bluuebunny/crossref_metadata_2025 huggingface dataset:
Deformation Development Mechanism in a Loess Slope With Seepage Fissures Subjected to Rainfall and Traffic Load
Authors: Leng Xianlun , Wang Chuan , Zhang Juan , Sheng Qian , Cao Shengliang , Chen Jian
Published: October 2021

Loess landslides induced by rainfall and traffic load are significant hazards during the construction and operation of highways in many loess-covered areas. Studies of the deformation and stability of loess slopes with seepage fissures are limited. In the study, a case study of the Yangpoyao loess slope with seepage fissures in China’s Loess Plateau was conducted to reveal the deformation development mechanism and assess the landslide hazards of such fissured loess slopes. First, the hydraulic-mechanical properties of the Q2 loess were investigated through experiments, and the mathematical expressions of the relationships between various mechanical parameters and water content were fitted, indicating that the mechanical parameters, such as cohesion, angle of internal friction, and deformation modulus, vary in a quasi-linear manner with the water content. Then, a new numerical method was proposed to simulate the mechanical behaviours of the loess considering its water sensitivity and transverse isotropy, where the water sensitivity was considered through the implementation of the mathematical expressions of the hydraulic-mechanical relationships, and the transverse isotropy was considered by the modified constitutive model that combined the logics of transversely elastic model and a ubiquitous-joint model. Finally, the deformation development mechanism of the fissured loess slope under rainfall and traffic load was revealed by using the proposed method. The roles of the rainfall and traffic load in the fissure propagation and deformation development process of the slope were explored, and some stabilisation measures are recommended for the prevention of its failure. The proposed method and findings arising therefrom may provide references for future studies of the stability and landslide hazard assessment of fissured loess slopes.
Prognostic Value of Preoperative Serum Calcitonin Levels for Predicting the Recurrence of Medullary Thyroid Carcinoma
Authors: Park Hyunju , Park So Young , Park Jun , Choe Jun Ho , Chung Man Ki , Woo Sook-Young , Choi Joon Young , Kim Sun Wook , Chung Jae Hoon , Kim Tae Hyuk
Published: October 2021

Background

Serum calcitonin level is a useful biomarker for predicting primary tumor size, the extent of lymph node, and distant metastasis in patients with medullary thyroid carcinoma (MTC). However, the association between preoperative serum calcitonin levels and long-term oncologic outcomes has not yet been established. The aims of this study were to determine the preoperative serum calcitonin cut-off value for predicting disease recurrence and to evaluate its prognostic value.

Methods

Patients with MTC (n = 169) who were treated at a tertiary referral hospital in Korea between 1995 and 2019 were enrolled. To determine the preoperative serum calcitonin cut-off value for predicting structural recurrence, the maximum of the standardized log-rank statistics of all possible cut-off values was used. Multivariable Cox regression analysis was used to determine prognostic factors for disease-free survival.

Results

The overall disease-free survival rate was 75.7%. The preoperative serum calcitonin cut-off value that predicted structural recurrence was 309 pg/mL. Preoperative serum calcitonin levels of > 309 pg/mL were the strongest independent predictor of disease recurrence (hazard ratio (HR) 5.33, 95% confidence interval (85% CI) 1.67–16.96; P = 0.005). Lateral lymph node metastasis (HR 3.70, 95% CI 1.61–8.51; P = 0.002) and positive resection margins (HR 3.57, 95% CI 1.44–8.88; P = 0.006) were also significant predictors of disease recurrence.

Conclusions

The preoperative serum calcitonin cut-off value is useful in clinical practice. It is also the best predictive factor for disease-free survival. Preoperative serum calcitonin levels may help determine the optimal postoperative follow-up strategy for patients with MTC.
Characterization and Duodenal Transcriptome Analysis of Chinese Beef Cattle With Divergent Feed Efficiency Using RNA-Seq
Authors: Yang Chaoyun , Han Liyun , Li Peng , Ding Yanling , Zhu Yun , Huang Zengwen , Dan Xingang , Shi Yuangang , Kang Xiaolong
Published: October 2021

Residual feed intake (RFI) is an important measure of feed efficiency for agricultural animals. Factors associated with cattle RFI include physiology, dietary factors, and the environment. However, a precise genetic mechanism underlying cattle RFI variations in duodenal tissue is currently unavailable. The present study aimed to identify the key genes and functional pathways contributing to variance in cattle RFI phenotypes using RNA sequencing (RNA-seq). Six bulls with extremely high or low RFIs were selected for detecting differentially expressed genes (DEGs) by RNA-seq, followed by conducting GO, KEGG enrichment, protein-protein interaction (PPI), and co-expression network (WGCNA, n = 10) analysis. A total of 380 differentially expressed genes was obtained from high and low RFI groups, including genes related to energy metabolism (ALDOA, HADHB, INPPL1), mitochondrial function (NDUFS1, RFN4, CUL1), and feed intake behavior (CCK). Two key sub-networks and 26 key genes were detected using GO analysis of DEGs and PPI analysis, such as TPM1 and TPM2, which are involved in mitochondrial pathways and protein synthesis. Through WGCNA, a gene network was built, and genes were sorted into 27 modules, among which the blue (r = 0.72, p = 0.03) and salmon modules (r = −0.87, p = 0.002) were most closely related with RFI. DEGs and genes from the main sub-networks and closely related modules were largely involved in metabolism; oxidative phosphorylation; glucagon, ribosome, and N-glycan biosynthesis, and the MAPK and PI3K-Akt signaling pathways. Through WGCNA, five key genes, including FN1 and TPM2, associated with the biological regulation of oxidative processes and skeletal muscle development were identified. Taken together, our data suggest that the duodenum has specific biological functions in regulating feed intake. Our findings provide broad-scale perspectives for identifying potential pathways and key genes involved in the regulation of feed efficiency in beef cattle.
Major Reorganization of Chromosome Conformation During Muscle Development in Pig
Authors: Marti-Marimon Maria , Vialaneix Nathalie , Lahbib-Mansais Yvette , Zytnicki Matthias , Camut Sylvie , Robelin David , Yerle-Bouissou Martine , Foissac Sylvain
Published: October 2021

The spatial organization of the genome in the nucleus plays a crucial role in eukaryotic cell functions, yet little is known about chromatin structure variations during late fetal development in mammals. We performed in situ high-throughput chromosome conformation capture (Hi-C) sequencing of DNA from muscle samples of pig fetuses at two late stages of gestation. Comparative analysis of the resulting Hi-C interaction matrices between both groups showed widespread differences of different types. First, we discovered a complex landscape of stable and group-specific Topologically Associating Domains (TADs). Investigating the nuclear partition of the chromatin into transcriptionally active and inactive compartments, we observed a genome-wide fragmentation of these compartments between 90 and 110 days of gestation. Also, we identified and characterized the distribution of differential cis- and trans-pairwise interactions. In particular, trans-interactions at chromosome extremities revealed a mechanism of telomere clustering further confirmed by 3D Fluorescence in situ Hybridization (FISH). Altogether, we report major variations of the three-dimensional genome conformation during muscle development in pig, involving several levels of chromatin remodeling and structural regulation.
Short Chain Fatty Acids Prevent Glyoxylate-Induced Calcium Oxalate Stones by GPR43-Dependent Immunomodulatory Mechanism
Authors: Jin Xi , Jian Zhongyu , Chen Xiaoting , Ma Yucheng , Ma Hongwen , Liu Yu , Gong Lina , Xiang Liyuan , Zhu Shiyu , Shu Xiaoling , Qi Shiqian , Li Hong , Wang Kunjie
Published: October 2021

Calcium oxalate (CaOx) stones are the most common type of kidney stones and are associated with high recurrence, short chain fatty acids (SCFAs), and inflammation. However, it remains uncertain whether SCFAs affect the formation of CaOx stones through immunomodulation. We first performed mass cytometry (CyTOF) and RNA sequencing on kidney immune cells with glyoxylate-induced CaOx crystals (to elucidate the landscape of the associated immune cell population) and explored the role of SCFAs in renal CaOx stone formation through immunomodulation. We identified 29 distinct immune cell subtypes in kidneys with CaOx crystals, where CX3CR1+CD24- macrophages significantly decreased and GR1+ neutrophils significantly increased. In accordance with the CyTOF data, RNA sequencing showed that most genes involved were related to monocytes and neutrophils. SCFAs reduced kidney CaOx crystals by increasing the frequency of CX3CR1+CD24- macrophages and decreasing GR1+ neutrophil infiltration in kidneys with CaOx crystals, which was dependent on the gut microbiota. GPR43 knockdown by transduction with adeno-associated virus inhibited the alleviation of crystal formation and immunomodulatory effects in the kidney, due to SCFAs. Moreover, CX3CR1+CD24- macrophages regulated GR1+ neutrophils via GPR43. Our results demonstrated a unique trilateral relationship among SCFAs, immune cells, and the kidneys during CaOx formation. These findings suggest that future immunotherapies may be used to prevent kidney stones using SCFAs.
The Partitioning of Newly Assimilated Linoleic and α-Linolenic Acids Between Synthesis of Longer-Chain Polyunsaturated Fatty Acids and Hydroxyoctadecaenoic Acids Is a Putative Branch Point in T-Cell Essential Fatty Acid Metabolism
Authors: von Gerichten Johanna , West Annette L. , Irvine Nicola A. , Miles Elizabeth A. , Calder Philip C. , Lillycrop Karen A. , Fielding Barbara A. , Burdge Graham C.
Published: October 2021

Longer-chain polyunsaturated fatty acids (LCPUFAs) ≥20 carbons long are required for leukocyte function. These can be obtained from the diet, but there is some evidence that leukocytes can convert essential fatty acids (EFAs) into LCPUFAs. We used stable isotope tracers to investigate LCPUFA biosynthesis and the effect of different EFA substrate ratios in human T lymphocytes. CD3+T cells were incubated for up to 48 h with or without concanavalin A in media containing a 18:2n-6:18:3n-3 (EFA) ratio of either 5:1 or 8:1 and [13C]18:3n-3 plus [d5]18:2n-6. Mitogen stimulation increased the amounts of 16:1n-7, 18:1n-9, 18:2n-6, 20:3n-6, 20:4n-6, 18:3n-3, and 20:5n-3 in T cells. Expression of the activation marker CD69 preceded increasedFADS2andFADS1mRNA expression and increased amounts of [d5]20:2n-6 and [13C]20:3n-3 at 48 h. In addition, 22-carbon n-6 or n-3 LCPUFA synthesis was not detected, consistent with the absence ofELOVL2expression. An EFA ratio of 8:1 reduced 18:3n-3 conversion and enhanced 20:2n-6 synthesis compared to a 5:1 ratio. Here, [d5]9- and [d5]-13-hydroxyoctadecadienoic (HODE) and [13C]9- and [13C]13-hydroxyoctadecatrienoic acids (HOTrE) were the major labelled oxylipins in culture supernatants; labelled oxylipins ≥20 carbons were not detected. An EFA ratio of 8:1 suppressed 9- and 13-HOTrE synthesis, but there was no significant effect on 9- and 13-HODE synthesis. These findings suggest that partitioning of newly assimilated EFA between LCPUFA synthesis and hydroxyoctadecaenoic acid may be a metabolic branch point in T-cell EFA metabolism that has implications for understanding the effects of dietary fats on T lymphocyte function.
Tim-1 Deficiency Aggravates High-Fat Diet-Induced Steatohepatitis in Mice
Authors: George Jasmine , Zhang Yuanyuan , Sloan Jacob , Sims Joya M. , Imig John D. , Zhao Xueying
Published: October 2021

Non-alcoholic fatty liver disease (NAFLD)/non-alcoholic steatohepatitis (NASH) is commonly associated with obesity and characterized by excessive lipid accumulation and liver inflammation. The T cell immunoglobulin and mucin domain 1 (Tim-1), also known as hepatitis A virus cellular receptor 1 (Havcr-1) and kidney injury molecule 1 (Kim-1), has been shown to affect innate immunity-driven proinflammatory cascade in liver ischemia-reperfusion injury. However, its contribution to obesity-related NAFLD/NASH remains unknown. Thus, this study was designed to evaluate the role of Tim-1 in obesity-related liver inflammation and injury in wild-type (WT) and Tim-1-deficient (Tim-1-/-) C57BL/6J mice fed a high-fat diet (HFD) for 5-6 months. HFD feeding induced steatosis and upregulated Tim-1 gene expression in the liver of WT mice. Surprisingly, Tim-1-/- mice on HFD diet exhibited an exacerbation of hepatic steatosis, accompanied with an elevation of protein levels of fatty acid translocase CD36 and sterol regulatory element binding protein 1 (SREBP1). Tim-1 deficiency also enhanced HFD-induced liver inflammation and injury, as evidenced by augmented increase in hepatic expression of pro-inflammatory factor lipocalin 2 and elevated serum alanine transaminase (ALT). In addition, gene expression of type I, III and IV collagens and liver fibrosis were greatly enhanced in HFD Tim-1-/- mice compared with HFD WT mice. HFD-induced hepatic expression of YM-1, a specific mouse M2 macrophage marker, was further upregulated by deletion of Tim-1. Together, these results show that Tim-1 deficiency aggravates the effects of HFD diet on lipid accumulation and liver fibrosis, most likely through enhanced infiltration and activation of inflammatory cells.
Identification of a Novel Serological Marker in Seronegative Rheumatoid Arthritis Using the Peptide Library Approach
Authors: Bason Caterina , Barbieri Alessandro , Martinelli Nicola , Olivieri Bianca , Argentino Giuseppe , Bartoloni Elena , Beri Ruggero , Jadav Gnaneshwer , Puccetti Antonio , Tinazzi Elisa , Lunardi Claudio
Published: October 2021

Rheumatoid arthritis (RA) is a systemic autoimmune disease characterized by chronic inflammation mainly affecting the joints leading to cartilage and bone destruction. The definition of seropositive or seronegative RA is based on the presence or absence of rheumatoid factor (RF) and anti-citrullinated peptide antibodies (ACPAs). Other autoantibodies have been identified in the last decade such as antibodies directed against carbamylated antigens, peptidyl-arginine deiminase type 4 and v-Raf murine sarcoma viral oncogene homologue B. In order to identify relevant autoantigens, we screened a random peptide library (RPL) with pooled IgGs obtained from 50 patients with seronegative RA. Patients’ sera were then used in an ELISA test to identify the most frequently recognized peptide among those obtained by screening the RPL. Sera from age- and sex-matched healthy subjects were used as controls. We identified a specific peptide (RA-peptide) recognized by RA patients’ sera, but not by healthy subjects or by patients with other immune-mediated diseases. The majority of sera from seronegative and seropositive RA patients (73.8% and 63.6% respectively) contained IgG antibodies directed against the RA-peptide. Interestingly, this peptide shares homology with some self-antigens, such as Protein-tyrosine kinase 2 beta, B cell scaffold protein, Liprin-alfa1 and Cytotoxic T lymphocyte protein 4. Affinity purified anti-RA-peptide antibodies were able to cross react with these autoantigens. In conclusion, we identified a peptide that is recognized by seropositive and, most importantly, by seronegative RA patients’ sera, but not by healthy subjects, conferring to this epitope a high degree of specificity. This peptide shares also homology with other autoantigens which can be recognized by autoantibodies present in seronegative RA sera. These newly identified autoantibodies, although present also in a percentage of seropositive RA patients, may be considered as novel serum biomarkers for seronegative RA, which lacks the presence of RF and/or ACPAs.
Immunopathophysiology of Juvenile Spondyloarthritis (jSpA): The “Out of the Box” View on Epigenetics, Neuroendocrine Pathways and Role of the Macrophage Migration Inhibitory Factor (MIF)
Authors: Harjacek Miroslav
Published: October 2021

Juvenile spondyloarthritis (jSpA) is a an umbrella term for heterogeneous group of related seronegative inflammatory disorders sharing common symptoms. Although it mainly affects children and adolescents, it often remains active during adulthood. Genetic and environmental factors are involved in its occurrence, although the exact underlying immunopathophysiology remains incompletely elucidated. Accumulated evidence suggests that, in affected patients, subclinical gut inflammation caused by intestinal dysbiosis, is pivotal to the future development of synovial–entheseal complex inflammation. While the predominant role of IL17/23 axis, TNF-α, and IL-7 in the pathophysiology of SpA, including jSpA, is firmly established, the role of the cytokine macrophage migration inhibitory factor (MIF) is generally overlooked. The purpose of this review is to discuss and emphasize the role of epigenetics, neuroendocrine pathways and the hypothalamic-pituitary (HPA) axis, and to propose a novel hypothesis of the role of decreased NLRP3 gene expression and possibly MIF in the early phases of jSpA development. The decreased NLRP3 gene expression in the latter, due to hypomethylation of promotor site, is (one of) the cause for inflammasome malfunction leading to gut dysbiosis observed in patients with early jSpA. In addition, we highlight the role of MIF in the complex innate, adaptive cellular and main effector cytokine network, Finally, since treatment of advanced bone pathology in SpA remains an unmet clinical need, I suggest possible new drug targets with the aim to ultimately improve treatment efficacy and long-term outcome of jSpA patients.
Performance Assessment of the Network Reconstruction Approaches on Various Interactomes
Authors: Arici M. Kaan , Tuncbag Nurcan
Published: October 2021

Beyond the list of molecules, there is a necessity to collectively consider multiple sets of omic data and to reconstruct the connections between the molecules. Especially, pathway reconstruction is crucial to understanding disease biology because abnormal cellular signaling may be pathological. The main challenge is how to integrate the data together in an accurate way. In this study, we aim to comparatively analyze the performance of a set of network reconstruction algorithms on multiple reference interactomes. We first explored several human protein interactomes, including PathwayCommons, OmniPath, HIPPIE, iRefWeb, STRING, and ConsensusPathDB. The comparison is based on the coverage of each interactome in terms of cancer driver proteins, structural information of protein interactions, and the bias toward well-studied proteins. We next used these interactomes to evaluate the performance of network reconstruction algorithms including all-pair shortest path, heat diffusion with flux, personalized PageRank with flux, and prize-collecting Steiner forest (PCSF) approaches. Each approach has its own merits and weaknesses. Among them, PCSF had the most balanced performance in terms of precision and recall scores when 28 pathways from NetPath were reconstructed using the listed algorithms. Additionally, the reference interactome affects the performance of the network reconstruction approaches. The coverage and disease- or tissue-specificity of each interactome may vary, which may result in differences in the reconstructed networks.
Proteomic Insights Into Susceptibility and Resistance to Chronic-Stress-Induced Depression or Anxiety in the Rat Striatum
Authors: Cai Xiao , Yang Chen , Chen Jin , Gong Weibo , Yi Faping , Liao Wei , Huang Rongzhong , Xie Liang , Zhou Jian
Published: October 2021

Chronic stress is a key factor for the onset of anxiety and depression disorders. However, the stress-induced common and unique molecular basis of the two psychiatric disorders is not fully known and still needs to be explored. Previously, we employed a chronic mild stress (CMS) procedure to induce a rat model including depression-susceptible (Dep-Sus), anxiety-susceptible (Anx-Sus), and insusceptible (Insus) cohorts. In this work, we continuously analyze the striatal proteomes of the three stressed cohorts by the use of comparative proteomics and bioinformatics approaches. Through isobaric tags for relative and absolute quantitation (iTRAQ)-based analysis, 386 abnormally expressed proteins in total were identified. These deregulated proteins are involved in various biological functions and significant pathways that are potentially connected with resistance and susceptibility to CMS-caused anxious- or depressive-like behaviors and, hence, could act as suggestive protein targets. A further parallel reaction monitoring-based independent investigation shows that alterations in Pak5, Dgkg, Scn4b, Rb1cc1, and Acin1; Ggps1, Fntb, Nudt19, Ufd1, and Ndufab1; and Dnajb12, Hbb2, Ap2s1, Ip6k1, and Stk4 were specifically connected with Dep-Sus, Anx-Sus, or Insus groups, respectively, potentially indicating that identical CMS treatment results in the different changes in the striatal protein regulations. Overall, our current proteomics study of the striatum provides an important molecular foundation and comprehensive insights into common and specific deregulations correlated with pathophysiological mechanisms that underlie resistance and susceptibility to chronic stress–induced anxiety or depression.
Sertraline for Functional Recovery After Acute Ischemic Stroke: A Prospective Observational Study
Authors: Stuckart Isabella , Siepmann Timo , Hartmann Christian , Pallesen Lars-Peder , Sedghi Annahita , Barlinn Jessica , Reichmann Heinz , Puetz Volker , Barlinn Kristian
Published: October 2021

Background: Neuroprotective and neurorestorative effects have been postulated for selective serotonin-reuptake inhibitors (SSRI). We hypothesized that sertraline, which is characterized by less severe adverse effects and more stable pharmacokinetics than classic SSRI, is associated with improved functional recovery in acute ischemic stroke patients with motor deficits.

Methods: Prospective observational study of consecutive acute ischemic stroke patients who received sertraline for clinically suspected post-stroke depression (PSD) or at high risk for PSD. Eligibility comprised acute motor deficit caused by ischemic stroke (≥2 points on NIHSS motor items) and functional independence pre-stroke (mRS ≤1). Decision to initiate treatment with SSRI during hospital stay was at the discretion of the treating stroke physician. Patients not receiving sertraline served as control group. Favorable functional recovery defined as mRS ≤2 was prospectively assessed at 3 months. Multivariable logistic regression analysis was used to explore the effects of sertraline on 3-months functional recovery. Secondary outcomes were frequency of any and incident PSD (defined by BDI ≥10) at 3 months.

Results: During the study period (03/2017–12/2018), 114 patients were assigned to sertraline (n = 72, 62.6%) or control group (n = 42, 37.4%). At study entry, patients in sertraline group were more severely neurologically affected than patients in the control group (NIHSS: 8 [IQR, 5–11] vs. 5 [IQR, 4–7]; p = 0.002). Also, motor NIHSS scores were more pronounced in sertraline than in control group (4 [IQR 2–7] vs. 2 [IQR 2–4], p = 0.001). After adjusting for age and baseline NIHSS, multivariable regression analysis revealed a significant association between sertraline intake and favorable functional outcome at 3 months (OR 3.10, 95% CI 1.02–9.41; p = 0.045). There was no difference between both groups regarding the frequency of any depression at 3 months (26/53 [49.1%] vs. 14/28 [50.0%] patients, p = 0.643, BDI ≥10). However, fewer incident depressions were observed in sertraline group patients compared to patients in control group (0/53 [0%] vs. 5/28 [17.9%] patients, p = 0.004).

Conclusions: In this non-randomized comparison, early treatment with sertraline tended to favor functional recovery in patients with acute ischemic stroke. While exploratory in nature, this hypothesis needs further investigation in a clinical trial.
Associations Between Binocular Depth Perception and Performance Gains in Laparoscopic Skill Acquisition
Authors: Hatzipanayioti Adamantini , Bodenstedt Sebastian , von Bechtolsheim Felix , Funke Isabel , Oehme Florian , Distler Marius , Weitz Jürgen , Speidel Stefanie , Li Shu-Chen
Published: October 2021

The ability to perceive differences in depth is important in many daily life situations. It is also of relevance in laparoscopic surgical procedures that require the extrapolation of three-dimensional visual information from two-dimensional planar images. Besides visual-motor coordination, laparoscopic skills and binocular depth perception are demanding visual tasks for which learning is important. This study explored potential relations between binocular depth perception and individual variations in performance gains during laparoscopic skill acquisition in medical students naïve of such procedures. Individual differences in perceptual learning of binocular depth discrimination when performing a random dot stereogram (RDS) task were measured as variations in the slope changes of the logistic disparity psychometric curves from the first to the last blocks of the experiment. The results showed that not only did the individuals differ in their depth discrimination; the extent with which this performance changed across blocks also differed substantially between individuals. Of note, individual differences in perceptual learning of depth discrimination are associated with performance gains from laparoscopic skill training, both with respect to movement speed and an efficiency score that considered both speed and precision. These results indicate that learning-related benefits for enhancing demanding visual processes are, in part, shared between these two tasks. Future studies that include a broader selection of task-varying monocular and binocular cues as well as visual-motor coordination are needed to further investigate potential mechanistic relations between depth perceptual learning and laparoscopic skill acquisition. A deeper understanding of these mechanisms would be important for applied research that aims at designing behavioral interventions for enhancing technology-assisted laparoscopic skills.
Inhibition of Return Decreases Early Audiovisual Integration: An Event-Related Potential Study
Authors: Peng Xing , Tang Xiaoyu , Jiang Hao , Wang Aijun , Zhang Ming , Chang Ruosong
Published: October 2021

Previous behavioral studies have found that inhibition of return decreases the audiovisual integration, while the underlying neural mechanisms are unknown. The current work utilized the high temporal resolution of event-related potentials (ERPs) to investigate how audiovisual integration would be modulated by inhibition of return. We employed the cue-target paradigm and manipulated the target type and cue validity. Participants were required to perform the task of detection of visual (V), auditory (A), or audiovisual (AV) targets shown in the identical (valid cue) or opposed (invalid cue) side to be the preceding exogenous cue. The neural activities between AV targets and the sum of the A and V targets were compared, and their differences were calculated to present the audiovisual integration effect in different cue validity conditions (valid, invalid). The ERPs results showed that a significant super-additive audiovisual integration effect was observed on the P70 (60∼90 ms, frontal-central) only under the invalid cue condition. The significant audiovisual integration effects were observed on the N1 or P2 components (N1, 120∼180 ms, frontal-central-parietal; P2, 200∼260 ms, frontal-central-parietal) in both valid cue as well as invalid cue condition. And there were no significant differences on the later components between invalid cue and valid cue. The result offers the first neural demonstration that inhibition of return modulates the early audiovisual integration process.
Dynamic Network Connectivity Reveals Markers of Response to Deep Brain Stimulation in Parkinson’s Disease
Authors: Wu Chengyuan , Matias Caio , Foltynie Thomas , Limousin Patricia , Zrinzo Ludvic , Akram Harith
Published: October 2021

Background: Neuronal loss in Parkinson’s Disease (PD) leads to widespread neural network dysfunction. While graph theory allows for analysis of whole brain networks, patterns of functional connectivity (FC) associated with motor response to deep brain stimulation of the subthalamic nucleus (STN-DBS) have yet to be explored.

Objective/Hypothesis: To investigate the distributed network properties associated with STN-DBS in patients with advanced PD.

Methods: Eighteen patients underwent 3-Tesla resting state functional MRI (rs-fMRI) prior to STN-DBS. Improvement in UPDRS-III scores following STN-DBS were assessed 1 year after implantation. Independent component analysis (ICA) was applied to extract spatially independent components (ICs) from the rs-fMRI. FC between ICs was calculated across the entire time series and for dynamic brain states. Graph theory analysis was performed to investigate whole brain network topography in static and dynamic states.

Results: Dynamic analysis identified two unique brain states: a relative hypoconnected state and a relative hyperconnected state. Time spent in a state, dwell time, and number of transitions were not correlated with DBS response. There were no significant FC findings, but graph theory analysis demonstrated significant relationships with STN-DBS response only during the hypoconnected state – STN-DBS was negatively correlated with network assortativity.

Conclusion: Given the widespread effects of dopamine depletion in PD, analysis of whole brain networks is critical to our understanding of the pathophysiology of this disease. Only by leveraging graph theoretical analysis of dynamic FC were we able to isolate a hypoconnected brain state that contained distinct network properties associated with the clinical effects of STN-DBS.
Olfactory Signatures in the Food Finding Test in Mice With Normal and Alzheimer’s Disease-Pathological Aging With Special Concerns on the Effects of Social Isolation
Authors: Marín-Pardo Daniela , Giménez-Llort Lydia
Published: October 2021

The temporal course and the severity of the involution of sensory systems through aging can be critical since they ensure the ability to perceive and recognize the world. In older people, sensory impairments significantly increase their risk of biological, psychological, and social impoverishment. Besides this, olfactory loss is considered an early biomarker in Alzheimer’s disease (AD) neurodegenerative process. Here we studied olfactory ethograms in middle-aged male and female gold-standard C57BL/6 mice and 3xTg-AD mice, a genetic model of AD that presents cognitive dysfunction and a conspicuous neuropsychiatric-like phenotype. A paradigm involving 1-day food deprivation was used to investigate the ethological patterns shown in the olfactory inspection of a new cage and the sniffing, finding, and eating of hidden food pellets. The sniffing–find–eat temporal patterns were independent of the loss of weight and unveiled (fast) olfactory signatures in Alzheimer’s disease, differing from those (slow progressive) in normal aging. Male 3xTg-AD mice exhibited an early signature than female mice, opposite to animals with normal aging. The sequence of actions was correlated in male and female 3xTg-AD mice in contrast to control mice. Social isolation, naturally occurring in male 3xTg-AD due to the death of cage mates, emphasized their olfactory patterns and disrupted the behavioral correlates. The paradigm provided distinct contextual, sex, and genotype olfactory ethogram signatures useful to investigate olfactory function in normal and AD-pathological aging. Isolation had an impact on enhancing the changes in the olfactory signature here described, for the first time, in the 3xTg-AD model of Alzheimer’s disease.
Stratification by Tumor Grade Groups in a Holistic Evaluation of Machine Learning for Brain Tumor Segmentation
Authors: Prabhudesai Snehal , Wang Nicholas Chandler , Ahluwalia Vinayak , Huan Xun , Bapuraj Jayapalli Rajiv , Banovic Nikola , Rao Arvind
Published: October 2021

Accurate and consistent segmentation plays an important role in the diagnosis, treatment planning, and monitoring of both High Grade Glioma (HGG), including Glioblastoma Multiforme (GBM), and Low Grade Glioma (LGG). Accuracy of segmentation can be affected by the imaging presentation of glioma, which greatly varies between the two tumor grade groups. In recent years, researchers have used Machine Learning (ML) to segment tumor rapidly and consistently, as compared to manual segmentation. However, existing ML validation relies heavily on computing summary statistics and rarely tests the generalizability of an algorithm on clinically heterogeneous data. In this work, our goal is to investigate how to holistically evaluate the performance of ML algorithms on a brain tumor segmentation task. We address the need for rigorous evaluation of ML algorithms and present four axes of model evaluation—diagnostic performance, model confidence, robustness, and data quality. We perform a comprehensive evaluation of a glioma segmentation ML algorithm by stratifying data by specific tumor grade groups (GBM and LGG) and evaluate these algorithms on each of the four axes. The main takeaways of our work are—(1) ML algorithms need to be evaluated on out-of-distribution data to assess generalizability, reflective of tumor heterogeneity. (2) Segmentation metrics alone are limited to evaluate the errors made by ML algorithms and their describe their consequences. (3) Adoption of tools in other domains such as robustness (adversarial attacks) and model uncertainty (prediction intervals) lead to a more comprehensive performance evaluation. Such a holistic evaluation framework could shed light on an algorithm's clinical utility and help it evolve into a more clinically valuable tool.
Deep Multimodal Learning From MRI and Clinical Data for Early Prediction of Neurodevelopmental Deficits in Very Preterm Infants
Authors: He Lili , Li Hailong , Chen Ming , Wang Jinghua , Altaye Mekibib , Dillman Jonathan R. , Parikh Nehal A.
Published: October 2021

The prevalence of disabled survivors of prematurity has increased dramatically in the past 3 decades. These survivors, especially, very preterm infants (VPIs), born ≤ 32 weeks gestational age, are at high risk for neurodevelopmental impairments. Early and clinically effective personalized prediction of outcomes, which forms the basis for early treatment decisions, is urgently needed during the peak neuroplasticity window—the first couple of years after birth—for at-risk infants, when intervention is likely to be most effective. Advances in MRI enable the noninvasive visualization of infants' brains through acquired multimodal images, which are more informative than unimodal MRI data by providing complementary/supplementary depicting of brain tissue characteristics and pathology. Thus, analyzing quantitative multimodal MRI features affords unique opportunities to study early postnatal brain development and neurodevelopmental outcome prediction in VPIs. In this study, we investigated the predictive power of multimodal MRI data, including T2-weighted anatomical MRI, diffusion tensor imaging, resting-state functional MRI, and clinical data for the prediction of neurodevelopmental deficits. We hypothesize that integrating multimodal MRI and clinical data improves the prediction over using each individual data modality. Employing the aforementioned multimodal data, we proposed novel end-to-end deep multimodal models to predict neurodevelopmental (i.e., cognitive, language, and motor) deficits independently at 2 years corrected age. We found that the proposed models can predict cognitive, language, and motor deficits at 2 years corrected age with an accuracy of 88.4, 87.2, and 86.7%, respectively, significantly better than using individual data modalities. This current study can be considered as proof-of-concept. A larger study with external validation is important to validate our approach to further assess its clinical utility and overall generalizability.
Supplemental L-Arginine Improves the Embryonic Intestine Development and Microbial Succession in a Chick Embryo Model
Authors: Dai Dong , Zhang Hai-jun , Qiu Kai , Qi Guang-hai , Wang Jing , Wu Shu-geng
Published: October 2021

Early colonization of intestinal microbiota plays an important role in intestinal development. However, the microbial succession at an embryonic stage and its assembly patterns induced by prenatal nutrition are unknown. In the present study, we used a chick embryo model to investigate the effects of in ovo feeding (IOF) of L-arginine (Arg) on the intestinal development and microbial succession of embryos. A total of 216 fertile eggs were randomly distributed into 2 groups including the non-injected control group and IOF of Arg group with 7 mg/egg. The results showed that IOF Arg increased the intestinal index, absolute weight of jejunum, and improved jejunal morphology in terms of villus width and surface area (p < 0.05). The relative mRNA expressions of mTOR and 4E-BP1 were up-regulated and accompanied by higher contents of Mucin-2 in the Arg group (p < 0.05). There was a significant elevation in contents of serum glucose and high-density lipoprotein cholesterol, whereas there was a decreased low-density lipoprotein cholesterol in the Arg group (p < 0.05). Additionally, Proteobacteria and Firmicutes were major intestinal bacteria species at the embryonic stage. However, Arg supplementation targeted to shape assembly patterns of microbial succession and then changed microbial composition (p = 0.05). Meanwhile, several short-chain fatty acids (SCFAs)-producing bacteria, such as Roseburia, Blautia, and Ruminococcus were identified as biomarkers in the Arg group (LDA > 3, p < 0.05). Accordingly, significant elevated concentrations of SCFAs, including lactic acid and formic acid, were observed in the Arg group (p < 0.05), accompanied by the higher concentration of butyric acid (0.05 < p < 0.10). In conclusion, prenatal Arg supplementation improved embryonic intestine development by regulating glucose and lipid homeostasis to supply more energy for chick embryos. The possible mechanism could be the roles of Arg in shaping the microbial assembly pattern and succession of the embryonic intestine, particularly the enrichment of potential probiotics. These findings may contribute to exploring nutritional strategies to establish health-promoting microbiota by manipulating prenatal host-microbe interactions for the healthy development of neonates.
Changes in Metabolite Patterns During Refrigerated Storage of Lamb's lettuce (Valerianella locusta L. Betcke)
Authors: Schmitzer Valentina , Senica Mateja , Slatnar Ana , Stampar Franci , Jakopic Jerneja
Published: October 2021

Lamb's lettuce is a popular winter salad, often grown in private vegetable plots, small local farms or in intensive vegetable production. It is usually marketed as a ready-to-eat produce in supermarkets. The aim of the study was to evaluate the changes in biochemical composition and degradation of bioactive compounds during consumer-relevant time of home-grown and store-bought Valerianella locusta “Vit” salad. Primary metabolites, assimilatory pigments as well as secondary metabolites were monitored during 1 week of refrigerated storage. Home-grown lamb's lettuce exhibited highest levels of total sugars, total organic acids, vitamin C, and total phenolic content as well as enhanced levels of most individual phenolic compounds and chloroplast pigments. Locally produced samples of lamb's lettuce also contained high levels of analyzed bioactive components. All samples retained most bioactive components during the entire period of refrigerated storage. The results underline the instability of vitamin C during refrigerated storage of lamb's lettuce and pinpoint this parameter as being the most affected by storage.
Mandibular Reconstruction With Fibula Flap and Dental Implants Through Virtual Surgical Planning and Three Different Techniques: Double-Barrel Flap, Implant Dynamic Navigation and CAD/CAM Mesh With Iliac Crest Graft
Authors: Antúnez-Conde Raúl , Salmerón José Ignacio , Díez-Montiel Alberto , Agea Marc , Gascón Dafne , Sada Ángela , Navarro Cuéllar Ignacio , Tousidonis Manuel , Ochandiano Santiago , Arenas Gema , Navarro Cuéllar Carlos
Published: October 2021

Introduction

Vertical discrepancy between the fibula flap and the native mandible results in difficult prosthetic rehabilitation. The aim of this study was to evaluate the outcomes of 3D reconstruction of the mandible in oncologic patients using three different techniques through virtual surgical planning (VSP), cutting guides, customized titanium mesh and plates with CAD/CAM technology, STL models and intraoperative dynamic navigation for implant placement. Material and methods

Material and Methods

Three different techniques for mandibular reconstruction and implant rehabilitation were performed in 14 oncologic patients. Five patients (36%) underwent VSP, cutting guides, STL models and a customized double-barrel titanium plate with a double-barrel flap and immediate implants. In six patients (43%), VSP, STL models and a custom-made titanium mesh (CAD/CAM) for 3D reconstruction with iliac crest graft over a fibula flap with deferred dental implants were performed. Three patients (21%) underwent VSP with cutting guides and customized titanium plates for mandibular reconstruction and implant rehabilitation using intraoperative dynamic navigation was accomplished. Vertical bone reconstruction, peri-implant bone resorption, implant success rate, effects of radiotherapy in vertical reconstruction, bone resorption and implant failure, mastication, aesthetic result and dysphagia were evaluated.

Results

Significant differences in bone growth between the double-barrel technique and iliac crest graft with titanium mesh technique were found (p<0.002). Regarding bone resorption, there were no significant differences between the techniques (p=0.11). 60 implants were placed with an osseointegration rate of 91.49%. Five implants were lost during the osseointegration period (8%). Peri-implant bone resorption was measured with a mean of 1.27 mm. There was no significant difference between the vertical gain technique used and implant survival (p>0.385). Implant survival rates were higher in non-irradiated patients (p<0.017). All patients were rehabilitated with a fixed implant-supported prosthesis reporting a regular diet (80%), normal swallowing (85.7%) and excellent aesthetic results.

Conclusions

Multi-stage implementation of VSP, STL models and cutting guides, CAD/CAM technology, customized plates and in-house dynamic implant navigation for mandibular defects increases bone-to-bone contact, resolves vertical discrepancy and improves operative efficiency with reduced complication rates and minimal bone resorption. It provides accurate reconstruction that optimizes implant placement, thereby improving facial symmetry, aesthetics and function.
Prognostic Value of Pretreatment Prognostic Nutritional Index in Patients With Renal Cell Carcinoma: A Meta-Analysis
Authors: Mao Changqing , Xu Weixin , Ma Weina , Wang Chun , Guo Zhaojiao , Yan Jun
Published: October 2021

Background

The pretreatment prognostic nutritional index (PNI) is correlated with poor prognosis in several malignancies. However, the prognostic role of PNI in patients with renal cell carcinoma (RCC) remains unclear. Therefore, we performed a meta-analysis to investigate the prognostic significance of PNI in patients with RCC.

Methods

We searched the PubMed, Web of Science, Embase, Scopus, and Cochrane Library databases up to February 2021. Pooled hazard ratios (HRs) and 95% confidence intervals (CIs) were used to estimate correlation between PNI and survival endpoints in RCC.

Results

Ten studies with 4,908 patients were included in the meta-analysis. The pooled results indicated that a low PNI associated with poor overall survival (HR = 2.10, 95% CI = 1.67–2.64, p<0.001), shorter progression-free survival, disease-free survival, recurrence-free survival (HR = 1.99, 95% CI = 1.67–2.36, p<0.001), and poor cancer-specific survival (HR = 2.95, 95% CI = 1.61–5.39, p<0.001). Additionally, the prognostic ability of PNI was not affected by subgroup analysis factors.

Conclusion

The meta-analysis indicated that low PNI associated with shorter survival outcomes in patients with RCC. Therefore, PNI could be used as an effective prognostic indicator in RCC.
Identification of a Somatic Mutation-Derived Long Non-Coding RNA Signatures of Genomic Instability in Renal Cell Carcinoma
Authors: Fang Xisheng , Liu Xia , Lu Lin , Liu Guolong
Published: October 2021

Background

Renal cell carcinoma (RCC) is a malignant tumor with high morbidity and mortality. It is characterized by a large number of somatic mutations and genomic instability. Long non-coding RNAs (lncRNAs) are widely involved in the expression of genomic instability in renal cell carcinoma. But no studies have identified the genome instability-related lncRNAs (GInLncRNAs) and their clinical significances in RCC.

Methods

Clinical data, gene expression data and mutation data of 943 RCC patients were downloaded from The Cancer Genome Atlas (TCGA) database. Based on the mutation data and lncRNA expression data, GInLncRNAs were screened out. Co-expression analysis, Gene Ontology (GO) enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis were conducted to explore their potential functions and related signaling pathways. A prognosis model was further constructed based on genome instability-related lncRNAs signature (GInLncSig). And the efficiency of the model was verified by receiver operating characteristic (ROC) curve. The relationships between the model and clinical information, prognosis, mutation number and gene expression were analyzed using correlation prognostic analysis. Finally, the prognostic model was verified in clinical stratification according to TCGA dataset.

Results

A total of 45 GInLncRNAs were screened out. Functional analysis showed that the functional genes of these GInLncRNAs were mainly enriched in chromosome and nucleoplasmic components, DNA binding in molecular function, transcription and complex anabolism in biological processes. Univariate and Multivariate Cox analyses further screened out 11 GInLncSig to construct a prognostic model (AL031123.1, AC114803.1, AC103563.7, AL031710.1, LINC00460, AC156455.1, AC015977.2, ‘PRDM16-dt’, AL139351.1, AL035661.1 and LINC01606), and the coefficient of each GInLncSig in the model was calculated. The area under the curve (AUC) value of the ROC curve was 0.770. Independent analysis of the model showed that the GInLncSig model was significantly correlated with the RCC patients’ overall survival. Furthermore, the GInLncSig model still had prognostic value in different subgroups of RCC patients.

Conclusion

Our study preliminarily explored the relationship between genomic instability, lncRNA and clinical characteristics of RCC patients, and constructed a GInLncSig model consisted of 11 GInLncSig to predict the prognosis of patients with RCC. At the same time, our study provided theoretical support for the exploration of the formation and development of RCC.