bluuebunny/crossref_metadata_2025 huggingface dataset:
Exploring the growing forest musk deer (Moschus berezovskii) dietary protein requirement based on gut microbiome
Authors: Gong Ruiguang , Song Shengjie , Ai Yaotian , Wang Shuhui , Dong Xianggui , Ren Zhanjun , Xie Hui , Jiang Benmo , Zhao Lixia
Published: March 2023

It is necessary to assess the appropriate dietary protein level of the forest musk deer (FMD), as nutritional needs are unclear. The microbiome in gastrointestinal tracts plays an important role in regulating nutrient utilization, absorption and host growth or development. Thus, we aimed to evaluate growth performance, nutrient digestibility and fecal microbiome of growing FMD supplied with different protein levels of diets. Eighteen 6-month-old male FMD with an initial weight 5.0 ± 0.2 kg were used in a 62-day trial. The animals were randomly distributed to three groups, the dietary crude protein (CP) level was 11.51% (L), 13.37% (M), and 15.48% (H). The results showed that the CP digestibility decreased as dietary CP level increased (p < 0.01). Compared with group L and H, FMD in M group has higher average daily gain, feed efficiency and neutral detergent fiber digestibility. For the fecal bacterial community, the percentage of Firmicutes was increased, Bacteroidetes was decreased and the diversity of microbiota significantly reduced (p < 0.05) with the increasing of dietary protein. The proportion of Ruminococcaceae_005, Ruminococcaceae_UCG-014 and uncultured_bacterium_f_Lachnospiraceae were significantly increased wtih rising CP, the proportions of Bacteroides and Rikenellaceae_RC9_gut_group were significantly decrease nevertheless at the genus level. The higher abundance of f_Prevotellaceae and g_Prevotellaceae_UCG_004 were found at M group by LEfSe analysis. The relative abundance of uncultured_bacterium_f_Ruminococcaceae was positively correlated with the average daily gain and feed conversion ratio (p < 0.05), whereas Family_XIII_AD3011_group was negatively correlated with feed conversion ratio (p < 0.05). The UPGMA tree showed L and M groups were closer in clustering relationship, while H group was clustered separately into a branch, which indicated that the bacterial structure had changed greatly with protein level increased from 13.37 to 15.48%. Overall, our results indicated that the optimum dietary CP for the growing FMD was 13.37%.
Inoculation strategies affect the physicochemical properties and flavor of Zhenjiang aromatic vinegar
Authors: Ye Xiaoting , Yu Yongjian , Liu Jiaxin , Zhu Yuanyuan , Yu Zhen , Liu Peng , Wang Yuqin , Wang Ke
Published: March 2023

Inoculation strategy is a significant determinant of the flavor quality of Zhenjiang aromatic vinegar. Herein, the comparative analyses of the effects of various inoculation strategies on the physicochemical properties, microbial community structure, and flavoring characteristics of Zhenjiang aromatic vinegar were performed. The results showed that the contents of total acid (6.91 g/100 g), organic acid (2099.63 ± 4.13 mg/100 g) and amino acid (3666.18 ± 14.40 mg/100 g) in the direct inoculation strategy were higher than those in the traditional inoculation strategy (6.21 ± 0.02 g/100 g, 1939.66 ± 4.16 mg/100 g and 3301.46 ± 13.41 mg/100 g). At the same time, it can effectively promote the production of acetoin. The diversity of strains under the traditional inoculation strategy was higher than that under the direct inoculation strategy, and the relative abundance of major microbial genera in the fermentation process was lower than that under the direct inoculation strategy. In addition, for two different inoculation strategies, pH was proved to be an important environmental factor affecting the microbial community structure during acetic acid fermentation. The correlation between main microbial species, organic acids, non-volatile acids, and volatile flavor compounds is more consistent. Therefore, this study may help to develop direct injection composite microbial inoculants to replace traditional starter cultures in future research.
Study on the removal characteristics and degradation pathways of highly toxic and refractory organic pollutants in real pharmaceutical factory wastewater treated by a pilot-scale integrated process
Authors: Dai Wei , Pang Ji-Wei , Ding Jie , Wang Yu-Qian , Zhang Lu-Yan , Ren Nan-Qi , Yang Shan-Shan
Published: March 2023

Introduction

Pharmaceutical wastewater frequently contains high levels of toxic pollutants. If they are discharged untreated, they pose a threat to the environment. The traditional activated sludge process and the advanced oxidation process do not sufficiently remove toxic and conventional pollutants from pharmaceutical wastewater treatment plants (PWWTPs).

Methods

We designed a pilot-scale reaction system to reduce toxic organic pollutants and conventional pollutants from pharmaceutical wastewater during the biochemical reaction stage. This system included a continuous stirred tank reactor (CSTR), microbial electrolysis cells (MECs), an expanded sludge bed reactor (EGSB), and a moving bed biofilm reactor (MBBR). We used this system to further investigate the benzothiazole degradation pathway.

Results and discussion

The system effectively degraded the toxic pollutants (benzothiazole, pyridine, indole, and quinoline) and the conventional chemicals (COD, NH4+-N, TN). During the stable operation of the pilot-scale plant, the total removal rates of benzothiazole, indole, pyridine, and quinoline were 97.66, 94.13, 79.69, and 81.34%, respectively. The CSTR and MECs contributed the most to the removal of toxic pollutants, while the EGSB and MBBR contributed less to the removal of the four toxic pollutants. Benzothiazoles can be degraded via two pathways: the benzene ring-opening reaction and the heterocyclic ring-opening reaction. The heterocyclic ring-opening reaction was more important in degrading the benzothiazoles in this study.

Conclusion

This study provides feasible design alternatives for PWWTPs to remove both toxic and conventional pollutants at the same time.
Intraspecific genetic diversity of the fish-infecting microsporidian parasite Pseudokabatana alburnus (Microsporidia)
Authors: Weng Meiqi , Zhang Xintong , Xin Zhaozhe , Xue Sijia , Zhang Qianqian , Li Aihua , Zhang Jinyong
Published: March 2023

Pseudokabatana alburnus is a xenoma-forming fish microsporidium, firstly described from the liver of the Culter alburnus from Poyang Lake in China. In the present study, P. alburnus was firstly reported from the ovary of 6 other East Asian minnows, including Squaliobarbus curriculus, Hemiculter leucisculus, Cultrichthys erythropterus, Pseudolaubuca engraulis, Toxabramis swinhonis, and Elopichthys bambusa. Genetic analysis revealed high sequence diversity in the ribosomal internal transcribed spacer region (ITS) and the largest subunit of RNA polymerase II (Rpb1) loci of P. alburnus isolated from different hosts and locations. The variation of Rpb1 mainly occurred in the 1,477–1737 bp regions. The presence of a wide variety of Rpb1 haplotypes within a single fish host, together with evidence of genetic recombination suggested that P. alburnus may have the intergenomic variation and sexual reproduction might be present in other hosts (possibly freshwater shrimp). Phylogenetic analysis and population genetic analysis showed that there was no geographical population divergence for P. alburnus. Homogeneity and high variability of ITS sequences indicates that ITS may be a suitable molecular marker to distinguish different P. alburnus isolates. Our data confirm the broad geographical distribution and host range of P. alburnus in the middle and lower reaches of the Yangtze River. Additionally, we emendated the genus Pseudokabatana to exclude the infection site, liver as one of the taxonomic criteria, and proposed that fish ovary was be the general infection site of P. alburnus.
Transcriptome analysis of auxin transcription factor OsARF17-mediated rice stripe mosaic virus response in rice
Authors: Ma Qiang , Wang Fengmin , Song Weiqi , Huang Chaorui , Xie Kaili , Wei Zhongyan , Li Yanjun , Chen Jianping , Zhang Hehong , Sun Zongtao
Published: March 2023

Introduction

Plant auxin response factors (ARFs) play an irreplaceable role in regulating the expression of auxin response genes. Our previous studies have indicated that auxin response factor OsARF17 plays a crucial role in plant defense against diverse rice viruses.

Methods

Utilizing a comparative transcriptome analysis of Rice stripe mosaic virus (RSMV)-inoculated OsARF17 mutant rice plants, to further elucidate the molecular mechanism of OsARF17 in antiviral defense pathway.

Results

KEGG enrichment analyses showed that the down-regulated differentially expressed genes (DEGs) belonged to plant-pathogen interaction and plant hormone signal transduction pathways were markedly enriched in OsARF17 mutants under RSMV inoculation. Furthermore, Gene ontology (GO) analyses revealed that these genes were enriched in a variety of hormone biosynthetic process, including jasmonic acid (JA), auxin, and abscisic acid (ABA). RT-qPCR assays showed that the induction of plant defense-related genes, such as WRKY transcription factors, OsAHT2 and OsDR8, and JA-related genes, were significantly suppressed in OsARF17 mutants in response to RSMV.

Discussion

Our study reveals that OsARF17-mediated antiviral immunity may be achieved through affecting the interaction between different phytohormones and regulating defense gene expression in rice. This study provides new insights into the molecular mechanisms of auxin signaling in the rice-virus interaction.
Variation in synonymous evolutionary rates in the SARS-CoV-2 genome
Authors: Sun Qianru , Zeng Jinfeng , Tang Kang , Long Haoyu , Zhang Chi , Zhang Jie , Tang Jing , Xin Yuting , Zheng Jialu , Sun Litao , Liu Siyang , Du Xiangjun
Published: March 2023

Introduction

Coronavirus disease 2019 is an infectious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Influential variants and mutants of this virus continue to emerge, and more effective virus-related information is urgently required for identifying and predicting new mutants. According to earlier reports, synonymous substitutions were considered phenotypically silent; thus, such mutations were frequently ignored in studies of viral mutations because they did not directly cause amino acid changes. However, recent studies have shown that synonymous substitutions are not completely silent, and their patterns and potential functional correlations should thus be delineated for better control of the pandemic.

Methods

In this study, we estimated the synonymous evolutionary rate (SER) across the SARS-CoV-2 genome and used it to infer the relationship between the viral RNA and host protein. We also assessed the patterns of characteristic mutations found in different viral lineages.

Results

We found that the SER varies across the genome and that the variation is primarily influenced by codon-related factors. Moreover, the conserved motifs identified based on the SER were found to be related to host RNA transport and regulation. Importantly, the majority of the existing fixed-characteristic mutations for five important virus lineages (Alpha, Beta, Gamma, Delta, and Omicron) were significantly enriched in partially constrained regions.

Discussion

Taken together, our results provide unique information on the evolutionary and functional dynamics of SARS-CoV-2 based on synonymous mutations and offer potentially useful information for better control of the SARS-CoV-2 pandemic.
Global prevalence and molecular characteristics of three clades within hepatitis B virus subgenotype C2: Predominance of the C2(3) clade in South Korea
Authors: Kim Dong Hyun , Choi Yu-Min , Jang Junghwa , Kim Bum-Joon
Published: March 2023

Hepatitis B Virus (HBV) genotypes reflect geographic, ethical or clinical traits and are currently divided into 10 genotypes (A–J). Of these, genotype C is mainly distributed in Asia, is the largest group and comprises more than seven subgenotypes (C1–C7). Subgenotype C2 is divided into three phylogenetically distinct clades, C2(1), C2(2), and C2(3), and is responsible for most genotype C infections in three East Asian nations, including China, Japan, and South Korea, which are major HBV endemic areas. However, despite the significance of subgenotype C2 with regard to clinical or epidemiologic aspects, its global distribution and molecular characteristics remain largely unknown. Here, we analyze the global prevalence and molecular characteristics between 3 clades within subgenotype C2 using 1,315 full genome sequences of HBV genotype C retrieved from public databases. Our data show that almost all HBV strains from South Korean patients infected with genotype C belong to clade C2(3) within subgenotype C2 [96.3%] but that HBV strains from Chinese or Japanese patients belong to diverse subgenotypes or clades within genotype C, suggesting clonal expansion of a specific HBV type, C2(3), among the Korean population. Our genome sequence analysis indicated a total of 21 signature sequences specific to the respective clades C2(1), C2(2), and C2(3). Of note, two types of four nonsynonymous C2(3) signature sequences, sV184A in HBsAg and xT36P in the X region, were detected in 78.9 and 82.9% of HBV C2(3) strains, respectively. In particular, HBV strains C2(3) versus C2(1) and C2(2) show a higher frequency of reverse transcriptase mutations related to nucleot(s)ide analog (NA) resistance, including rtM204I and rtL180M, suggesting an increased possibility of C2(3) infection in those with NA treatment failure. In conclusion, our data show that HBV subgenotype C2(3) is extremely prevalent in Korean patients with chronic HBV infection, which is distinct from two other East Asian nations, China and Japan, where diverse subgenotypes or clades within genotype C coexist. This epidemiologic trait might affect distinct virological and clinical traits in chronic HBV patients in Korea, where exclusively C2(3) infection is predominant.
Alterations in bacterial community dynamics from noncancerous to Gastric cancer
Authors: Peng Xuan , Yao Siqi , Huang Jing , Zhao Yiming , Chen Hao , Chen Liyu , Yu Zheng
Published: March 2023

Gastric microbiome has been shown to contribute to gastric carcinogenesis, understanding how alterations in gastric microbiome is helpful to the prevention and treatment of gastric cancer (GC). However, few studies have focused on the change of microbiome during the gastric carcinogenesis. In this study, the microbiome of gastric juice samples from healthy control (HC), gastric precancerous lesions (GPL) and gastric cancer (GC) was investigated by 16S rRNA gene sequencing. Our results showed that the alpha diversity of patients with GC was significantly lower than other groups. Compared to other groups, some genera in GC group were shown to be up-regulated (e.g., Lautropia and Lactobacillus) and down-regulated (e.g., Peptostreptococcus and Parvimonas). More importantly, the emergence of Lactobacillus was closely related to the occurrence and development of GC. Moreover, the microbial interactions and networks in GPL exhibited higher connectivity, complexity and lower clustering property, while GC showed the opposite trend. Taken together, we suggest that changes in the gastric microbiome are associated with GC and perform a key function in maintaining the tumor microenvironment. Therefore, our findings will provide new ideas and references for the treatment of GC.
Molecular evolution, diversity, and adaptation of foot-and-mouth disease virus serotype O in Asia
Authors: Li Fangtao , Li Yan , Ma Jianrong , Wu Ruizhi , Zou Xingqi , Liu Yebing , Zhao Qizu , Zhu Yuanyuan
Published: March 2023

Foot-and-mouth disease (FMD) is highly contagious and affects the economy of many countries worldwide. Serotype O is the most prevalent and is present in many regions of Asia. Lineages O/SEA/Mya-98, O/Middle East-South Asia (ME-SA)/PanAsia, O/Cathay and O/ME-SA/Ind-2001 have been circulating in Asian countries. Low antigenic matching between O/Cathay strains and current vaccine strains makes the disease difficult to control, therefore, analyzing the molecular evolution, diversity, and host tropisms of FMDV Serotype O in Asia may be helpful. Our results indicate that Cathay, ME-SA, and SEA are the predominant topotypes of FMDV serotype O circulating in Asia in recent years. Cathay topotype FMDV evolves at a higher rate compared with ME-SA and SEA topotypes. From 2011 onwards, the genetic diversity of the Cathay topotype has increased substantially, while large reductions were found in the genetic diversity of both ME-SA and SEA topotypes, suggesting a trend that infections sustained by the Cathay topotype were becoming a more severe epidemic in recent years. Analyzing the distributions of host species through time in the dataset, we found that the O/Cathay topotype was characterized by a highly swine-adapted tropism in contrast with a distinct host preference for O/ME-SA. The O/SEA topotype strains identified in Asia were isolated mainly from cattle until 2010. It is worth noting that there may be a fine-tuned tropism of the SEA topotype viruses for host species. To further explore the potential molecular mechanism of host tropism divergence, we analyzed the distribution of structure variations on the whole genome. Our findings suggest that deletions in the PK region may reflect a common pattern of altering the host range of serotype O FMDVs. In addition, the divergence of host tropism may be due to accumulated structural variations across the viral genome, rather than a single indel mutation.
Striatal fibrinogen extravasation and vascular degeneration correlate with motor dysfunction in an aging mouse model of Alzheimer’s disease
Authors: Berk-Rauch Hanna E. , Choudhury Arnab , Richards Allison T. , Singh Pradeep K. , Chen Zu-Lin , Norris Erin H. , Strickland Sidney , Ahn Hyung Jin
Published: March 2023

Introduction: Alzheimer’s Disease (AD) patients exhibit signs of motor dysfunction, including gait, locomotion, and balance deficits. Changes in motor function often precede other symptoms of AD as well as correlate with increased severity and mortality. Despite the frequent occurrence of motor dysfunction in AD patients, little is known about the mechanisms by which this behavior is altered.

Methods and Results: In the present study, we investigated the relationship between cerebrovascular impairment and motor dysfunction in a mouse model of AD (Tg6799). We found an age-dependent increase of extravasated fibrinogen deposits in the cortex and striatum of AD mice. Interestingly, there was significantly decreased cerebrovascular density in the striatum of the 15-month-old as compared to 7-month-old AD mice. We also found significant demyelination and axonal damage in the striatum of aged AD mice. We analyzed striatum-related motor function and anxiety levels of AD mice at both ages and found that aged AD mice exhibited significant impairment of motor function but not in the younger AD mice.

Discussion: Our finding suggests an enticing correlation between extravasated fibrinogen, cerebrovascular damage of the striatum, and motor dysfunction in an AD mouse model, suggesting a possible mechanism underlying motor dysfunction in AD.
Identification of key genes and signaling pathways associated with dementia with Lewy bodies and Parkinson's disease dementia using bioinformatics
Authors: Xu Jing , Li Jia , Sun Ya-juan , Quan Wei , Liu Li , Zhang Qing-hui , Qin Yi-dan , Pei Xiao-chen , Su Hang , Chen Jia-jun
Published: March 2023

Objective

Dementia with Lewy bodies (DLB) and Parkinson's disease dementia (PDD) are collectively known as Lewy body dementia (LBD). Considering the heterogeneous nature of LBD and the different constellations of symptoms with which patients can present, the exact molecular mechanism underlying the differences between these two isoforms is still unknown. Therefore, this study aimed to explore the biomarkers and potential mechanisms that distinguish between PDD and DLB.

Methods

The mRNA expression profile dataset of GSE150696 was acquired from the Gene Expression Omnibus (GEO) database. Differentially expressed genes (DEGs) between 12 DLB and 12 PDD were identified from Brodmann area 9 of human postmortem brains using GEO2R. A series of bioinformatics methods were applied to identify the potential signaling pathways involved, and a protein–protein interaction (PPI) network was constructed. Weighted gene co-expression network analysis (WGCNA) was used to further investigate the relationship between gene co-expression and different LBD subtypes. Hub genes that are strongly associated with PDD and DLB were obtained from the intersection of DEGs and selected modules by WGCNA.

Results

A total of 1,864 DEGs between PDD and DLB were filtered by the online analysis tool GEO2R. We found that the most significant GO- and KEGG-enriched terms are involved in the establishment of the vesicle localization and pathways of neurodegeneration-multiple diseases. Glycerolipid metabolism and viral myocarditis were enriched in the PDD group. A B-cell receptor signaling pathway and one carbon pool by folate correlated with DLB in the results obtained from the GSEA. We found several clusters of co-expressed genes which we designated by colors in our WGCNA analysis. Furthermore, we identified seven upregulated genes, namely, SNAP25, GRIN2A, GABRG2, GABRA1, GRIA1, SLC17A6, and SYN1, which are significantly correlated with PDD.

Conclusion

The seven hub genes and the signaling pathways we identified may be involved in the heterogeneous pathogenesis of PDD and DLB.
Clinical impact of carbapenems in critically ill patients with valproic acid therapy: A propensity-matched analysis
Authors: Hsiao Shu-Chen , Lai Wei-Hung , Chen I-Ling , Shih Fu-Yuan
Published: March 2023

Background

Valproic acid (VPA) is one of the most widely used broad-spectrum antiepileptic drugs, and carbapenems (CBPs) remain the drug of choice for severe infection caused by multidrug-resistant bacteria in critically ill patients. The interaction between VPA and CBPs can lead to a rapid depletion of serum VPA level. This may then cause status epilepticus (SE), which is associated with significant mortality. However, the prognostic impact of drug interactions in critically ill patients remains an under-investigated issue.

Objective

The aim of this study was to compare the prognosis of critically ill patients treated with VPA and concomitant CBPs or other broad-spectrum antibiotics.

Methods

Adult patients admitted to a medical center intensive care unit between January 2007 and December 2017 who concomitantly received VPA and antibiotics were enrolled. The risk of reduced VPA serum concentration, seizures and SE, mortality rate, length of hospital stay (LOS), and healthcare expenditure after concomitant administration were analyzed after propensity score matching.

Results

A total of 1,277 patients were included in the study, of whom 264 (20.7%) concomitantly received VPA and CBPs. After matching, the patients who received CBPs were associated with lower VPA serum concentration (15.8 vs. 60.8 mg/L; p < 0.0001), a higher risk of seizures (51.2 vs. 32.4%; adjusted odds ratio [aOR], 2.19; 95% CI, 1.48–3.24; p < 0.0001), higher risk of SE (13.6 vs. 4.7%; aOR, 3.20; 95% CI, 1.51–6.74; p = 0.0014), higher in-hospital mortality rate (33.8 vs. 24.9%; aOR, 1.57; 95% CI, 1.03–2.20; p = 0.036), longer LOS after concomitant therapy (41 vs. 30 days; p < 0.001), and increased healthcare expenditure (US$20,970 vs. US$12,848; p < 0.0001) than those who received other broad-spectrum antibiotics.

Conclusion

The administration of CBPs in epileptic patients under VPA therapy was associated with lower VAP serum concentration, a higher risk of seizures and SE, mortality, longer LOS, and significant utilization of healthcare resources. Healthcare professionals should pay attention to the concomitant use of VPA and CBPs when treating patients with epilepsy. Further studies are warranted to investigate the reason for the poor outcomes and whether avoiding the co-administration of VPA and CBP can improve the outcomes of epileptic patients.
DBS of the ANT for refractory epilepsy: A single center experience of seizure reduction, side effects and neuropsychological outcomes
Authors: Olaciregui Dague Karmele , Witt Juri-Alexander , von Wrede Randi , Helmstaedter Christoph , Surges Rainer
Published: March 2023

Objective

Evaluation of the antiseizure efficacy, side effects and neuropsychological effects of Deep brain stimulation (DBS) of the anterior nucleus of the thalamus (ANT). ANT-DBS is a treatment option for patients with difficult-to-treat epilepsy. Though several works outline the cognitive and/or mood effects of ANT-DBS for the treatment of epilepsy, data on the intersection between antiseizure efficacy, cognitive and undesired effects are scarce.

Methods

We retrospectively analyzed the data of our cohort of 13 patients. Post-implantation seizure frequencies were measured at 6 months, 12 months and last follow-up, as well as averaged throughout follow-up. These values were then compared with mean seizure frequencies in the 6 months before implantation. To address acute cognitive effects of DBS a baseline assessment was performed after implantation and before stimulation, and a follow-up assessment was conducted under DBS. The long-term effects of DBS on cognition were assessed by comparing the preoperative neuropsychological profile with a long-term follow-up under DBS.

Results

In the entire cohort, 54.5% of patients were responders, with an average seizure reduction of 73.6%. One of these patients achieved temporary seizure freedom and near-total seizure reduction during the entire follow-up. Seizure reduction of <50% was achieved in 3 patients. Non-responders suffered an average seizure increase of 27.3%. Eight of twenty-two active electrodes (36,4%) were off-target. Two of our patients had both electrodes implanted off-target. When removing these two patients from the analysis and averaging seizure frequency during the entire follow-up period, four patients (44.4%) were responders and three experienced a seizure reduction of <50%. Intolerable side effects arose in 5 patients, mostly psychiatric. Regarding acute cognitive effects of DBS, only one patient showed a significant decline in executive functions. Long-term neuropsychological effects included significant intraindividual changes in verbal learning and memory. Figural memory, attention and executive functions, confrontative naming and mental rotation were mostly unchanged, and improved in few cases.

Significance

In our cohort, more than half of patients were responders. Psychiatric side effects seem to have been more prevalent compared to other published cohorts. This may be partially explained by a relatively high occurrence of off-target electrodes.
Podoplanin: A potential therapeutic target for thrombotic diseases
Authors: Huang Yaqian , Lu Manli , Wang Yi , Zhang Chunyuan , Cao Yongjun , Zhang Xia
Published: March 2023

As a specific lymphatic marker and a key ligand of C-type lectin-like receptor 2 (CLEC-2), podoplanin (Pdpn) is involved in various physiological and pathological processes such as growth and development, respiration, blood coagulation, lymphangiogenesis, angiogenesis, and inflammation. Thrombotic diseases constitute a major cause of disability and mortality in adults, in which thrombosis and inflammation play a crucial role. Recently, increasing evidence demonstrates the distribution and function of this glycoprotein in thrombotic diseases such as atherosclerosis, ischemic stroke, venous thrombosis, ischemic-reperfusion injury (IRI) of kidney and liver, and myocardial infarction. Evidence showed that after ischemia, Pdpn can be acquired over time by a heterogeneous cell population, which may not express Pdpn in normal conditions. In this review, the research progresses in understanding the roles and mechanisms of podoplanin in thromobotic diseases are summarized. The challenges of podoplanin-targeted approaches for disease prognosis and preventions are also discussed.
From circuits to behavior: Amygdala dysfunction in fragile X syndrome
Authors: Svalina Matthew N. , Sullivan Regina , Restrepo Diego , Huntsman Molly M.
Published: March 2023

Fragile X syndrome (FXS) is a neurodevelopmental disorder caused by a repeat expansion mutation in the promotor region of the FMR1 gene resulting in transcriptional silencing and loss of function of fragile X messenger ribonucleoprotein 1 protein (FMRP). FMRP has a well-defined role in the early development of the brain. Thus, loss of the FMRP has well-known consequences for normal cellular and synaptic development leading to a variety of neuropsychiatric disorders including an increased prevalence of amygdala-based disorders. Despite our detailed understanding of the pathophysiology of FXS, the precise cellular and circuit-level underpinnings of amygdala-based disorders is incompletely understood. In this review, we discuss the development of the amygdala, the role of neuromodulation in the critical period plasticity, and recent advances in our understanding of how synaptic and circuit-level changes in the basolateral amygdala contribute to the behavioral manifestations seen in FXS.
Alzheimer’s disease as a synaptopathy: Evidence for dysfunction of synapses during disease progression
Authors: Meftah Soraya , Gan Jian
Published: March 2023

The synapse has consistently been considered a vulnerable and critical target within Alzheimer’s disease, and synapse loss is, to date, one of the main biological correlates of cognitive decline within Alzheimer’s disease. This occurs prior to neuronal loss with ample evidence that synaptic dysfunction precedes this, in support of the idea that synaptic failure is a crucial stage within disease pathogenesis. The two main pathological hallmarks of Alzheimer’s disease, abnormal aggregates of amyloid or tau proteins, have had demonstrable effects on synaptic physiology in animal and cellular models of Alzheimer’s disease. There is also growing evidence that these two proteins may have a synergistic effect on neurophysiological dysfunction. Here, we review some of the main findings of synaptic alterations in Alzheimer’s disease, and what we know from Alzheimer’s disease animal and cellular models. First, we briefly summarize some of the human evidence to suggest that synapses are altered, including how this relates to network activity. Subsequently, animal and cellular models of Alzheimer’s disease are considered, highlighting mouse models of amyloid and tau pathology and the role these proteins may play in synaptic dysfunction, either in isolation or examining how the two pathologies may interact in dysfunction. This specifically focuses on neurophysiological function and dysfunction observed within these animal models, typically measured using electrophysiology or calcium imaging. Following synaptic dysfunction and loss, it would be impossible to imagine that this would not alter oscillatory activity within the brain. Therefore, this review also discusses how this may underpin some of the aberrant oscillatory patterns seen in animal models of Alzheimer’s disease and human patients. Finally, an overview of some key directions and considerations in the field of synaptic dysfunction in Alzheimer’s disease is covered. This includes current therapeutics that are targeted specifically at synaptic dysfunction, but also methods that modulate activity to rescue aberrant oscillatory patterns. Other important future avenues of note in this field include the role of non-neuronal cell types such as astrocytes and microglia, and mechanisms of dysfunction independent of amyloid and tau in Alzheimer’s disease. The synapse will certainly continue to be an important target within Alzheimer’s disease for the foreseeable future.
Bioactive nutraceuticals oligo-lactic acid and fermented soy extract alleviate cognitive decline in mice in part via anti-neuroinflammation and modulation of gut microbiota
Authors: Abdolmaleky Hamid M. , Sheng Yin , Zhou Jin-Rong
Published: March 2023

Introduction

Cognition decline is associated with aging and certain diseases, such as neurodegenerative or neuropsychiatric disorders, diabetes and chronic kidney disease. Inflammation/neuroinflammation is considered an important causal factor, and experimental evidence suggests that anti-inflammatory natural compounds may effectively prevent cognitive decline. The goal of this study was to evaluate the effects of two natural bioactive agents, oligo-lactic acid (LAP) and fermented soy extract (ImmunBalance, IMB), on cognition in an adenine-induced cognitive impairment mouse model and to investigate the modulation of related biomarkers.

Methods

Male C57 black mice were randomly assigned into the following experimental groups and received the corresponding treatments for 2 weeks before the use of adenine for model development: (1) negative control; (2) model control: injection of adenine at 50 mg/kg daily for 4 weeks; (3, 4) IMB groups: adenine injection and IMB oral gavage at 250 and 1,000 mg/kg BW, respectively; and (5) LAP group: adenine injection and LAP oral gavage at 1,000 mg/kg BW. One week after the model was developed, mice were evaluated for cognitive performances by using Y maze test, novel object recognition test, open field test, and Barnes maze tests. At the end of the experiment, brain tissues and cecum fecal samples were collected for analysis of gene expression and gut microbiota.

Results

Mice treated with LAP or IMB had significantly improved spatial working memory, spatial recognition memory (LAP only), novel object recognition, and spatial learning and memory, compared with those in the model group. Gene expression analysis showed that, among a panel of cognition related genes, six of them (ELOVL2, GLUT4, Nestein, SNCA, TGFB1, and TGFB2) were significantly altered in the model group. LAP treatment significantly reversed expression levels of inflammatory/neuroinflammatory genes (SNCA, TGFB1), and IMB significantly reversed expression levels of genes related to inflammation/neuroinflammation, neurogenesis, and energy metabolism (ELOVL2, GLUT4, Nestin, TGFB1, and TGFB2). The altered microbiome was attenuated only by IMB.

Discussion

In conclusion, our data showed that LAP improved cognition associated with regulating biomarkers related to neuroinflammation and energy metabolism, whereas IMB improved cognition associated with regulating biomarkers related to neuroinflammation, energy metabolism, and neurogenesis, and modulating gut microbiota. Our results suggest that LAP and IMB may improve cognitive performance in mice via distinct mechanisms of action.
Global human obesity and global social index: Relationship and clustering
Authors: Munir Mubbasher , Zakaria Zahrahtul Amani , Nisar Haseeb , Ahmed Zahoor , Korma Sameh A. , Esatbeyoglu Tuba
Published: March 2023

Introduction

Obesity, a complex, multifactorial disease, is considered a global disease burden widely affecting the quality of life across different populations. Factors involved in obesity involve genetics, behavior and socioeconomic and environmental origins, each contributing to the risk of debilitating morbidity and mortality. However, the trends across the world vary due to various globalization parameters.

Methods

This article tends to identify the global social indicators, compiled into a global index, and develop a correlation between the global social index created by using the human development index, social and political globalization, the global happiness index, and the quality of infrastructure, institutions, and individuals using the internet factors and its effect on global obesity.

Results and Discussion

Our results identified a positive correlation between medium human development levels with obesity compared to low and very high human development levels. Economic stability due to rapid industrialization has increased the buying capacity and changed the global food system, which seems to be the major driver of the rise of global obesity.

Conclusion

The results decipher that global social indicators and overall social index have positively affected global obesity, which will help policymakers and governmental organizations monitor the obesity patterns across their regions by a significant contribution from globally influenced social factors.
Effects of vitamin D supplementation on the regulation of blood lipid levels in prediabetic subjects: A meta-analysis
Authors: Yang Yixue , Yan Shoumeng , Yao Nan , Guo Yinpei , Wang Han , Sun Mengzi , Hu Wenyu , Li Xiaotong , Wang Ling , Li Bo
Published: March 2023

This meta-analysis aimed to systematically investigate whether vitamin D supplementation reduces blood lipid—total cholesterol (TC), LDL cholesterol (LDL-C), HDL cholesterol (HDL-C), and triglyceride (TG)—levels in prediabetic individuals. Pubmed, Web of Science, Cochrane Library, Embase, CNKI, and WANFANG databases were searched for studies published before 13 February 2022 (including 13 February 2022). Five articles were included. The results showed that vitamin D intervention led to a significant reduction in TG compared with control or placebo treatment (−0.42 [−0.59, −0.25], P < 0.001). Subgroup analyses showed that this effect was particularly significant among the studies that included obese subjects (−0.46 [−0.65, −0.28], P < 0.001), the studies that also included men (not only women) (−0.56 [−0.78, −0.34], P < 0.001), and the studies with intervention durations longer than 1 year (−0.46 [−0.65, −0.28], P < 0.001). Both relatively low doses of 2,857 IU/day (−0.65 [−0.92, −0.38], P < 0.001) and relatively high doses of 8,571 IU/day (−0.28 [−0.54, −0.02] P = 0.04) of vitamin D supplementation reduced TG levels, and the effect was observed both in Northern Europe (−0.65 [−0.92, −0.38], P < 0.001) and Asian (−0.25 [−0.48, −0.03], P = 0.03) country subgroups. No significant effects on TC, HDL-C, and LDL-C were shown. In conclusion, vitamin D supplementation might beneficially affect TG levels in individuals with prediabetes. Particularly longer durations of treatment, more than 1 year, with doses that correct vitamin deficiency/insufficiency, can have a beneficial effect. This meta-analysis was registered at www.crd.york.ac.uk/prospero (CRD42020160780).
Fully automated bladder tumor segmentation from T2 MRI images using 3D U-Net algorithm
Authors: Coroamă Diana Mihaela , Dioșan Laura , Telecan Teodora , Andras Iulia , Crișan Nicolae , Medan Paul , Andreica Anca , Caraiani Cosmin , Lebovici Andrei , Boca Bianca , Bálint Zoltán
Published: March 2023

Introduction

Bladder magnetic resonance imaging (MRI) has been recently integrated in the diagnosis pathway of bladder cancer. However, automatic recognition of suspicious lesions is still challenging. Thus, development of a solution for proper delimitation of the tumor and its separation from the healthy tissue is of primordial importance. As a solution to this unmet medical need, we aimed to develop an artificial intelligence-based decision support system, which automatically segments the bladder wall and the tumor as well as any suspect area from the 3D MRI images.

Materials

We retrospectively assessed all patients diagnosed with bladder cancer, who underwent MRI at our department (n=33). All examinations were performed using a 1.5 Tesla MRI scanner. All images were reviewed by two radiologists, who performed manual segmentation of the bladder wall and all lesions. First, the performance of our fully automated end-to-end segmentation model based on a 3D U-Net architecture (by considering various depths of 4, 5 or 6 blocks) trained in two data augmentation scenarios (on 5 and 10 augmentation datasets per original data, respectively) was tested. Second, two learning setups were analyzed by training the segmentation algorithm with 7 and 14 MRI original volumes, respectively.

Results

We obtained a Dice-based performance over 0.878 for automatic segmentation of bladder wall and tumors, as compared to manual segmentation. A larger training dataset using 10 augmentations for 7 patients could further improve the results of the U-Net-5 model (0.902 Dice coefficient at image level). This model performed best in terms of automated segmentation of bladder, as compared to U-Net-4 and U-Net-6. However, in this case increased time for learning was needed as compared to U-Net-4. We observed that an extended dataset for training led to significantly improved segmentation of the bladder wall, but not of the tumor.

Conclusion

We developed an intelligent system for bladder tumors automated diagnostic, that uses a deep learning model to segment both the bladder wall and the tumor. As a conclusion, low complexity networks, with less than five-layers U-Net architecture are feasible and show good performance for automatic 3D MRI image segmentation in patients with bladder tumors.
An inflammation-related gene landscape predicts prognosis and response to immunotherapy in virus-associated hepatocellular carcinoma
Authors: Gao Ying-jie , Li Shi-rong , Huang Yuan
Published: March 2023

Background

Due to the viral infection, chronic inflammation significantly increases the likelihood of hepatocellular carcinoma (HCC) development. Nevertheless, an inflammation-based signature aimed to predict the prognosis and therapeutic effect in virus-related HCC has rarely been established.

Method

Based on the integrated analysis, inflammation-associated genes (IRGs) were systematically assessed. We comprehensively investigated the correlation between inflammation and transcriptional profiles, prognosis, and immune cell infiltration. Then, an inflammation-related risk model (IRM) to predict the overall survival (OS) and response to treatment for virus-related HCC patients was constructed and verified. Also, the potential association between IRGs and tumor microenvironment (TME) was investigated. Ultimately, hub genes were validated in plasma samples and cell lines via qRT-PCR. After transfection with shCCL20 combined with overSLC7A2, morphological change of SMMC7721 and huh7 cells was observed. Tumorigenicity model in nude mouse was established.

Results

An inflammatory response-related gene signature model, containing MEP1A, CCL20, ADORA2B, TNFSF9, ICAM4, and SLC7A2, was constructed by conjoint analysis of least absolute shrinkage and selection operator (LASSO) Cox regression and gaussian finite mixture model (GMM). Besides, survival analysis attested that higher IRG scores were positively relevant to worse survival outcomes in virus-related HCC patients, which was testified by external validation cohorts (the ICGC cohort and GSE84337 dataset). Univariate and multivariate Cox regression analyses commonly proved that the IRG was an independent prognostic factor for virus-related HCC patients. Thus, a nomogram with clinical factors and IRG was also constructed to superiorly predict the prognosis of patients. Featured with microsatellite instability-high, mutation burden, and immune activation, lower IRG score verified a superior OS for sufferers. Additionally, IRG score was remarkedly correlated with the cancer stem cell index and drug susceptibility. The measurement of plasma samples further validated that CCL20 upexpression and SLC7A2 downexpression were positively related with virus-related HCC patients, which was in accord with the results in cell lines. Furthermore, CCL20 knockdown combined with SLC7A2 overexpression availably weakened the tumor growth in vivo.

Conclusions

Collectively, IRG score, serving as a potential candidate, accurately and stably predicted the prognosis and response to immunotherapy in virus-related HCC patients, which could guide individualized treatment decision-making for the sufferers.
Adjuvant transarterial chemoembolization timing after radical resection is an independent prognostic factor for patients with hepatocellular carcinoma
Authors: Sun Hongfa , Wang Hanlin , Wang Youpeng , Zhong Wenqing , Meng Yushan , Lv Ziqiang , Guo Weidong , Han Bing
Published: March 2023

Background

It has been reported that postoperative adjuvant TACE (PA-TACE) treatment decreases recurrence and significantly improves the survival of patients who undergo radical resection of hepatocellular carcinoma (HCC) with high-risk recurrence factors. However, when to perform PA-TACE has not been fully studied.

Methods

We retrospectively collected the clinicopathologic characteristics of the patients with HCC between October 2013 and June 2020. The optimal cutoff value for PA-TACE time was determined based on the R package “maxstat”. Logistic regression and Cox regression analysis were used to determine the effect of the choice of PA-TACE timing on prognosis.

Results

The analysis was performed on 789 patients with HCC, and 484 patients were finally involved and were divided into training cohort (378) and validation cohort (106). The PA-TACE timing was found to be associated with survival outcomes. Multivariate logistic analysis found independent predictors of the PA-TACE timing, including gender and history of HBV. Multivariate Cox analysis showed that Ki-67, tumor size, MVI and the PA-TACE timing were independent prognostic factors for RFS in HCC patients.

Conclusions

Based on this study, HCC patients with high-risk recurrence factors can receive personalized assistance in undergoing PA-TACE treatment and improve their survival outcomes.
Therapeutic drug monitoring guided dosing versus standard dosing of alectinib in advanced ALK positive non-small cell lung cancer patients: Study protocol for an international, multicenter phase IV randomized controlled trial (ADAPT ALEC)
Authors: Meertens Marinda , Muntinghe-Wagenaar M. Benthe , Sikkema Barend J. , Lopez-Yurda Marta , Retèl Valesca P. , Paats Marthe S. , Ter Heine Rob , Schuuring Ed , Timens Wim , Touw Daan J. , van Boven Job F. M. , de Langen Adrianus. J. , Hashemi Sayed M. S. , Hendriks Lizza E. L. , Croes Sander , van den Heuvel Michel M. , Dingemans Anne-Marie C. , Mathijssen Ron H. J. , Smit Egbert F. , Huitema Alwin D. R. , Steeghs Neeltje , van der Wekken Anthonie J.
Published: March 2023

Background

Alectinib is first-line therapy in patients with stage IV non-small cell lung carcinoma (NSCLC) and an anaplastic lymphoma kinase (ALK) fusion. A shorter median progression-free survival (mPFS) was observed when alectinib minimum plasma concentrations during steady state (Cmin,SS) were below 435 ng/mL. This may suggest that patients should have an alectinib Cmin,SS ≥ 435 ng/mL for a more favorable outcome. This potential target could be attained by using therapeutic drug monitoring (TDM), i.e. adjusting the dose based on measured plasma trough concentrations. Hypothetically, this will increase mPFS, but this has not yet been evaluated in a randomized controlled trial (RCT). Therefore, the ADAPT ALEC trial is designed, with the primary objective to prolong mPFS in NSCLC patients treated with alectinib by using TDM.

Methods

ADAPT ALEC is a multicenter, phase IV RCT, in which patients aged ≥ 18 years with advanced ALK positive (+) NSCLC eligible for alectinib in daily care are enrolled. Participants will be randomized (1:1 ratio) into intervention arm A (TDM) or B (control), stratified by brain metastases and prior ALK treatments. Starting dose in both arms is the approved flat fixed dose of alectinib 600 mg taken twice daily with food. In case of alectinib Cmin,SS < 435 ng/mL, arm A will receive increased doses of alectinib till Cmin,SS ≥ 435 ng/mL when considered tolerable. The primary outcome is mPFS, where progressive disease is defined according to RECIST v1.1 or all-cause death and assessed by CT-scans and MRI brain. Secondary endpoints are feasibility and tolerability of TDM, patient and physician adherence, overall response rate, median overall survival, intracranial PFS, quality of life, toxicity, alectinib-M4 concentrations and cost-effectiveness of TDM. Exploratory endpoints are circulating tumor DNA and body composition.

Discussion

The ADAPT ALEC will show whether treatment outcomes of patients with advanced ALK+ NSCLC improve when using TDM-guided dosing of alectinib instead of fixed dosing. The results will provide high quality evidence for deciding whether TDM should be implemented as standard of care and this will have important consequences for the prescribing of alectinib.

Clinical trial registration

ClinicalTrials.gov, identifier NCT05525338.