the initiation, promotion, and progression of solid tumors. Among its constitutions, immunologic cells emerge as critical players, facilitating immune evasion and tumor progression. Apart from their indirect impact on anti-tumor immunity, immunocytes directly influence neoplastic cells, either bolstering or impeding tumor advancement. However, current therapeutic modalities aimed at alleviating immunosuppression from regulatory cells on effector immune cell populations may not consistently yield satisfactory results in various solid tumors, such as breast carcinoma, colorectal cancer, etc. Therefore, this review outlines and summarizes the direct, dualistic effects of immunocytes such as T cells, innate lymphoid cells, B cells, eosinophils, and tumor-associated macrophages on tumor cells within the tumor microenvironment. The review also delves into the underlying mechanisms involved and presents the outcomes of clinical trials based on these direct effects, aiming to propose innovative and efficacious therapeutic strategies for addressing solid tumors.
Interpretable machine learning for predicting the response duration to Sintilimab plus chemotherapy in patients with advanced gastric or gastroesophageal junction cancer
Authors: Wang Dan-qi , Xu Wen-huan , Cheng Xiao-wei , Hua Lei , Ge Xiao-song , Liu Li , Gao Xiang
Published: May 2024

Background

Sintilimab plus chemotherapy has proven effective as a combination immunotherapy for patients with advanced gastric and gastroesophageal junction adenocarcinoma (GC/GEJC). A multi-center study conducted in China revealed a median progression-free survival (PFS) of 7.1 months. However, the prediction of response duration to this immunotherapy has not been thoroughly investigated. Additionally, the potential of baseline laboratory features in predicting PFS remains largely unexplored. Therefore, we developed an interpretable machine learning (ML) framework, iPFS-SC, aimed at predicting PFS using baseline (pre-treatment) laboratory features and providing interpretations of the predictions.

Materials and methods

A cohort of 146 patients with advanced GC/GEJC, along with their baseline laboratory features, was included in the iPFS-SC framework. Through a forward feature selection process, predictive baseline features were identified, and four ML algorithms were developed to categorize PFS duration based on a threshold of 7.1 months. Furthermore, we employed explainable artificial intelligence (XAI) methodologies to elucidate the relationship between features and model predictions.

Results

The findings demonstrated that LightGBM achieved an accuracy of 0.70 in predicting PFS for advanced GC/GEJC patients. Furthermore, an F1-score of 0.77 was attained for identifying patients with PFS durations shorter than 7.1 months. Through the feature selection process, we identified 11 predictive features. Additionally, our framework facilitated the discovery of relationships between laboratory features and PFS.

Conclusion

A ML-based framework was developed to predict Sintilimab plus chemotherapy response duration with high accuracy. The suggested predictive features are easily accessible through routine laboratory tests. Furthermore, XAI techniques offer comprehensive explanations, both at the global and individual level, regarding PFS predictions. This framework enables patients to better understand their treatment plans, while clinicians can customize therapeutic approaches based on the explanations provided by the model.
Using chlorophyllic organic matter degradation in the deep St. Lawrence Estuary as an indicator of water column remineralization
Authors: Lévesque David , Lebeuf Michel , Starr Michel
Published: May 2024

Coastal hypoxia, driven by remineralization of chlorophyllic particulate organic matter (POM) in dark environments, poses a threat to deep estuarine and shelf ecosystems. To better understand the fate of POM along a depth gradient, we investigated the degradation of chloropigments, particulate organic carbon (POC), and nitrogen (PON) across the water column in the St. Lawrence Estuary, one of the largest and deepest estuarine system in the world that is facing strong persistent and increasing hypoxia. Our objectives were to establish causal relationships among suspended POM descriptors and assess the potential of a chlorophyll-based degradation index, known as the chlorin index (CI), in evaluating OM degradation within the water column. The CI, ranging from 0.2 for pure chlorophyll to almost 1 for highly degraded pigments, was initially developed for uses in the sediments. Water samples from multiple depths were collected, characterized, and statistically analyzed with a combination of variation partitioning, non-linear regressions and piecewise structural equation modeling (pSEM). We found that the combined influence of chloropigments and depth explained 84.0% of POC and 90.0% of PON variations; the pure fraction attributed to chloropigments accounted for 73.4% and 75.6% (R2adj, both with p< 0.001), respectively. The decline of chloropigments, PON, and POC with increasing depth was reflected by the concomitant increase in CI, whose rate decreases as particles sink resulting in reduced degradation due to less labile organic matter. The pSEM causal model indicated that CI increased with depth and POC concentration, while it decreased in the presence of elevated PON concentrations, known for their high reactivity. The direct effect of depth on CI could be linked to the distinct water column properties influencing particle residence time and thus the degradation potential by biotic and abiotic factors. Finally, CI explained 86% (R2) of the apparent oxygen utilization highlighting the strong connection between POM degradation and hypoxia of deep coastal ecosystems. Our study underscores the utility of the chlorin index as a simple yet robust tool for monitoring OM degradation in the water column, particularly in the St. Lawrence Estuary.
Clinical implications of synovial tissue phenotypes in rheumatoid arthritis
Authors: Bykerk Vivian P.
Published: May 2024

Autoimmune forms of inflammatory arthritis, such as Rheumatoid Arthritis (RA), are clinically heterogeneous in presentation and disease course. Treatment-related outcomes vary despite patient exposure to similar treatment strategies. It is likely that variation seen in synovial pathogenesis influences outcomes and is heterogeneous outcomes influenced by patient factors, including environmental exposures, microbiota, behaviors, timely access to therapy, and synovial cell variation. Patients’ unique complex factors manifest as specific synovial phenotypes characterized by clusters of synovial cell types and states. Precision medicine aims to use such clinical and biological data to identify the right treatment for the right patient at the right time, enabling patients to achieve sustained remission. Identifying synovial targets susceptible to a given treatment, enabling the choice of effective therapy for a given patient, will realize the goals of precision medicine. Over the last 7 years, improved acquisition and processing of synovial tissue obtained by ultra-sound guided biopsy has enabled researchers to define synovial pathotypes using histologic features and predominant cell types associated with clinical manifestations. Technical advances have enabled single-cell simultaneous sequencing of proteins and gene expression that, through increasingly sophisticated bioinformatics methods, have taken transcriptional and proteomic data to identify diverse and novel cell types and states that cluster in the RA synovium to further define patient subgroups. Synovial pathotypes and endotypes are now integrated into clinical studies and trials to explain clinical heterogeneity in disease course and treatment response. Rapidly evolving clinical-translational research has linked an expanded understanding of RA synovial pathogenesis with clinically meaningful subgroups and treatment outcomes and the clinical heterogeneity in RA.
What improvements do general exercise training and traditional Chinese exercises have on knee osteoarthritis? A narrative review based on biological mechanisms and clinical efficacy
Authors: Du Xingbin , Fan Rao , Kong Jianda
Published: May 2024

Background

Knee osteoarthritis (KOA) is a disease that significantly affects the quality of life of patients, with a complex pathophysiology that includes degeneration of cartilage and subchondral bone, synovitis, and associations with mechanical load, inflammation, metabolic factors, hormonal changes, and aging.

Objective

This article aims to comprehensively review the biological mechanisms and clinical effects of general exercise training and traditional Chinese exercises (such as Tai Chi and Qigong) on the treatment of KOA, providing references for the development of clinical exercise prescriptions.

Methods

A systematic search of databases including PubMed, Web of Science, Google Scholar, and China National Knowledge Infrastructure (CNKI) was conducted, reviewing studies including randomized controlled trials (RCTs), observational studies, systematic reviews, and meta-analyses. Keywords included “knee osteoarthritis,” “exercise therapy,” “physical activity,” and “traditional Chinese exercise.”

Results and conclusion

General exercise training positively affects KOA by mechanisms such as promoting blood circulation, improving the metabolism of inflammatory factors, enhancing the expression of anti-inflammatory cytokines, and reducing cartilage cell aging. Traditional Chinese exercises, like Tai Chi and Qigong, benefit the improvement of KOA symptoms and tissue repair by regulating immune function and alleviating joint inflammation. Clinical studies have shown that both types of exercise can improve physical function, quality of life, and pain relief in patients with KOA. Both general exercise training and traditional Chinese exercises are non-pharmacological treatment options for KOA that can effectively improve patients’ physiological function and quality of life. Future research should further explore the long-term effects and biological mechanisms of these exercise interventions and develop personalized exercise programs based on the specific needs of patients.
Goethite dissolution by acidophilic bacteria
Authors: Stanković Srdjan , Schippers Axel
Published: May 2024

Previous studies have reported the role of some species of acidophilic bacteria in accelerating the dissolution of goethite under aerobic and anaerobic conditions. This has relevance for environments impacted by acid mine drainage and for the potential bioleaching of limonitic laterite ores. In this study, natural well-characterized goethite mineral samples and synthetic goethite were used in aerobic and anaerobic laboratory batch culture incubation experiments with ferric iron-reducing, acidophilic bacteria, including the lithoautotrophic species Acidithiobacillus (At.) thiooxidans, At. ferrooxidans, and At. caldus, as well as two strains of the organoheterotrophic species Acidiphilium cryptum. All bacteria remained alive throughout the experiments and efficiently reduced soluble ferric iron in solution in positive control assays. However, goethite dissolution was low to negligible in all experimental assays with natural goethite, while some dissolution occurred with synthetic goethite in agreement with previous publications. The results indicate that ferric iron-reducing microbial activity at low pH is less relevant for goethite dissolution than the oxidation of elemental sulfur to sulfuric acid. Microbial ferric iron reduction enhances but does not initiate goethite dissolution in very acidic liquors.
Effects of nitrogen application on ammonium assimilation and microenvironment in the rhizosphere of drip-irrigated sunflower under plastic mulch
Authors: Chi Zhaonan , Li Yuxin , Zhang Jiapeng , Hu Min , Wu Yixuan , Fan Xueqin , Li Zhen , Miao Qingfeng , Li Weiping
Published: May 2024

This study investigated the effect of nitrogen application on the rhizosphere soil microenvironment of sunflower and clarified the relationship between ammonium assimilation and the microenvironment. In a field experiment high (HN, 190 kg/hm2), medium (MN, 120 kg/hm2) and low nitrogen (CK, 50 kg/hm2) treatments were made to replicate plots of sunflowers using drip irrigation. Metagenomic sequencing was used to analyze the community structure and functional genes involved in the ammonium assimilation pathway in rhizosphere soil. The findings indicated that glnA and gltB played a crucial role in the ammonium assimilation pathway in sunflower rhizosphere soil, with Actinobacteria and Proteobacteria being the primary contributors. Compared with CK treatment, the relative abundance of Actinobacteria increased by 15.57% under MN treatment, while the relative abundance decreased at flowering and maturation stages. Conversely, the relative abundance of Proteobacteria was 28.57 and 61.26% higher in the MN treatment during anthesis and maturation period, respectively, compared with the CK. Furthermore, during the bud stage and anthesis, the abundance of Actinobacteria, Proteobacteria, and their dominant species were influenced mainly by rhizosphere soil EC, ammonium nitrogen (NH4+-N), and nitrate nitrogen (NO3--N), whereas, at maturity, soil pH and NO3--N played a more significant role in shaping the community of ammonium-assimilating microorganisms. The MN treatment increased the root length density, surface area density, and root volume density of sunflower at the bud, flowering, and maturity stages compared to the CK. Moreover, root exudates such as oxalate and malate were positively correlated with the dominant species of Actinobacteria and Proteobacteria during anthesis and the maturation period. Under drip irrigation, applying 120 kg/hm2 of nitrogen to sunflowers effectively promoted the community structure of ammonium-assimilating microorganisms in rhizosphere soil and had a positive influence on the rhizosphere soil microenvironment and sunflower root growth.
Carbonate precipitation and phosphate trapping by microbialite isolates from an alkaline insular lake (Bagno dell'Acqua, Pantelleria Island, Italy)
Authors: Mazzoni Cristina , Piacentini Agnese , Di Bella Letizia , Aldega Luca , Perinelli Cristina , Conte Aida Maria , Ingrassia Michela , Ruspandini Tania , Bonfanti Andrea , Caraba Benedetta , Falese Francesco Giuseppe , Chiocci Francesco Latino , Fazi Stefano
Published: May 2024

The Bagno dell'Acqua lake is characterized by CO2 emissions, alkaline waters (pH = 9) and Eh values which indicate strongly oxidizing conditions. A typical feature of the lake is the presence of actively growing microbialites rich in calcium carbonates and silica precipitates. Mineralogy, petrography and morphology analyses of the microbialites were coupled with the analysis of the microbial community, combining molecular and cultivation approaches. The DNA sequencing revealed distinct patterns of microbial diversity, showing pronounced differences between emerged and submerged microbialite, with the upper layer of emerged samples exhibiting the most distinctive composition, both in terms of prokaryotes and eukaryotes. In particular, the most representative phyla in the microbial community were Proteobacteria, Actinobacteriota, and Bacteroidota, while Cyanobacteria were present only with an average of 5%, with the highest concentration in the submerged intermediate layer (12%). The role of microorganisms in carbonate mineral formation was clearly demonstrated as most of the isolates were able to precipitate calcium carbonate and five of them were characterized at molecular level. Interestingly, when microbial isolates were cultivated only in filtered water, the precipitation of hazenite was observed (up to 85%), opening new prospective in P (phosphate) recovery from P depleted environments.
Screening of drug targets for tuberculosis on the basis of transcription factor regulatory network and mRNA sequencing technology
Authors: Wang Shuai , Yan Na , Yang Yue , Sun Li , Huang Yingxin , Zhang Jian , Xu Guangyu
Published: May 2024

Background

Tuberculosis is a worldwide epidemic disease, posing a serious threat to human health. To find effective drug action targets for Mycobacterium tuberculosis, differentially expressed genes in tuberculosis patients and healthy people were screened by mRNA sequencing in this study. A total of 556 differentially expressed genes in tuberculosis patients and healthy people were screened out by mRNA sequencing technology. 26 transcription factors and 66 corresponding target genes were screened out in the AnimalTFDB 3.0 database, and a transcription factor regulatory network was constructed.

Results

Three key transcription factors (TP53, KLF5 and GATA2) and one key gene (AKT1) were screened as new potential drug targets and diagnostic targets for tuberculosis by MCODE cluster analysis, and the key genes and key transcription factors were verified by RT-PCR. Finally, we constructed the and a key factor and KEGG signaling pathway regulatory network to clarify the possible molecular pathogenesis of tuberculosis.

Conclusion

This study suggested M. tuberculosis may activate the AKT1 gene expression by regulating transcription factors TP53, KLF5, and GATA2, thus activating the B cell receptor signaling pathway to induce the infection and invasion of M. tuberculosis. AKT1, TP53, KLF5, and GATA2 can be used as new potential drug targets for tuberculosis.
P-hydroxybenzaldehyde protects Caenorhabditis elegans from oxidative stress and β-amyloid toxicity
Authors: Yu Xingzhi , Tao Jie , Xiao Tian , Duan Xiaohua
Published: May 2024

Introduction

Gastrodia elata is the dried tuber of the orchid Gastrodia elata Bl. It is considered a food consisting of a source of precious medicinal herbs, whose chemical composition is relatively rich. Gastrodia elata and its extracted fractions have been shown to have neuroprotective effects. P-hydroxybenzaldehyde (p-HBA), as one of the main active components of Gastrodia elata, has anti-inflammatory, antioxidative stress, and cerebral protective effects, which has potential for the treatment of Alzheimer’s disease (AD). The aim of this study was to verify the role of p-HBA in AD treatment and to investigate its mechanism of action in depth based using the Caenorhabditis elegans (C. elegans) model.

Methods

In this study, we used paralysis, lifespan, behavioral and antistress experiments to investigate the effects of p-HBA on AD and aging. Furthermore, we performed reactive oxygen species (ROS) assay, thioflavin S staining, RNA-seq analysis, qPCR validation, PCR Array, and GFP reporter gene worm experiment to determine the anti-AD effects of p-HBA, as well as in-depth studies on its mechanisms.

Results

p-HBA was able to delay paralysis, improve mobility and resistance to stress, and delay aging in the AD nematode model. Further mechanistic studies showed that ROS and lipofuscin levels, Aβ aggregation, and toxicity were reduced after p-HBA treatment, suggesting that p-HBA ameliorated Aβ-induced toxicity by enhancing antioxidant and anti-aging activity and inhibiting Aβ aggregation. p-HBA had a therapeutic effect on AD by improving stress resistance, as indicated by the down-regulation of NLP-29 and UCR-11 expression and up-regulation of PQN-75 and LYS-3 expression. In addition, the gene microarray showed that p-HBA treatment played a positive role in genes related to AD, anti-aging, ribosomal protein pathway, and glucose metabolism, which were collectively involved in the anti-AD mechanism of p-HBA. Finally, we also found that p-HBA promoted nuclear localization of DAF-16 and increased the expression of SKN-1, SOD-3, and GST-4, which contributed significantly to inhibition of Aβ toxicity and enhancement of antioxidative stress.

Conclusion

Our work suggests that p-HBA has some antioxidant and anti-aging activities. It may be a viable candidate for the treatment and prevention of Alzheimer’s disease.
Synaptic vesicle release regulates pre-myelinating oligodendrocyte-axon interactions in a neuron subtype-specific manner
Authors: Gronseth James R. , Nelson Heather N. , Johnson Taylor L. , Mallon Taryn A. , Martell Madeline R. , Pfaffenbach Katrina A. , Duxbury Bailey B. , Henke John T. , Treichel Anthony J. , Hines Jacob H.
Published: May 2024

Oligodendrocyte-lineage cells are central nervous system (CNS) glia that perform multiple functions including the selective myelination of some but not all axons. During myelination, synaptic vesicle release from axons promotes sheath stabilization and growth on a subset of neuron subtypes. In comparison, it is unknown if pre-myelinating oligodendrocyte process extensions selectively interact with specific neural circuits or axon subtypes, and whether the formation and stabilization of these neuron–glia interactions involves synaptic vesicle release. In this study, we used fluorescent reporters in the larval zebrafish model to track pre-myelinating oligodendrocyte process extensions interacting with spinal axons utilizing in vivo imaging. Monitoring motile oligodendrocyte processes and their interactions with individually labeled axons revealed that synaptic vesicle release regulates the behavior of subsets of process extensions. Specifically, blocking synaptic vesicle release decreased the longevity of oligodendrocyte process extensions interacting with reticulospinal axons. Furthermore, blocking synaptic vesicle release increased the frequency that new interactions formed and retracted. In contrast, tracking the movements of all process extensions of singly-labeled oligodendrocytes revealed that synaptic vesicle release does not regulate overall process motility or exploratory behavior. Blocking synaptic vesicle release influenced the density of oligodendrocyte process extensions interacting with reticulospinal and serotonergic axons, but not commissural interneuron or dopaminergic axons. Taken together, these data indicate that alterations to synaptic vesicle release cause changes to oligodendrocyte-axon interactions that are neuron subtype specific.
Elucidating the interaction between stretch and stiffness using an agent-based spring network model of progressive pulmonary fibrosis
Authors: Hall Joseph K. , Bates Jason H. T. , Krishnan Ramaswamy , Kim Jae Hun , Deng Yuqing , Lutchen Kenneth R. , Suki Béla
Published: May 2024

Pulmonary fibrosis is a deadly disease that involves the dysregulation of fibroblasts and myofibroblasts, which are mechanosensitive. Previous computational models have succeeded in modeling stiffness-mediated fibroblasts behaviors; however, these models have neglected to consider stretch-mediated behaviors, especially stretch-sensitive channels and the stretch-mediated release of latent TGF-β. Here, we develop and explore an agent-based model and spring network model hybrid that is capable of recapitulating both stiffness and stretch. Using the model, we evaluate the role of mechanical signaling in homeostasis and disease progression during self-healing and fibrosis, respectively. We develop the model such that there is a fibrotic threshold near which the network tends towards instability and fibrosis or below which the network tends to heal. The healing response is due to the stretch signal, whereas the fibrotic response occurs when the stiffness signal overpowers the stretch signal, creating a positive feedback loop. We also find that by changing the proportional weights of the stretch and stiffness signals, we observe heterogeneity in pathological network structure similar to that seen in human IPF tissue. The system also shows emergent behavior and bifurcations: whether the network will heal or turn fibrotic depends on the initial network organization of the damage, clearly demonstrating structure’s pivotal role in healing or fibrosis of the overall network. In summary, these results strongly suggest that the mechanical signaling present in the lungs combined with network effects contribute to both homeostasis and disease progression.
Neurocognitive outcome in children with sickle cell disease after myeloimmunoablative conditioning and haploidentical hematopoietic stem cell transplantation: a non-randomized clinical trial
Authors: Braniecki Suzanne , Vichinsky Elliott , Walters Mark C. , Shenoy Shalini , Shi Qiuhu , Moore Theodore B. , Talano Julie-An , Parsons Susan K. , Flower Allyson , Panarella Anne , Fabricatore Sandra , Morris Erin , Mahanti Harshini , Milner Jordan , McKinstry Robert C. , Duncan Christine N. , van de Ven Carmella , Cairo Mitchell S.
Published: May 2024

Background

Due to the risk of cerebral vascular injury, children and adolescents with high-risk sickle cell disease (SCD) experience neurocognitive decline over time. Haploidentical stem cell transplantation (HISCT) from human leukocyte antigen-matched sibling donors may slow or stop progression of neurocognitive changes.

Objectives

The study is to determine if HISCT can ameliorate SCD-associated neurocognitive changes and prevent neurocognitive progression, determine which specific areas of neurocognitive functioning are particularly vulnerable to SCD, and determine if there are age-related differences in neurocognitive functioning over time.

Methods

We performed neurocognitive and neuroimaging in SCD recipients following HISCT. Children and adolescents with high-risk SCD who received parental HISCT utilizing CD34+ enrichment and mononuclear cell (T-cell) addback following myeloimmunoablative conditioning received cognitive evaluations and neuroimaging at three time points: pre-transplant, 1 and 2 years post-transplant.

Results

Nineteen participants (13.1 ± 1.2 years [3.3–20.0]) received HISCT. At 2 years post-transplant, neuroimaging and cognitive function were stable. Regarding age-related differences pre-transplantation, older children (≥13 years) had already experienced significant decreases in language functioning (p < 0.023), verbal intelligence quotient (p < 0.05), non-verbal intelligence quotient (p < 0.006), and processing speed (p < 0.05), but normalized post-HISCT in all categories.

Conclusion

Thus, HISCT has the potential to ameliorate SCD-associated neurocognitive changes and prevent neurocognitive progression. Further studies are required to determine if neurocognitive performance remains stable beyond 2 years post-HISCT.

Clinical trial registration: The study was conducted under an investigator IND (14359) (MSC) and registered at clinicaltrials.gov (NCT01461837).
Establishment and validation of a 3-month prediction model for poor functional outcomes in patients with acute cardiogenic cerebral embolism related to non-valvular atrial fibrillation
Authors: Hu Lan , Qiao Zhenguo , Xu Mengshi , Feng Jie , Shan Qingting , Sheng Xihua , Xu Guoli , Xu Yuan , Hu Wenze , Wang Guojun , Jin Xuehong
Published: May 2024

Objectives

Cardiogenic cerebral embolism (CCE) poses a significant health risk; however, there is a dearth of published prognostic prediction models addressing this issue. Our objective is to establish prognostic prediction models (PM) for predicting poor functional outcomes at 3 months in patients with acute CCE associated with non-valvular atrial fibrillation (NVAF) and perform both internal and external validations.

Methods

We included a total of 730 CCE patients in the development cohort. The external regional validation cohort comprised 118 patients, while the external time-sequential validation cohort included 63 patients. Multiple imputation by chained equations (MICE) was utilized to address missing values and the least absolute shrink and selection operator (LASSO) regression was implemented through the glmnet package, to screen variables.

Results

The 3-month prediction model for poor functional outcomes, denoted as N-ABCD2, was established using the following variables: NIHSS score at admission (N), Age (A), Brain natriuretic peptide (BNP), C-reactive protein (CRP), D-dimer polymers (D), and discharge with antithrombotic medication (D). The model’s Akaike information criterion (AIC) was 637.98, and the area under Curve (AUC) for the development cohort, external regional, and time-sequential cohorts were 0.878 (95% CI, 0.854–0.902), 0.918 (95% CI, 0.857–0.979), and 0.839 (95% CI, 0.744–0.934), respectively.

Conclusion

The N-ABCD2 model can accurately predict poor outcomes at 3 months for CCE patients with NVAF, demonstrating strong prediction abilities. Moreover, the model relies on objective variables that are readily obtainable in clinical practice, enhancing its convenience and applicability in clinical settings.
Narrative analysis in individuals with Parkinson’s disease following intensive voice treatment: secondary outcome variables from a randomized controlled trial
Authors: Ramage Amy E. , Greenslade Kathryn J. , Cote Kaila , Lee Jessica N. , Fox Cynthia M. , Halpern Angela , Ramig Lorraine O.
Published: May 2024

Communication is often impaired in individuals with Parkinson’s disease (PD), typically secondary to sensorimotor deficits impacting voice and speech. Language may also be diminished in PD, particularly for production and comprehension of verbs. Evidence exists that verb processing is influenced by motor system modulation suggesting that verb deficits in PD are underpinned by similarities in the neural representations of actions that span motor and semantic systems. Conversely, subtle differences in cognition in PD may explain difficulty in processing of complex syntactic forms, which increases cognitive demand and is linked to verb use. Here we investigated whether optimizing motor system support for vocal function (improving loudness) affects change in lexical semantic, syntactic, or informativeness aspects of spoken discourse. Picture description narratives were compared for 20 Control participants and 39 with PD, 19 of whom underwent Lee Silverman Voice Treatment (LSVT LOUD®). Treated PD narratives were also contrasted with those of untreated PD and Control participants at Baseline and after treatment. Controls differed significantly from the 39 PD participants for verbs per utterance, but this difference was largely driven by untreated PD participants who produced few utterances but with verbs, inflating their verbs per utterance. Given intervention, there was a significant increase in vocal loudness but no significant changes in language performance. These data do not support the hypothesis that targeting this speech motor system results in improved language production. Instead, the data provide evidence of considerable variability in measures of language production across groups, particularly in verbs per utterance.
Breast metastasis from lung adenocarcinoma: a case report and review of the literature
Authors: Ding Jialing , Gu Huayan , Yang Zhi , Lu Yiqiao , Guo Guilong
Published: May 2024

Lung cancer (LC) is one of the most lethal and most prevalent malignant tumors, and lung adenocarcinoma (LUAD) is the most common pathological type of lung cancer. Breast cancer (BC) is the most common cancer worldwide, but metastases to the breast from extramammary neoplasms are rare, especially from the lung. Early diagnosis and differentiation of primary from metastatic breast carcinoma are essential. Here, we present a case of metastases to the breast from lung adenocarcinoma, the treatment options varied according to disease progression.
Multidimensional biological characteristics of ground glass nodules
Authors: Chen Furong , Li Jiangtao , Li Lei , Tong Lunbing , Wang Gang , Zou Xuelin
Published: May 2024

The detection rate of ground glass nodules (GGNs) has increased in recent years because of their malignant potential but relatively indolent biological behavior; thus, correct GGN recognition and management has become a research focus. Many scholars have explored the underlying mechanism of the indolent progression of GGNs from several perspectives, such as pathological type, genomic mutational characteristics, and immune microenvironment. GGNs have different major mutated genes at different stages of development; EGFR mutation is the most common mutation in GGNs, and p53 mutation is the most abundant mutation in the invasive stage of GGNs. Pure GGNs have fewer genomic alterations and a simpler genomic profile and exhibit a gradually evolving genomic mutation profile as the pathology progresses. Compared to advanced lung adenocarcinoma, GGN lung adenocarcinoma has a higher immune cell percentage, is under immune surveillance, and has less immune escape. However, as the pathological progression and solid component increase, negative immune regulation and immune escape increase gradually, and a suppressive immune environment is established gradually. Currently, regular computer tomography monitoring and surgery are the main treatment strategies for persistent GGNs. Stereotactic body radiotherapy and radiofrequency ablation are two local therapeutic alternatives, and systemic therapy has been progressively studied for lung cancer with GGNs. In the present review, we discuss the characterization of the multidimensional molecular evolution of GGNs that could facilitate more precise differentiation of such highly heterogeneous lesions, laying a foundation for the development of more effective individualized treatment plans.
Clinicopathological characteristics and prognosis of synchronous brain metastases from non-small cell lung cancer compared with metachronous brain metastases
Authors: Li Jing , Zhang Xiaofang , Wang Ye , Jin Yi , Song Yingqiu , Wang Tianlu
Published: May 2024

Purpose

Brain metastasis (BM) from non-small cell lung cancer (NSCLC) is a serious complication severely affecting patients’ prognoses. We aimed to compare the clinicopathological features and prognosis of synchronous and metachronous BM from NSCLC.

Methods

Clinical data of 461 patients with brain metastases from NSCLC who visited the Cancer Hospital of China Medical University from 2005 to 2017 were retrospectively collected. We analyzed the pathophysiological characteristics of synchronous and metachronous BM from NSCLC and survival rates of the patients. Propensity score matching analysis was used to reduce bias between groups. In addition, we used the Kaplan-Meier method for survival analysis, log-rank test to compare survival rates, and Cox proportional hazards regression model for multivariate prognosis analysis.

Results

Among 461 patients with BM, the number of people who met the inclusion criteria was 400 cases, and after 1:2 propensity score matching,130 had synchronous BM and 260 had metachronous BM. The survival time was longer for metachronous BM in driver mutation-negative patients with squamous cell carcinoma than synchronous BM. Conversely, metachronous and synchronous BM with gene mutations and adenocarcinoma showed no differences in survival time. Multivariate analysis showed that metachronous BM was an independent prognostic factor for overall survival. Furthermore, the pathological type squamous cell carcinoma and Karnofsky Performance Status score <80 were independent risk factors affecting overall survival.

Conclusion

BM status is an independent factor influencing patient outcome. Moreover, synchronous and metachronous BM from NSCLC differ in gene mutation profile, pathological type, and disease progression and hence require different treatments.