bluuebunny/crossref_metadata_2025 huggingface dataset:
A Victorian Dantofilo: Henry Clark Barlow’s Paradiso 7
Authors: Gillespie Stuart
Published: July 2024

Henry Clark Barlow (1806–1876) was a lifelong student of Dante, publishing copious amounts of scholarship and a major edition of the Divina Commedia. He was also given to composing English poetry. He translated just one canto of Dante’s Commedia into English verse, which he never published: Paradiso 7. In this note the translation is introduced and transcribed from the University College London archive containing Barlow’s papers.
Preparation of microspheres with sustained ketoprofen release by electrospray for the treatment of aseptic inflammation
Authors: Dai Xinyi , Nie Wei , Duan Chuanyou , Shen Yi
Published: July 2024

The treatment of aseptic inflammation has always been a clinical challenge. At present, non-steroidal drug-loaded microspheres have been widely used in the treatment of aseptic inflammation due to their excellent injectable and sustained release capabilities. In this study, ketoprofen-loaded shellac microspheres (Keto-SLAC) were prepared by electrospray. Alterations of Keto-SLAC morphology was observed in response to changed shellac concentration in ethanol solution through electrospray. Further examination revealed that ketoprofen presented as amorphous solid dispersion in the shellac microspheres. Most importantly, it was also shown that ketoprofen can be slowly released from the shellac matrix for up to 3 weeks. In vitro cell experiments verified that the microspheres had favorable cell compatibility. We therefore proposed that the prepared microspheres, being readily available in use in a variety of clinical settings through topical application, have promising therapeutic potential for the treatment of aseptic inflammation.
Spatial immune landscapes of SARS-CoV-2 gastrointestinal infection: macrophages contribute to local tissue inflammation and gastrointestinal symptoms
Authors: Xian Shi-Ping , Li Zhan-Yu , Li Wei , Yang Peng-Fei , Huang Shen-Hao , Liu Ye , Tang Lei , Lai Jun , Zeng Fa-Min , He Jian-Zhong , Liu Yang
Published: July 2024

Background

In some patients, persistent gastrointestinal symptoms like abdominal pain, nausea, and diarrhea occur as part of long COVID-19 syndrome following acute respiratory symptoms caused by SARS-CoV-2. However, the characteristics of immune cells in the gastrointestinal tract of COVID-19 patients and their association with these symptoms remain unclear.

Methodology

Data were collected from 95 COVID-19 patients. Among this cohort, 11 patients who exhibited gastrointestinal symptoms and underwent gastroscopy were selected. Using imaging mass cytometry, the gastrointestinal tissues of these patients were thoroughly analyzed to identify immune cell subgroups and investigate their spatial distribution.

Results

Significant acute inflammatory responses were found in the gastrointestinal tissues, particularly in the duodenum, of COVID-19 patients. These alterations included an increase in the levels of CD68+ macrophages and CD3+CD4+ T-cells, which was more pronounced in tissues with nucleocapsid protein (NP). The amount of CD68+ macrophages positively correlates with the number of CD3+CD4+ T-cells (R = 0.783, p < 0.001), additionally, spatial neighborhood analysis uncovered decreased interactions between CD68+ macrophages and multiple immune cells were noted in NP-positive tissues. Furthermore, weighted gene coexpression network analysis was employed to extract gene signatures related to clinical features and immune responses from the RNA-seq data derived from gastrointestinal tissues from COVID-19 patients, and we validated that the MEgreen module shown positive correlation with clinical parameter (i.e., Total bilirubin, ALT, AST) and macrophages (R = 0.84, p = 0.001), but negatively correlated with CD4+ T cells (R = −0.62, p = 0.004). By contrast, the MEblue module was inversely associated with macrophages and positively related with CD4+ T cells. Gene function enrichment analyses revealed that the MEgreen module is closely associated with biological processes such as immune response activation, signal transduction, and chemotaxis regulation, indicating its role in the gastrointestinal inflammatory response.

Conclusion

The findings of this study highlight the role of specific immune cell groups in the gastrointestinal inflammatory response in COVID-19 patients. Gene coexpression network analysis further emphasized the importance of the gene modules in gastrointestinal immune responses, providing potential molecular targets for the treatment of COVID-19-related gastrointestinal symptoms.
Roles of synoptic characteristics and microphysics processes on the heavy rain event over Beijing region during 29 July to 2 August 2023
Authors: Li Xiang , Zhao Shuwen , Wang Donghai
Published: July 2024

The “23.7” event, an extreme rainstorm that affected North China from July 29 to 2 August 2023, was simulated using the Weather Research and Forecasting (WRF) model, version 4.2. We focus on dynamically diagnosing and analyzing the mass and latent heat budgets of rainwater during the extreme precipitation event on July 31 in the Beijing area, where the hourly rainfall reached an extraordinary 111.8 mm. Generally, the model effectively simulated the rainstorm, enabling further assessment of the extreme precipitation. Results indicated that under the combined influence of three major weather systems—the residual circulation of Typhoon Doksuri (a low-pressure system after typhoon landfall), the embryonic stage of Typhoon Khanun, and the North China high-pressure dam—a continuous influx of moisture and energy was transported to the North China region, promoting heavy precipitation. Application of vorticity equation diagnostics indicates that the horizontal transport term is the primary source term. Mass balance analysis reveals that the primary source of rainwater is the accretion of cloud droplets by rain, and the condensation of water vapor into cloud droplets is the main contributor to the latent heat.
Strategic implementation of ED&I: unveiling the multifaceted impact on innovation, governance, and ethical conduct in engineering organizations
Authors: Atescan-Yuksek Yagmur , Patsavellas John , Salonitis Konstantinos
Published: July 2024

In contemporary organizational landscapes, Equity, Diversity, and Inclusion (ED&I) stand as pivotal pillars for fostering innovation, resilience, and sustainable growth. This article explores the critical importance of ED&I within engineering organizations, focusing on the strategies for understanding ED&I dynamics, implementing inclusive environments, and extending ED&I principles through the industrial value chain. It investigates the complexities of individual identities, the significance of intersectionality, and the strategic advantage of diversity for organizational performance. By exploring comprehensive governance of ED&I initiatives, the role of leadership in fostering diversity, and the impact of ED&I on organizational sustainability and innovation, this study provides a holistic view of the challenges and opportunities in creating inclusive workplaces.
Circ_BBS9 as an early diagnostic biomarker for lung adenocarcinoma: direct interaction with IFIT3 in the modulation of tumor immune microenvironment
Authors: Peng Daijun , Liang Mingyu , Li Lingyu , Yang Haisheng , Fang Di , Chen Lingling , Guan Bing
Published: July 2024

Background

Introduction: Circular RNAs (circRNAs) have been identified as significant contributors to the development and advancement of cancer. The objective of this study was to examine the expression and clinical implications of circRNA circ_BBS9 in lung adenocarcinoma (LUAD), as well as its potential modes of action.

Methods

The expression of Circ_BBS9 was examined in tissues and cell lines of LUAD through the utilization of microarray profiling, quantitative real-time polymerase chain reaction (qRT-PCR), and western blot analysis. In this study, we assessed the impact of circ_BBS9 on the proliferation of LUAD cells, as well as its influence on ferroptosis and tumor formation. To analyze these effects, we employed CCK-8 assays and ferroptosis assays. The identification of proteins that interact with Circ_BBS9 was achieved through the utilization of RNA pull-down and mass spectrometry techniques. A putative regulatory network comprising circ_BBS9, miR-7150, and IFIT3 was established using bioinformatics study. The investigation also encompassed the examination of the correlation between the expression of IFIT3 and the invasion of immune cells.

Results

Circ_BBS9 was significantly downregulated in LUAD tissues and cell lines. Low circ_BBS9 expression correlated with poor prognosis. Functional experiments showed that circ_BBS9 overexpression inhibited LUAD cell proliferation and promoted ferroptosis in vitro and suppressed tumor growth in vivo. Mechanistically, circ_BBS9 was found to directly interact with IFIT3 and regulate its expression by acting as a sponge for miR-7150. Additionally, IFIT3 expression correlated positively with immune infiltration in LUAD.

Conclusion

Circ_BBS9 has been identified as a tumor suppressor in lung adenocarcinoma (LUAD) and holds promise as a diagnostic biomarker. The potential mechanism of action involves the modulation of ferroptosis and the immunological microenvironment through direct interaction with IFIT3 and competitive binding to miR-7150. The aforementioned findings offer new perspectives on the pathophysiology of LUAD and highlight circ_BBS9 as a potentially valuable target for therapeutic interventions.
Sialic acids on T cells are crucial for their maintenance and survival
Authors: Schmidt Michael , Linder Alexandra T. , Korn Marina , Schellenberg Nick , Meyer Sarah J. , Nimmerjahn Falk , Werner Anja , Abeln Markus , Gerardy-Schahn Rita , Münster-Kühnel Anja K. , Nitschke Lars
Published: July 2024

Sialic acids are found as terminal sugars on glycan structures on cellular surfaces. T cells carry these sialoglycans abundantly, and they are thought to serve multiple functions in cell adhesion, cell migration, and protection from complement attack. We studied the role of sialoglycans on T cells in a mouse model with a T cell-specific deletion of cytidine monophosphate-sialic acid synthase (CMAS), the enzyme that is crucial for the synthesis of sialoglycans. These mice showed a T-cell deficiency in peripheral lymphoid organs. Many T cells with an undeleted Cmas allele were found in the periphery, suggesting that they escaped the Cre-mediated deletion. The remaining peripheral T cells of T cell-specific Cmas KO mice had a memory-like phenotype. Additional depletion of the complement factor C3 could not rescue the phenotype, showing that the T-cell defect was not caused by a host complement activity. Cmas-deficient T cells showed a high level of activated caspase 3, indicating an ongoing apoptosis. In bone marrow chimeric cellular transfer experiments, we observed a strong competitive disadvantage of Cmas-deficient T cells compared to wild-type T cells. These results show that sialoglycans on the surface of T cells are crucial for T-cell survival and maintenance. This function has not been recognized before and is similar to the function of sialoglycans on B cells.
Severe thermal and major traumatic injury results in elevated plasma concentrations of total heme that are associated with poor clinical outcomes and systemic immune suppression
Authors: Tullie Sebastian , Nicholson Thomas , Bishop Jonathan R. B. , McGee Kirsty C. , Asiri Ali , Sullivan Jack , Chen Yung-Yi , Sardeli Amanda V. , Belli Antonio , Harrison Paul , Moiemen Naiem S. , Lord Janet M. , Hazeldine Jon
Published: July 2024

Background

Traumatic and thermal injuries result in a state of systemic immune suppression, yet the mechanisms that underlie its development are poorly understood. Released from injured muscle and lysed red blood cells, heme is a damage associated molecular pattern with potent immune modulatory properties. Here, we measured plasma concentrations of total heme in over 200 traumatic and thermally-injured patients in order to examine its relationship with clinical outcomes and post-injury immune suppression.

Methods

Blood samples were collected from 98 burns (≥15% total body surface area) and 147 traumatically-injured (injury severity score ≥8) patients across the ultra-early (≤1 hour) and acute (4–72 hours) post-injury settings. Pro-inflammatory cytokine production by lipopolysaccharide (LPS) challenged whole blood leukocytes was studied, and plasma concentrations of total heme, and its scavengers haptoglobin, hemopexin and albumin measured, alongside the expression of heme-oxygenase-1 (HO-1) in peripheral blood mononuclear cells (PBMCs). LPS-induced tumour necrosis factor-alpha (TNF-α) production by THP-1 cells and monocytes following in vitro heme treatment was also examined.

Results

Burns and traumatic injury resulted in significantly elevated plasma concentrations of heme, which coincided with reduced levels of hemopexin and albumin, and correlated positively with circulating levels of pro and anti-inflammatory cytokines. PBMCs isolated from trauma patients 4–12 and 48–72 hours post-injury exhibited increased HO-1 gene expression. Non-survivors of burn injury and patients who developed sepsis, presented on day 1 with significantly elevated heme levels, with a difference of 6.5 µM in heme concentrations corresponding to a relative 52% increase in the odds of post-burn mortality. On day 1 post-burn, heme levels were negatively associated with ex vivo LPS-induced TNF-α and interleukin-6 production by whole blood leukocytes. THP-1 cells and monocytes pre-treated with heme exhibited significantly reduced TNF-α production following LPS stimulation. This impairment was associated with decreased gene transcription, reduced activation of extracellular signal-regulated kinase 1/2 and an impaired glycolytic response.

Conclusions

Major injury results in elevated plasma concentrations of total heme that may contribute to the development of endotoxin tolerance and increase the risk of poor clinical outcomes. Restoration of the heme scavenging system could be a therapeutic approach by which to improve immune function post-injury.
The profile and prognostic significance of bone marrow T-cell differentiation subsets in adult AML at diagnosis
Authors: Sun Kai , Shi Zong-Yan , Wang Ya-Zhe , Xie Dai-Hong , Liu Yan-Rong , Jiang Qian , Jiang Hao , Huang Xiao-Jun , Qin Ya-Zhen
Published: July 2024

Background

T lymphocytes in tumor microenvironment play a pivotal role in the anti-tumor immunity, and the memory of T cells contributes to the long-term protection against tumor antigens. Compared to solid tumors, studies focusing on the T-cell differentiation in the acute myeloid leukemia (AML) bone marrow (BM) microenvironment remain limited.

Patients and methods

Fresh BM specimens collected from 103 adult AML patients at diagnosis and 12 healthy donors (HDs) were tested T-cell differentiation subsets by multi-parameter flow cytometry.

Results

CD4 and CD8 T-cell compartments had different constituted profiles of T-cell differentiated subsets, which was similar between AML patients and HDs. Compared to HDs, AML patients as a whole had a significantly higher proportion of CD8 effector T cells (Teff, P = 0.048). Moreover, the T-cell compartment of AML patients with no DNMT3A mutations skewed toward terminal differentiation at the expense of memory T cells (CD4 Teff: P = 0.034; CD8 Teff: P = 0.030; CD8 memory T: P = 0.017), whereas those with mutated DNMT3A had a decrease in CD8 naïve T (Tn) and CD4 effector memory T cells (Tem) as well as an increase in CD4 central memory T cells (Tcm) (P = 0.037, 0.053 and 0.053). Adverse ELN genetic risk correlated with a lower proportion of CD8 Tn. In addition, the low proportions of CD4 Tem and CD8 Tn independently predicted poorer relapse-free survival (RFS, HR [95%CI]: 5.7 (1.4–22.2), P = 0.017 and 4.8 [1.3–17.4], P = 0.013) and event-free survival (EFS, HR [95% CI]: 3.3 (1.1–9.5), P = 0.029; 4.0 (1.4–11.5), P = 0.010), respectively.

Conclusions

AML patients had abnormal profiles of BM T-cell differentiation subsets at diagnosis, which was related to DNMT3A mutations. The low proportions of CD4 Tem and CD8 Tn predicted poor outcomes.
Inhalation of nicotine-containing electronic cigarette vapor exacerbates the features of COPD by inducing ferroptosis in βENaC-overexpressing mice
Authors: Han Hongwei , Meister Maureen , Peng Guangda , Yuan Yi , Qiao Jingjuan , Yang Jenny J. , Liu Zhi-Ren , Ji Xiangming
Published: July 2024

Introduction

Chronic obstructive pulmonary disease (COPD) is currently listed as the 3rd leading cause of death in the United States. Accumulating data shows the association between COPD occurrence and the usage of electronic nicotine delivery systems (ENDS) in patients. However, the underlying pathogenesis mechanisms of COPD have not been fully understood.

Methods

In the current study, bENaC-overexpressing mice (bENaC mice) were subjected to whole-body ENDS exposure. COPD related features including emphysema, mucus accumulation, inflammation and fibrosis are examined by tissue staining, FACS analysis, cytokine measurement. Cell death and ferroptosis of alveolar epithelial cells were further evaluated by multiple assays including staining, FACS analysis and lipidomics.

Results

ENDS-exposed mice displayed enhanced emphysema and mucus accumulation, suggesting that ENDS exposure promotes COPD features. ENDS exposure also increased immune cell number infiltration in bronchoalveolar lavage and levels of multiple COPD-related cytokines in the lungs, including CCL2, IL-4, IL-13, IL-10, M-CSF, and TNF-α. Moreover, we observed increased fibrosis in ENDS-exposed mice, as evidenced by elevated collagen deposition and a-SMA+ myofibroblast accumulation. By investigating possible mechanisms for how ENDS promoted COPD, we demonstrated that ENDS exposure induced cell death of alveolar epithelial cells, evidenced by TUNEL staining and Annexin V/PI FACS analysis. Furthermore, we identified that ENDS exposure caused lipid dysregulations, including TAGs (9 species) and phospholipids (34 species). As most of these lipid species are highly associated with ferroptosis, we confirmed ENDS also enhanced ferroptosis marker CD71 in both type I and type II alveolar epithelial cells.

Discussion

Overall, our data revealed that ENDS exposure exacerbates features of COPD in bENaC mice including emphysema, mucus accumulation, abnormal lung inflammation, and fibrosis, which involves the effect of COPD development by inducing ferroptosis in the lung.
A potent, broadly neutralizing human monoclonal antibody that efficiently protects hACE2-transgenic mice from infection with the Wuhan, BA.5, and XBB.1.5 SARS-CoV-2 variants
Authors: Guselnikov Sergey V. , Baranov Konstantin O. , Kulemzin Sergey V. , Belovezhets Tatyana N. , Chikaev Anton N. , Murasheva Svetlana V. , Volkova Olga Y. , Mechetina Ludmila V. , Najakshin Alexander M. , Chikaev Nikolai A. , Solodkov Pavel P. , Sergeeva Maria V. , Smirnov Alexander V. , Serova Irina A. , Serov Oleg L. , Markhaev Alexander G. , Kononova Yulia V. , Alekseev Alexander Y. , Gulyaeva Marina A. , Danilenko Daria M. , Battulin Nariman R. , Shestopalov Alexander M. , Taranin Alexander V.
Published: July 2024

The COVID-19 pandemic has uncovered the high genetic variability of the SARS-CoV-2 virus and its ability to evade the immune responses that were induced by earlier viral variants. Only a few monoclonal antibodies that have been reported to date are capable of neutralizing a broad spectrum of SARS-CoV-2 variants. Here, we report the isolation of a new broadly neutralizing human monoclonal antibody, iC1. The antibody was identified through sorting the SARS-CoV-1 RBD-stained individual B cells that were isolated from the blood of a vaccinated donor following a breakthrough infection. In vitro, iC1 potently neutralizes pseudoviruses expressing a wide range of SARS-CoV-2 Spike variants, including those of the XBB sublineage. In an hACE2-transgenic mouse model, iC1 provided effective protection against the Wuhan strain of the virus as well as the BA.5 and XBB.1.5 variants. Therefore, iC1 can be considered as a potential component of the broadly neutralizing antibody cocktails resisting the SARS-CoV-2 mutation escape.
Efficacy of a single ultrasound-guided injection of high molecular weight hyaluronic acid combined with collagen tripeptide in patients with knee osteoarthritis and chondrocalcinosis
Authors: Porta Francesco , Filippucci Emilio , Cipolletta Edoardo , La Grua Marco , Barni Xenia , Sirotti Silvia , Vreju Florentin Ananu
Published: July 2024

Introduction

Osteoarthritis (OA) and calcium pyrophosphate deposition (CPPD) often co-exist, this resulting in a clinical condition characterized by amplified inflammation and more severe and faster cartilage degeneration compared to OA alone. Our study aims to explore the efficacy of a therapeutic approach that addresses both conditions, using a combination of a high molecular weight hyaluronic acid (HMWHA) and collagen tripeptide (CTP). Additionally, safety profile and baseline characteristic predictive value were evaluated.

Methods

We conducted a retrospective study on patients diagnosed with symptomatic knee OA (KOA) and CPPD treated by ultrasound (US) guided intraarticular injections of HMWHA-CT in the outpatient clinics of the Interdisciplinary Pain Medicine Unit at Santa Maria Maddalena Hospital, Occhiobello, Italy and in the Rheumatology Unit of the Emergency County Hospital Craiova, Romania (ECH Craiova). All the patients underwent clinical and US evaluation at baseline, 1, 3, and 6 months. From clinical point of view, Numeric Rating Scale (NRS) pain and Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) were recorded. US data included detection of synovitis, cartilage damage, osteophytes, and CPPD deposits. Clinical efficacy was defined with NRS and WOMAC variations in respect to baseline and using the minimal clinically important difference values: an improvement of 2 point for NRS pain and 10 for the total score for WOMAC.

Results

Twenty-nine patients (34 knees) were injected and evaluated. Overall pain levels, as measured by NRS, demonstrated a consistent decrease in patients across all follow-up intervals, with the most substantial improvement at the 6-month compared to baseline measurements. A significative proportion of patients achieved the minimum clinically detectable improvement, specifically 79% for NRS and 83% for WOMAC (19 and 20 patients, respectively).

Conclusion

Our data showed a significant efficacy of ultrasound guided HMWHA-CT, in patients with KOA and CPPD, thus making it reasonable to consider that the combination of HMWHA and CTP can provide a strong anti-inflammatory effect.
Seasonal dynamics of free-living (FL) and particle-attached (PA) bacterial communities in a plateau reservoir
Authors: Yang Yang , Chen Chen , Yao Kai , Grossart Hans-Peter
Published: July 2024

In terms of lifestyle, bacterioplankton can be classified as free-living (FL) and particle-attached (PA) forms, and both play essential roles in biogeochemical cycling in aquatic ecosystems. Structure, distribution, and community assembly of FL and PA bacteria in plateau riverine waterbodies are largely unknown. Therefore, we explored the seasonal dynamics of FLand PA bacterial communities in the Wujiangdu reservoir, Yungui Plateau using 16S rRNA gene high-throughput sequencing. Results revealed there was a significant environmental heterogeneity in Wujiangdu reservoir seasonally. The dominant phylum was Actinomycetota for FL and Pseudomonadota for PA bacteria. Species richness and diversity was higher in autumn and winter compared to spring and summer. In general, PA diversity was greater than FL, but with some temporal variations. Species turnover was the major contributor to β-diversity of both FL and PA lifestyles, and significant differences were noticed between FL and PA bacterial community composition. Distinct co-occurrence network patterns implied that more connections exist between FL bacteria, while more complex PA networks were in parallel to their greater diversity and stronger interactions in biofilms on particles. Dispersal limitation was the major driving force for both FL and PA bacterial community assembly. Deterministic processes were of relatively low importance, with homogeneous selection for FL and heterogeneous selection for PA bacteria. Temperature was the most important environmental driver of seasonal bacterial dynamics, followed by nitrate for FL and Secchi depth for PA bacteria. This study allows for a better understanding of the temporal variability of different bacteria lifestyles in reservoirs in the vulnerable and rapidly changing plateau environment, facilitating further microbial research related to global warming and eutrophication.
Lamivudine modulates the expression of neurological impairment-related genes and LINE-1 retrotransposons in brain tissues of a Down syndrome mouse model
Authors: Borgognone Alessandra , Casadellà Maria , Martínez de Lagrán María , Paredes Roger , Clotet Bonaventura , Dierssen Mara , Elizalde-Torrent Aleix
Published: July 2024

Elevated activity of retrotransposons is increasingly recognized to be implicated in a wide range of neurodegenerative and neurodevelopmental diseases, including Down syndrome (DS), which is the most common chromosomal condition causing intellectual disability globally. Previous research by our group has revealed that treatment with lamivudine, a reverse transcriptase inhibitor, improved neurobehavioral phenotypes and completely rescued hippocampal-dependent recognition memory in a DS mouse model, Ts65Dn. We hypothesized that retrotransposition rates would increase in the Ts65Dn mouse model, and lamivudine could block retrotransposons. We analyzed the differentially expressed long interspersed element-1 (LINE-1 or L1) mapping on MMU16 and 17, and showed for the first time that retrotransposition could be associated with Ts65Dn’s pathology, as misregulation of L1 was found in brain tissues associated with trisomy. In the cerebral cortex, 6 out of 26 upregulated L1s in trisomic treated mice were located in the telomeric region of MMU16 near Ttc3, Kcnj6, and Dscam genes. In the hippocampus, one upregulated L1 element in trisomic treated mice was located near the Fgd4 gene on MMU16. Moreover, two downregulated L1s rescued after treatment with lamivudine were located in the intronic region of Nrxn1 (MMU17) and Snhg14 (MMU7), implicated in a variety of neurodegenerative disorders. To gain further insight into the mechanism of this improvement, we here analyzed the gene expression profile in the hippocampus and cerebral cortex of trisomic mice treated and no-treated with lamivudine compared to their wild-type littermates. We found that treatment with lamivudine rescued the expression of 24% of trisomic genes in the cortex (located on mouse chromosome (MMU) 16 and 17) and 15% in the hippocampus (located in the human chromosome 21 orthologous regions), with important DS candidate genes such as App and Ets2, rescued in both regions.
Surrogate modelling of heartbeat events for improved J-peak detection in BCG using deep learning
Authors: Schranz Christoph , Halmich Christina , Mayr Sebastian , Heib Dominik P. J.
Published: July 2024

Sleep, or the lack thereof, has far-reaching consequences on many aspects of human physiology, cognitive performance, and emotional wellbeing. To ensure undisturbed sleep monitoring, unobtrusive measurements such as ballistocardiogram (BCG) are essential for sustained, real-world data acquisition. Current analysis of BCG data during sleep remains challenging, mainly due to low signal-to-noise ratio, physical movements, as well as high inter- and intra-individual variability. To overcome these challenges, this work proposes a novel approach to improve J-peak extraction from BCG measurements using a supervised deep learning setup. The proposed method consists of the modeling of the discrete reference heartbeat events with a symmetric and continuous kernel-function, referred to as surrogate signal. Deep learning models approximate this surrogate signal from which the target heartbeats are detected. The proposed method with various surrogate signals is compared and evaluated with state-of-the-art methods from both signal processing and machine learning approaches. The BCG dataset was collected over 17 nights using inertial measurement units (IMUs) embedded in a mattress, together with an ECG for reference heartbeats, for a total of 134 h. Moreover, we apply for the first time an evaluation metric specialized for the comparison of event-based time series to assess the quality of heartbeat detection. The results show that the proposed approach demonstrates superior accuracy in heartbeat estimation compared to existing approaches, with an MAE (mean absolute error) of 1.1 s in 64-s windows and 1.38 s in 8-s windows. Furthermore, it is shown that our novel approach outperforms current methods in detecting the location of heartbeats across various evaluation metrics. To the best of our knowledge, this is the first approach to encode temporal events using kernels and the first systematic comparison of various event encodings for event detection using a regression-based sequence-to-sequence model.
Higher incidence of acute symptomatic seizures in probable antibody-negative pediatric autoimmune encephalitis than in major antibody-positive autoimmune encephalitis
Authors: Yamada Naoki , Inoue Takeshi , Kuki Ichiro , Yamamoto Naohiro , Fukuoka Masataka , Nukui Megumi , Okuno Hideo , Ishikawa Junichi , Amo Kiyoko , Togawa Masao , Sakuma Hiroshi , Okazaki Shin
Published: July 2024

Purpose

To delineate the characteristics of probable antibody-negative pediatric autoimmune encephalitis (probable Ab-negative AE), we compared the clinical features of probable Ab-negative AE to those of major antibody-positive AE.

Methods

We retrospectively reviewed the clinical features of 18 patients with probable Ab-negative AE, 13 with anti-N-methyl-D-aspartate receptor encephalitis (NMDARE), and 13 with myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD). Clinical characteristics, neuroimaging findings, treatments, and outcomes were analyzed.

Results

The age of onset and length of hospital stay were significantly higher in the NMDARE group than in the other groups (p = 0.02 and p < 0.01). Regarding initial neurological symptoms, acute symptomatic seizures in the probable Ab-negative AE group (67%) were significantly more frequent than in the NMDARE (15%) and MOGAD (23%) groups (p < 0.01). Paraclinical evidence of neuroinflammation within 1 month of disease onset revealed that single-photon emission computed tomography (SPECT) detected abnormal alterations in 14/14 (100%), cerebrospinal fluid (CSF) analysis in 15/18 (83%), and magnetic resonance imaging (MRI) in 11/18 (61%) in patients with probable Ab-negative AE. In the probable Ab-negative AE group, seven patients (39%) developed autoimmune-associated epilepsy, whereas one patient (8%) had both NMDARE and MOGAD (not statistically significant, p = 0.07).

Conclusion

Patients with probable Ab-negative AE exhibited acute symptomatic seizures as initial neurological symptoms significantly more frequently. They developed autoimmune-associated epilepsy more frequently than those with NMDARE and MOGAD, which was not statistically significant. SPECT within 1 month of disease onset might be a valuable surrogate marker of ongoing neuroinflammation and neuronal dysfunction, even in patients with negative MRI findings.
White matter microstructure, traumatic brain injury, and disruptive behavior disorders in girls and boys
Authors: Guberman Guido I. , Theaud Guillaume , Hawes Samuel W. , Ptito Alain , Descoteaux Maxime , Hodgins Sheilagh
Published: July 2024

Introduction

Girls and boys presenting disruptive behavior disorders (DBDs) display differences in white matter microstructure (WMM) relative to typically developing (TD) sex-matched peers. Boys with DBDs are at increased risk for traumatic brain injuries (TBIs), which are also known to impact WMM. This study aimed to disentangle associations of WMM with DBDs and TBIs.

Methods

The sample included 673 children with DBDs and 836 TD children, aged 9–10, from the Adolescent Brain Cognitive Development Study. Thirteen white matter bundles previously associated with DBDs were the focus of study. Analyses were undertaken separately by sex, adjusting for callous-unemotional traits (CU), attention-deficit hyperactivity disorder (ADHD), age, pubertal stage, IQ, ethnicity, and family income.

Results

Among children without TBIs, those with DBDs showed sex-specific differences in WMM of several tracts relative to TD. Most differences were associated with ADHD, CU, or both. Greater proportions of girls and boys with DBDs than sex-matched TD children had sustained TBIs. Among girls and boys with DBDs, those who had sustained TBIs compared to those not injured, displayed WMM alterations that were robust to adjustment for all covariates. Across most DBD/TD comparisons, axonal density scores were higher among children presenting DBDs.

Discussion

In conclusion, in this community sample of children, those with DBDs were more likely to have sustained TBIs that were associated with additional, sex-specific, alterations of WMM. These additional alterations further compromise the future development of children with DBDs.
Burden of ischemic stroke attributable to a high red meat diet in China, 1990–2019: analysis based on the 2019 Global Burden of Disease Study
Authors: Jin Shuai , Xia Kaide , Sun Baofei , Xie Lang , Zhang Haiwang
Published: July 2024

Background

The burden of ischemic stroke (IS) linked to high consumption of red meat is on the rise. This study aimed to analyze the mortality and disability-adjusted life years (DALYs) trends for IS attributed to high red meat intake in China between 1990 and 2019 and to compare these trends with global trends.

Methods

This study extracted data on IS attributed to diets high in red meat in China from 1990 to 2019 from the Global Burden of Disease Study (GBD) database. Key measures, including mortality, DALYs, age-standardized mortality rates (ASMR), and age-standardized DALYs rates (ASDR), were used to estimate the disease burden. The estimated annual percentage change and joinpoint regression models were employed to assess the trends over time. An age-period-cohort analysis was used to assess the contribution of a diet high in red meat to the age, period, and cohort effects of IS ASMR and ASDR.

Results

Between 1990 and 2019, deaths and DALYs from IS attributed to a diet high in red meat in China, along with corresponding age-standardized rates, significantly increased. The overall estimated annual percentage change for the total population and across sex categories ranged from 1.01 to 2.08. The average annual percentage changes for overall ASDR and ASMR were 1.4 and 1.33, respectively, with male ASDR and ASMR average annual percentage changes at 1.69 and 1.69, respectively. Contrastingly, female ASDR and ASMR average annual percentage changes were 1.07 and 0.87, respectively. Except for a few periods of significant decrease in females, all other periods indicated a significant increase or nonsignificant changes. Incidence of IS linked to a diet high in red meat rose sharply with age, displaying increasing period and cohort effects in ASDR. Female ASMR period and cohort effect ratios initially increased and then decreased, whereas the male ratio showed an upward trend.

Conclusion

This study comprehensively analyzed epidemiological characteristics that indicated a marked increase in mortality and DALYs from IS attributable to high red meat consumption, contrasting with a global downtrend. This increase was more pronounced in males than females. This research provides valuable insights for enhancing IS prevention in China.
Obstacles to global implementation of CAR T cell therapy in myeloma and lymphoma
Authors: Medina-Olivares Fernando J. , Gómez-De León Andrés , Ghosh Nilanjan
Published: July 2024

Chimeric Antigen Receptor T-cell (CAR-T) therapies are transforming the treatment of B-cell lymphoproliferative disorders and multiple myeloma, yet global access challenges and barriers for their implementation persist. Global access disparities persist, particularly for persons living in low and middle-income countries and for underserved populations in high income countries. In this review we address patient-related factors including age, comorbidities, fitness, race and ethnicity, and geographic location for CAR-T access. Also, we review disease-related and health system barriers like disease biology, potential for short and long-term toxicity, insurance access, referrals, supply and manufacturing, regulation, costs and treatment center capacity. Lastly, alternatives for overcoming these barriers exemplified by research efforts worldwide are discussed, emphasizing the need for a multifaceted approach from all stakeholders to improve global accessibility and ensure equitable access and improved outcomes for patients worldwide.
Hypoxanthine in the microenvironment can enable thiopurine resistance in acute lymphoblastic leukemia
Authors: Wang Xiaohong , Ostergaard Jason , Kang Jongseok , Sagong Grace , Twite Rachel , Vargas-Morales Andrea , Gordon Peter M.
Published: July 2024

Acute lymphoblastic leukemia (ALL) is the most common pediatric malignancy, with relapse being a major obstacle to successful treatment. Our understanding of the mechanisms driving chemotherapy resistance and ultimately relapse in leukemia remains incomplete. Herein, we investigate the impact of the tumor microenvironment on leukemia cell drug responses using human plasma-like media (HPLM), designed to mimic physiological conditions more accurately ex vivo. We demonstrate that while most chemotherapeutics maintain an efficacy in HPLM comparable to standard tissue culture media, the thiopurines 6-mercaptopurine (6-MP) and 6-thioguanine (6-TG) exhibit significantly reduced potency and efficacy against both B- and T- leukemia cells in HPLM. By merging our understanding of thiopurines’ mechanism of action with the metabolites supplemented in HPLM compared to standard media, we proposed and subsequently validated the hypothesis that hypoxanthine, a purine derivative, is responsible for conferring resistance to the thiopurines. Importantly, the concentration of hypoxanthine required for resistance is comparable to physiological levels found in vivo, supporting clinical relevance. Our findings demonstrate the utility of a more physiologic media in identifying and characterizing mechanisms by which the microenvironment can enable resistance. Understanding such interactions may inform strategies to overcome drug resistance and improve therapeutic outcomes in pediatric leukemia.
Effects and safety of Ophiocordyceps sinensis preparation in the adjuvant treatment for dialysis patients: a systematic review and meta-analysis
Authors: Liu Meixi , Cui Chengji , Chang Tianying , Zhou Qingshan , Cui Yingzi , Zhang Shoulin , Liao Xing
Published: July 2024

Ethnopharmacological relevance

Ophiocordyceps sinensis (O. sinensis), a genus of ascomycete fungi, has been widedly used in China as a dietary supplement or natural remedy and intensively studied in various disease models with its immunomodulatory potentials. It is a rich source of various bioactive compounds and used for treating end-stage renal disease. This systematic review with clinical evidence aimed to highlight the efficacy and safety of O. Sinensis as an adjuvant treatment for patients undergoing dialysis.

Materials and methods

A systematic search through nine electronic databases up to 31 April 2024, was conducted for related studies. The Cochrane risk-of-bias tool was used to evaluate the quality of studies. The Grading of Recommendations Assessment, Development, and Evaluation system was used to assess the certainty of evidence. Two researchers independently searched the literature and evaluated the risk of bias.

Results

After the screening, 35 randomized controlled trials (RCTs) involving 2,914 patients were eventually included. The meta-analysis showed that using O. sinensis effectively reduced the following outcomes in patients undergoing dialysis: C-reactive protein (15RCTs, MD = −2.22, 95% CI −3.24 to −1.20; very low certainty evidence); creatinine (22RCTs, MD =1.33, 95% CI −1.79 to −0.87; very low certainty evidence); blood urea nitrogen (21RCTs, MD = −1.57, 95% CI −2.07 to −1.07; low certainty evidence);. It could also effectively improve the following outcomes in patients undergoing dialysis: albumin (20RCTs, MD = −0.81, 95% CI −1.21 to −0.41; low certainty evidence); hemoglobin (19RCTs, MD = −1.00, 95% CI −1.43 to −0.57; low certainty evidence). The rate of adverse drug reactions was higher in the control group than in the experimental group (4RCTs, MD = 1.81, 95% CI 0.88–3.74).

Conclusion

The current evidence indicates that patients with dialysis receiving O. sinensis in the adjuvant treatment may improve nutritional and micro-inflammatory status and renal function for both hemodialysis and peritoneal dialysis patients. However, some limitation affected the generalizability of our findings. High-quality studies evaluating mortality outcomes of patients with different dialytic modalities in CKD are warranted in future.

Systematic Review Registration

https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42022324508, registration number CRD42022324508.
Ginsenosides ameliorates high altitude-induced hypoxia injury in lung and kidney tissues by regulating PHD2/HIF-1α/EPO signaling pathway
Authors: Ji Peng , Zhang Zepeng , Mingyao E. , Liu Qing , Qi Hongyu , Hou Tong , Zhao Daqing , Li Xiangyan
Published: July 2024

Background: The primary constituent of ginseng, known as ginsenosides (GS), has been scientifically demonstrated to possess anti-fatigue, anti-hypoxia, anti-inflammatory, and antioxidant properties. However, the effect and mechanisms of GS on tissue injury induced by high-altitude hypoxia still remain unclear.

Aim of the study: This study aims to investigate the protective effect of GS on a high-altitude hypoxia model and explore its mechanism.

Materials and methods: Sprague-Dawley rats were placed in a high-altitude simulation chamber for 48 h (equivalent to an altitude of 6,000 m) to establish a high-altitude hypoxia model. We assessed the anti-hypoxic efficacy of GS through blood gas analysis, complete blood count, and hemorheology analysis. We used H&E and hypoxia probe assays to evaluate the protective effect of GS on organ ischemia-induced injury. Further, we used ELISA and qPCR analysis to detect the levels of inflammatory factors and oxidative stress markers. Immunohistochemistry and immunofluorescence staining were performed to determinate protein expression of hypoxia inducible factor 1-alpha (HIF-1α), erythropoietin (EPO), and prolyl hydroxylase 2 (PHD2).

Results: In the survival experiment of anoxic mice, 100 mg/kg of GS had the best anti-anoxic effect. GS slowed down the weight loss rate of rats in hypoxic environment. In the fluorescence detection of hypoxia, GS reduced the fluorescence signal value of lung and kidney tissue and alleviated the hypoxia state of tissue. Meanwhile GS improved blood biochemical and hematological parameters. We also observed that GS treatment significantly decreased oxidative stress damage in lung and kidney tissues. Further, the levels of inflammatory factors, IL-1β, IL-6, and TNF-α were reduced by GS. Finally, GS regulated the PHD2/HIF-1α/EPO signaling pathway to improve blood viscosity and tissue hyperemia damage.

Conclusion: GS could alleviate high-altitude induced lung and kidney damage by reducing the level of inflammation and oxidative stress, improving blood circulation through the PHD2/HIF-1α/EPO pathway.
Melatonin modulates TLR4/MyD88/NF-κB signaling pathway to ameliorate cognitive impairment in sleep-deprived rats
Authors: Yin Chao , Zhang Meiya , Cheng Li , Ding Li , Lv Qing , Huang Zixuan , Zhou Jiaqi , Chen Jianmei , Wang Ping , Zhang Shunbo , You Qiuyun
Published: July 2024

Sleep deprivation (SD) is commonplace in today’s fast-paced society. SD is a severe public health problem globally since it may cause cognitive decline and even neurodegenerative disorders like Alzheimer’s disease. Melatonin (MT) is a natural chemical secreted by the pineal gland with neuroprotective effects. The purpose of this study was to investigate the protective effect and mechanism of MT on chronic sleep deprivation-induced cognitive impairment. A 3-week modified multi-platform method was used to create the SD rat model. The Morris water maze test (MWM), Tissue staining (including Hematoxylin and Eosin (H & E) staining, Nissl staining, and immunofluorescence), Western blot, Enzyme-linked immunosorbent assay (ELISA), and Quantitative real-time polymerase chain reaction (qPCR) were used to investigate the protective effect and mechanism of MT in ameliorating cognitive impairment in SD rats. The results showed that MT (50 and 100 mg/kg) significantly improved cognitive function in rats, as evidenced by a shortening of escape latency and increased time of crossing the platform and time spent in the quadrant. Additionally, MT therapy alleviated hippocampus neurodegeneration and neuronal loss while lowering levels of pathogenic factors (LPS) and inflammatory indicators (IL-1β, IL-6, TNF-α, iNOS, and COX2). Furthermore, MT treatment reversed the high expression of Aβ42 and Iba1 as well as the low expression of ZO-1 and occludin, and inhibited the SD-induced TLR4/MyD88/NF-κB signaling pathway. In summary, MT ameliorated spatial recognition and learning memory dysfunction in SD rats by reducing neuroinflammation and increasing neuroprotection while inhibiting the TLR4/MyD88/NF-κB signaling pathway. Our study supports the use of MT as an alternate treatment for SD with cognitive impairment.
Impact of intravascular hemolysis on functional and molecular alterations in the urinary bladder: implications for an overactive bladder in sickle cell disease
Authors: Silveira Tammyris Helena Rebecchi e , Pereira Dalila Andrade , Pereira Danillo Andrade , Calmasini Fabiano Beraldi , Burnett Arthur L. , Costa Fernando Ferreira , Silva Fábio Henrique
Published: July 2024

Patients with sickle cell disease (SCD) display an overactive bladder (OAB). Intravascular hemolysis in SCD is associated with various severe SCD complications. However, no experimental studies have evaluated the effect of intravascular hemolysis on bladder function. This study aimed to assess the effects of intravascular hemolysis on the micturition process and the contractile mechanisms of the detrusor smooth muscle (DSM) in a mouse model with phenylhydrazine (PHZ)-induced hemolysis; furthermore, it aimed to investigate the role of intravascular hemolysis in the dysfunction of nitric oxide (NO) signaling and in increasing oxidative stress in the bladder. Mice underwent a void spot assay, and DSM contractions were evaluated in organ baths. The PHZ group exhibited increased urinary frequency and increased void volumes. DSM contractile responses to carbachol, KCl, α-β-methylene-ATP, and EFS were increased in the PHZ group. Protein expression of phosphorylated endothelial NO synthase (eNOS) (Ser-1177), phosphorylated neuronal NO synthase (nNOS) (Ser-1417), and phosphorylated vasodilator-stimulated phosphoprotein (VASP) (Ser-239) decreased in the bladder of the PHZ group. Protein expression of oxidative stress markers, NOX-2, 3-NT, and 4-HNE, increased in the bladder of the PHZ group. Our study shows that intravascular hemolysis promotes voiding dysfunction correlated with alterations in the NO signaling pathway in the bladder, as evidenced by reduced levels of p-eNOS (Ser-1177), nNOS (Ser-1417), and p-VASP (Ser-239). The study also showed that intravascular hemolysis increases oxidative stress in the bladder. Our study indicates that intravascular hemolysis promotes an OAB phenotype similar to those observed in patients and mice with SCD.