bluuebunny/crossref_metadata_2025 huggingface dataset:
Diabetes Is Associated With Rapid Progression of Aortic Stenosis: A Single-Center Retrospective Cohort Study
Authors: Han Kangning , Shi Dongmei , Yang Lixia , Xie Meng , Zhong Rongrong , Wang Zhijian , Gao Fei , Ma Xiaoteng , Zhou Yujie
Published: February 2022

Background

Mounting evidence indicates that rapid progression of aortic stenosis (AS) is significantly associated with poor prognosis. Whether diabetes accelerates the progression of AS remains controversial.

Objectives

The purpose of the present study was to investigate whether diabetes was associated with rapid progression of AS.

Methods

We retrospectively analyzed 276 AS patients who underwent transthoracic echocardiography at least twice with a maximum interval ≥ 180 days from January 2016 to June 2021. AS severity was defined by specific threshold values for peak aortic jet velocity (Vmax) and/or mean pressure gradient. An increase of Vmax ≥ 0.3 m/s/year was defined as rapid progression. The binary Logistic regression models were used to determine the association between diabetes and rapid progression of AS.

Results

At a median echocardiographic follow-up interval of 614 days, the annual increase of Vmax was 0.16 (0.00–0.41) m/s. Compared with those without rapid progression, patients with rapid progression were older and more likely to have diabetes (P = 0.040 and P = 0.010, respectively). In the univariate binary Logistic regression analysis, diabetes was associated with rapid progression of AS (OR = 2.02, P = 0.011). This association remained significant in the multivariate analysis based on model 2 and model 3 (OR = 1.93, P = 0.018; OR = 1.93, P = 0.022). After propensity score-matching according to Vmax, diabetes was also associated rapid progression of AS (OR = 2.57, P = 0.045).

Conclusions

Diabetes was strongly and independently associated with rapid progression of AS.
Post-transplant Lymphoproliferative Disorder Following Cardiac Transplantation
Authors: Asleh Rabea , Alnsasra Hilmi , Habermann Thomas M. , Briasoulis Alexandros , Kushwaha Sudhir S.
Published: February 2022

Post-transplant lymphoproliferative disorder (PTLD) is a spectrum of lymphoid conditions frequently associated with the Epstein Barr Virus (EBV) and the use of potent immunosuppressive drugs after solid organ transplantation. PTLD remains a major cause of long-term morbidity and mortality following heart transplantation (HT). Epstein-Barr virus (EBV) is a key pathogenic driver in many PTLD cases. In the majority of PTLD cases, the proliferating immune cell is the B-cell, and the impaired T-cell immune surveillance against infected B cells in immunosuppressed transplant patients plays a key role in the pathogenesis of EBV-positive PTLD. Preventive screening strategies have been attempted for PTLD including limiting patient exposure to aggressive immunosuppressive regimens by tailoring or minimizing immunosuppression while preserving graft function, anti-viral prophylaxis, routine EBV monitoring, and avoidance of EBV seromismatch. Our group has also demonstrated that conversion from calcineurin inhibitor to the mammalian target of rapamycin (mTOR) inhibitor, sirolimus, as a primary immunosuppression was associated with a decreased risk of PTLD following HT. The main therapeutic measures consist of immunosuppression reduction, treatment with rituximab and use of immunochemotherapy regimens. The purpose of this article is to review the potential mechanisms underlying PTLD pathogenesis, discuss recent advances, and review potential therapeutic targets to decrease the burden of PTLD after HT.
Ventriculo-Arterial Coupling Is Associated With Oxygen Consumption and Tissue Perfusion in Acute Circulatory Failure
Authors: Andrei Stefan , Nguyen Maxime , Longrois Dan , Popescu Bogdan A. , Bouhemad Belaid , Guinot Pierre-Grégoire
Published: February 2022

Introduction

The determination of ventriculo-arterial coupling is gaining an increasing role in cardiovascular and sport medicine. However, its relevance in critically ill patients is still under investigation. In this study we measured the association between ventriculo-arterial coupling and oxygen consumption (VO2) response after hemodynamic interventions in cardiac surgery patients with acute circulatory instability.

Material and Methods

Sixty-one cardio-thoracic ICU patients (67 ± 12 years, 80% men) who received hemodynamic therapeutic interventions (fluid challenge or norepinephrine infusion) were included. Arterial pressure, cardiac output, heart rate, arterial (EA), and ventricular elastances (EV), total indexed peripheral resistances were assessed before and after hemodynamic interventions. VO2 responsiveness was defined as VO2 increase >15% following the hemodynamic intervention. Ventriculo-arterial coupling was assessed measuring the EA/EV ratio by echocardiography. The left ventricle stroke work to pressure volume area ratio (SW/PVA) was also calculated.

Results

In the overall cohort, 24 patients (39%) were VO2 responders, and 48 patients had high ventriculo-arterial (EA/EV) coupling ratio with a median value of 1.9 (1.6–2.4). Most of those patients were classified as VO2 responders (28 of 31 patients, p = 0.031). Changes in VO2 were correlated with those of indexed total peripheral resistances, EA, EA/EV and cardiac output. EA/EV ratio predicted VO2 increase with an AUC of 0.76 [95% CI: 0.62–0.87]; p = 0.001. In principal component analyses, EA/EV and SW/PVA ratios were independently associated (p < 0.05) with VO2 response following interventions.

Conclusions

VO2 responders were characterized by baseline high ventriculo-arterial coupling ratio due to high EA and low EV. Baseline EA/EV and SW/PVA ratios were associated with VO2 changes independently of the hemodynamic intervention used. These results underline the pathophysiological significance of measuring ventriculo-arterial coupling in patients with hemodynamic instability, as a potential therapeutic target.
MODIT: MOtif DIscovery in Temporal Networks
Authors: Grasso Roberto , Micale Giovanni , Ferro Alfredo , Pulvirenti Alfredo
Published: February 2022

Temporal networks are graphs where each edge is linked with a timestamp, denoting when an interaction between two nodes happens. According to the most recently proposed definitions of the problem, motif search in temporal networks consists in finding and counting all connected temporal graphs Q (called motifs) occurring in a larger temporal network T, such that matched target edges follow the same chronological order imposed by edges in Q. In the last few years, several algorithms have been proposed to solve motif search, but most of them are limited to very small or specific motifs due to the computational complexity of the problem. In this paper, we present MODIT (MOtif DIscovery in Temporal Networks), an algorithm for counting motifs of any size in temporal networks, inspired by a very recent algorithm for subgraph isomorphism in temporal networks, called TemporalRI. Experiments show that for big motifs (more than 3 nodes and 3 edges) MODIT can efficiently retrieve them in reasonable time (up to few hours) in many networks of medium and large size and outperforms state-of-the art algorithms.
Swarm-TEC Satellite Measurements as a Potential Earthquake Precursor Together With Other Swarm and CSES Data: The Case of Mw7.6 2019 Papua New Guinea Seismic Event
Authors: Akhoondzadeh Mehdi , De Santis Angelo , Marchetti Dedalo , Shen Xuhui
Published: February 2022

On May 14, 2019, a strong Mw = 7.6 shallow earthquake occurred in Papua New Guinea. This paper explores for the first time the analysis of total electron content (TEC) products measured for 6 months by GPS antenna onboard Swarm satellites, to detect possible seismo-ionospheric anomalies around the time and location of the above-mentioned earthquake. The night-time vertical total electron content (VTEC) time series measured using Swarm satellites Alpha and Charlie, inside the earthquake Dobrovolsky’s area show striking anomalies 31 and 35 days before the event. We successfully verified the possible presence of concomitant anomalous values of in situ electron density detected by the new Chinese satellite dedicated to search for electromagnetic earthquake precursors [China Seismo-Electromagnetic Satellite (CSES)-01]. On the other hand, the analysis of VTEC night time measured by Swarm Bravo shows gradual and abnormal increase of the VTEC parameter from about 23 days before the earthquake, which descends 3 days before the earthquake and reaches its lowest level around the earthquake day. We also analyzed the time series and tracks of other six in situ parameters measured by Swarm satellites, electron density from CSES, and also GPS-TEC measurements. As it is expected from the theory, the electron density anomalous variations acknowledge the Swarm VTEC anomalies, confirming that those anomalies are real and not an artifact of the analysis. The comparative analysis with measurements of other Swarm and CSES sensors emphasizes striking anomalies about 2.5 weeks before the event, with a clear pattern of the whole anomalies typical of a critical system as the earthquake process is for Earth. A confutation analysis outside the Dobrovolsky area and without significant seismicity shows no anomalies. Therefore based on our study, the VTEC products of Swarm satellites could be an appropriate precursor aside from the other measured plasma and magnetic parameters using Alpha, Bravo, and Charlie Swarm and CSES satellites that can be simultaneously analyzed to reduce the overall uncertainty.
Trends and Transitions in Silicate Weathering in the Asian Interior (NE Tibet) Since 53 Ma
Authors: Yang Yibo , Han Wenxia , Ye Chengcheng , Galy Albert , Fang Xiaomin
Published: February 2022

The relationship between silicate weathering, Tibetan Plateau uplift, and global cooling during the Cenozoic provides a valuable case study for understanding the interaction of tectonics and climate. The Tibetan Plateau uplift is considered to have caused Cenozoic cooling via the atmospheric CO2 drawdown by increased silicate weathering. However, this hypothesis has been intensively debated over the past few decades due to the lack of complete silicate weathering records from the continental interior, which can directly track the effects of uplift on weathering. We provide the first complete long (past 53 Myr) continental silicate weathering record from the NE Tibetan Plateau, combined with a comprehensive analysis on its evolution pattern, critical transitions, and associated driving forces. The silicate weathering intensity in NE Tibet is characterized by a long-term Paleogene decrease, modulated by global cooling, and a Neogene increase that may be related to the East Asian summer monsoon (EASM) intensification. Three major system transitions in regional silicate weathering are identified at ∼26–23 Ma, ∼16 Ma and ∼8 Ma, which are linked to enhanced EASM forced primarily by tectonic uplift at these intervals, with some surbordinate influences from global climate at ∼16 Ma. We also capture an intensification of the 100-kyr cycle at ∼16 Ma and ∼8 Ma in the obtained silicate weathering record, which is in coincidence in time with the enhancement of the EASM. This might suggest some contribution of the Antarctic ice sheets on modulating the regional silicate weathering in the NE Tibetan Plateau on a timescale of 105–106 years, through its influences on the EASM as proposed by previous studies.
A New Repeated Mining Method With Preexisting Damage Zones Filled for Ultra-Thick Coal Seam Extraction – Case Study
Authors: Chen Liang , Zhang Dongsheng , Fan Gangwei , Zhang Shizhong , Wang Xufeng , Zhang Wei
Published: February 2022

Arbitrary mining activities done by previous small-scale mines left many irregular damage zones in the ultra-thick coal seam, consequently leading to serious roof caving disasters and recovery ratio decline during repeated mining. Pre-filling the damage zones is an effective method to prevent mining-induced geological disasters. In this study, a novel method regarding damage zone filling–based repeated mining (FBRM) was proposed by combining the lower cutting layer (LCL) with the upper key bearing layer (UKBL) based on analyzing the disaster state when the workface passes through damage zones. To determine filling thickness, a method for calculating UKBL thickness was developed to preliminarily identify the filling thickness parameters of UKBL. On this basis, a numerical model incorporating damage zones and coal extractions was established to investigate the impact of UKBL thickness on fracture propagation and the maximum principal stress profiles around the damage zones. The proposed FBRM method was verified using the ground pressure data collected from Panel B909 of Pingshuo No.2 Colliery. The results show that 1) filling material with low strength and good cuttability is suitable for LCL, while material with high strength and robust bearing capacity is suitable for UKBL; 2) with increasing the UKBL filling thickness, the height of fracturing decreases, obeying a negative exponential function, suggesting a good effectiveness of the damage zone pre-filling technique; 3) as the UKBL filling thickness rises to 5 m, the maximum principal stress relocates from the area above both damage zones to the area closely in front of the workface, indicating a filling thickness threshold of 5 m that can ensure roof stability; 4) the maximum working resistance and bed separation were 11,800 kN and 26 mm, respectively, when the workface passed through damage zones B and E, favoring a good reliability of the FBRM method. The research can provide best-practice references for preventing roof caving disasters while exploiting the ultra-thick coal deposits affected by previous mining activities.
Tropical Cyclone Activities Over the Western North Pacific in Summer 2020: Transition From Silence in July to Unusually Active in August
Authors: Gong Zhensong , Liu Yunyun , Hu Zeng-Zhen , Liang Ping
Published: February 2022

In the summer of 2020, tropical cyclone (TC) activities experienced a contrastive transition over the western North Pacific (WNP), from silence in July to unusually active in August. Furthermore, the generation location of TCs was further northwestward in August 2020, resulting in more typhoons landing, and three TCs successively moving northward, which is rare in history. Based on diagnoses with the total genesis potential index (GPI) in July and August 2020, it is suggested that the variation of mid-tropospheric relative humidity and upward convective motion is the major factor for the transition of TC genesis in summer 2020, while the changes of SST, low-level vorticity, and vertical wind shear anomalies played a secondary role. The exceptional variation of the Madden–Julian Oscillation (MJO) activity from July to August 2020 contributed to the transition of the environmental conditions over WNP. In July 2020, MJO was restricted in the Indian Ocean, thus generating an anomalous low-level anticyclone over WNP that intensified the WNP subtropical high. While in early August, MJO propagated eastward to enhance convective activities over the South China Sea and the Philippine Sea, favorable to TC genesis. Thus, MJO activity is a potential predictability source for intraseasonal variation of TC genesis anomalies in WNP.
Resilience to Historical Human Manipulations in the Genomic Variation of Italian Wild Boar Populations
Authors: Scandura Massimo , Fabbri Giulia , Caniglia Romolo , Iacolina Laura , Mattucci Federica , Mengoni Chiara , Pante Giulio , Apollonio Marco , Mucci Nadia
Published: February 2022

Human activities can globally modify natural ecosystems determining ecological, demographic and range perturbations for several animal species. These changes can jeopardize native gene pools in different ways, leading either to genetic homogenization, or conversely, to the split into genetically divergent demes. In the past decades, most European wild boar (Sus scrofa) populations were heavily managed by humans. Anthropic manipulations have strongly affected also Italian populations through heavy hunting, translocations and reintroductions that might have deeply modified their original gene pools. In this study, exploiting the availability of the well-mapped porcine genome, we applied genomic tools to explore genome-wide variability in Italian wild boar populations, investigate their genetic structure and detect signatures of possible introgression from domestic pigs and non-native wild boar. Genomic data from 134 wild boar sampled in six areas of peninsular Italy and in Sardinia were gathered using the Illumina Porcine SNP60 BeadChip (60k Single Nucleotide Polymorphisms – SNPs) and compared with reference genotypes from European specimens and from domestic pigs (both commercial and Italian local breeds), using multivariate and maximum-likelihood approaches. Pairwise FST values, multivariate analysis and assignment procedures indicated that Italian populations were highly differentiated from all the other analyzed European wild boar populations. Overall, a lower heterozygosity was found in the Italian population than in the other European regions. The most diverging populations in Castelporziano Presidential Estate and Maremma Regional Park can be the result of long-lasting isolation, reduced population size and genetic drift. Conversely, an unexpected similarity was found among Apennine populations, even at high distances. Signatures of introgression from both non-Italian wild boar and domestic breeds were very limited. To summarize, we successfully applied genome-wide procedures to explore, for the first time, the genomic diversity of Italian wild boar, demonstrating that they represent a strongly heterogeneous assemblage of demes with different demographic and manipulation histories. Nonetheless, our results suggest that a native component of genomic variation is predominant over exogenous ones in most populations.
KIR-HLA Functional Repertoire Influences Trastuzumab Efficiency in Patients With HER2-Positive Breast Cancer
Authors: Muraro Elena , De Zorzi Mariangela , Miolo Gianmaria , Lombardi Davide , Scalone Simona , Spazzapan Simon , Massarut Samuele , Perin Tiziana , Dolcetti Riccardo , Steffan Agostino , De Re Valli
Published: February 2022

Trastuzumab induced a high rate of pathological Complete Response (pCR) in patients affected by locally advanced HER2-positive Breast Cancer (HER2-BC), by exploiting immune-mediated mechanisms as Antibody-Dependent Cell Cytotoxicity (ADCC) involving Natural Killer (NK) cells. Host’s immune genetics could influence the response to therapy, through the expression of variants that characterize NK receptors involved in ADCC effectiveness. Killer cell immunoglobin-like receptors (KIRs) modulate NK cell activity through their binding to class-I Human Leukocyte Antigens (HLA). The impact of the KIR/HLA repertoire in HER2-BC is under study. We characterized KIR genotypes of 36 patients with locally advanced HER2-BC treated with neoadjuvant chemotherapy including trastuzumab. We monitored pCR achievement before surgery and Disease-Free Survival (DFS) and Overall Survival (OS) after adjuvant therapy. HLA, and Fc gamma receptor IIIa (FcγR3A) and IIa (FcγR2A) were genotyped through targeted PCR and Sanger sequencing in 35/36 patients. The KIR-HLA combinations were then described as functional haplotypes and divided in two main categories as inhibitory tel A and stimulatory tel B. Trastuzumab-dependent ADCC activity was monitored with an in vitro assay using a HER2-BC model and patients’ NK cells.We observed a higher frequency of KIR activators in patients who achieved a pCR compared to partial responders. During the study of functional haplotypes, individuals carrying a tel B haplotype showed greater ADCC efficiency than tel A cases. In subjects with the tel A haplotype the presence of the favorite V allele in FcγR3A receptor improved their low ADCC levels. Regardless of the haplotypes detected, the presence of KIR3DL2/HLA-A03 or A11 was always associated with the FcγR3A V allele, and therefore correlated with greater ADCC efficiency. However, this particular KIR receptor appeared to harm DFS and OS. Indeed, patients with tel B haplotype without KIR3DL2/HLA-A03 or A11 showed a better outcome. Our data, although preliminary, suggested a potential predictive role for KIR haplotype tel B, in identifying patients who achieve a pCR after neoadjuvant treatment with trastuzumab, and supported a negative prognostic impact of KIR3DL2/HLA-A03 or A11 in the adjuvant setting.
Case Report: Evolution of Humoral and Cellular Immunity in Two COVID-19 Breakthrough Infections After BNT162b2 Vaccine
Authors: Gallais Floriane , Gantner Pierre , Planas Delphine , Solis Morgane , Bruel Timothée , Pierre Florian , Soulier Eric , Rossolillo Paola , Fourati Slim , Sibilia Jean , Schwartz Olivier , Fafi-Kremer Samira
Published: February 2022

Background

SARS-CoV-2 breakthrough infections after complete vaccination are increasing whereas their determinants remain uncharacterized.

Methods

We analyzed two cases of post-vaccination SARS-CoV-2 infections by α and β variants, respectively. For each participant both humoral (binding and neutralizing antibodies) and cellular (activation markers and cytokine expression) immune responses were characterized longitudinally.

Results

The first participant (P1) was infected by an α variant and displayed an extended and short period of viral excretion and symptom. Analysis of cellular and humoral response 72 h post-symptom onset revealed that P1 failed at developing neutralizing antibodies and a potent CD4 memory response (lack of SARS-CoV-2 specific CD4+IL-2+ cells) and CD8 effector response (CD8+IFNγ+ cells). The second participant (P2) developed post-vaccination SARS-CoV-2 infection by a β variant, associated with a short period of viral excretion and symptoms. Despite displaying initially high levels and polyfunctional T cell responses, P2 lacked initial β-directed neutralizing antibodies. Both participants developed and/or increased their neutralization activity and cellular responses against all variants, namely, β and δ variants that lasts up to 3 months after breakthrough infection.

Conclusions

An analysis of cellular and humoral response suggests two possible mechanisms of breakthrough infection: a poor immune response to vaccine and viral evasion to neutralizing antibodies.
The Research Progress of Antiangiogenic Therapy, Immune Therapy and Tumor Microenvironment
Authors: Hu Haoyue , Chen Yue , Tan Songtao , Wu Silin , Huang Yan , Fu Shengya , Luo Feng , He Jun
Published: February 2022

Anti-angiogenesis therapy, a promising strategy against cancer progression, is limited by drug-resistance, which could be attributed to changes within the tumor microenvironment. Studies have increasingly shown that combining anti-angiogenesis drugs with immunotherapy synergistically inhibits tumor growth and progression. Combination of anti-angiogenesis therapy and immunotherapy are well-established therapeutic options among solid tumors, such as non-small cell lung cancer, hepatic cell carcinoma, and renal cell carcinoma. However, this combination has achieved an unsatisfactory effect among some tumors, such as breast cancer, glioblastoma, and pancreatic ductal adenocarcinoma. Therefore, resistance to anti-angiogenesis agents, as well as a lack of biomarkers, remains a challenge. In this review, the current anti-angiogenesis therapies and corresponding drug-resistance, the relationship between tumor microenvironment and immunotherapy, and the latest progress on the combination of both therapeutic modalities are discussed. The aim of this review is to discuss whether the combination of anti-angiogenesis therapy and immunotherapy can exert synergistic antitumor effects, which can provide a basis to exploring new targets and developing more advanced strategies.
IL-7-Treated Periodontal Ligament Cells Regulate Local Immune Homeostasis by Modulating Treg/Th17 Cell Polarization
Authors: Yu Xin-Yi , Zhang Zhao-Qiang , Huang Jia-Chang , Lin Jia-Yu , Cai Xue-Pei , Liu Chu-Feng
Published: February 2022

Both interleukin (IL)-7 and human periodontal ligament cells (hPDLCs) have immunomodulatory properties. However, their combined effect on CD4+T cells has never been studied. In this study, we aimed to investigate the effect of conditioned medium of hPDLCs treated with rhIL-7 on the differentiation of CD4+T cells into regulatory T cells/T helper 17 cells (Treg/Th17 cells) and observe the effect of IL-7 on the immunomodulatory properties of PDLCs. After hPDLCs were treated with different concentrations of rhIL-7 for 24 h, the collected supernatants were used to incubate CD4+T cells for 3 days. A gamma-secretase inhibitor (DAPT) was used to suppress the activation of the Notch1 signaling pathway. Cell proliferation, apoptosis, and necrosis were determined using the cell counting kit-8 (CCK-8) and flow cytometry (FCM). The expressions of forkhead box P3 (Foxp3) in CD4+T cells and transforming growth factor (TGF-β) and IL-6 in the supernatants were determined by ELISA. Reverse transcription-quantitative PCR (RT-qPCR), and the Western blot (WB) determined the mRNA levels and protein expression of various target factors. FCM was used to detect the mean fluorescence intensity of PD-L1 in hPDLCs and to analyze the differentiation of Treg/Th17 cells. Our results showed that IL-7 promoted proliferation and inhibited apoptosis in hPDLCs, promoted the expression of TGF-β, PD-L1, Notch1, Jagged1, and Hes1, and inhibited the levels of hypoxia-inducible factor (HIF)-1α and TCF7, whereas the addition of DAPT effectively reversed these effects. Importantly, we found that the conditioned medium of hPDLCs treated with rhIL-7 promoted the polarization of CD4+T cells into Treg cells but had no significant effect on the differentiation of Th17 cells. Our study indicated that treatment of PDLCs with IL-7 can promote the polarization of CD4+T cells into Treg cells by modulating the expression of inflammatory factors and signaling molecules through activating the Notch1 signaling pathway, thus participating in the regulation of immune homeostasis in the periodontal microenvironment.
Changes in Bulk and Rhizosphere Soil Microbial Diversity and Composition Along an Age Gradient of Chinese Fir (Cunninghamia lanceolate) Plantations in Subtropical China
Authors: Wang Yuzhe , Jiao Pengyu , Guo Wen , Du Dajun , Hu Yalin , Tan Xiang , Liu Xian
Published: February 2022

Soil microorganisms play key roles in biogeochemical cycling in forest ecosystems. However, whether the responses of microbial community with stand development differed in rhizosphere and bulk soils remains unknown. We collected rhizosphere and bulk soil in Chinese fir plantations with different stand ages (7a, 15a, 24a, and 34a) in subtropical China, and determined bacterial and fungal community variation via high-throughput sequencing. The results showed that soil bacterial, but not fungal, community diversity significantly differed among stand ages and between rhizosphere and bulk soils (p < 0.05). The differences in Shannon–Wiener and Simpson’s indices between rhizosphere and bulk soil varied with stand age, with significant higher soil bacterial diversity in rhizosphere than bulk soils in 7a and 34a plantations (p < 0.05), but there were no significant difference in soil bacterial diversity between rhizosphere and bulk soils in 15a and 24a plantations (p > 0.05). Soil microbial community composition varied significantly with stand age but not between the rhizosphere and bulk soil. The dominant bacterial phyla at all ages were Acidobacteria and Proteobacteria, while the dominant fungal phyla were Ascomycota and Basidiomycota in both rhizosphere and bulk soil. They showed inconsistent distribution patterns along stand age gradient (7–34a) in the rhizosphere and bulk soil, suggesting distinct ecological strategy (r-strategist vs. k-strategist) of different microbial taxa, as well as changes in the microenvironment (i.e., nutrient stoichiometry and root exudates). Moreover, bacterial and fungal community composition in rhizosphere and bulk soil were governed by distinct driving factors. TP and NH4+–N are the two most important factors regulating bacterial and fungal community structure in rhizosphere soil, while pH and NO3––N, DON, and TN were driving factors for bacterial and fungal community structure in bulk soil, respectively. Collectively, our results demonstrated that the changes in microbial diversity and composition were more obvious along stand age gradients than between sampling locations (rhizosphere vs. bulk soil) in Chinese fir plantations.
Metformin Combining PD-1 Inhibitor Enhanced Anti-Tumor Efficacy in STK11 Mutant Lung Cancer Through AXIN-1-Dependent Inhibition of STING Ubiquitination
Authors: Wang Zhiguo , Lu Conghua , Zhang Kejun , Lin Caiyu , Wu Fang , Tang Xiaolin , Wu Di , Dou Yuanyao , Han Rui , Wang Yubo , Hou Chao , Ouyang Qin , Feng Mingxia , He Yong , Li Li
Published: February 2022

Background: Non-small-cell lung cancer (NSCLC) with STK11 mutation showed primary resistance to immune checkpoint inhibitors (ICIs). The glucose-lowering drug metformin exerted anti-cancer effect and enhanced efficacy of chemotherapy in NSCLC with KRAS/STK11 co-mutation, yet it is unknown whether metformin may enhance ICI efficacy in STK11 mutant NSCLC.

Methods: We studied the impact of metformin on ICI efficacy in STK11 mutant NSCLC in vitro and in vivo using colony formation assay, cell viability assay, Ki67 staining, ELISA, CRISPR/Cas9-mediated knockout, and animal experiments.

Results: Through colony formation assay, Ki67 incorporation assay, and CCK-8 assay, we found that metformin significantly enhanced the killing of H460 cells and A549 cells by T cells. In NOD-SCID xenografts, metformin in combination with PD-1 inhibitor pembrolizumab effectively decreased tumor growth and increased infiltration of CD8+ T cells. Metformin enhanced stabilization of STING and activation of its downstream signaling pathway. siRNA-mediated knockdown of STING abolished the effect of metformin on T cell-mediated killing of tumor cells. Next, we found that CRISPR/Cas9-mediated knockout of the scaffold protein AXIN-1 abolished the effect of metformin on T cell-mediated killing and STING stabilization. Immunoprecipitation and confocal macroscopy revealed that metformin enhanced the interaction and colocalization between AXIN-1 and STING. Protein-protein interaction modeling indicated that AXIN-1 may directly bind to STING at its K150 site. Next, we found that metformin decreased K48-linked ubiquitination of STING and inhibited the interaction of E3-ligand RNF5 and STING. Moreover, in AXIN-1−/− H460 cells, metformin failed to alter the interaction of RNF5 and STING.

Conclusion: Metformin combining PD-1 inhibitor enhanced anti-tumor efficacy in STK11 mutant lung cancer through inhibition of RNF5-mediated K48-linked ubiquitination of STING, which was dependent on AXIN-1.
Bioinformatics-Guided Analysis Uncovers AOX1 as an Osteogenic Differentiation-Relevant Gene of Human Mesenchymal Stem Cells
Authors: Sun Lingtong , Ma Jianfei , Chen Juan , Pan Zhijun , Li Lijun
Published: February 2022

Background: The available therapeutic options of bone defects, fracture nonunion, and osteoporosis remain limited, which are closely related to the osteogenic differentiation of bone marrow–derived mesenchymal stem cells (BMSCs). Thus, there remains an urgent demand to develop a prediction method to infer osteogenic differentiation–related genes in BMSCs.

Method: We performed differential expression analysis between hBMSCs and osteogenically induced samples. Association analysis, co-expression analysis, and PPI analysis are then carried out to identify potential osteogenesis-related regulators. GO enrichment analysis and GSEA are performed to identify significantly enriched pathways associated with AOX1. qRT-PCR and Western blotting were employed to investigate the expression of genes on osteogenic differentiation, and plasmid transfection was used to overexpress the gene AOX1 in hBMSCs.

Result: We identified 25 upregulated genes and 17 downregulated genes. Association analysis and PPI network analysis among these differentially expressed genes show that AOX1 is a potential regulator of osteogenic differentiation. GO enrichment analysis and GSEA show that AOX1 is significantly associated with osteoblast-related pathways. The experiments revealed that AOX1 level was higher and increased gradually in differentiated BMSCs compared with undifferentiated BMSCs, and AOX1 overexpression significantly increased the expression of osteo-specific genes, thereby clearly indicating that AOX1 plays an important role in osteogenic differentiation. Moreover, our method has ability in discriminating genes with osteogenic differentiation properties and can facilitate the process of discovery of new osteogenic differentiation–related genes.

Conclusion: These findings collectively demonstrate that AOX1 is an osteogenic differentiation-relevant gene and provide a novel method established with a good performance for osteogenic differentiation-relevant genes prediction.
Changes of Small Non-coding RNAs by Severe Acute Respiratory Syndrome Coronavirus 2 Infection
Authors: Wu Wenzhe , Choi Eun-Jin , Wang Binbin , Zhang Ke , Adam Awadalkareem , Huang Gengming , Tunkle Leo , Huang Philip , Goru Rohit , Imirowicz Isabella , Henry Leanne , Lee Inhan , Dong Jianli , Wang Tian , Bao Xiaoyong
Published: February 2022

The ongoing pandemic of coronavirus disease 2019 (COVID-19), which results from the rapid spread of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a significant global public health threat, with molecular mechanisms underlying its pathogenesis largely unknown. In the context of viral infections, small non-coding RNAs (sncRNAs) are known to play important roles in regulating the host responses, viral replication, and host-virus interaction. Compared with other subfamilies of sncRNAs, including microRNAs (miRNAs) and Piwi-interacting RNAs (piRNAs), tRNA-derived RNA fragments (tRFs) are relatively new and emerge as a significant regulator of host-virus interactions. Using T4 PNK‐RNA‐seq, a modified next-generation sequencing (NGS), we found that sncRNA profiles in human nasopharyngeal swabs (NPS) samples are significantly impacted by SARS-CoV-2. Among impacted sncRNAs, tRFs are the most significantly affected and most of them are derived from the 5′-end of tRNAs (tRF5). Such a change was also observed in SARS-CoV-2-infected airway epithelial cells. In addition to host-derived ncRNAs, we also identified several small virus-derived ncRNAs (svRNAs), among which a svRNA derived from CoV2 genomic site 346 to 382 (sv-CoV2-346) has the highest expression. The induction of both tRFs and sv-CoV2-346 has not been reported previously, as the lack of the 3′-OH ends of these sncRNAs prevents them to be detected by routine NGS. In summary, our studies demonstrated the involvement of tRFs in COVID-19 and revealed new CoV2 svRNAs.
No Association Between Loneliness, Episodic Memory and Hippocampal Volume Change in Young and Healthy Older Adults: A Longitudinal European Multicenter Study
Authors: Solé-Padullés Cristina , Macià Dídac , Andersson Micael , Stiernstedt Mikael , Pudas Sara , Düzel Sandra , Zsoldos Enikő , Ebmeier Klaus P. , Binnewies Julia , Drevon Christian A. , Brandmaier Andreas M. , Mowinckel Athanasia M. , Fjell Anders M. , Madsen Kathrine Skak , Baaré William F. C. , Lindenberger Ulman , Nyberg Lars , Walhovd Kristine B. , Bartrés-Faz David
Published: February 2022

Background

Loneliness is most prevalent during adolescence and late life and has been associated with mental health disorders as well as with cognitive decline during aging. Associations between longitudinal measures of loneliness and verbal episodic memory and brain structure should thus be investigated.

Methods

We sought to determine associations between loneliness and verbal episodic memory as well as loneliness and hippocampal volume trajectories across three longitudinal cohorts within the Lifebrain Consortium, including children, adolescents (N = 69, age range 10–15 at baseline examination) and older adults (N = 1468 over 60). We also explored putative loneliness correlates of cortical thinning across the entire cortical mantle.

Results

Loneliness was associated with worsening of verbal episodic memory in one cohort of older adults. Specifically, reporting medium to high levels of loneliness over time was related to significantly increased memory loss at follow-up examinations. The significance of the loneliness-memory change association was lost when eight participants were excluded after having developed dementia in any of the subsequent follow-up assessments. No significant structural brain correlates of loneliness were found, neither hippocampal volume change nor cortical thinning.

Conclusion

In the present longitudinal European multicenter study, the association between loneliness and episodic memory was mainly driven by individuals exhibiting progressive cognitive decline, which reinforces previous findings associating loneliness with cognitive impairment and dementia.
Role of Artificial Intelligence in Unruptured Intracranial Aneurysm: An Overview
Authors: Marasini Anurag , Shrestha Alisha , Phuyal Subash , Zaidat Osama O. , Kalia Junaid Siddiq
Published: February 2022

Intracranial aneurysms (IAs) are a significant public health concern. In populations without comorbidity and a mean age of 50 years, their prevalence is up to 3.2%. An efficient method for identifying subjects at high risk of an IA is warranted to provide adequate radiological screening guidelines and effectively allocate medical resources. Artificial intelligence (AI) has received worldwide attention for its impressive performance in image-based tasks. It can serve as an adjunct to physicians in clinical settings, improving diagnostic accuracy while reducing physicians' workload. AI can perform tasks such as pattern recognition, object identification, and problem resolution with human-like intelligence. Based on the data collected for training, AI can assist in decisions in a semi-autonomous manner. Similarly, AI can identify a likely diagnosis and also, select a suitable treatment based on health records or imaging data without any explicit programming (instruction set). Aneurysm rupture prediction is the holy grail of prediction modeling. AI can significantly improve rupture prediction, saving lives and limbs in the process. Nowadays, deep learning (DL) has shown significant potential in accurately detecting lesions on medical imaging and has reached, or perhaps surpassed, an expert-level of diagnosis. This is the first step to accurately diagnose UIAs with increased computational radiomicis. This will not only allow diagnosis but also suggest a treatment course. In the future, we will see an increasing role of AI in both the diagnosis and management of IAs.
Multimodal Brain Connectomics-Based Prediction of Parkinson’s Disease Using Graph Attention Networks
Authors: Safai Apoorva , Vakharia Nirvi , Prasad Shweta , Saini Jitender , Shah Apurva , Lenka Abhishek , Pal Pramod Kumar , Ingalhalikar Madhura
Published: February 2022

Background

A multimodal connectomic analysis using diffusion and functional MRI can provide complementary information on the structure–function network dynamics involved in complex neurodegenerative network disorders such as Parkinson’s disease (PD). Deep learning-based graph neural network models generate higher-level embeddings that could capture intricate structural and functional regional interactions related to PD.

Objective

This study aimed at investigating the role of structure–function connections in predicting PD, by employing an end-to-end graph attention network (GAT) on multimodal brain connectomes along with an interpretability framework.

Methods

The proposed GAT model was implemented to generate node embeddings from the structural connectivity matrix and multimodal feature set containing morphological features and structural and functional network features of PD patients and healthy controls. Graph classification was performed by extracting topmost node embeddings, and the interpretability framework was implemented using saliency analysis and attention maps. Moreover, we also compared our model with unimodal models as well as other state-of-the-art models.

Results

Our proposed GAT model with a multimodal feature set demonstrated superior classification performance over a unimodal feature set. Our model demonstrated superior classification performance over other comparative models, with 10-fold CV accuracy and an F1 score of 86% and a moderate test accuracy of 73%. The interpretability framework highlighted the structural and functional topological influence of motor network and cortico-subcortical brain regions, among which structural features were correlated with onset of PD. The attention maps showed dependency between large-scale brain regions based on their structural and functional characteristics.

Conclusion

Multimodal brain connectomic markers and GAT architecture can facilitate robust prediction of PD pathology and provide an attention mechanism-based interpretability framework that can highlight the pathology-specific relation between brain regions.
Using Home-Cage Monitoring to Determine the Impact of Timed Mating on Male Mouse Welfare
Authors: Moore Joanna L. , Brook Eloisa I.
Published: February 2022

Some of our breeding programs include the use of Prm1 male Homozygous mice which are naturally sterile. This removes the need to use vasectomized males to induce pseudopregnancy in female mice. These males can be kept for up to 9 months and are housed with a companion female. During the timed mating period the companion female is replaced with a new female. This procedure can occur at regular intervals causing a significant increase in cage activity; one of our objectives was to determine whether this was as a result of timed mating. We wanted to investigate the disruption caused to mice during the day of the swap and how long it would take for the cage activity to return to pre-replacement baseline levels. We hypothesized that this impact would be reflected as a significant increase in cage activity, which in itself may not be a result of a negative experience but the potential of repeated disruption to their activity pattern should be considered. We used a well-known home-cage monitoring system to assess changes to the activity pattern in cages when a companion female is replaced. Data from our initial study showed that in the 2-h period after the female is replaced there is a significant increase in cage activity compared to the same time frame on the previous day. In the subsequent study, where no cage change occurred, an increase in activity was also observed when females were replaced; this returned to baseline after approximately 4 h. Prolonged activity during the rest period of mice (over 2 h) could lead to them being fatigued during their active period; therefore, as a refinement we propose that timed matings be performed later in the day, at a time when the animals are active.
Frontotemporal Dementia and Glucose Metabolism
Authors: Garrett Liam Rodney , Niccoli Teresa
Published: February 2022

Frontotemporal dementia (FTD), hallmarked by antero-temporal degeneration in the human brain, is the second most common early onset dementia. FTD is a diverse disease with three main clinical presentations, four different identified proteinopathies and many disease-associated genes. The exact pathophysiology of FTD remains to be elucidated. One common characteristic all forms of FTD share is the dysregulation of glucose metabolism in patients’ brains. The brain consumes around 20% of the body’s energy supply and predominantly utilizes glucose as a fuel. Glucose metabolism dysregulation could therefore be extremely detrimental for neuronal health. Research into the association between glucose metabolism and dementias has recently gained interest in Alzheimer’s disease. FTD also presents with glucose metabolism dysregulation, however, this remains largely an unexplored area. A better understanding of the link between FTD and glucose metabolism may yield further insight into FTD pathophysiology and aid the development of novel therapeutics. Here we review our current understanding of FTD and glucose metabolism in the brain and discuss the evidence of impaired glucose metabolism in FTD. Lastly, we review research potentially suggesting a causal relationship between FTD proteinopathies and impaired glucose metabolism in FTD.
Regulation of Cell Delamination During Cortical Neurodevelopment and Implication for Brain Disorders
Authors: Sokpor Godwin , Brand-Saberi Beate , Nguyen Huu Phuc , Tuoc Tran
Published: February 2022

Cortical development is dependent on key processes that can influence apical progenitor cell division and progeny. Pivotal among such critical cellular processes is the intricate mechanism of cell delamination. This indispensable cell detachment process mainly entails the loss of apical anchorage, and subsequent migration of the mitotic derivatives of the highly polarized apical cortical progenitors. Such apical progenitor derivatives are responsible for the majority of cortical neurogenesis. Many factors, including transcriptional and epigenetic/chromatin regulators, are known to tightly control cell attachment and delamination tendency in the cortical neurepithelium. Activity of these molecular regulators principally coordinate morphogenetic cues to engender remodeling or disassembly of tethering cellular components and external cell adhesion molecules leading to exit of differentiating cells in the ventricular zone. Improper cell delamination is known to frequently impair progenitor cell fate commitment and neuronal migration, which can cause aberrant cortical cell number and organization known to be detrimental to the structure and function of the cerebral cortex. Indeed, some neurodevelopmental abnormalities, including Heterotopia, Schizophrenia, Hydrocephalus, Microcephaly, and Chudley-McCullough syndrome have been associated with cell attachment dysregulation in the developing mammalian cortex. This review sheds light on the concept of cell delamination, mechanistic (transcriptional and epigenetic regulation) nuances involved, and its importance for corticogenesis. Various neurodevelopmental disorders with defective (too much or too little) cell delamination as a notable etiological underpinning are also discussed.