bluuebunny/crossref_metadata_2025 huggingface dataset:
The Importance of Environmental Variability and Transient Population Dynamics for a Northern Ungulate
Authors: Gilbert Sophie L. , Hundertmark Kris J. , Lindberg Mark S. , Person David K. , Boyce Mark S.
Published: January 2021

The pathways through which environmental variability affects population dynamics remain poorly understood, limiting ecological inference and management actions. Here, we use matrix-based population models to examine the vital rate responses to environmental variability and individual traits, and subsequent transient dynamics of the population in response to the environment. Using Sitka black-tailed deer (Odocoileus hemionus sitkensis) in Southeast Alaska as a study system, we modeled effects of inter-annual process variance of covariates on female survival, pregnancy rate, and fetal rate, and summer and winter fawn survival. To examine the influence of environmental variance on population dynamics, we compared asymptotic and transient perturbation analysis (elasticity analysis, a life-table response experiment, and transience simulation). We found that summer fawn survival was primarily determined by black bear (Ursus americanus) predation and was positively influenced by mass at birth and female sex. Winter fawn survival was determined by malnutrition in deep-snow winters and was influenced by an interaction between date of birth and snow depth, with late-born fawns at greater risk in deep-snow winters. Adult female survival was the most influential vital rate based on classic elasticity analysis, however, elasticity analysis based on process variation indicated that winter and summer fawn survival were most variable and thus most influential to variability in population growth. Transient dynamics produced by non-stable stage distributions produced realized annual growth rates different from predicted asymptotic growth rates in all years, emphasizing the importance of winter perturbations to population dynamics of this species.
Pan-Cancer Analysis of Head-to-Head Gene Pairs in Terms of Transcriptional Activity, Co-expression and Regulation
Authors: Chen Yunqin , Li Hong , Li Yuan-Yuan , Li Yixue
Published: January 2021

Background

Head-to-Head (H2H) gene pairs are regulated by bidirectional promoters and divergently transcribed from opposite DNA strands with transcription start sites (TSSs) separated within 1 kb. H2H organization is ancient and conserved, and H2H pairs tend to exhibit similar expression patterns. Although some H2H genes have been reported to be associated with disease and cancer, there is a lack of systematic studies on H2H organization in the scenario of cancer development.

Methods

Human H2H gene pairs were identified based on GENCODE hg19 and the functional relevance of H2H pairs was explored through function enrichment and semantic similarity analysis. To investigate the association between H2H organization and carcinogenesis, pan-cancer differential analysis of H2H genes about transcriptional activity, co-expression and transcriptional regulation by transcription factors and enhancers were performed based on data from The Cancer Genome Atlas. Cox proportional hazards regression model and log-rank test were used to determine the prognostic powers of H2H pairs.

Results

In the present study, we first updated H2H genes from 1,447 to 3,150 pairs, from which the peak group with TSS distance of 1–100 was observed as expected in our previous work. It was found that housekeeping genes, mitochondrial-functional associated genes and cancer genes tend to be organized in H2H arrangement. Pan-cancer analysis indicates that H2H genes are transcriptionally active than random genes in both normal and cancer tissues, but H2H pairs display higher correlation in cancer than in normal. Particularly, housekeeping H2H pairs are differentially correlated much more significantly than non-housekeeping H2H pairs are. Some of differentially correlated H2H pairs were found to be associated with prognosis. The alteration of TF similarity seems to contribute to differential co-expression of H2H pairs during carcinogenesis; meanwhile remote enhancers also at least partly explain the differential co-expression and co-regulation of H2H pairs.

Conclusion

H2H pairs tend to show much stronger positive expression correlation in cancer than in normal due to differential regulation of bidirectional promoters. The study provides insights into the significance of H2H organization in carcinogenesis and the underlying dysfunctional regulation mechanisms. Those differentially correlated H2H pairs associated with survival have the potential to be prognostic biomarkers and therapeutic targets for cancer.
Genetic and Epigenetic Changes Are Rapid Responses of the Genome to the Newly Synthesized Autotetraploid Carassius auratus
Authors: Wang Chongqing , Zhou Yuwei , Qin Huan , Zhao Chun , Yang Li , Yu Tingting , Zhang Yuxin , Xu Tao , Qin Qinbo , Liu Shaojun
Published: January 2021

Whole genome duplication events have occurred frequently during the course of vertebrate evolution. To better understand the influence of polyploidization on the fish genome, we herein used the autotetraploidCarassius auratus(4n = 200, RRRR) (4nRR) resulting from the whole genome duplication ofCarassius auratus(2n = 100, RR) (RCC) to explore the genomic and epigenetic alterations after polyploidization. We subsequently performed analyses of full-length transcriptome dataset, amplified fragment length polymorphism (AFLP) and methylation sensitive amplification polymorphism (MSAP) on 4nRR and RCC. By matching the results of 4nRR and RCC isoforms with reference genome in full-length transcriptome dataset, 649 and 1,971 novel genes were found in the RCC and 4nRR full-length geneset, respectively. Compared toCarassius auratusandMegalobrama amblycephala, 4nRR presented 3,661 unexpressed genes and 2,743 expressed genes. Furthermore, GO enrichment analysis of expressed genes in 4nRR revealed that they were enriched in meiosis I, whereas KEGG enrichment analysis displayed that they were mainly enriched in proteasome. Using AFLP analysis, we noted that 32.61% of RCC fragments had disappeared, while 32.79% of new bands were uncovered in 4nRR. Concerning DNA methylation, 4nRR exhibited a lower level of global DNA methylation than RCC. Additionally, 60.31% of methylation patterns in 4nRR were altered compared to RCC. These observations indicated that transcriptome alterations, genomic changes and regulation of DNA methylation levels and patterns had occurred in the newly established autotetraploid genomes, suggesting that genetic and epigenetic alterations were influenced by autotetraploidization. In summary, this study provides valuable novel insights into vertebrate genome evolution and generates relevant information for fish breeding.
Engineering NK Cells for CAR Therapy—Recent Advances in Gene Transfer Methodology
Authors: Schmidt Paula , Raftery Martin J. , Pecher Gabriele
Published: January 2021

The development of chimeric antigen receptor (CAR) T cell therapy has introduced a new and effective strategy to guide and promote the immune response against tumors in the clinic. More recently, in an attempt to enhance its utility, this method has been expanded to novel cell types. One of the more successful variants has proven to be the expression of CARs in Natural Killer (NK) cells (CAR-NK). Gene engineering NK cells to express an exogenous CAR receptor allows the innate anti-tumor ability of NK cells to be harnessed and directed against a target tumor antigen. In addition, the biology of NK cells allows the development of an allogeneic cell therapeutic product useable with most or all patient haplotypes. NK cells cause little or no graft versus host disease (GvHD) and are therefore suitable for development of an “off the shelf” therapeutic product. Initial trials have also shown that CAR-NK cells rarely cause cytokine release syndrome. However, despite their potential NK cells have proven to be difficult to engineer, with high sensitivity to apoptosis and low levels of gene expression. The creation of optimized methods to introduce genes into NK cells will promote the widespread application of CAR-NK in research laboratories and the clinics.
Induction of Trained Immunity by Recombinant Vaccines
Authors: Covián Camila , Ríos Mariana , Berríos-Rojas Roslye V. , Bueno Susan M. , Kalergis Alexis M.
Published: January 2021

Vaccines represent an important strategy to protect humans against a wide variety of pathogens and have even led to eradicating some diseases. Although every vaccine is developed to induce specific protection for a particular pathogen, some vaccine formulations can also promote trained immunity, which is a non-specific memory-like feature developed by the innate immune system. It is thought that trained immunity can protect against a wide variety of pathogens other than those contained in the vaccine formulation. The non-specific memory of the trained immunity-based vaccines (TIbV) seems beneficial for the immunized individual, as it may represent a powerful strategy that contributes to the control of pathogen outbreaks, reducing morbidity and mortality. A wide variety of respiratory viruses, including respiratory syncytial virus (hRSV) and metapneumovirus (hMPV), cause serious illness in children under 5 years old and the elderly. To address this public health problem, we have developed recombinant BCG vaccines that have shown to be safe and immunogenic against hRSV or hMPV. Besides the induction of specific adaptive immunity against the viral antigens, these vaccines could generate trained immunity against other respiratory pathogens. Here, we discuss some of the features of trained immunity induced by BCG and put forward the notion that recombinant BCGs expressing hRSV or hMPV antigens have the capacity to simultaneously induce specific adaptive immunity and non-specific trained immunity. These recombinant BCG vaccines could be considered as TIbV capable of inducing simultaneously the development of specific protection against hRSV or hMPV, as well as non-specific trained-immunity-based protection against other pathogenic viruses.
Characterizing Marine Heatwaves in the Kerguelen Plateau Region
Authors: Su Zimeng , Pilo Gabriela S. , Corney Stuart , Holbrook Neil J. , Mori Mao , Ziegler Philippe
Published: January 2021

Marine heatwaves (MHWs) are prolonged extreme oceanic warm water events. Globally, the frequency and intensity of MHWs have been increasing in recent years, and it is expected that this trend is reflected in the Kerguelen Plateau region. MHWs can negatively impact the structure of marine biodiversity, marine ecosystems, and commercial fisheries. Considering that the KP is a hot-spot for marine biodiversity, characterizing MHWs and their drivers for this region is important, but has not been performed. Here, we characterize MHWs in the KP region between January 1994 and December 2016 using a combination of remotely sensed observations and output from a publicly available model hindcast simulation. We describe a strong MHW event that starts during the 2011/2012 austral summer and persists through winter, dissipating in late 2012. During the winter months, the anomalous temperature signal deepens from the surface to a depth of at least 150 m. We show that downwelling-favorable winds occur in the region during these months. At the end of 2012, as the MHW dissipates, upwelling-favorable winds prevail. We also show that the ocean temperature on the KP is significantly correlated with key modes of climate variability. Over the KP, temperature at both the ocean surface and at a depth of 150 m correlates significantly with the Indian Ocean Dipole. To the south of the KP, temperature variations are significantly correlated with the El Niño Southern Oscillation, and to both the north and south of the KP, with the Southern Annular Mode. These results suggest there may be potential predictability in ocean temperatures, and their extremes, in the KP region. Strong MHWs, like the event in 2012, may be detrimental to the unique ecosystem of this region, including economically relevant species, such as the Patagonian Toothfish.
Quantifying Contemporary Organic Carbon Stocks of the Baltic Sea Ecosystem
Authors: Scheffold Maike Iris Esther , Hense Inga
Published: January 2021

The identification of carbon pools and the quantification of carbon stocks is necessary to (1) track changes in ecosystem dynamics, (2) inform science-based ecosystem and blue-carbon management, and (3) evaluate ecosystem and food web models. However, estimates of organic carbon stocks in marine ecosystems are incomplete or inconsistent. Therefore, we provide a first consistent estimate of relevant organic carbon stocks of a distinct marine ecosystem- the Baltic Sea. We estimate its contemporary standing stocks of 18 non-living and living organic carbon pools using data from literature and open-access databases. In contrast to existing data, our estimates are valid for the entire Baltic Sea, include necessary pools and are verifiable, as we describe data sources, methods and the associated uncertainties in detail to allow reproduction and critical evaluation. The total organic carbon (TOC) in the Baltic Sea ecosystem amounts to 1,050 ± 90 gC/m2 (440 ± 40 Mt). The non-living stocks account for about 98.8% and the living stocks for 1.2% of the TOC. Our estimates indicate that benthos has the highest living organic carbon stock and that the stock of particulate organic carbon (POC) has been underestimated in some previous studies. In addition, we find a partially inverted biomass distribution with a higher stock of primary consumers than primary producers. Our estimates provide a baseline of the size and distribution of the organic carbon in the Baltic Sea for the current period. Analyses of inorganic carbon stocks and the interplay between inorganic and organic stocks must follow to further define the baseline of total carbon stocks in the Baltic Sea.
The Protective Effect of Aspirin Eugenol Ester on Paraquat-Induced Acute Liver Injury Rats
Authors: Zhang Zhen-Dong , Yang Ya-Jun , Liu Xi-Wang , Qin Zhe , Li Shi-Hong , Li Jian-Yong
Published: January 2021

Aspirin eugenol ester (AEE) possesses anti-inflammatory and anti-oxidative effects. The study was conducted to evaluate the protective effect of AEE on paraquat-induced acute liver injury (ALI) in rats. AEE was against ALI by decreasing alanine transaminase and aspartate transaminase levels in blood, increasing superoxide dismutase, catalase, and glutathione peroxidase levels, and decreasing malondialdehyde levels in blood and liver. A total of 32 metabolites were identified as biomarkers by using metabolite analysis of liver homogenate based on ultra-performance liquid chromatography-tandem mass spectrometry, which belonged to purine metabolism, phenylalanine, tyrosine and tryptophan biosynthesis, glycerophospholipid metabolism, primary bile acid biosynthesis, aminoacyl-tRNA biosynthesis, phenylalanine metabolism, histidine metabolism, pantothenate, and CoA biosynthesis, ether lipid metabolism, beta-Alanine metabolism, lysine degradation, cysteine, and methionine metabolism. Western blotting analyses showed that Bax, cytochrome C, caspase-3, caspase-9, and apoptosis-inducing factor expression levels were obviously decreased, whereas Bcl-2 expression levels obviously increased after AEE treatment. AEE exhibited protective effects on PQ-induced ALI, and the underlying mechanism is correlated with antioxidants that regulate amino acid, phospholipid and energy metabolism metabolic pathway disorders and alleviate liver mitochondria apoptosis.
Serum Metabolomic Profiling in Rheumatoid Arthritis Patients With Interstitial Lung Disease: A Case–Control Study
Authors: Furukawa Hiroshi , Oka Shomi , Shimada Kota , Okamoto Akira , Hashimoto Atsushi , Komiya Akiko , Saisho Koichiro , Yoshikawa Norie , Katayama Masao , Matsui Toshihiro , Fukui Naoshi , Migita Kiyoshi , Tohma Shigeto
Published: January 2021

Objectives: Interstitial lung disease (ILD) is an extra-articular manifestation in rheumatoid arthritis (RA), detected in 10.7% of patients, and causing a poor prognosis. Hence, biomarkers for ILD are urgently required in RA. Low molecular weight metabolites can be assessed by metabolomic analyses, and although these have been conducted in RA and in idiopathic pulmonary fibrosis, few have been carried out for ILD in the context of RA. Therefore, we analyzed serum metabolomic profiles of ILD in RA to identify novel biomarkers.

Methods: Serum samples from 100 RA patients with ILD and 100 matched RA patients without chronic lung disease (CLD) were collected. These samples were subjected to metabolomic analyses using capillary electrophoresis time-of-flight mass spectrometry.

Results: A total of 299 metabolites were detected in the metabolomic analysis. By univariate analysis, serum levels of decanoic acid and morpholine were lower in RA with ILD (false discovery rate Q = 1.87 × 10−11 and 7.09 × 10−6, respectively), and glycerol was higher (Q = 1.20 × 10−6), relative to RA without CLD. Serum levels of these metabolites in RA with usual interstitial pneumonia or RA with non-specific interstitial pneumonia were also altered. The partial least squares-discriminant analysis model generated from these three metabolites could successfully discriminate ILD in RA (area under the curve: 0.919, 95% confidence interval: 0.867–0.968, sensitivity 0.880, specificity 0.780).

Conclusions: Serum levels of some metabolites were significantly different in RA with ILD compared with RA without CLD. It is concluded that metabolomic profiling will be useful for discovering candidate screening biomarkers for ILD in RA.
The Effects of Earthworms on Fungal Diversity and Community Structure in Farmland Soil With Returned Straw
Authors: Song Ke , Sun Yafei , Qin Qin , Sun Lijuan , Zheng Xianqing , Terzaghi William , Lv Weiguang , Xue Yong
Published: January 2021

Background

To promote the decomposition of returned straw, reduce the incidence of soil-borne diseases caused by returned straw, and accelerate the conversion of straw carbon into soil carbon, we inoculated earthworms into fields with returned straw. The earthworms accelerated straw degradation and promoted carbon conversion. However, the impact of externally inoculated earthworms on the farmland soil ecosystem, especially the structure and the function of its microbial community, remains unclear.

Methods

We analyzed the effects of straw return and earthworms on the diversity of fungal populations and the community structure of dominant fungal taxa in soil by quantifying fungal population size and community composition via PCR amplification of internal transcribed spacer genes and 18S rRNA gene sequencing.

Results

The results showed that earthworm inoculation significantly accelerated the degradation of rice straw and promoted the conversion of straw carbon to soil carbon. Both fungal abundance and α-diversity (Sobs and Shannon indices) were higher in the plots with surface straw but without earthworms than in those inoculated with earthworms and in the CK. Principal component analysis indicated that straw return increased the diversity and the abundance of the fungal community, whereas earthworms inhibited this expansion of the fungal community caused by straw return. Interestingly, the overall differences in fungal community composition were smallest in plots with straw return, while the dominant fungal community features in plots inoculated with earthworms were closer to those of the CK.

Conclusion

Generally, straw return stimulated unclassified_K_fungi, Pseudeurotium, and Fusarium with strong cellulolytic ability. In contrast, the abundances of Stachybotrys, unclassified_c_Sordariomycetes, unclassified_f_Lasiosphaeriaceae, and Schizothecium were higher in the plots inoculated with earthworms and in the CK. Furthermore, evolutionary analysis showed that the evolution of soil fungal communities tended to diverge after straw return, and the evolutionary directions of fungal species in the plots inoculated with earthworms were similar to those in the CK.
Metabolic Signature of Articular Cartilage Following Mechanical Injury: An Integrated Transcriptomics and Metabolomics Analysis
Authors: Southan Jennifer , McHugh Emily , Walker Heather , Ismail Heba M.
Published: January 2021

Mechanical injury to the articular cartilage is a key risk factor in joint damage and predisposition to osteoarthritis. Integrative multi-omics approaches provide a valuable tool to understand tissue behavior in response to mechanical injury insult and help to identify key pathways linking injury to tissue damage. Global or untargeted metabolomics provides a comprehensive characterization of the metabolite content of biological samples. In this study, we aimed to identify the metabolic signature of cartilage tissue post injury. We employed an integrative analysis of transcriptomics and global metabolomics of murine epiphyseal hip cartilage before and after injury. Transcriptomics analysis showed a significant enrichment of gene sets involved in regulation of metabolic processes including carbon metabolism, biosynthesis of amino acids, and steroid biosynthesis. Integrative analysis of enriched genes with putatively identified metabolite features post injury showed a significant enrichment for carbohydrate metabolism (glycolysis, galactose, and glycosylate metabolism and pentose phosphate pathway) and amino acid metabolism (arginine biosynthesis and tyrosine, glycine, serine, threonine, and arginine and proline metabolism). We then performed a cross analysis of global metabolomics profiles of murine and porcine ex vivo cartilage injury models. The top commonly modulated metabolic pathways post injury included arginine and proline metabolism, arginine biosynthesis, glycolysis/gluconeogenesis, and vitamin B6 metabolic pathways. These results highlight the significant modulation of metabolic responses following mechanical injury to articular cartilage. Further investigation of these pathways would provide new insights into the role of the early metabolic state of articular cartilage post injury in promoting tissue damage and its link to disease progression of osteoarthritis.
RASPD+: Fast Protein-Ligand Binding Free Energy Prediction Using Simplified Physicochemical Features
Authors: Holderbach Stefan , Adam Lukas , Jayaram B. , Wade Rebecca C. , Mukherjee Goutam
Published: January 2021

The virtual screening of large numbers of compounds against target protein binding sites has become an integral component of drug discovery workflows. This screening is often done by computationally docking ligands into a protein binding site of interest, but this has the drawback of a large number of poses that must be evaluated to obtain accurate estimates of protein-ligand binding affinity. We here introduce a fast pre-filtering method for ligand prioritization that is based on a set of machine learning models and uses simple pose-invariant physicochemical descriptors of the ligands and the protein binding pocket. Our method, Rapid Screening with Physicochemical Descriptors + machine learning (RASPD+), is trained on PDBbind data and achieves a regression performance that is better than that of the original RASPD method and traditional scoring functions on a range of different test sets without the need for generating ligand poses. Additionally, we use RASPD+ to identify molecular features important for binding affinity and assess the ability of RASPD+ to enrich active molecules from decoys.
CD155 Overexpression Correlates With Poor Prognosis in Primary Small Cell Carcinoma of the Esophagus
Authors: Zhao Kaikai , Ma Lin , Feng Lei , Huang Zhaoqin , Meng Xiangjiao , Yu Jinming
Published: January 2021

CD155/TIGIT overexpression has been detected in various human malignancies; however, its expression status in primary small cell carcinoma of the esophagus (PSCCE) and its prognostic significance remain unclear. In this study, we aimed to explore the expression and prognostic value of CD155 and TIGIT in PSCCE. We detected CD155 and TIGIT expression in 114 cases of PSCCE using immunohistochemistry (IHC) and evaluated their relationship with the clinicopathological characteristics and survival of the patients. Survival analyses were performed using the Kaplan-Meier method and Cox proportional hazards model. Nomogram performance was assessed via the concordance index (C-index) and calibration plots. Decision curve analysis (DCA) was performed to evaluate the net benefit of the nomogram. We found that CD155 and TIGIT were overexpressed in PSCCE tissues, CD155 expression correlated positively with TIGIT (p < 0.001) and was significantly associated with tumor size, T stage, distant metastasis, TNM stage, and Ki-67 score. TIGIT expression was also significantly associated with T stage, distant metastasis, and TNM stage. Patients with high CD155 and TIGIT expression had a significantly shorter overall survival (OS) and progression-free survival (PFS), while the multivariate model showed that CD155 expression and the therapeutic strategy are independent prognostic factors for PSCCE. In the validation step, OS was shown to be well-calibrated (C-index = 0.724), and a satisfactory clinical utility was proven by DCA. In conclusion, our findings revealed that CD155 and TIGIT are highly expressed in patients with PSCCE and are associated with shorter OS and PFS, supporting their role as prognostic biomarker.
Elemental and Configural Associative Learning in Spatial Tasks: Could Zebrafish be Used to Advance Our Knowledge?
Authors: Buatois Alexis , Gerlai Robert
Published: January 2021

Spatial learning and memory have been studied for several decades. Analyses of these processes pose fundamental scientific questions but are also relevant from a biomedical perspective. The cellular, synaptic and molecular mechanisms underlying spatial learning have been intensively investigated, yet the behavioral mechanisms/strategies in a spatial task still pose unanswered questions. Spatial learning relies upon configural information about cues in the environment. However, each of these cues can also independently form part of an elemental association with the specific spatial position, and thus spatial tasks may be solved using elemental (single CS and US association) learning. Here, we first briefly review what we know about configural learning from studies with rodents. Subsequently, we discuss the pros and cons of employing a relatively novel laboratory organism, the zebrafish in such studies, providing some examples of methods with which both elemental and configural learning may be explored with this species. Last, we speculate about future research directions focusing on how zebrafish may advance our knowledge. We argue that zebrafish strikes a reasonable compromise between system complexity and practical simplicity and that adding this species to the studies with laboratory rodents will allow us to gain a better understanding of both the evolution of and the mechanisms underlying spatial learning. We conclude that zebrafish research will enhance the translational relevance of our findings.
An “Outside-In” and “Inside-Out” Consideration of Complement in the Multiple Sclerosis Brain: Lessons From Development and Neurodegenerative Diseases
Authors: Morgan B. Paul , Gommerman Jennifer L. , Ramaglia Valeria
Published: January 2021

The last 15 years have seen an explosion of new findings on the role of complement, a major arm of the immune system, in the central nervous system (CNS) compartment including contributions to cell migration, elimination of synapse during development, aberrant synapse pruning in neurologic disorders, damage to nerve cells in autoimmune diseases, and traumatic injury. Activation of the complement system in multiple sclerosis (MS) is typically thought to occur as part of a primary (auto)immune response from the periphery (the outside) against CNS antigens (the inside). However, evidence of local complement production from CNS-resident cells, intracellular complement functions, and the more recently discovered role of early complement components in shaping synaptic circuits in the absence of inflammation opens up the possibility that complement-related sequelae may start and finish within the brain itself. In this review, the complement system will be introduced, followed by evidence that implicates complement in shaping the developing, adult, and normal aging CNS as well as its contribution to pathology in neurodegenerative conditions. Discussion of data supporting “outside-in” vs. “inside-out” roles of complement in MS will be presented, concluded by thoughts on potential approaches to therapies targeting specific elements of the complement system.
Dysfunctional Autophagy and Endolysosomal System in Neurodegenerative Diseases: Relevance and Therapeutic Options
Authors: Giovedì Silvia , Ravanelli Margherita Maria , Parisi Barbara , Bettegazzi Barbara , Guarnieri Fabrizia Claudia
Published: January 2021

Autophagy and endolysosomal trafficking are crucial in neuronal development, function and survival. These processes ensure efficient removal of misfolded aggregation-prone proteins and damaged organelles, such as dysfunctional mitochondria, thus allowing the maintenance of proper cellular homeostasis. Beside this, emerging evidence has pointed to their involvement in the regulation of the synaptic proteome needed to guarantee an efficient neurotransmitter release and synaptic plasticity. Along this line, an intimate interplay between the molecular machinery regulating synaptic vesicle endocytosis and synaptic autophagy is emerging, suggesting that synaptic quality control mechanisms need to be tightly coupled to neurosecretion to secure release accuracy. Defects in autophagy and endolysosomal pathway have been associated with neuronal dysfunction and extensively reported in Alzheimer’s, Parkinson’s, Huntington’s and amyotrophic lateral sclerosis among other neurodegenerative diseases, with common features and emerging genetic bases. In this review, we focus on the multiple roles of autophagy and endolysosomal system in neuronal homeostasis and highlight how their defects probably contribute to synaptic default and neurodegeneration in the above-mentioned diseases, discussing the most recent options explored for therapeutic interventions.
Endocrine Therapy for the Functional Recovery of Spinal Cord Injury
Authors: Wang Hui , Zhou Wen-xian , Huang Jin-feng , Zheng Xuan-qi , Tian Hai-jun , Wang Bin , Fu Wei-li , Wu Ai-min
Published: January 2021

Spinal cord injury (SCI) is a major cause of physical disability and leads to patient dissatisfaction with their quality of life. Patients with SCI usually exhibit severe clinical symptoms, including sensory and motor dysfunction below the injured levels, paraplegia, quadriplegia and urinary retention, which can exacerbate the substantial medical and social burdens. The major pathological change observed in SCI is inflammatory reaction, which induces demyelination, axonal degeneration, and the apoptosis and necrosis of neurons. Traditional medical treatments are mainly focused on the recovery of motor function and prevention of complications. To date, numerous studies have been conducted to explore the cellular and molecular mechanism of SCI and have proposed lots of effective treatments, but the clinical applications are still limited due to the complex pathogenesis and poor prognosis after SCI. Endocrine hormones are kinds of molecules that are synthesized by specialized endocrine organs and can participate in the regulation of multiple physiological activities, and their protective effects on several disorders have been widely discussed. In addition, many studies have identified that endocrine hormones can promote nerve regeneration and functional recovery in individuals with central nervous system diseases. Therefore, studies investigating the clinical applications of endocrine hormones as treatments for SCI are necessary. In this review, we described the neuroprotective roles of several endocrine hormones in SCI; endocrine hormone administration reduces cell death and promotes functional repair after SCI. We also proposed novel therapies for SCI.
Equilibrative Nucleoside Transporters-1 Inhibitors Act as Anti-epileptic Agents by Inhibiting Glutamatergic Transmission
Authors: Ho Shih-Yin , Chen I-Chun , Chang Kai-Chieh , Lin Hsiao-Ru , Tsai Che-Wen , Lin Chun-Jung , Liou Horng-Huei
Published: January 2021

Background and Purpose: Adenosine dysregulation is associated with the occurrence of the epilepsy and equilibrative nucleoside transporters-1 (ENT-1) functions as an important regulator of extracellular adenosine in the brain. This study was aimed to prove the anti-epileptic effect of BBB permeable ENT-1 inhibitors, JMF1907 and J4, on animal models of various epilepsy, and the mechanisms that are involved.

Experimental Approach: Maximal electroshock seizure (MES), pentylenetetrazol (PTZ)-induced seizure and kindling models were used as mouse models of generalized tonic-clonic epilepsy, generalized myoclonic epilepsy, and partial epilepsy, respectively. The epilepsy frequency, duration, and Racine score were evaluated. Whole-cell recordings were made from the hippocampal dentate granule cells by using a patch-clamp technique in the brain slice of the mice.

Key Results: In MES, JMF1907 at a dose of 5 mg kg–1 was efficacious in decreasing hindlimb extension, while J4 did not decrease hindlimb extension until a higher dose (10 mg kg–1). Both JMF1907 and J4 were more potent in lengthening onset latency than ethosuximide (ETH) in PTZ-induced myoclonic epilepsy model, whereas ETH had better effects on the Racine score. In kindling model, JMF1907 and J4 at a dose of 1 mg kg–1 had effects on seizure frequency and duration, and the effects of JMF1907 were comparable with those of carbamazepine. Both JMF1907 and J4 can reduce the glutamatergic spontaneous excitatory post-synaptic currents (sEPSCs) frequency. The maximal inhibition was about 50% for JMF1907 at a concentration of 1 μg L–1, whereas J4 only inhibited 40% of sEPSCs frequency at a dose of 10 μg L–1.

Conclusion and Implications: ENT-1 inhibitors, JMF1907 and J4, showed anti-epileptic effects in different epilepsy models and the effects involved pre-synaptic neuronal modulation.
Mild Traumatic Brain Injury Induces Transient, Sequential Increases in Proliferation, Neuroblasts/Immature Neurons, and Cell Survival: A Time Course Study in the Male Mouse Dentate Gyrus
Authors: Clark Lyles R. , Yun Sanghee , Acquah Nana K. , Kumar Priya L. , Metheny Hannah E. , Paixao Rikley C. C. , Cohen Akivas S. , Eisch Amelia J.
Published: January 2021

Mild traumatic brain injuries (mTBIs) are prevalent worldwide. mTBIs can impair hippocampal-based functions such as memory and cause network hyperexcitability of the dentate gyrus (DG), a key entry point to hippocampal circuitry. One candidate for mediating mTBI-induced hippocampal cognitive and physiological dysfunction is injury-induced changes in the process of DG neurogenesis. There are conflicting results on how TBI impacts the process of DG neurogenesis; this is not surprising given that both the neurogenesis process and the post-injury period are dynamic, and that the quantification of neurogenesis varies widely in the literature. Even within the minority of TBI studies focusing specifically on mild injuries, there is disagreement about if and how mTBI changes the process of DG neurogenesis. Here we utilized a clinically relevant rodent model of mTBI (lateral fluid percussion injury, LFPI), gold-standard markers and quantification of the neurogenesis process, and three time points post-injury to generate a comprehensive picture of how mTBI affects adult hippocampal DG neurogenesis. Male C57BL/6J mice (6-8 weeks old) received either sham surgery or mTBI via LFPI. Proliferating cells, neuroblasts/immature neurons, and surviving cells were quantified via stereology in DG subregions (subgranular zone [SGZ], outer granule cell layer [oGCL], molecular layer, and hilus) at short-term (3 days post-injury, dpi), intermediate (7 dpi), and long-term (31 dpi) time points. The data show this model of mTBI induces transient, sequential increases in ipsilateral SGZ/GCL proliferating cells, neuroblasts/immature neurons, and surviving cells which is suggestive of mTBI-induced neurogenesis. In contrast to these ipsilateral hemisphere findings, measures in the contralateral hemisphere were not increased in key neurogenic DG subregions after LFPI. Our work in this mTBI model is in line with most literature on other and more severe models of TBI in showing TBI stimulates the process of DG neurogenesis. However, as our DG data in mTBI provide temporal, subregional, and neurogenesis-stage resolution, these data are important to consider in regard to the functional importance of TBI-induction of the neurogenesis process and future work assessing the potential of replacing and/or repairing DG neurons in the brain after TBI.
Increased Right Frontal Brain Activity During the Mandarin Hearing-in-Noise Test
Authors: Song Fengxiang , Zhan Yi , Ford James C. , Cai Dan-Chao , Fellows Abigail M. , Shan Fei , Song Pengrui , Chen Guochao , Soli Sigfrid D. , Shi Yuxin , Buckey Jay C.
Published: January 2021

Purpose

Previous studies have revealed increased frontal brain activation during speech comprehension in background noise. Few, however, used tonal languages. The normal pattern of brain activation during a challenging speech-in-nose task using a tonal language remains unclear. The Mandarin Hearing-in-Noise Test (HINT) is a well-established test for assessing the ability to interpret speech in background noise. The current study used Mandarin HINT (MHINT) sentences and functional magnetic resonance imaging (fMRI) to assess brain activation with MHINT sentences.

Methods

Thirty native Mandarin-speaking subjects with normal peripheral hearing were recruited. Functional MRI was performed while subjects were presented with either HINT “clear” sentences with low-level background noise [signal-to-noise ratio (SNR) = +3 dB] or “noisy” sentences with high-level background noise (SNR = −5 dB). Subjects were instructed to answer with a button press whether a visually presented target word was included in the sentence. Brain activation between noisy and clear sentences was compared. Activation in each condition was also compared to a resting, no sentence presentation, condition.

Results

Noisy sentence comprehension showed increased activity in areas associated with tone processing and working memory, including the right superior and middle frontal gyri [Brodmann Areas (BAs) 46, 10]. Reduced activity with noisy sentences was seen in auditory, language, memory and somatosensory areas, including the bilateral superior and middle temporal gyri, left Heschl’s gyrus (BAs 21, 22), right temporal pole (BA 38), bilateral amygdala-hippocampus junction, and parahippocampal gyrus (BAs 28, 35), left inferior parietal lobule extending to left postcentral gyrus (BAs 2, 40), and left putamen.

Conclusion

Increased frontal activation in the right hemisphere occurred when comprehending noisy spoken sentences in Mandarin. Compared to studies using non-tonal languages, this activation was strongly right-sided and involved subregions not previously reported. These findings may reflect additional effort in lexical tone perception in this tonal language. Additionally, this continuous fMRI protocol may offer a time-efficient way to assess group differences in brain activation with a challenging speech-in-noise task.
Modulation of the Acetylcholine Receptor Clustering Pathway Improves Neuromuscular Junction Structure and Muscle Strength in a Mouse Model of Congenital Myasthenic Syndrome
Authors: Spendiff Sally , Howarth Rachel , McMacken Grace , Davey Tracey , Quinlan Kaitlyn , O'Connor Emily , Slater Clarke , Hettwer Stefan , Mäder Armin , Roos Andreas , Horvath Rita , Lochmüller Hanns
Published: January 2021

Introduction: Congenital myasthenic syndromes (CMS) are a diverse group of inherited neuromuscular disorders characterized by a failure of synaptic transmission at the neuromuscular junction (NMJ). CMS often present early with fatigable weakness and can be fatal through respiratory complications. The AGRN gene is one of over 30 genes known to harbor mutations causative for CMS. In this study, we aimed to determine if a compound (NT1654), developed to stimulate the acetylcholine receptor (AChR) clustering pathway, would benefit a mouse model of CMS caused by a loss-of-function mutation in Agrn (Agrnnmf380 mouse).

Methods:Agrnnmf380 mice received an injection of either NT1654 or vehicle compound daily, with wild-type litter mates used for comparison. Animals were weighed daily and underwent grip strength assessments. After 30 days of treatment animals were sacrificed, and muscles collected. Investigations into NMJ and muscle morphology were performed on collected tissue.

Results: While minimal improvements in NMJ ultrastructure were observed with electron microscopy, gross NMJ structure analysis using fluorescent labelling and confocal microscopy revealed extensive postsynaptic improvements in Agrnnmf380 mice with NT1654 administration, with variables frequently returning to wild type levels. An improvement in muscle weight and myofiber characteristics helped increase forelimb grip strength and body weight.

Conclusions: We conclude that NT1654 restores NMJ postsynaptic structure and improves muscle strength through normalization of muscle fiber composition and the prevention of atrophy. We hypothesize this occurs through the AChR clustering pathway in Agrnnmf380 mice. Future studies should investigate if this may represent a viable treatment option for patients with CMS, especially those with mutations in proteins of the AChR clustering pathway.
Neuroproteomics in Epilepsy: What Do We Know so Far?
Authors: do Canto Amanda M. , Donatti Amanda , Geraldis Jaqueline C. , Godoi Alexandre B. , da Rosa Douglas C. , Lopes-Cendes Iscia
Published: January 2021

Epilepsies are chronic neurological diseases that affect approximately 2% of the world population. In addition to being one of the most frequent neurological disorders, treatment for patients with epilepsy remains a challenge, because a proportion of patients do not respond to the antiseizure medications that are currently available. This results in a severe economic and social burden for patients, families, and the healthcare system. A characteristic common to all forms of epilepsy is the occurrence of epileptic seizures that are caused by abnormal neuronal discharges, leading to a clinical manifestation that is dependent on the affected brain region. It is generally accepted that an imbalance between neuronal excitation and inhibition generates the synchronic electrical activity leading to seizures. However, it is still unclear how a normal neural circuit becomes susceptible to the generation of seizures or how epileptogenesis is induced. Herein, we review the results of recent proteomic studies applied to investigate the underlying mechanisms leading to epilepsies and how these findings may impact research and treatment for these disorders.
A Five-lncRNAs Signature-Derived Risk Score Based on TCGA and CGGA for Glioblastoma: Potential Prospects for Treatment Evaluation and Prognostic Prediction
Authors: Niu Xuegang , Sun Jiangnan , Meng Lingyin , Fang Tao , Zhang Tongshuo , Jiang Jipeng , Li Huanming
Published: January 2021

Accumulating studies have confirmed the crucial role of long non-coding RNAs (ncRNAs) as favorable biomarkers for cancer diagnosis, therapy, and prognosis prediction. In our recent study, we established a robust model which is based on multi-gene signature to predict the therapeutic efficacy and prognosis in glioblastoma (GBM), based on Chinese Glioma Genome Atlas (CGGA) and The Cancer Genome Atlas (TCGA) databases. lncRNA-seq data of GBM from TCGA and CGGA datasets were used to identify differentially expressed genes (DEGs) compared to normal brain tissues. The DEGs were then used for survival analysis by univariate and multivariate COX regression. Then we established a risk score model, depending on the gene signature of multiple survival-associated DEGs. Subsequently, Kaplan-Meier analysis was used for estimating the prognostic and predictive role of the model. Gene set enrichment analysis (GSEA) was applied to investigate the potential pathways associated to high-risk score by the R package “cluster profile” and Wiki-pathway. And five survival associated lncRNAs of GBM were identified: LNC01545, WDR11-AS1, NDUFA6-DT, FRY-AS1, TBX5-AS1. Then the risk score model was established and shows a desirable function for predicting overall survival (OS) in the GBM patients, which means the high-risk score significantly correlated with lower OS both in TCGA and CGGA cohort. GSEA showed that the high-risk score was enriched with PI3K-Akt, VEGFA-VEGFR2, TGF-beta, Notch, T-Cell pathways. Collectively, the five-lncRNAs signature-derived risk score presented satisfactory efficacies in predicting the therapeutic efficacy and prognosis in GBM and will be significant for guiding therapeutic strategies and research direction for GBM.
RETRACTED: FNDC1 Promotes the Invasiveness of Gastric Cancer via Wnt/β-Catenin Signaling Pathway and Correlates With Peritoneal Metastasis and Prognosis
Authors: Jiang Tao , Gao Wenyu , Lin Shengjie , Chen Hao , Du Bin , Liu Qing , Lin Xiaoyan , Chen Qiang
Published: January 2021

Background

Gastric cancer (GC) has a high morbidity and mortality rate, with peritoneal metastasis (PM) identified as the main site of metastasis. Our previous study found that FNDC1 has a higher frequency of mutations in patients with PM by high-throughput sequencing assay, suggesting that it may be associated with GC invasion and PM, however the specific mechanism remains unclear.

Methods

First, the correlation between FNDC1 and PM and prognosis of GC was clarified by bioinformatics and clinicopathological analysis. Next, the effect of FNDC1 expression on the invasion and metastasis ability of GC was investigated in vivo and in vitro. Finally, the signaling pathways involved in the regulation of FNDC1 were explored.

Results

FNDC1 was highly expressed in GC and was associated with PM and poor prognosis. FNDC1 was also associated with epithelial-mesenchymal transition (EMT) in GC cells. Through in vivo and in vitro experiments, it was clarified that knockdown of FNDC1 could inhibit the proliferation, invasion, and migration of GC cells. In addition, it was elucidated that FNDC1 promotes EMT through the Wnt/β-catenin signaling pathway.

Conclusion

FNDC1 may be associated with the invasion of GC and PM after surgery. FNDC1 was highly expressed in GC tissues and cell lines, while significantly associated with poor DFS and OS in GC patients. Both univariate and multivariate analyses suggested that the expression of FNDC1 was an independent factor for GC. Knockdown of FNDC1 also significantly inhibited the proliferation, migration, and activity of GC cells. FNDC1 may promote EMT in GC cells through the regulation of Wnt/β-catenin signaling pathway. FNDC1 has the potential to be used as a predictor of PM and may also be studied in depth as a therapeutic target for GC, which has potential clinical utility and is worthy of further validation.