bluuebunny/crossref_metadata_2025 huggingface dataset:
Dual inhibition of EZH2 and G9A/GLP histone methyltransferases by HKMTI-1-005 promotes differentiation of acute myeloid leukemia cells
Authors: Sbirkov Y. , Schenk T. , Kwok C. , Stengel S. , Brown R. , Brown G. , Chesler L. , Zelent A. , Fuchter M. J. , Petrie K.
Published: March 2023

All-trans-retinoic acid (ATRA)-based differentiation therapy of acute promyelocytic leukemia (APL) represents one of the most clinically effective examples of precision medicine and the first example of targeted oncoprotein degradation. The success of ATRA in APL, however, remains to be translated to non-APL acute myeloid leukemia (AML). We previously showed that aberrant histone modifications, including histone H3 lysine 4 (H3K4) and lysine 27 (H3K27) methylation, were associated with this lack of response and that epigenetic therapy with small molecule inhibitors of the H3K4 demethylase LSD1/KDM1A could reprogram AML cells to respond to ATRA. Serving as the enzymatic component of Polycomb Repressive Complex 2, EZH2/KMT6A methyltransferase plays a critical role in normal hematopoiesis by affecting the balance between self-renewal and differentiation. The canonical function of EZH2 is methylation of H3K27, although important non-canonical roles have recently been described. EZH2 mutation or deregulated expression has been conclusively demonstrated in the pathogenesis of AML and response to treatment, thus making it an attractive therapeutic target. In this study, we therefore investigated whether inhibition of EZH2 might also improve the response of non-APL AML cells to ATRA-based therapy. We focused on GSK-343, a pyridone-containing S-adenosyl-L-methionine cofactor-competitive EZH2 inhibitor that is representative of its class, and HKMTI-1-005, a substrate-competitive dual inhibitor targeting EZH2 and the closely related G9A/GLP H3K9 methyltransferases. We found that treatment with HKMTI-1-005 phenocopied EZH2 knockdown and was more effective in inducing differentiation than GSK-343, despite the efficacy of GSK-343 in terms of abolishing H3K27 trimethylation. Furthermore, transcriptomic analysis revealed that in contrast to treatment with GSK-343, HKMTI-1-005 upregulated the expression of differentiation pathway genes with and without ATRA, while downregulating genes associated with a hematopoietic stem cell phenotype. These results pointed to a non-canonical role for EZH2, which was supported by the finding that EZH2 associates with the master regulator of myeloid differentiation, RARα, in an ATRA-dependent manner that was enhanced by HKMTI-1-005, possibly playing a role in co-regulator complex exchange during transcriptional activation. In summary, our results strongly suggest that addition of HKMTI-1-005 to ATRA is a new therapeutic approach against AML that warrants further investigation.
Alterations of gut microbes and their correlation with clinical features in middle and end-stages chronic kidney disease
Authors: Chen Hao , Wang Jingyan , Ouyang Qin , Peng Xinyue , Yu Zheng , Wang Jianwen , Huang Jing
Published: March 2023

Gut microecosystem has been shown to play an important role in human health. In recent years, the concept of the gut-kidney axis has been proposed to explain the potential association between gut microbiota and chronic kidney disease (CKD). Here, a cohort of fecal samples collected from patients with CKD (n = 13) were involved. The composition of gut microbial communities and clinical features in CKD and end-stage renal disease (ESRD) were characterized. Our study focused on the changes in gut microbiome and the correlation with clinical features in patients with CKD and ESRD by analyzing high-throughput sequencing results of collected feces. We elucidated the alterations of gut microbiota in CKD patients at different stages of disease and initially identified the gut microbiota associated with CKD progression. We also combined correlation analysis to identify clinical features closely related to the gut microbiome. Our results offered the possibility of using non-invasive gut microbiome in the early diagnosis of course from CKD to ESRD and provide new insights into the association between clinical features and gut microbiota in CKD.
A predictive model for early clinical diagnosis of spinal tuberculosis based on conventional laboratory indices: A multicenter real-world study
Authors: Hu Xiaojiang , Zhang Guang , Zhang Hongqi , Tang Mingxing , Liu Shaohua , Tang Bo , Xu Dongcheng , Zhang Chengran , Gao Qile
Published: March 2023

Background

Early diagnosis of spinal tuberculosis (STB) remains challenging. The aim of this study was to develop a predictive model for the early diagnosis of STB based on conventional laboratory indicators.

Method

The clinical data of patients with suspected STB in four hospitals were included, and variables were screened by Lasso regression. Eighty-five percent of the cases in the dataset were randomly selected as the training set, and the other 15% were selected as the validation set. The diagnostic prediction model was established by logistic regression in the training set, and the nomogram was drawn. The diagnostic performance of the model was verified in the validation set.

Result

A total of 206 patients were included in the study, including 105 patients with STB and 101 patients with NSTB. Twelve variables were screened by Lasso regression and modeled by logistic regression, and seven variables (TB.antibody, IGRAs, RBC, Mono%, RDW, AST, BUN) were finally included in the model. AUC of 0.9468 and 0.9188 in the training and validation cohort, respectively.

Conclusion

In this study, we developed a prediction model for the early diagnosis of STB which consisted of seven routine laboratory indicators.
Identification of vulnerable non-culprit lesions by coronary computed tomography angiography in patients with chronic coronary syndrome and diabetes mellitus
Authors: Zhao Jia , Zhang Hong , Liu Chang , Zhang Ying , Xie Cun , Wang Minghui , Wang Chengjian , Wang Shuo , Xue Yuanyuan , Liang Shuo , Gao Yufan , Cong Hongliang , Li Chunjie , Zhou Jia
Published: March 2023

Background

Among patients with diabetes mellitus (DM) and chronic coronary syndrome (CCS), non-culprit lesions (NCLs) are responsible for a substantial number of future major adverse cardiovascular events (MACEs). Thus, we aimed to establish the natural history relationship between adverse plaque characteristics (APCs) of NCLs non-invasively identified by coronary computed tomography angiography (CCTA) and subsequent MACEs in these patients.

Methods

Between January 2016 and January 2019, 523 patients with DM and CCS were included in the present study after CCTA and successful percutaneous coronary intervention (PCI). All patients were followed up for MACEs (the composite of cardiac death, myocardial infarction, and unplanned coronary revascularization) until January 2022, and the independent clinical event committee classified MACEs as indeterminate, culprit lesion (CL), and NCL-related. The primary outcome was MACEs arising from untreated NCLs during the follow-up. The association between plaque characteristics detected by CCTA and primary outcomes was determined by Marginal Cox proportional hazard regression.

Results

Overall, 1,248 NCLs of the 523 patients were analyzed and followed up for a median of 47 months. The cumulative rates of indeterminate, CL, and NCL-related MACEs were 2.3%, 14.5%, and 20.5%, respectively. On multivariate analysis, NCLs associated with recurrent MACEs were more likely to be characterized by a plaque burden >70% [hazard ratio (HR), 4.35, 95% confidence interval (CI): 2.92–6.44], a low-density non-calcified plaque (LDNCP) volume >30 mm3 (HR: 3.40, 95% CI: 2.07–5.56), a minimal luminal area (MLA) <4 mm2 (HR: 2.30, 95% CI: 1.57–3.36), or a combination of three APCs (HR: 13.69, 95% CI: 9.34–20.12, p < 0.0001) than those not associated with recurrent MACEs. Sensitivity analysis regarding all indeterminate MACEs as NCL-related ones demonstrated similar results.

Conclusions

In DM patients who presented with CCS and underwent PCI, half of the MACEs occurring during the follow-up were attributable to recurrence at the site of NCLs. NCLs responsible for unanticipated MACEs were frequently characterized by a large plaque burden and LDNCP volume, a small MLA, or a combination of these APCs, as determined by CCTA.
A large-scale machine learning study of sociodemographic factors contributing to COVID-19 severity
Authors: Tumbas Marko , Markovic Sofija , Salom Igor , Djordjevic Marko
Published: March 2023

Understanding sociodemographic factors behind COVID-19 severity relates to significant methodological difficulties, such as differences in testing policies and epidemics phase, as well as a large number of predictors that can potentially contribute to severity. To account for these difficulties, we assemble 115 predictors for more than 3,000 US counties and employ a well-defined COVID-19 severity measure derived from epidemiological dynamics modeling. We then use a number of advanced feature selection techniques from machine learning to determine which of these predictors significantly impact the disease severity. We obtain a surprisingly simple result, where only two variables are clearly and robustly selected—population density and proportion of African Americans. Possible causes behind this result are discussed. We argue that the approach may be useful whenever significant determinants of disease progression over diverse geographic regions should be selected from a large number of potentially important factors.
Study on the restraint control of an isolation pile on an existing high-speed railway during the close passing of a shield machine
Authors: Tao Yang , Shuailei Liu , Hao Zhao , Xingru Li
Published: March 2023

The impact of shield construction on the close lateral passing of high-speed railways can threaten the safety of operating high-speed railways. To study the deformation characteristics of the shield structure after the application of isolation piles from the ground surface and the deformation characteristics of the bridge piers of an overpassing high-speed railway, we analyze the mechanism of isolation pile restraint control and establish a three-dimensional numerical model of a shield structure to study the situation of a high-speed railway with a metro interval under passing a high-speed railway passenger line project. Combined with the measured data and numerical simulation data of the same construction stage, we study the impact of shield structure lateral passing on high-speed railway piers and surrounding ground surface in terms of the disturbance changes and the effect of isolation, as well as the effect of the lateral passing of the shield tunnel on the surface of the bridge piers and the surrounding area and the control effect of the isolation piles on the deformation. The results show that the isolation pile can block the development of the soil layer rupture surface and the stress path. The isolation pile has a good control effect on the vertical displacement of the bridge pier. The vertical displacement of the bridge pier decreases from 0.6 mm to 1.1 mm after the single- and double-track tunneling, and the displacement changes along the depth direction from non-uniform to relatively uniform. The vertical displacement of the ground surface includes both uplift and settlement, which occur at the same time. When the shield tunneling advances, the form of the ground settlement trough is changed from a “V” shape formed by the right single-track tunneling to a “W” shape after the double-track tunneling. The isolation pile can effectively control the influence range of tunnel excavation; its lateral displacement form changes regularly, and the lateral uplift is always in a “double-C outward expansion” shape. The initial excavation greatly disturbs the initial stress field, so it is necessary to pay attention to the control and management of measures to destroy the initial stress field.
Mapping global citizenship: A Bibliometric analysis of the field of education for sustainable development
Authors: Pedraja-Rejas Liliana , Rodríguez-Ponce Emilio , Laroze David , Muñoz-Fritis Camila
Published: March 2023

Since the approval of the Sustainable Development Goals, global citizenship education (GCE) is increasingly capturing the attention of researchers worldwide. In this context, the aim of this manuscript is to review the existing literature on GCE (up to 2021) in journals indexed in the Web of Science. Particularly, it seeks to: (1) document the volume and growth trajectory of knowledge production, (2) identify countries, journals, authors, and key publications (both of the sample analyzed and of the references cited), (3) perform a science mapping of the knowledge base on GCE, and (4) discover the thematic foci of empirical works. For this purpose, a bibliometric analysis of the selected articles (n = 350) and a content analysis of the sample’s empirical papers (n = 210) was carried out. The main findings evidence that: the number of articles on the subject has increased notably since 2016; there is a concentration of knowledge production in countries of the Global North, driven mainly by the United States; geographical proximity, and even common language, seem not to be the main factors influencing international scientific collaborations; and, GCE is linked in the empirical articles in the sample mainly to the concept of internationalization of education. The conclusion is that, although the production of knowledge on GCE has recently increased considerably, it continues to lag behind other areas of the educational field.
Monogenic diabetes in New Zealand - An audit based revision of the monogenic diabetes genetic testing pathway in New Zealand
Authors: Harrington Francesca , Greenslade Mark , Colclough Kevin , Paul Ryan , Jefferies Craig , Murphy Rinki
Published: March 2023

Aims

To evaluate (a) the diagnostic yield of genetic testing for monogenic diabetes when using single gene and gene panel-based testing approaches in the New Zealand (NZ) population, (b) whether the MODY (Maturity Onset Diabetes of the Young) pre-test probability calculator can be used to guide referrals for testing in NZ, (c) the number of referrals for testing for Māori/Pacific ethnicities compared to NZ European, and (d) the volume of proband vs cascade tests being requested.

Methods

A retrospective audit of 495 referrals, from NZ, for testing of monogenic diabetes genes was performed. Referrals sent to LabPlus (Auckland) laboratory for single gene testing or small multi-gene panel testing, or to the Exeter Genomics Laboratory, UK, for a large gene panel, received from January 2014 – December 2021 were included. Detection rates of single gene, small multi-gene and large gene panels (neonatal and non-neonatal), and cascade testing were analysed. Pre-test probability was calculated using the Exeter MODY probability calculator and ethnicity data was also collected.

Results

The diagnostic detection rate varied across genes, from 32% in GCK, to 2% in HNF4A, with single gene or small gene panel testing averaging a 12% detection rate. Detection rate by type of panel was 9% for small gene panel, 23% for non-neonatal monogenic diabetes large gene panel and 40% for neonatal monogenic diabetes large gene panel. 45% (67/147) of patients aged 1-35 years at diabetes diagnosis scored <20% on MODY pre-test probability, of whom 3 had class 4/5 variants in HNF1A, HNF4A or HNF1B. Ethnicity data of those selected for genetic testing correlated with population diabetes prevalence for Māori (15% vs 16%), but Pacific People appeared under-represented (8% vs 14%). Only 1 in 6 probands generated a cascade test.

Conclusions

A new monogenic diabetes testing algorithm for NZ is proposed, which directs clinicians to choose a large gene panel in patients without syndromic features who score a pre-test MODY probability of above 20%.
The association between total bile acid and bone mineral density among patients with type 2 diabetes
Authors: Yang Song , Li Hongyun , Gu Yuanyuan , Wang Qiang , Dong Li , Xu Chao , Fan Yuxin , Liu Ming , Guan Qingbo , Ma Lixing
Published: March 2023

Objective

Bile acids have underlying protective effects on bones structure. Long-term diabetes also causes skeletal disorders including osteoporosis, Charcot arthropathy and renal osteodystrophy. Nevertheless, few studies have reported whether bile acid is associated with bone metabolism in diabetics. This study aimed to explore the relationship between total bile acid (TBA) and bone mineral density (BMD) among patients with type 2 diabetes mellitus (T2DM).

Methods

We retrospectively included 1,701 T2DM patients who were hospitalized in Taian City Central Hospital (TCCH), Shandong Province, China between January 2017 to December 2019. The participants were classified into the osteopenia (n = 573), osteoporosis (n= 331) and control groups (n= 797) according to BMD in the lumbar spine and femoral. The clinical parameters, including TBA, bilirubin, vitamin D, calcium, phosphorus and alkaline phosphatase were compared between groups. Multiple linear regression was used to analyze the relationship between TBA and BMD in lumbar spine, femoral, trochiter, ward’s triangle region. A logistic regression was conducted to develop a TBA-based diagnostic model for differentiating abnormal bone metabolism from those with normal BMD. We evaluated the performance of model using ROC curves.

Results

The TBA level was significantly higher in patients with osteoporosis (Median[M]= 3.300 μmol/L, interquartile range [IQR] = 1.725 to 5.250 μmol/L) compared to the osteopenia group (M = 3.200 μmol/L, IQR = 2.100 to 5.400 μmol/L) and control group (M = 2.750 μmol/L, IQR = 1.800 to 4.600 μmol/L) (P <0.05). Overall and subgroup analyses indicated that TBA was negatively associated with BMD after adjusted for the co-variates (i.e., age, gender, diabetes duration, BMI, total bilirubin, direct bilirubin, indirect bilirubin) (P <0.05). Logistic regression revealed that higher TBA level was associated with increased risk for abnormal bone metabolism (OR = 1.044, 95% CI = 1.005 to 1.083). A TBA-based diagnostic model was established to identify individuals with abnormal bone metabolism (T-score ≤ -1.0). The area under ROC curve (AUC) of 0.767 (95% CI = 0.730 to 0.804).

Conclusion

Our findings demonstrated the potential role of bile acids in bone metabolism among T2DM patients. The circulating TBA might be employed as an indicator of abnormal bone metabolism.
Empirical analysis of R&D spending, transport infrastructure development and CO2 emissions in China
Authors: Han Ling Mei , You Jian Qiang , Meng Jie Ning , Fu Yu Long , Wu Song Ling
Published: March 2023

Over the past few decades, the transportation sector has been the largest contributor to CO2 emissions in China. Research and Development spending leads to technological innovation in the country and could affect the CO2 emission in the country. Therefore, this study analyzes the nexus between CO2 emissions, transport infrastructure and R&D spending in China. A QARDL approach was used for the data analysis, which revealed Research and Development and Transport infrastructure has a positive impact on CO2 emissions. R&D was only significant in the first 25% quantile, while transportation was significant in almost all quantiles. These results suggest that R&D spending in China is mainly allocated to the sectors that emit the CO2 emission. It is recommended that government should allocate more R&D to carbon-reducing sectors. Furthermore, the government should consider green transportation investments and renewable energy projects in the transportation sector to reduce CO2 emissions in the country.
Global-feature of autoimmune glomerulonephritis using proteomic analysis of laser capture microdissected glomeruli
Authors: Dong Jingjing , Zheng Fengping , Liu Fanna , He Jingquan , Li Shanshan , Pu Wenjun , Xu Huixuan , Luo Zhifeng , Liu Shizhen , Yin Lianghong , Tang Donge , Dai Yong
Published: March 2023

Background

IgA nephropathy (IgAN), (LN), membranous nephropathy (MN), and minimal change nephropathy (MCN) are all belonged to autoimmune glomerulonephritis. This study aimed to identify the specific proteomic characteristics of the four GNs diseases in order to provide frameworks for developing the appropriate drug for patients diagnosed with GNs disease.

Methods

Liquid chromatography−tandem mass spectrometry (LC-MS/MS) was utilized to investigate proteomic features of glomerular tissues obtained by laser capture microdissection (LCM). 8 normal control cases, 11 IgAN cases, 19 LN cases, 5 MN cases, and 3 MCN cases in this study were selected for bioinformatics analyses.

Results

The shared overlapping proteins among the top 100 DEPs of each GNs type were mostly downregulated, in which only FLII was significantly downregulated in the four GNs diseases. A2M was significantly upregulated in MN, IgAN, and LN subgroups. The pathway of complement and coagulation cascades was notably activated with NES value ranging 2.77 to 3.39 among MCN, MN, IgAN, and LN diseases, but the pattern of protein expression level were significantly different. In LN patients, the increased activity of complement and coagulation cascades was contributed by the high expression of multiple complements (C1QB, C3, C4A, C4B, C6, C8B, C8G, C9). Meanwhile, both C1QC and C4B were remarkably upregulated in MN patients. On the contrary, complement-regulating proteins (CD59) was substantially decreased in MCN and IgAN subgroup.

Conclusions

The integrative proteomics analysis of the four GNs diseases provide insights into unique characteristics of GNs diseases and further serve as frameworks for precision medicine diagnosis and provide novel targets for drug development.
Anti-tumor memory CD4 and CD8 T-cells quantified by bulk T-cell receptor (TCR) clonal analysis
Authors: Gao Yanhua , Bergman Ira
Published: March 2023

Simple, reliable methods to detect anti-tumor memory T-cells are necessary to develop a clinical tumor vaccination program. A mouse model of curative viral onco-immunotherapy found that peritoneal tumor challenge following cure identified an oligoclonal anti-tumor memory CD4 and CD8 T-cell response. Clonotypes differed among the challenged animals but were congruent in blood, spleen and peritoneal cells (PC) of the same animal. Adoptive transfer demonstrated that the high-frequency responding T-cells were tumor specific. Tetramer analysis confirmed that clonotype frequency determined by T-cell receptor (TCR)- chain (TRB) analysis closely approximated cell clone frequency. The mean frequency of resting anti-tumor memory CD4 T-cells in unchallenged spleen was 0.028% and of memory CD8 T-cells was 0.11% which was not high enough to distinguish them from background. Stimulation produced a mean ~10-fold increase in splenic and 100-fold increase in peritoneal anti-tumor memory T-cell clonotypes. This methodology can be developed to use blood and tissue sampling to rapidly quantify the effectiveness of a tumor vaccine or any vaccine generating therapeutic T-cells.
Immune profiles according to EGFR mutant subtypes and correlation with PD-1/PD-L1 inhibitor therapies in lung adenocarcinoma
Authors: Koh Young Wha , Park Bumhee , Jung Se Hee , Han Jae-Ho , Haam Seokjin , Lee Hyun Woo
Published: March 2023

Background

We examined the distributions of 22 immune cell types and the responses to PD-1/PD-L1 inhibitors according to EGFR mutation profile, in three independent datasets of lung adenocarcinoma (LUAD).

Methods

We used CIBERSORTx to analyze the distributions of immune cells, and tumor immune dysfunction and exclusion (TIDE) or tumor mutation burden (TMB) to analyze responses to anti-PD-1/PD-L1 therapy, in two public LUAD datasets. The results were verified with a validation set that included patients treated with PD-1/PD-L1 inhibitors.

Results

Compared to EGFR mutants, EGFR wild-type carcinomas had higher numbers of CD8+ T cells, CD4 memory activated T cells and neutrophils, and lower numbers of resting dendritic cells and resting mast cells, in two of the datasets. In our subgroup analyses, CD8+ T cells and CD4 memory activated T cells were more numerous in EGFR rare variants than in wild-types, L858R mutants, and exon 19 deletion mutants. In our TIDE or TMB analyses, EGFR rare variants were predicted to respond better to PD-1/PD-L1 inhibitors than wild-types, L858R mutants, and exon 19 deletion mutants. In the validation set verified by immunohistochemical staining, levels of CD8+ T cells in the EGFR rare variant or wild-type groups were significantly higher than in the EGFR L858R and exon 19 deletion groups. In patients treated with PD-1/PD-L1 inhibitors, the survival rates of patients with EGFR wild-type and rare mutant carcinomas were higher than those with L858R and exon 19 deletion carcinomas.

Conclusion

The EGFR rare mutation form of LUAD shows a higher immune activation state compared to wild-type, L858R, and exon 19 deletion variants, indicating it as a potential target for PD-1/PD-L1 inhibitor therapy.
Total neoadjuvant treatment and PD-1/PD-L1 checkpoint inhibitor in locally advanced rectal cancer
Authors: Xiao Weiwei , Luo Huilong , Yao Ye , Wang Yaqin , Liu Shuang , Sun Rui , Chen Gong
Published: March 2023

For local advanced rectal cancer (LARC), total neoadjuvant treatment (TNT) has shown more complete response (CR), reduced risk of distant metastasis (DM) and increase of the sphincter preservation rate. Now it is the one and only recommendation for high-risk group of LARC according to National Comprehensive Cancer Network (NCCN) rectal cancer guideline, while it is also preferentially recommended for low-risk group of LARC. TNT is also beneficial for distant rectal cancer patients who have need for organ preservation. Even though the prognostic value of programmed cell death-ligand 1 (PD-L1) in the neoadjuvant chemoradiotherapy (NACRT) of LARC patients is undetermined yet, the combination of NACRT and programmed cell death-1 (PD-1)/PD-L1 antibodies seem bring new hope for mismatch repair proficient (pMMR)/microsatellite stable (MSS) LARC patients. Accumulating small sample sized studies have shown that combining NACRT with PD-1/PD-L1 antibody yield better short-term outcomes for pMMR/MSS LARC patients than historic data. However, ideal total dose and fractionation of radiotherapy remains one of unresolved issues in this combination setting. Thorough understanding the impact of radiotherapy on the tumor microenvironment and their interaction is needed for in-depth understanding and exquisite design of treatments combination model.
A post-transcriptional regulatory landscape of aging in the female mouse hippocampus
Authors: Winsky-Sommerer Raphaelle , King Helen A. , Iadevaia Valentina , Möller-Levet Carla , Gerber André P.
Published: March 2023

Aging is associated with substantial physiological changes and constitutes a major risk factor for neurological disorders including dementia. Alterations in gene expression upon aging have been extensively studied; however, an in-depth characterization of post-transcriptional regulatory events remains elusive. Here, we profiled the age-related changes of the transcriptome and translatome in the female mouse hippocampus by RNA sequencing of total RNA and polysome preparations at four ages (3-, 6-, 12-, 20-month-old); and we implemented a variety of bioinformatics approaches to unravel alterations in transcript abundance, alternative splicing, and polyadenylation site selection. We observed mostly well-coordinated transcriptome and translatome expression signatures across age including upregulation of transcripts related to immune system processes and neuroinflammation, though transcripts encoding ribonucleoproteins or associated with mitochondrial functions, calcium signaling and the cell-cycle displayed substantial discordant profiles, suggesting translational control associated with age-related deficits in hippocampal-dependent behavior. By contrast, alternative splicing was less preserved, increased with age and was associated with distinct functionally-related transcripts encoding proteins acting at synapses/dendrites, RNA-binding proteins; thereby predicting regulatory roles for RBM3 and CIRBP. Only minor changes in polyadenylation site selection were identified, indicating pivotal 3′-end selection in young adults compared to older groups. Overall, our study provides a comprehensive resource of age-associated post-transcriptional regulatory events in the mouse hippocampus, enabling further examination of the molecular features underlying age-associated neurological diseases.
Leveraging conscious and nonconscious learning for efficient AI
Authors: St. Clair Rachel , Coward L. Andrew , Schneider Susan
Published: March 2023

Various interpretations of the literature detailing the neural basis of learning have in part led to disagreements concerning how consciousness arises. Further, artificial learning model design has suffered in replicating intelligence as it occurs in the human brain. Here, we present a novel learning model, which we term the “Recommendation Architecture (RA) Model” from prior theoretical works proposed by Coward, using a dual-learning approach featuring both consequence feedback and non-consequence feedback. The RA model is tested on a categorical learning task where no two inputs are the same throughout training and/or testing. We compare this to three consequence feedback only models based on backpropagation and reinforcement learning. Results indicate that the RA model learns novelty more efficiently and can accurately return to prior learning after new learning with less computational resources expenditure. The final results of the study show that consequence feedback as interpretation, not creation, of cortical activity creates a learning style more similar to human learning in terms of resource efficiency. Stable information meanings underlie conscious experiences. The work provided here attempts to link the neural basis of nonconscious and conscious learning while providing early results for a learning protocol more similar to human brains than is currently available.
Microglial activation persists beyond clinical recovery following sport concussion in collegiate athletes
Authors: Neumann Kiel D. , Seshadri Vikram , Thompson Xavier D. , Broshek Donna K. , Druzgal Jason , Massey James C. , Newman Benjamin , Reyes Jose , Simpson Spenser R. , McCauley Katelyenn S. , Patrie James , Stone James R. , Kundu Bijoy K. , Resch Jacob E.
Published: March 2023

Introduction

In concussion, clinical and physiological recovery are increasingly recognized as diverging definitions. This study investigated whether central microglial activation persisted in participants with concussion after receiving an unrestricted return-to-play (uRTP) designation using [18F]DPA-714 PET, an in vivo marker of microglia activation.

Methods

Eight (5 M, 3 F) current athletes with concussion (Group 1) and 10 (5 M, 5 F) healthy collegiate students (Group 2) were enrolled. Group 1 completed a pre-injury (Visit1) screen, follow-up Visit2 within 24 h of a concussion diagnosis, and Visit3 at the time of uRTP. Healthy participants only completed assessments at Visit2 and Visit3. At Visit2, all participants completed a multidimensional battery of tests followed by a blood draw to determine genotype and study inclusion. At Visit3, participants completed a clinical battery of tests, brain MRI, and brain PET; no imaging tests were performed outside of Visit3.

Results

For Group 1, significant differences were observed between Visits 1 and 2 (p < 0.05) in ImPACT, SCAT5 and SOT performance, but not between Visit1 and Visit3 for standard clinical measures (all p > 0.05), reflecting clinical recovery. Despite achieving clinical recovery, PET imaging at Visit3 revealed consistently higher [18F]DPA-714 tracer distribution volume (VT) of Group 1 compared to Group 2 in 10 brain regions (p < 0.001) analyzed from 164 regions of the whole brain, most notably within the limbic system, dorsal striatum, and medial temporal lobe. No notable differences were observed between clinical measures and VT between Group 1 and Group 2 at Visit3.

Discussion

Our study is the first to demonstrate persisting microglial activation in active collegiate athletes who were diagnosed with a sport concussion and cleared for uRTP based on a clinical recovery.
Leptin deficiency-caused behavioral change – A comparative analysis using EthoVision and DeepLabCut
Authors: Bühler Daniel , Power Guerra Nicole , Müller Luisa , Wolkenhauer Olaf , Düffer Martin , Vollmar Brigitte , Kuhla Angela , Wolfien Markus
Published: March 2023

Introduction

Obese rodents e.g., the leptin-deficient (ob/ob) mouse exhibit remarkable behavioral changes and are therefore ideal models for evaluating mental disorders resulting from obesity. In doing so, female as well as male ob/ob mice at 8, 24, and 40 weeks of age underwent two common behavioral tests, namely the Open Field test and Elevated Plus Maze, to investigate behavioral alteration in a sex- and age dependent manner. The accuracy of these tests is often dependent on the observer that can subjectively influence the data.

Methods

To avoid this bias, mice were tracked with a video system. Video files were further analyzed by the compared use of two software, namely EthoVision (EV) and DeepLabCut (DLC). In DLC a Deep Learning application forms the basis for using artificial intelligence in behavioral research in the future, also with regard to the reduction of animal numbers.

Results

After no sex and partly also no age-related differences were found, comparison revealed that both software lead to almost identical results and are therefore similar in their basic outcomes, especially in the determination of velocity and total distance movement. Moreover, we observed additional benefits of DLC compared to EV as it enabled the interpretation of more complex behavior, such as rearing and leaning, in an automated manner.

Discussion

Based on the comparable results from both software, our study can serve as a starting point for investigating behavioral alterations in preclinical studies of obesity by using DLC to optimize and probably to predict behavioral observations in the future.
Ensemble learning with speaker embeddings in multiple speech task stimuli for depression detection
Authors: Liu Zhenyu , Yu Huimin , Li Gang , Chen Qiongqiong , Ding Zhijie , Feng Lei , Yao Zhijun , Hu Bin
Published: March 2023

Introduction

As a biomarker of depression, speech signal has attracted the interest of many researchers due to its characteristics of easy collection and non-invasive. However, subjects’ speech variation under different scenes and emotional stimuli, the insufficient amount of depression speech data for deep learning, and the variable length of speech frame-level features have an impact on the recognition performance.

Methods

The above problems, this study proposes a multi-task ensemble learning method based on speaker embeddings for depression classification. First, we extract the Mel Frequency Cepstral Coefficients (MFCC), the Perceptual Linear Predictive Coefficients (PLP), and the Filter Bank (FBANK) from the out-domain dataset (CN-Celeb) and train the Resnet x-vector extractor, Time delay neural network (TDNN) x-vector extractor, and i-vector extractor. Then, we extract the corresponding speaker embeddings of fixed length from the depression speech database of the Gansu Provincial Key Laboratory of Wearable Computing. Support Vector Machine (SVM) and Random Forest (RF) are used to obtain the classification results of speaker embeddings in nine speech tasks. To make full use of the information of speech tasks with different scenes and emotions, we aggregate the classification results of nine tasks into new features and then obtain the final classification results by using Multilayer Perceptron (MLP). In order to take advantage of the complementary effects of different features, Resnet x-vectors based on different acoustic features are fused in the ensemble learning method.

Results

Experimental results demonstrate that (1) MFCC-based Resnet x-vectors perform best among the nine speaker embeddings for depression detection; (2) interview speech is better than picture descriptions speech, and neutral stimulus is the best among the three emotional valences in the depression recognition task; (3) our multi-task ensemble learning method with MFCC-based Resnet x-vectors can effectively identify depressed patients; (4) in all cases, the combination of MFCC-based Resnet x-vectors and PLP-based Resnet x-vectors in our ensemble learning method achieves the best results, outperforming other literature studies using the depression speech database.

Discussion

Our multi-task ensemble learning method with MFCC-based Resnet x-vectors can fuse the depression related information of different stimuli effectively, which provides a new approach for depression detection. The limitation of this method is that speaker embeddings extractors were pre-trained on the out-domain dataset. We will consider using the augmented in-domain dataset for pre-training to improve the depression recognition performance further.
Reduced eye optical quality contributes to worse chromatic thresholds in aging
Authors: Costa Marcelo Fernandes , Rego Livia Soledade , Henriques Leonardo Dutra , Martins Gaddi Carlo , Souza Givago Silva
Published: March 2023

Purpose

Aging causes substantial changes in the intraocular lens, which leads to a reduction in chromatic perception. We aimed to measure the ocular light dispersion component in relation to the reduction in color vision by aging.

Methods

Intraocular straylight was quantified psychophysically by C-Quant for light dispersion [Log(s)], reliability of the results (ESD), and psychometric sampling quality (Q). The Cambridge Color Test Trivector protocol measured the chromaticity thresholds for protan, deutan, and tritan color confusion axis in CIE 1976 u’ v’ units. We tested 224 subjects aged 24–68 years (106 men) with normal best-corrected visual acuity and without clinical evidence of cataracts.

Results

A significant positive correlation was found between ocular dispersion of light and chromaticity thresholds for protan (r = 0.42; p < 0.001), deutan (r = 0.49; p < 0.001) and tritan (r = 0.51; p < 0.0001) color confusion axes with a moderate effect size (η2 = 0.39). However, a weak contribution of the logarithm of the straylight in predicting the chromaticity threshold for protan (b = 0.15; p = 0.025), deutan (b = 0.27; p = 0.001) and tritan (b = 0.21; p = 0.001) color confusion axes was verified in the regression coefficients. The other two measurement quality parameters estimated in the C-Quant were not correlated with chromaticity thresholds, suggesting that there are no problems with the quality of the measurement performed.

Conclusion

An increase in ocular light dispersion that occurs physiologically with aging negatively impacts the chromaticity threshold in a similar manner across all three color confusion axes. The weak regression effects suggest that neural rather than optical processes were more related to the reduction in chromaticity in aging.
Dietary supplementation with spray-dried animal plasma improves vaccine protection in aged mice
Authors: Miró Lluïsa , Rosell-Cardona Cristina , Amat Concepció , Polo Javier , Moretó Miquel , Pérez-Bosque Anna
Published: March 2023

Background

Senescence is characterized by an aggravated inflammatory state that reduces vaccine responsiveness. Dietary supplementation with spray-dried porcine plasma (SDP) exerts anti-inflammatory effects in different mucosal areas. We aimed to determine if the anti-inflammatory properties of SDP improve the efficiency of immunization in senescent animals.

Methods

Experiments were performed in 2-month-old and 6-month-old male SAMP8 mice fed control or SDP (8%) feeds for 4  months. The mice received nasal doses of 2.5  μg of Staphylococcus aureus enterotoxin B (SEB) or vehicle every 15  days (i.e., 3 times). Fifteen days after the last dose, a lethal shock was induced by intraperitoneal administration of SEB and LPS.

Results

Immunization increased anti-SEB IgA in intestinal and bronchoalveolar fluid (p < 0.05). After the lethal shock, all immunized aged mice that were supplemented with SDP survived, in contrast to only 66% of those fed the control feed (p < 0.05). Moreover, after the lethal challenge, aged mice showed higher expression levels of pro-inflammatory cytokines (Il-6, Tnf-α, Ifn-γ, and Il-1β) in jejunal and (Tnf-α, and Il-1β) in lung tissues (p < 0.05), which were reduced by SDP supplementation (p < 0.05). Furthermore, in senescent mice, SDP supplementation augmented Il-4 and Il-10 expression in both tissues (p < 0.05).

Conclusion

SDP reduces the mucosal inflammation associated with aging, improving vaccine protection in senescent mice.
Dietary patterns and their association with cardiovascular risk factors in Ethiopia: A community-based cross-sectional study
Authors: Kumma Wondimagegn Paulos , Loha Eskindir
Published: March 2023

Purpose

To identify the dietary patterns and their association with cardiovascular risk factors among adult people in urban and rural areas of Wolaita, southern Ethiopia.

Methods

A total of 2,483 participants aged 25–64 years were selected using a three-stage random sampling. Data for this study were collected using structured questionnaires, the previous 24-h dietary intake assessment, anthropometric, blood pressure, and biochemical measurements. We used factor analysis to identify dietary patterns. Factors associated with dietary patterns were analyzed using multiple linear regression models. The adjusted regression coefficients with their 95% CI were used to ascertain the association.

Result

We identified three major dietary patterns that explained 51% of the variance in food consumption. Thewestern dietary patternwas characterized by the consumption of meat/organ meat, biscuits/sweets, chicken stew, pasta-macaroni recipes, butter, white wheat bread, egg recipe, and Ethiopian dishshiro-wet, and was positively associated with urban residence, obesity, hypertension, blood glucose, and total cholesterol levels. Adherence to the consumption of tubers, whole-grain maize products, coffee leaves-and-herbs beverage, legumes, and sweet potatoes featured thetraditional dietary pattern. Thetraditional dietary patternshowed a positive relationship with rural residence, physical activity, and obesity, and it had a negative relationship with hypertension. Thehealthy dietary patternwas characterized by the intake of green leafy vegetables, green pepper, and whole-grain maize products, and negatively related to obesity, and hypertension, while positively related to urban residence.

Conclusion

The coexistence ofwestern, traditional, and healthy dietary patternsin the present study indicates the transition to a new dietary pattern in the study area. All dietary patterns were associated with one or more cardiovascular risk factors, but the western dietary pattern was associated with most of these, while the traditional diet showed fewer such associations. Therefore, it might be useful to promotehealthy and traditional dietary patternsalong with physical activity. Interventions related to the current findings, if initiated early in life, may benefit the public in preventing cardiovascular risk factors such as obesity, hypertension, and type 2-diabetes.
Effectiveness of immunosuppressant use for the treatment of immune checkpoint inhibitor-induced liver injury: A systematic review and meta-analysis
Authors: Chen Kefan , He Junhao , Xu Jing , Chen Jie
Published: March 2023

Background

Immune-mediated liver injury caused by checkpoint inhibitors (ILICI) is a challenging clinical management issue. Although immunosuppressants are widely used to manage ILICI, no large-scale studies have proved definitive evidence for the most effective form of patient management.

Aim

Analysis of the effectiveness of immunosuppression for immune-related liver injury.

Methods

We performed a systematic review and meta-analysis of the clinical outcomes of immunosuppressive treatment of ILICI patients. A literature search of PubMed, Ovid, and Cochrane Library was completed for dates from 2000 to January 1, 2022. The primary outcome was the response rate to immunosuppressive therapy for ILICI, with subgroup analysis based on the type of cancer, immune checkpoint inhibitor regimen, and severity of liver injury. The secondary outcome was the median time to recovery from ILICI with immunosuppressive therapy.

Results

A total of 30 studies that included 1120 patients were collected. The pooled ILICI response rate was 79% (95% CI 0.73-0.84) for treatment with corticosteroids and 93% (95% CI 0.79-1.0) for treatment with mycophenolate mofetil. For ILICI treated with corticosteroids, the median recovery time was 47.59 (95% CI 39.79-55.40) days compared to 37.74 (95% CI 31.12-44.35) days for all forms of immunosuppression.

Conclusion

Findings support the effectiveness of corticosteroids and mycophenolate mofetil for the treatment of ILICI. The identified median time to recovery is a beneficial guide for patients and physicians, allowing for realistic expectations and appropriate treatment management. Future prospective randomized controlled trials are required to define a standardized management approach to immunosuppressive therapy of ILICI.

Systematic review registration

https://www.crd.york.ac.uk/PROSPERO/, identifier CRD42022313454.
Endoscopic submucosal excavation for gastric plexiform fibromyxoma: A case report and systematic review of literature
Authors: Xia Ziqin , Zhou Zhidai , Guo Wei , Wang Hongling , Wang Fan , Zhou Feng
Published: March 2023

Plexiform fibromyxoma (PF) is a rare mesenchymal tumor of which the pathogenesis and molecular changes are still unclear. Histologically, it is characterized by a cluster of bland spindle or ovoid cells growing in the mucoid or fibromyxoid stroma rich in small blood vessels. At present, surgical resection is the primary treatment for PF.
Integrative analysis of transcriptomic landscape and urinary signature reveals prognostic biomarkers for clear cell renal cell carcinoma
Authors: Zhang Wei , Liu Wenqiang , Yang Yiren , Xiao Chengwu , Xiao Yutian , Tan Xiaojie , Pang Qingyang , Wu Han , Hua Meimian , Shi Xiaolei
Published: March 2023

Background

Clear cell renal cell carcinoma (ccRCC) patients with venous tumor thrombus (VTT) have poor prognosis. We aimed to reveal features of ccRCC with VTT and develop a urine-based prognostic classifier to predict ccRCC prognosis through integrative analyses of transcriptomic landscape and urinary signature.

Methods

RNA sequencing was performed in five patients with ccRCC thrombus-tumor-normal tissue triples, while mass spectrometry was performed for urine samples from 12 ccRCC and 11 healthy controls. A urine-based classifier consisting of three proteins was developed to predict patients’ survival and validated in an independent cohort.

Results

Transcriptomic analysis identified 856 invasion-associated differentially expressed genes (DEGs). Furthermore, proteomic analysis showed 133 differentially expressed proteins (DEPs). Integration of transcriptomic landscape and urinary signature reveals 6 urinary detectable proteins (VSIG4, C3, GAL3ST1, TGFBI, AKR1C3, P4HB) displaying abundance changes consistent with corresponding genes in transcriptomic profiling. According to TCGA database, VSIG4, TGFBI, and P4HB were significantly overexpressed in patients with shorter survival and might be independent prognostic factors for ccRCC (all p<0.05). A prognostic classifier consisting of the three DEPs highly associated with survival performed satisfactorily in predicting overall survival (HR=2.0, p<0.01) and disease-free survival (HR=1.6, p<0.001) of ccRCC patients. The ELISA analysis of urine samples from an independent cohort confirmed the satisfied predictive power of the classifier for pathological grade (AUC=0.795, p<0.001) and stage (AUC=0.894, p<0.001).

Conclusion

Based on integrative analyses of transcriptomic landscape and urinary signature, the urine-based prognostic classifier consisting of VSIG4, TGFBI, and P4HB has satisfied predictive power of ccRCC prognosis and may facilitate ccRCC molecular subtyping and treatment.