bluuebunny/crossref_metadata_2025 huggingface dataset:
Towards a concurrency platform for scalable multi-axial real-time hybrid simulation
Authors: Sudvarg Marion , Bell Oren , Martin Tyler , Standaert Benjamin , Zhang Tao , Kwon Sun-Beom , Gill Chris , Prakash Arun
Published: September 2024

Multi-axial real-time hybrid simulation (maRTHS) uses multiple hydraulic actuators to apply loads and deform experimental substructures, enacting both translational and rotational motion. This allows for an increased level of realism in seismic testing. However, this also demands the implementation of multiple-input, multiple-output control strategies with complex nonlinear behaviors. To realize true real-time hybrid simulation at the necessary sub-millisecond timescales, computational platforms will need to support these complexities at scale, while still providing deadline assurance. This paper presents initial work towards supporting (and is influenced by the need for) envisioned larger-scale future experiments based on the current maRTHS benchmark: it discusses aspects of hardware, operating system kernels, runtime middleware, and scheduling theory that may be leveraged or developed to meet those goals. This work aims to create new concurrency platforms capable of managing task scheduling and adaptive event handling for computationally intensive numerical simulation and control models like those for the maRTHS benchmark problem. These should support real-time behavior at millisecond timescales, even for large complex structures with thousands of degrees of freedom. Temporal guarantees should be maintained across behavioral and computational mode changes, e.g., linear to nonlinear control. Pursuant to this goal, preliminary scalability analysis is conducted towards designing future maRTHS experiments. The results demonstrate that the increased capabilities of modern hardware architectures are able to handle larger finite element models compared to prior work, while imposing the same latency constraints. However, the results also illustrate a subtle challenge: with larger numbers of CPU cores, thread coordination incurs more overhead. These results provide insight into the computational requirements to support envisioned future experiments that will take the maRTHS benchmark problem to nine stories and beyond in scale. In particular, this paper (1) re-evaluates scalability of prior work on current platform hardware, and (2) assesses the resource demands of a basic smaller scale model from which to gauge the projected scalability of the new maRTHS benchmark as ever larger and more complex models are integrated within it.
Mast cells: a double-edged sword in inflammation and fibrosis
Authors: Wang Xufang , Zhang Peipei , Tang Yuxin , Chen Yanlin , Zhou Enchao , Gao Kun
Published: September 2024

As one of the key components of the immune system, mast cells are well known for their role in allergic reactions. However, they are also involved in inflammatory and fibrotic processes. Mast cells participate in all the stages of acute inflammatory responses, playing an immunomodulatory role in both innate and adaptive immunity. Mast cell-derived histamine, TNF-α, and IL-6 contribute to the inflammatory processes, while IL-10 mediates the suppression of inflammation. Crosstalk between mast cells and other immune cells is also involved in the development of inflammation. The cell–cell adhesion of mast cells and fibroblasts is crucial for fibrosis. Mast cell mediators, including cytokines and proteases, play contradictory roles in the fibrotic process. Here, we review the double-edged role of mast cells in inflammation and fibrosis.
The signal that stimulates mammalian embryo development
Authors: Machaty Zoltan
Published: September 2024

Embryo development is stimulated by calcium (Ca2+) signals that are generated in the egg cytoplasm by the fertilizing sperm. Eggs are formed via oogenesis. They go through a cell division known as meiosis, during which their diploid chromosome number is halved and new genetic combinations are created by crossing over. During formation the eggs also acquire cellular components that are necessary to produce the Ca2+ signal and also, to support development of the newly formed embryo. Ionized calcium is a universal second messenger used by cells in a plethora of biological processes and the eggs develop a “toolkit”, a set of molecules needed for signaling. Meiosis stops twice and these arrests are controlled by a complex interaction of regulatory proteins. The first meiotic arrest lasts until after puberty, when a luteinizing hormone surge stimulates meiotic resumption. The cell cycle proceeds to stop again in the middle of the second meiotic division, right before ovulation. The union of the female and male gametes takes place in the oviduct. Following gamete fusion, the sperm triggers the release of Ca2+ from the egg’s intracellular stores which in mammals is followed by repetitive Ca2+ spikes known as Ca2+ oscillations in the cytosol that last for several hours. Downstream sensor proteins help decoding the signal and stimulate other molecules whose actions are required for proper development including those that help to prevent the fusion of additional sperm cells to the egg and those that assist in the release from the second meiotic arrest, completion of meiosis and entering the first mitotic cell division. Here I review the major steps of egg formation, discuss the signaling toolkit that is essential to generate the Ca2+ signal and describe the steps of the signal transduction mechanism that activates the egg’s developmental program and turns it into an embryo.
Pulling away from the trigger: the influences of purpose in life and self-affirmation on decisions to shoot
Authors: Burd Kayla A. , Burrow Anthony L. , Guyll Max
Published: September 2024

Introduction

Recent data suggests significant racial disparities in police killings in the United States: Much research finds that Black men are killed by police officers at higher rates than White men, and many individuals killed by police have been unarmed.

Method

Toward addressing psychological mechanisms at play in these complicated decision contexts, the current study tested the effectiveness of two writing tasks at reducing the unjustified shooting of unarmed targets using a virtual shooting-decision platform. Participants wrote either about their sense of purpose, self-affirming values, or a control topic and then played a first-person shooter video game, which randomly presented pictures of Black and White armed and unarmed targets. Participants were instructed not to shoot unarmed targets and to shoot armed targets.

Results

Results indicated that relative to controls, writing about either purpose or self-affirming values reduced the probability of shooting unarmed targets, without negatively impacting shooting decision reaction time.
Enhancing ECU identification security in CAN networks using distortion modeling and neural networks
Authors: Hafeez Azeem , Malik Hafiz , Irtaza Aun , Uddin Md Zia , Noori Farzan M.
Published: September 2024

A novel technique for electronic control unit (ECU) identification is proposed in this study to address security vulnerabilities of the controller area network (CAN) protocol. The reliable ECU identification has the potential to prevent spoofing attacks launched over the CAN due to the lack of message authentication. In this regard, we model the ECU-specific random distortion caused by the imperfections in the digital-to-analog converter and semiconductor impurities in the transmitting ECU for fingerprinting. Afterward, a 4-layered artificial neural network (ANN) is trained on the feature set to identify the transmitting ECU and the corresponding ECU pin. The ECU-pin identification is also a novel contribution of this study and can be used to prevent voltage-based attacks. We have evaluated our method using ANNs over a dataset generated from 7 ECUs with 6 pins, each having 185 records, and 40 records for each pin. The performance evaluation against state-of-the-art methods revealed that the proposed method achieved 99.4% accuracy for ECU identification and 96.7% accuracy for pin identification, which signifies the reliability of the proposed approach.
Case Report: The application of novel imaging technologies in lower extremity peripheral artery disease: NIR-II imaging, OCTA, and LSFG
Authors: Ning Yijie , Hu Jie , Li Haifeng , Lu Chuanlong , Zhang Zeyu , Yan Sheng , Shi Peilu , Gao Tingting , Wang Heng , Zhang Ruijing , Dong Honglin
Published: September 2024

Lower extremity peripheral artery disease (PAD) is a growing global health problem. New methods to diagnose PAD have been explored in recent years. At present, the majority of imaging methods for PAD focus on the macrovascular blood flow, and the exploration of microcirculation and tissue perfusion of PAD remains largely insufficient. In this report, we applied three new imaging technologies, i.e., second near-infrared region (NIR-II, 900–1,880 nm wavelengths) imaging, optical coherence tomography angiography (OCTA), and laser speckle flowgraphy (LSFG), in a PAD patient with a healthy human subject as control. Our results showed that the PAD patient had poorer tissue perfusion than the control without observed adverse effects. Moreover, compared with the first near-infrared region (NIR-I, 700–900 nm wavelengths) imaging results, NIR-II imaging had a higher signal-to-background ratio and resolution than NIR-I imaging and detected microvessels that were not detected by NIR-I imaging. These observations suggested that NIR-II imaging, OCTA, and LSFG are potentially safe and effective methods for diagnosing PAD.
“Letting the ancestors speak”: collaborative archaeology at the Hastings Natural History Reservation
Authors: Sanchez Gabriel M. , Apodaca Alec , Gonzalez Ariadna , Gonzalez Carolina , Nason Tom Little Bear , Herthel Cari , Nason Jana , Byram Scott , Hunter Jen
Published: September 2024

Since 2021, collaborative research at the University of California (UC), Berkeley's Hastings Natural History Reservation between the Esselen Tribe of Monterey County, UC-Berkeley, and the University of Oregon has demonstrated the mutual benefits of a co-created and Indigenous-centered archaeological research program within North America. While initial archaeological studies on the Hastings Reservation occurred over five decades ago, our project represents one of the first Tribal-centered archaeological field programs within the UC Natural Reserve System and, therefore, a model of collaborative research in the post-NAGPRA and CalNAGPRA era. The broader purpose of our research is to work with the Esselen Tribe to collect historical ecological information about the legacies of Native people and their relationship with the environment to help inform contemporary stewardship goals in their Tribal territory. Our archaeological research has confirmed the Indigenous occupation at the Hastings Reserve before, during, and after the Spanish Colonial period (1769–1821) in central California. By weaving archaeology, ethnobotany, ethnohistory, historical documents, ethnography, and Indigenous knowledge, this project documents the critical role of maintaining a connection to cultural landscapes despite three successive waves of European and Euro-American colonialism in the region. These findings provide an alternative narrative of cultural persistence, survivance, and resilience contrary to the narratives of culture loss and erasure espoused by 20th-century California anthropology regarding the Indigenous societies that occupied the central California coast.
Toward a continuous improvement for justice
Authors: Sandoval Carlos , Neri Rebecca Colina
Published: September 2024

In recent years, improvement researchers have sought to foreground equity in continuous improvement (CI) in efforts to better advance the position of Black, Brown, and other marginalized students in educational settings using CI. While we view these efforts as noble and necessary, we argue in this paper that CI has largely centered equity and pushed justice to the periphery. In particular, we argue that the field of CI in education has focused squarely on equity—what we define as reducing racial and other gaps in dominant outcomes. In so doing, CI has deprioritized justice, which we define as improving outcomes that center on the comfort, agency, and dignity of all students, but minoritized students (i.e., Black, Brown, LGBTQ+, disabled, multilingual youth, and working-class) in particular. In so doing, CI efforts risk upholding dominant schooling outcomes and accompanying practices that sort students into unequal categories, limiting the capability of minoritized students to reach their full potential, erasing and demeaning students' cultural wealth, knowledge, and identities, and restricting their access to rich learning opportunities. We argue for a continuous improvement for justice that: (a) confronts dominant outcomes rather than uncritically prioritizing them; and (b) aims to use its tools to create systems that prioritize outcomes that grant comfort, agency, and dignity to minoritized students and communities.
Evaluating chatGPT-4 and chatGPT-4o: performance insights from NAEP mathematics problem solving
Authors: Wei Xin
Published: September 2024

This study assesses the capabilities of OpenAI’s ChatGPT-4 and ChatGPT-4o in solving mathematics problems from the National Assessment of Educational Progress (NAEP) across grades 4, 8, and 12. Results indicate that ChatGPT-4o slightly outperform ChatGPT-4 and both models generally surpass U.S. students’ performance across all grades, content areas, item type, and difficulty level. However, both models perform worse on geometry and measurement than on algebra and face more difficulties with high-difficulty mathematics items. This investigation highlights the strengths and limitations of AI as a supplementary educational tool, pinpointing areas for improvement in spatial intelligence and complex mathematical problem-solving. These findings suggest that while AI has the potential to support instruction in specific mathematical areas like algebra, there remains a need for careful integration and teacher-mediated strategies in areas where AI is less effective.
Transverse resonance technique for analysis of a symmetrical open stub in a microstrip transmission line
Authors: Rassokhina Yulia V. , Krizhanovski Vladimir G.
Published: September 2024

Open stubs in a strip (microstrip) transmission line are one of the most common elements of planar circuits used in numerous devices in the various types of wireless systems. Therefore, the urgent problem is to develop an analyzing method for discontinuities in the form of the open stub in a microstrip transmission line at frequencies at which the high-frequency effects must be considered. In the paper, a technique of scattering characteristics calculating on a symmetrical microstrip open stub by transverse resonance method is presented. Boundary value problems for a rectangular volume resonator based on a microstrip transmission line with a symmetric open stub are solved for the three options boundary conditions in the symmetry plane and on the longitudinal boundaries. The intersection of the spectral curves obtained by the numerical solution of the “electric” and “magnetic” boundary value problems determines the minima of a reflection or transmission coefficients of fundamental wave on discontinuities. To algebraize the boundary value problems for the eigen frequencies of volume resonator with discontinuity, the corresponding two-dimensional functions of the magnetic potential are constructed, through which the components of the current density on the strip are determined. The functions of magnetic potential were defined by decomposing them into expansion by Fourier series, which ensures stable convergence of the series and numerical calculation algorithm. The developed technique has been tested by calculating the eigenfrequency spectra of an open microstrip stub using the transverse resonance method on the example of an open stub in a microstrip transmission line with a resonant frequency of about 3.0 GHz. Also, a technique for numerical solutions of “electric” and “magnetic” boundary-value problems for resonators with two electrodynamically coupled symmetric open stubs in a microstrip transmission line is developed.
Low brain-derived neurotrophic factor and high vascular cell adhesion molecule-1 levels are associated with chronic kidney disease in patients with type 2 diabetes mellitus
Authors: Chiang Yu-Hsin , Li Yu-Hsuan , Chan Yin-Ching , Cheng Yu-Cheng , Wu Junyi , Lin Jer-An , Huang Wei-Chang , Lee I-Te
Published: September 2024

Background

Patients with type 2 diabetes mellitus (DM) have a high prevalence of chronic kidney disease (CKD). Energy imbalance and inflammation may be involved in the pathogenesis of CKD. We examined the effects of brain-derived neurotrophic factor (BDNF) and vascular cell adhesion molecule-1 (VCAM-1) on CKD in patients with type 2 DM.

Methods

Patients with type 2 DM were enrolled for this cross-sectional study. Fasting serum was prepared to measure the BDNF and VCAM-1 levels. An estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2 was used as the criterion for identifying patients with CKD.

Results

Of the 548 enrolled participants, 156 had CKD. Patients with CKD exhibited significantly lower BDNF (median of 21.4 ng/mL, interquartile range [IQR]: 17.0–27.0 ng/mL vs. median of 25.9 ng/mL, IQR: 21.0–30.4 ng/mL, P <0.001) and higher VCAM-1 (median of 917 ng/mL, IQR: 761–1172 ng/mL vs. median of 669 ng/mL, IQR: 552–857 ng/mL, P <0.001) levels than those without CKD. Serum BDNF levels were inversely correlated with VCAM-1 levels (Spearman’s rank correlation coefficient = -0.210, P <0.001). The patients were divided into four subgroups based on median BDNF and VCAM-1 levels (24.88 ng/mL and 750 ng/mL, respectively). Notably, patients in the high VCAM-1 and low BDNF group had the highest prevalence (50%) of CKD. Multivariate logistic regression revealed a significantly higher odds ratio (OR) of CKD in the high VCAM-1 and low BDNF group (OR = 3.885, 95% CI: 1.766–8.547, P <0.001), followed by that in the high VCAM-1 and high BDNF group (OR = 3.099, 95% CI: 1.373–6.992, P =0.006) compared with that in the low VCAM-1 and high BDNF group. However, the risk of CKD in the low VCAM-1 and low BDNF group was not significantly different from that in the low VCAM-1 and high BDNF group (P =0.266).

Conclusion

CKD in patients with type 2 DM is associated with low serum BDNF and high VCAM-1 levels. BDNF and VCAM-1 have a synergistic effect on CKD. Thus, BDNF and VCAM-1 can be potential biomarkers for CKD risk stratification in patients with type 2 DM.
Steroidogenic differentiation of human amniotic membrane-derived mesenchymal stem cells into a progesterone-/androgen-producing cell lineage by SF-1 and an estrogen-producing cell lineage by WT1−KTS
Authors: Miyazaki Yumiko , Orisaka Makoto , Fujita Yuko , Mizutani Tetsuya , Yazawa Takashi , Yoshida Yoshio
Published: September 2024

Background

Sex steroid hormones, primarily synthesized by gonadal somatic cells, are pivotal for sexual development and reproduction. Mice studies have shown that two transcription factors, steroidogenic factor 1 (SF-1) and Wilms’ tumor 1 (WT1), are involved in gonadal development. However, their role in human gonadal somatic differentiation remains unclear. We therefore aimed to investigate the roles of SF-1 and WT1 in human gonadal steroidogenic cell differentiation.

Methods

Using a transient lentivirus-mediated gene expression system, we assessed the effects of SF-1 and WT1 expression on the steroidogenic potential of human amniotic membrane-derived mesenchymal stem cells (hAmMSCs).

Results

SF-1 and WT1−KTS, a splice variant of WT1, played distinct roles in human steroidogenic differentiation of hAmMSCs. SF-1 induced hAmMSC differentiation into progesterone- and androgen-producing cell lineages, whereas WT1−KTS promoted hAmMSC differentiation into estrogen-producing cell lineages.

Conclusion

Our findings revealed that SF-1 and WT1−KTS play important roles in human gonadal steroidogenic cell differentiation, especially during ovarian development. These findings may pave the way for future studies on human ovarian differentiation and development.
Influence of sex and functional status on the value of serum steroid profiling in discriminating adrenocortical carcinoma from adrenocortical adenoma
Authors: Weng Yan , Tang Ju-Ying , Zhang Xiao-Yun , Lin Diao-Zhu , Guo Ying , Liang Ying , Wang Lin , Zhou Jing , Yan Li , Lin Tian-Xin , Zhang Shao-Ling
Published: September 2024

Background

It is challenging for clinicians to distinguish adrenocortical carcinoma (ACC) from benign adrenocortical adenomas (ACA) in their early stages. This study explored the value of serum steroid profiling as a complementary biomarker for malignancy diagnosis of ACC other than diameter and explored the influence of sex and functional status.

Methods

In this retrospective study, a matched cohort of patients diagnosed with either ACC or ACA based on histopathology was meticulously paired in a 1:1 ratio according to sex, age, and functional status. Eight serum steroids including 11-deoxycortisol, 11-deoxycorticosterone, progesterone, androstenedione, dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulfate (DHEAS), 17-hydroxyprogesterone, and estradiol, were quantified by liquid chromatography tandem mass spectrometry. We conducted a comparative analysis of the clinical characteristics and serum steroid profiles of patients with ACC and ACA, with further subgroup analysis.

Results

The study included 31 patients with ACC and 31 matched patients with ACA. Patients with ACC exhibited significantly larger tumor diameters, lower body mass index (BMI), and higher levels of 11-deoxycortisol, progesterone, and androstenedione than those with ACA. 11-deoxycortisol was the only valuable index for discriminating ACC from ACA, regardless of functional status and sex. Progesterone, DHEA, and DHEAS levels were higher in the functional ACC group than in the non-functional ACC group. Female ACC patients, especially in postmenopausal female exhibited higher levels of androstenedione than male patients. The area under the curve of tumor diameter, 11-deoxycortisol, and BMI was 0.947 (95% CI 0.889–1.000), with a sensitivity of 96.8% and specificity of 90.3%.

Conclusion

Serum steroid profiling serves as a helpful discriminative marker for ACC and ACA, with 11-deoxycortisol being the most valuable marker. For other steroid hormones, consideration of sex differences and functional status is crucial.
Heavy metal changes related to land use changes in a karst area: a case study in Changshun, Guizhou Province, China
Authors: Jiang Xin , Wang Xingfu , Liu Yi , Huang Yu , Huang Xianfei
Published: September 2024

Karst areas are often characterized by fragile ecological systems, and environmental pollution has increased the pressures on people living in such regions. This study aimed to investigate the status of pollution caused by heavy metals (Pb, Cd, Hg, As, and Cu) in soils based on different land uses in Changshun County, a karst area in southwestern China. Soil samples were collected from natural forestlands (NFLs), natural brush lands (NBLs), natural pasture lands (NPLs), artificial forestlands (AFLs), artificial brush lands (ABLs), and artificial pasture lands (APLs) for evaluation. The results suggest that the soil profile characteristics of the heavy metals studied herein vary significantly among different land uses. The heavy metal concentrations in all soil samples collected from NFLs were lower than those in samples from other land uses. Forest trees can protect soil from heavy metal pollution caused by atmospheric deposition; this is especially true for Hg. In cultivated forestlands and brush lands, special attention should be devoted to Cd pollution in the soil, which may be caused by the use of fertilizers. Changing both natural and artificial pastoral lands to forestlands could benefit the local ecosystems as it may reduce Hg contamination.
Assessment of mangrove structures and biomass on islands along the Java Sea: a case study on Bawean Islands and Karimunjawa Islands
Authors: Asadi Muhammad Arif , Al-kareem Alvu Sya’ban , Aprilianto Riqki Yoga , Sartimbul Aida , Yamindago Ade , Saputra Dhira Khurniawan , Riyadi Achmad
Published: September 2024

Mangroves on the islands along the Java Sea play a crucial role in supporting biodiversity, protecting coastlines, and sequestering carbon. However, there is a lack of information on mangrove structure and biomass in the area. This study aimed to assess the mangrove structures and biomass on Desa Daun, located on the Bawean Islands, and Kemujan Island, located on the Karimunjawa Islands, respectively. The study utilized a combination of line transect and quadrant plot methods with a size plot of 10x10 m. We established 7 line transects and 28 quadrant plots in the mangrove forest of Desa Daun and similarly set up 7 line transects and 21 quadrant plots on Kemujan Island. Within each quadrant, the mangrove species were identified, and their diameters at breast height (DBH) were recorded. To assess the relative significance of each species, the importance value index (IVI) was calculated, and allometric equations were applied to estimate biomass and carbon storage in the trees. PlanetScope imagery was also used to quantify the carbon stock of mangroves on those islands. In Desa Daun, 13 mangrove species were identified, while 12 species were recorded on Kemujan Island. The species Nypa fruticans and Excoecaria agallocha exhibited the highest IVI in Desa Daun and Kemujan Island, respectively. Notably, Rhizophora apiculata demonstrated the greatest biomass in both locations, with measurements of 43.08 Mg B/ha in Desa Daun and 102.22 Mg B/ha in Kemujan Island. Overall, mangrove stands on Desa Daun stored biomass of 113.60 Mg B/ha and carbon of 50.98 Mg C/ha, whereas mangrove stands on Kemujan Island stored biomass of 295.04 Mg B/ha and carbon of 131.95 Mg C/ha. Mangrove stands of the whole Bawean Islands sequestered 22,941 Mg C, while Karimunjawa Islands hold much higher C stocks, 79,451 Mg C. Despite being smaller in size, the Karimunjawa Islands have more extensive mangrove coverage compared to the Bawean Islands due to their geomorphological characteristics, which in turn influence their mangrove structures and carbon stocks. However, the loss of mangroves in the Karimunjawa Islands due to aquaculture expansions could increase carbon loss in the islands.
Bidirectional two-sample Mendelian randomization analysis investigates causal associations between cathepsins and inflammatory bowel disease
Authors: Wang Na , Liu Jun , Chai Bao , Yao Jianhong , Du Xufang , Mei Qi , Wang Xuena
Published: September 2024

Background

Cathepsins, key regulators of the pathology of gastrointestinal disorders such as inflammatory bowel disease (IBD), are a target protease that has attracted much attention in recent years. IBD is a chronic and relapsing inflammatory disorder of the gut. Traditional studies have shown a correlation between cathepsin and the risk of IBD, while the causal relationship remains unclear.

Methods

This study utilized Mendelian randomization techniques to evaluate the causal relationships between eleven cathepsins and the subtypes of IBD, such as ulcerative colitis (UC) and Crohn’s disease (CD). We also performed a series of sensitivity analyses to validate the primary Mendelian randomization (MR) results, including Cochran’s Q test, the MR-PRESSO global test, and the MR pleiotropy test.

Results

The forward MR analyses showed no significant association between cathepsins and IBD. Reverse Mendelian randomization analyses suggested that UC might lead to elevated cathepsin G levels [inverse-variance weighted (IVW): p = 0.038, b = 9.966], and CD might cause a decrease in cathepsin B levels [IVW: p = 0.002, b = −10.525] and cathepsin L1 levels [IVW: p = 0.045, b = −4.742].

Conclusions

Our findings offer novel and comprehensive evidence on the impact of UC or CD on cathepsins, potentially providing valuable insights into the treatment and prognosis of IBD.
Monozygotic triplets with juvenile-onset autoimmunity and 18p microdeletion involving PTPRM
Authors: Herlin Morten Krogh , Bernth Jensen Jens Magnus , Andreasen Lotte , Petersen Mikkel Steen , Lønskov Jonas , Thorup Mette Bendixen , Birkebæk Niels , Mogensen Trine H. , Herlin Troels , Deleuran Bent
Published: September 2024

Abnormal gene dosage from copy number variants has been associated with susceptibility to autoimmune disease. This includes 18p deletion syndrome, a chromosomal disorder with an estimated prevalence of 1 in 50,000 characterized by intellectual disability, facial dysmorphology, and brain abnormalities. The underlying causes for autoimmune manifestations associated with 18p deletions, however, remain unknown. Our objective was to investigate a distinctive case involving monozygotic triplets concordant for developmental delay, white matter abnormalities, and autoimmunity, specifically juvenile-onset Graves’ thyroiditis. By chromosomal microarray analysis and whole genome sequencing, we found the triplets to carry a de novo interstitial 5.9 Mb deletion of chromosome 18p11.31p11.21 spanning 19 protein-coding genes. We conducted a literature review to pinpoint genes affected by the deletion that could be associated with immune dysregulation and identified PTPRM as a potential candidate. Through dephosphorylation, PTPRM serves as a negative regulator of STAT3, a key factor in the generation of Th17 cells and the onset of specific autoimmune manifestations. We hypothesized that PTPRM hemizygosity results in increased STAT3 activation. We therefore performed assays investigating PTPRM expression, STAT3 phosphorylation, Th1/Th2/Th17 cell fractions, Treg cells, and overall immunophenotype, and in support of the hypothesis, our investigations showed an increase in cells with phosphorylated STAT3 and higher levels of Th17 cells in the triplets. We propose that PTPRM hemizygosity can serve as a contributing factor to autoimmune susceptibility in 18p deletion syndrome. If confirmed in unrelated 18p/PTPRM deletion patients, this susceptibility could potentially be treated by targeted inhibition of IL-17.
Neural architecture search for adversarial robustness via learnable pruning
Authors: Li Yize , Zhao Pu , Ding Ruyi , Zhou Tong , Fei Yunsi , Xu Xiaolin , Lin Xue
Published: September 2024

The convincing performances of deep neural networks (DNNs) can be degraded tremendously under malicious samples, known as adversarial examples. Besides, with the widespread edge platforms, it is essential to reduce the DNN model size for efficient deployment on resource-limited edge devices. To achieve both adversarial robustness and model sparsity, we propose a robustness-aware search framework, an Adversarial Neural Architecture Search by the Pruning policy (ANAS-P). The layer-wise width is searched automatically via the binary convolutional mask, titled Depth-wise Differentiable Binary Convolutional indicator (D2BC). By conducting comprehensive experiments on three classification data sets (CIFAR-10, CIFAR-100, and Tiny-ImageNet) utilizing two adversarial losses TRADES (TRadeoff-inspired Adversarial DEfense via Surrogate-loss minimization) and MART (Misclassification Aware adveRsarial Training), we empirically demonstrate the effectiveness of ANAS in terms of clean accuracy and adversarial robust accuracy across various sparsity levels. Our proposed approach, ANAS-P, outperforms previous representative methods, especially in high-sparsity settings, with significant improvements.
Tonsil explants as a human in vitro model to study vaccine responses
Authors: Bonaiti Elena , Muraro Manuele G. , Robert Philippe A. , Jakscha Jens , Dirnhofer Stefan , Martin Ivan , Berger Christoph T.
Published: September 2024

Introduction

Vaccination is one of the most effective infection prevention strategies. Viruses with high mutation rates -such as influenza- escape vaccine-induced immunity and represent significant challenges to vaccine design. Influenza vaccine strain selection is based on circulating strains and immunogenicity testing in animal models with limited predictive outcomes for vaccine effectiveness in humans.

Methods

We developed a human in vitro vaccination model using human tonsil tissue explants cultured in 3D perfusion bioreactors to be utilized as a platform to test and improve vaccines.

Results

Tonsils cultured in bioreactors showed higher viability, metabolic activity, and more robust immune responses than those in static cultures. The in vitro vaccination system responded to various premanufactured vaccines, protein antigens, and antigen combinations. In particular, a multivalent in vitro immunization with three phylogenetically distant H3N2 influenza strains showed evidence for broader B cell activation and induced higher antibody cross-reactivity than combinations with more related strains. Moreover, we demonstrate the capacity of our in vitro model to generate de novo humoral immune responses to a model antigen.

Discussion

Perfusion-cultured tonsil tissue may be a valuable human in vitro model for immunology research with potential application in vaccine candidate selection.
Efficacy and safety of first-line treatments for advanced hepatocellular carcinoma patients: a systematic review and network meta-analysis
Authors: Li Jingyi , Yang Bowen , Teng Zan , Liu Yunpeng , Li Danni , Qu Xiujuan
Published: September 2024

Background

The first-line treatment for advanced hepatocellular carcinoma has evolved significantly. This study aimed to identify the most beneficial regimen.

Methods

A systematic search was conducted from July 2012 to August 2024 across the following four databases: PubMed, Embase, Cochrane Library, and ClinicalTrials.gov. This search focused on phase III prospective randomized controlled trials that compared first-line treatment for advanced hepatocellular carcinoma.

Results

Seventeen studies involving 10322 patients were included in this network meta-analysis. Of the studies we included, twelve studies were global multicenter clinical studies, four were initiated in China, and one was initiated in Korea. The results of our statistical analysis suggest that Hepatic artery infusion chemotherapy with oxaliplatin plus fluorouracil (HAIC-FO) demonstrated significant overall survival (OS) benefits compared with most treatments, including various immune checkpoint inhibitors (ICIs) and anti-vascular endothelial growth factor tyrosine kinase inhibitors (VEGF-TKIs). In terms of OS, HAIC had shown similar efficacy with sorafenib plus FOLFOX (HR, 0.88; 95% CI: 0.37-2.09) and transcatheter arterial chemoembolization (TACE) combined with lenvatinib (HR, 0.69; 95% CI: 0.30-1.56). Notably, immune-related treatments, such as ICIs combined with anti-VEGF therapies, also showed improved OS compared with anti-VEGF-TKIs alone. In terms of progression-free survival (PFS), HAIC-FO outperformed anti-VEGF-TKI monotherapy, ICI monotherapy, and several ICI combinations. However, it was not superior to lenvatinib plus TACE or lenvatinib plus pembrolizumab. Based on the Surface Under the Cumulative Ranking Curve (SUCRA) values, HAIC-FO was ranked the most effective in terms of OS (SUCRA = 0.961) and objective response rate (ORR) (SUCRA = 0.971). The results of the subgroup analysis suggested that HAIC-FO achieved the best OS benefit in the macrovascular invasion (MVI) and extrahepatic spread (EHS) subgroup (SUCRA = 0.99) and that tremelimumab combined with durvalumab achieved the best OS benefit in the Asian subgroup (SUCRA = 0.88).

Conclusion

This systematic review and network meta-analysis suggest that HAIC-based therapies may become a potential first-line treatment option for advanced HCC, especially for patients in Mainland China with MVI and EHS. Additionally, immune-related treatments may be more suitable for Asian populations.
Differential lipid signaling from CD4+ and CD8+ T cells contributes to type 1 diabetes development
Authors: White Tayleur D. , Almutairi Abdulaziz , Gai-Tusing Ying , Stephenson Daniel J. , Stephenson Benjamin D. , Chalfant Charles E. , Lei Xiaoyong , Lu Brian , Hammock Bruce D. , DiLorenzo Teresa P. , Ramanadham Sasanka
Published: September 2024

Introduction

We reported that Ca2+-independent phospholipase A2β (iPLA2β)–derived lipids (iDLs) contribute to type 1 diabetes (T1D) onset. As CD4+ and CD8+ T cells are critical in promoting β-cell death, we tested the hypothesis that iDL signaling from these cells participates in T1D development.

Methods

CD4+ and CD8+ T cells from wild-type non-obese diabetic (NOD) and NOD.iPLA2β+/- (NOD.HET) mice were administered in different combinations to immunodeficient NOD.scid.

Results

In mice receiving only NOD T cells, T1D onset was rapid (5 weeks), incidence 100% by 20 weeks, and islets absent. In contrast, onset was delayed 1 week and incidence reduced 40%–50% in mice receiving combinations that included NOD.HET T cells. Consistently, islets from these non-diabetic mice were devoid of infiltrate and contained insulin-positive β-cells. Reduced iPLA2β led to decreased production of proinflammatory lipids from CD4+ T cells including prostaglandins and dihydroxyeicosatrienoic acids (DHETs), products of soluble epoxide hydrolase (sEH), and inhibition of their signaling decreased (by 82%) IFNγ+CD4+ cells abundance. However, only DHETs production was reduced from CD8+ T cells and was accompanied by decreases in sEH and granzyme B.

Discussion

These findings suggest that differential select iDL signaling in CD4+ and CD8+ T cells contributes to T1D development, and that therapeutics targeting such signaling might be considered to counter T1D.
Identification of telomere-related lncRNAs and immunological analysis in ovarian cancer
Authors: Xu Weina , Sang Shuliu , Wang Jun , Guo Shanshan , Zhang Xiao , Zhou Hailun , Chen Yijia
Published: September 2024

Background

Ovarian cancer (OC) is a global malignancy characterized by metastatic invasiveness and recurrence. Long non-coding RNAs (lncRNAs) and Telomeres are closely connected with several cancers, but their potential as practical prognostic markers in OC is less well-defined.

Methods

Relevant mRNA and clinical data for OC were sourced from The Cancer Genome Atlas (TCGA) database. The telomere-related lncRNAs (TRLs) prognostic model was established by univariate/LASSO/multivariate regression analyses. The effectiveness of the TRLs model was evaluated and measured via the nomogram. Additionally, immune infiltration, tumor mutational load (TMB), and drug sensitivity were evaluated. We validated the expression levels of prognostic genes. Subsequently, PTPRD-AS1 knockdown was utilized to perform the CCK8 assay, colony formation assay, transwell assay, and wound healing assay of CAOV3 cells.

Results

A six-TRLs prognostic model (PTPRD-AS1, SPAG5-AS1, CHRM3-AS2, AC074286.1, FAM27E3, and AC018647.3) was established, which can effectively predict patient survival rates and was successfully validated using external datasets. According to the nomogram, the model could effectively predict prognosis. Furthermore, we detected the levels of regulatory T cells and M2 macrophages were comparatively higher in the high-risk TRLs group, but the levels of activated CD8 T cells and monocytes were the opposite. Finally, the low-risk group was more sensitive to anti-cancer drugs. The mRNA levels of PTPRD-AS1, SPAG5-AS1, FAM27E3, and AC018647.3 were significantly over-expressed in OC cell lines (SKOV3, A2780, CAOV3) in comparison to normal IOSE-80 cells. AC074286.1 were over-expressed in A2780 and CAOV3 cells and CHRM3-AS2 only in A2780 cells. PTPRD-AS1 knockdown decreased the proliferation, cloning, and migration of CAOV3 cells.

Conclusion

Our study identified potential biomarkers for the six-TRLs model related to the prognosis of OC.
Host heterogeneity in humoral bactericidal activity can be complement independent
Authors: Abe Ryuichiro , Ram-Mohan Nikhil , Zudock Elizabeth Jordan , Lewis Shawna , Carroll Karen C. , Yang Samuel
Published: September 2024

Background

Humoral bactericidal activity was first recognized nearly a century ago. However, the extent of inter-individual heterogeneity and the mechanisms underlying such heterogeneity beyond antibody or complement systems have not been well studied.

Methods

The plasma bactericidal activity of five healthy volunteers were tested against 30 strains of Gram-negative uropathogens, Klebsiella pneumoniae and Escherichia coli, associated with bloodstream infections. IgG and IgM titers specific to K. pneumoniae strains KP13883 and KPB1 were measured by ELISA, and complement inhibitor was used to measure the contribution of complement-induced killing. Furthermore, MALDI-TOF mass spectrometry was conducted to determine the metabolomic components of plasma with bactericidal properties in 25 healthy individuals using Bayesian inference of Pearson correlation between peak intensity and colony counts of surviving bacteria.

Results

Plasma bactericidal activity varied widely between individuals against various bacterial strains. While individual plasma with higher IgM titers specific to K. pneumoniae strain KP13883 showed more efficient killing of the strain, both IgM and IgG titers for K. pneumoniae strain KPB1 did not correlate well with the killing activity. Complement inhibition assays elucidated that the complement-mediated killing was not responsible for the inter-individual heterogeneity in either isolate. Subsequently, using MALDI-TOF mass spectrometry on plasmas of 25 healthy individuals, we identified several small molecules including gangliosides, pediocins, or saponins as candidates that showed negative correlation between peak intensities and colony forming units of the test bacteria.

Conclusion

This is the first study to demonstrate the inter-individual heterogeneity of constitutive innate humoral bactericidal function quantitatively and that the heterogeneity can be independent of antibody or the complement system.
The role of immune cells in the pathogenesis of connective tissue diseases-associated pulmonary arterial hypertension
Authors: Li Zhe , Ma Juan , Wang Xuejing , Zhu Liquan , Gan Yu , Dai Baoquan
Published: September 2024

Connective tissue diseases-related pulmonary arterial hypertension (CTD-PAH) is a disease characterized by an elevated pulmonary artery pressure that arises as a complication of connective tissue diseases. The number of patients with CTD-PAH accounts for 25.3% of all PAH patients. The main pathological features of CTD-PAH are thickening of intima, media and adventitia of pulmonary arterioles, increased pulmonary vascular resistance, autoimmune activation and inflammatory reaction. It is worth noting that abnormal immune activation will produce autoantibodies and release cytokines, and abnormal immune cell recruitment will promote inflammatory environment and vascular remodeling. Therefore, almost all forms of connective tissue diseases are related to PAH. In addition to general therapy and targeted drug therapy for PAH, high-dose glucocorticoid combined with immunosuppressant can quickly alleviate and stabilize the basic CTD-PAH disease. Given this, the development of therapeutic approaches targeting immune dysregulation and heightened inflammation is recognized as a promising strategy to prevent or reverse the progression of CTD-PAH. This review explores the potential mechanisms by which immune cells contribute to the development of CTD-PAH and examines the clinical application of immunosuppressive therapies in managing CTD-PAH.
A TMSBL underwater acoustic channel estimation method based on dictionary learning denoising
Authors: Xing Chuanxi , Ran Yanling , Lu Mao , Tan Guangzhi , Meng Qiang
Published: September 2024

The shallow sea underwater acoustic channel exhibits a significant sparse multipath structure. The temporally multiple sparse Bayesian learning (TMSBL) algorithm can effectively estimate this sparse multipath channel. However, the complexity of the algorithm is high, the signal-to-noise ratio (SNR) of shallow-sea underwater acoustic communication is low, and the estimation performance of the TMSBL algorithm is greatly affected by noise. To address this problem, an improved TMSBL underwater acoustic channel estimation method based on a dictionary learning noise reduction algorithm is proposed. Firstly, the K-Singular Value Decomposition (K-SVD) dictionary learning method is used to reduce the noise of the received pilot matrix, reducing the influence of noise on the signal. Then, the Generalized Orthogonal Matching Pursuit (GOMP) channel estimation method is combined to obtain a priori information such as the perceptual matrix and hyperparameter matrix for TMSBL channel estimation; and the noise variance is obtained by using the null subcarrier calculation instead of iteratively updating the noise variance in the TMSBL, to improve the estimation accuracy and reduce the algorithmic complexity. Finally, the TMSBL channel estimation method is used to estimate the underwater acoustic channels of different symbols jointly. The simulation results show that the normalized mean square error of the channel estimation of the improved TMSBL method is reduced by about 92.2% compared with the TMSBL algorithm, obtaining higher estimation accuracy; running time is reduced by about 45.6%, and there is also better performance in terms of the running speed, which provides a reference for underwater acoustic channel estimation.
Qualitative variability of dissolved organic matter in the Baltic Sea sediments apparent from fluxes and optical properties
Authors: Loginova Alexandra N. , Wünsch Urban J. , Zabłocka Monika , Cherkasheva Aleksandra , Szymczycha Beata , Kuliński Karol , Winogradow Aleksandra , Kowalczuk Piotr
Published: September 2024

The release of dissolved organic matter (DOM) from sediments serves as an important part of the carbon cycle. Here, we address pore water DOM quality and its release from shallow sediments (0–10 cm) of the central and southern Baltic Sea - Gdansk, Bornholm, and Eastern Gotland Basins - using excitation–emission matrix spectroscopy and size-exclusion chromatography. DOM release from sediments displayed spatial variability, with diffusive DOC fluxes ranging from 0.02 to 1.06 mmol m−2 d−1, and basin-averaged fluxes increased in the order Gotland < Bornholm < Gdansk. DOM qualitative characteristics also varied among investigated basins. In the oxygen-limited study sites from the Gdansk Basin, we observed elevated abundances of low apparent molecular weight DOM fraction and proteinaceous-like fluorescent DOM, while in the Bornholm Basin, pore water DOM was generally more humic-like and of higher apparent molecular weight. Pore waters from the deepest study sites in the Gotland Basin were qualitatively very similar to those of the pore waters from the upper sediment layers (0–4 cm) from all other investigated sites, suggesting little organic matter reworking at depth at those stations. Our results suggest that the spatial variability in the magnitude of DOM release may be linked to the qualitative differences of DOM in sediments.