bluuebunny/crossref_metadata_2025 huggingface dataset:
Bulk and single-cell RNA-sequencing analyses along with abundant machine learning methods identify a novel monocyte signature in SKCM
Authors: Liu Yuyao , Zhang Haoxue , Mao Yan , Shi Yangyang , Wang Xu , Shi Shaomin , Hu Delin , Liu Shengxiu
Published: May 2023

Background

Global patterns of immune cell communications in the immune microenvironment of skin cutaneous melanoma (SKCM) haven’t been well understood. Here we recognized signaling roles of immune cell populations and main contributive signals. We explored how multiple immune cells and signal paths coordinate with each other and established a prognosis signature based on the key specific biomarkers with cellular communication.

Methods

The single-cell RNA sequencing (scRNA-seq) dataset was downloaded from the Gene Expression Omnibus (GEO) database, in which various immune cells were extracted and re-annotated according to cell markers defined in the original study to identify their specific signs. We computed immune-cell communication networks by calculating the linking number or summarizing the communication probability to visualize the cross-talk tendency in different immune cells. Combining abundant analyses of communication networks and identifications of communication modes, all networks were quantitatively characterized and compared. Based on the bulk RNA sequencing data, we trained specific markers of hub communication cells through integration programs of machine learning to develop new immune-related prognostic combinations.

Results

An eight-gene monocyte-related signature (MRS) has been built, confirmed as an independent risk factor for disease-specific survival (DSS). MRS has great predictive values in progression free survival (PFS) and possesses better accuracy than traditional clinical variables and molecular features. The low-risk group has better immune functions, infiltrated with more lymphocytes and M1 macrophages, with higher expressions of HLA, immune checkpoints, chemokines and costimulatory molecules. The pathway analysis based on seven databases confirms the biological uniqueness of the two risk groups. Additionally, the regulon activity profiles of 18 transcription factors highlight possible differential regulatory patterns between the two risk groups, suggesting epigenetic event-driven transcriptional networks may be an important distinction. MRS has been identified as a powerful tool to benefit SKCM patients. Moreover, the IFITM3 gene has been identified as the key gene, validated to express highly at the protein level via the immunohistochemical assay in SKCM.

Conclusion

MRS is accurate and specific in evaluating SKCM patients’ clinical outcomes. IFITM3 is a potential biomarker. Moreover, they are promising to improve the prognosis of SKCM patients.
Ubiquitin-specific protease 29 attenuates hepatic ischemia-reperfusion injury by mediating TGF-β-activated kinase 1 deubiquitination
Authors: Chen Zhongbao , Hu Fengjiao , Zhang Yalong , Zhang Long , Wang Tianyu , Kong Chenyang , Hu Haochong , Guo Jiayu , Chen Qi , Yu Bo , Liu Yiting , Zou Jilin , Zhou Jiangqiao , Qiu Tao
Published: May 2023

Background and aims

In the course of clinical practice, hepatic ischemia/reperfusion (I/R) injury is a prevalent pathophysiological event and is caused by a combination of complex factors that involve multiple signaling pathways such as MAPK and NF-κB. USP29 is a deubiquitinating enzyme important during the development of tumors, neurological diseases, and viral immunity. However, it is unknown how USP29 contributes to hepatic I/R injury.

Methods and results

We systematically investigated the role of the USP29/TAK1-JNK/p38 signaling pathway in hepatic I/R injury. We first found reduced USP29 expression in both mouse hepatic I/R injury and the primary hepatocyte hypoxia-reoxygenation (H/R) models. We established USP29 full knockout mice (USP29-KO) and hepatocyte-specific USP29 transgenic mice (USP29-HTG), and we found that USP29 knockout significantly exacerbates the inflammatory infiltration and injury processes during hepatic I/R injury, whereas USP29 overexpression alleviates liver injury by decreasing the inflammatory response and inhibiting apoptosis. Mechanistically, RNA sequencing results showed the effects of USP29 on the MAPK pathway, and further studies revealed that USP29 interacts with TAK1 and inhibits its k63-linked polyubiquitination, thereby preventing the activation of TAK1 and its downstream signaling pathways. Consistently, 5z-7-Oxozeaneol, an inhibitor of TAK1, blocked the detrimental effects of USP29 knockout on H/R-induced hepatocyte injury, further confirming that USP29 plays a regulatory role in hepatic I/R injury by targeting TAK1.

Conclusion

Our findings imply that USP29 is a therapeutic target with promise for the management of hepatic I/R injury via TAK1-JNK/p38 pathway-dependent processes.
Self-assembled albumin nanoparticles induce pyroptosis for photodynamic/photothermal/immuno synergistic therapies in triple-negative breast cancer
Authors: Yang Jianquan , Guo Wen , Huang Rong , Bian Jiaojiao , Zhang Siqi , Wei Ting , He Chuanshi , Hu Ziyue , Li Juan , Zhou Chunyang , Lu Man
Published: May 2023

Triple-negative breast cancer (TNBC) is characterized by a high degree of malignancy, early metastasis, limited treatment, and poor prognosis. Immunotherapy, as a new and most promising treatment for cancer, has limited efficacy in TNBC because of the immunosuppressive tumor microenvironment (TME). Inducing pyroptosis and activating the cyclic guanosine monophosphate-adenosine monophosphate synthase/interferon gene stimulator (cGAS/STING) signaling pathway to upregulate innate immunity have become an emerging strategy for enhancing tumor immunotherapy. In this study, albumin nanospheres were constructed with photosensitizer-IR780 encapsulated in the core and cGAS–STING agonists/H2S producer-ZnS loaded on the shell (named IR780-ZnS@HSA). In vitro, IR780-ZnS@HSA produced photothermal therapy (PTT) and photodynamic therapy (PDT) effects. In addition, it stimulated immunogenic cell death (ICD) and activated pyroptosis in tumor cells via the caspase-3–GSDME signaling pathway. IR780-ZnS@HSA also activated the cGAS–STING signaling pathway. The two pathways synergistically boost immune response. In vivo, IR780-ZnS@HSA + laser significantly inhibited tumor growth in 4T1 tumor-bearing mice and triggered an immune response, improving the efficacy of the anti-APD-L1 antibody (aPD-L1). In conclusion, IR780-ZnS@HSA, as a novel inducer of pyroptosis, can significantly inhibit tumor growth and improve the efficacy of aPD-L1.
Controlling factor analysis of oceanic surface pCO2 in the South China Sea using a three-dimensional high-resolution biogeochemical model
Authors: Zhang Miaoyin , Zhu Xueming , Ji Xuanliang , Zhang Anmin , Zheng Jingjing
Published: May 2023

The oceanic surface pressure of CO2 (pCO2) is an essential parameter for understanding the global and regional carbon cycle and the oceanic carbon uptake capacity. We constructed a three-dimensional physical-biogeochemical model with a high resolution of 1/30° for the South China Sea (SCS) to compensate for the limited temporal coverage and limited spatial resolution of the observations and numerical models. The model simulated oceanic surface pCO2 from 1992 to 2021, and the empirical orthogonal function analysis (EOF) of the model results is conducted for a better understanding of the seasonal and interannual variations of oceanic surface pCO2 in this region. The model results showed that the SCS serves as an atmospheric CO2 source from March to October and a sink from November to February, with a domain-averaged climatological oceanic surface pCO2 value that varies between 357 and 408 μatm, and the temporal variation was positively correlated with the variation of sea surface temperature (SST). The majority of the SCS showed a long-term increasing trend for oceanic surface pCO2 with a value of (1.19±0.60) μatm/a, which is in response to the continuously rising atmospheric CO2 concentration. The first EOF mode is positively correlated with the Niño 3 index with a correlation coefficient of 0.51 when the Niño 3 leads 5 months, and the second EOF mode is correlated with the PDO index when the PDO leads 7 months, which suggests an influence of climate variability on the carbonate system. Moreover, it was found that the long-term trend rate of oceanic surface pCO2 was mainly controlled by total CO2 (TCO2) through the decomposition of influence factors, and SST variation took a dominant role in seasonal variations of pCO2. With rapid global warming and continuous release of CO2, the carbonate system in the SCS may change leading to calcite and aragonite saturation.
Pick-up of fluoroquinolones from the aqueous phase via magnetically propeled microrobots: kinetics, thermodynamics, and site energy distribution analysis
Authors: Tang Yongzheng , Jia Wenpeng , Bao Mutai , Qiu Shengyao , Pi YongRui , Liu Chongfeng , Zhao Jinchen
Published: May 2023

Removing fluoroquinolones (FQs) in marine culture tailwater is crucial for the coastal marine environment. The application of a bacteria-based microrobot for FQ removal was discussed. Norfloxacin (NOR) and levofloxacin (LEV) had static maximum adsorption capacities of 114.8 and 49.4 mg/g, respectively, by a magnetic microrobot. The experimental results of NOR adsorption by a magnetic microrobot were well supported by the Langmuir isotherm and Elovich kinetic models. Both the Langmuir isotherm model and the pseudo-second-order kinetic model may be able to accurately represent the LEV adsorption process. The mass transfer mechanism of the NOR and LEV adsorptions was divided into two steps and described better using the intraparticle diffusion (IPD) model. The exothermic and spontaneity of the sorption process were demonstrated through the study of thermodynamics. The magnetic microrobot’s heterogeneous surface was validated by the examination of site energy distribution. Additionally, this study demonstrated that the majority of the NOR and LEV sorption took place at sites with energies over 4.25 and 17.36 kJ/mol, respectively, supporting the notion that NOR and LEV adsorption constitute physical–chemical processes. Based on the above results, a magnetic microrobot, as a new-style green bio-adsorbent, can potentially be used to remove NOR and LEV from the mariculture in an inexpensive and effective manner.
An advanced towed CTD chain for physical-biological high resolution in situ upper ocean measurements
Authors: Kock Thomas , Baschek Burkard , Wobbe Florian , Heineke Martina , Riethmueller Rolf , Deschner Stephan C. , Seidel Gerd , Calil Paulo H. R.
Published: May 2023

Submesoscale eddies, fronts, and filaments are ubiquitous in the upper ocean and play an important role in biogeochemical and mixing processes as well as in the energy budget. To capture the high spatial variability of submesoscale processes, it is desirable to simultaneously resolve the vertical and horizontal gradients of hydrographic properties on scales of 10 m to 10 km. We present a revised towed CTD chain, for rapid quasi-synoptic in situ measurements of submesoscale oceanographic features, that is lighter, more robust and scientifically more useful than previous towed CTD chains. This new instrument provides a horizontal resolution of O(1 m) and can be towed at speeds of up to 5 ms-1 for measurements of the upper 100 m of the water column while providing a reasonable vertical resolution of O(1 m – 10 m). Individual CTD probes are equipped with temperature, conductivity, pressure and either rapid response dissolved oxygen or fluorescence sensors at multiple depths, enabling both hydrographic and biogeochemical studies at high resolution. A flexible probe hardware allows either real-time data collection or internal data logging for offline post-processing. Finally, we outline the necessary post-processing steps and provide data examples. With the presented data examples we show and conclude that the advanced towed CTD chain is a flexible and lightweight take on the towed CTD chain concept. It can easily be adapted to scientific needs and provides high quality very high resolution oceanographic data.
Understanding nitrogen dynamics in coral holobionts: comprehensive review of processes, advancements, gaps, and future directions
Authors: Li Moyang , Sheng Hua-Xia , Dai Mengyao , Kao Shuh-Ji
Published: May 2023

Coral reefs are known for being highly productive ecosystems in oligotrophic oceans, which is commonly referred to as the Darwin’s Paradox. Nitrogen is an essential component of organisms, but it limits primary productivity in most euphotic ocean, including the coral reef system. Therefore, understanding nitrogen’s transfer and transformation within the coral holobiont is essential to comprehend the holobiont homeostasis and functioning mechanisms, which may help to explain the Darwin’s Paradox. Previous studies have pointed out the fundamental importance of nitrogen cycling between coral host and symbiotic algae. Recently, increasing researches, particularly in quantitative aspect, have significantly improved our understandings of the various roles of nitrogen pathways in regulating the inter-relationship among coral host and symbiotic algae and the associated microbiome. In this paper, we synthesized knowledge advances of different nitrogen processes in coral holobionts standing on the nitrogen cycle perspective. We extracted consensus and contradictions from published research results regarding nitrogen flows of coral holobiont. This review presented the temporal and spatial variation of nitrogen fixation and analyzed the global nitrogen processes rates in coral holobionts. We also summarized projections of specific nitrogen processes of coral holobionts facing climate change from limited reports. We realized that there are significant gaps in our understanding of nitrogen processes in coral holobionts, which hindering our comprehension of nitrogen balance in coral holobionts and, therefore, the coral reef systems. These gaps include the roles and relative importance of nitrification, denitrification, and DNRA in coral holobionts, as well as the self-regulation mechanisms to maintain nitrogen-homeostasis in short-term and long-term, particularly in the context of environmental changes. At the end, we provide our opinions on research methods regarding quantitative coral research in the future.
Comparison of oral sodium phosphate tablets and polyethylene glycol lavage solution for colonoscopy preparation: a systematic review and meta-analysis of randomized clinical trials
Authors: Yao-dong Li , Yi-ping Wang , Gang Mai , Yang-yun Han , Ling-ling Zhu , Hong Deng , Jia-zheng Deng , Rong-chao Xiang , You-wei Li , Ming Zhao , Shun-bin Ding , Jing Ling , Yang Shen , Jia-qi Dong , Lei Deng , Xiong-feng Song , You-jian Zhang , Zuo-qiong Zhou
Published: May 2023

Objective

To systematically compare the bowel cleaning ability, patient tolerance and safety of oral sodium phosphate tablets (NaPTab) and oral polyethylene glycol electrolyte lavage solution (PEGL) to inform clinical decision making.

Methods

PubMed, Embase, CBM, WanFang Data, CNKI, and VIP databases were searched for studies that used randomized controlled trials (RCTs) to compare the roles of NaPTab and PEGL in bowel preparation before colonoscopy. Two reviewers independently screened the studies, extracted data, and assessed the risk of bias in the included papers. A meta-analysis was performed using RevMan 5.3 software.

Results

A total of 13 RCTs were eligible for inclusion, including 2,773 patients (1,378 and 1,395 cases in the NaPTab and PEGL groups, respectively). Meta-analysis revealed no significant difference in the cleansing quality of the NaPTab and PEGL groups [RR 1.02, 95% CI (0.96–1.08), P = 0.46]. The incidence of nausea was lower in the NaPTab group than in the PEGL group [RR 0.67, 95% CI (0.58–0.76), p < 0.00001]. Patients rated the taste of NaPTab higher than PEGL [RR 1.33, 95% CI (1.26–1.40), P < 0.00001]. Willingness to repeat the treatment was also higher in the NaPTab group than in the PEGL group [RR 1.52, 95% CI (1.28–1.80), P < 0.00001]. Both serum potassium and serum calcium decreased in both groups after the preparation; however, meta-analysis revealed that both minerals decreased more in the NaPTab group than in the PEGL group [MD = 0.38, 95% CI (0.13–0.62), P = 0.006 for serum potassium and MD = 0.41, 95% CI (0.04–0.77), P = 0.03 for serum calcium]. Meanwhile, serum phosphorus increased in both groups after the preparation; however, levels increased more in the NaPTab group than in the PEGL group [MD 4.51, (95% CI 2.9–6.11), P < 0.00001].

Conclusions

While NaP tablets and PEGL were shown to have a similar cleaning effect before colonoscopy, NaP tablets had improved patient tolerance. However, NaP tablets had a strong effect on serum potassium, calcium, and phosphorus levels. For patients with low potassium, low calcium, and renal insufficiency, NaP tablets should be prescribed with caution. For those at high-risk for acute phosphate nephropathy, NaP tablets should be avoided. Given the low number and quality of included studies, these conclusions will require additional verification by large high-quality studies.

Systematic review registration

10.37766/inplasy2023.5.0013, identifier: NPLASY202350013.
Enemy or friend: the personal and the factual patient-physician relationship
Authors: Keller Frieder , Ludwig Ulla , Huber-Lang Markus
Published: May 2023

Physicians are expected to place the patient’s interests above their own. Such prioritization has worldwide consent. It constitutes the difference between medicine and other professions. The present conceptual opinion paper summarizes the authors’ clinical experience with patient care and student teaching during the last 45 years. The authors comment on their own conception by referring to present debates and prominent statements from the past. Fundamental changes in medicine have taken place over the last five decades. New diseases have emerged while diagnostic and therapeutic options for patients have grown steadily – along with healthcare costs. At the same time, economic and legal constraints for physicians have increased, as has moral pressure. The interaction of physicians with patients has gradually shifted from a personal to a factual relationship. In the factual, more formal relationship, the patient and physician represent equal partners of a legal contract, which jeopardizes the prioritization of the patient’s interests. The formal relationship implies defensiveness. By contrast, in the personal relationship, the physician adopts an existentialist commitment while simultaneously enabling and respecting the patient’s autonomous decision-making. The authors argue for the personal relationship. However, the patient and physician are no friends. Consequently, the physician in effect competes with the patient from a knowledge-based but opposite position. Both need to make efforts to consent and maintain the relationship even when they dissent. This implies that the physician does not simply comply with the patient’s wishes.
Physiological and transcriptional studies reveal Cr(VI) reduction mechanisms in the exoelectrogen Cellulomonas fimi Clb-11
Authors: Cao Lianbin , Lu Mingguo , Zhao Mengrui , Zhang Yifan , Nong Yiping , Hu Mengxue , Wang Ya , Li Tongbiao , Chen Fujia , Wang Mingcheng , Liu Junhe , Li Enzhong , Sun Hongmei
Published: May 2023

A facultative exoelectrogen, Cellulomonas fimi strain Clb-11, was isolated from polluted river water. This strain could generate electricity in microbial fuel cells (MFCs) with carboxymethyl cellulose (CMC) as the carbon source, and the maximum output power density was 12.17 ± 2.74 mW·m−2. In addition, Clb-11 could secrete extracellular chromate reductase or extracellular electron mediator to reduce Cr(VI) to Cr(III). When the Cr(VI) concentration was less than 0.5 mM in Luria-Bertani (LB) medium, Cr(VI) could be completely reduced by Clb-11. However, the Clb-11 cells swelled significantly in the presence of Cr(VI). We employed transcriptome sequencing analysis to identify genes involved in different Cr(VI) stress responses in Clb-11. The results indicate that 99 genes were continuously upregulated while 78 genes were continuously downregulated as the Cr(VI) concentration increased in the growth medium. These genes were mostly associated with DNA replication and repair, biosynthesis of secondary metabolites, ABC transporters, amino sugar and nucleotide sugar metabolism, and carbon metabolism. The swelling of Clb-11 cells might have been related to the upregulation of the genes atoB, INO1, dhaM, dhal, dhak, and bccA, which encode acetyl-CoA C-acetyltransferase, myo-inositol-1-phosphate synthase, phosphoenolpyruvate-glycerone phosphotransferase, and acetyl-CoA/propionyl-CoA carboxylase, respectively. Interestingly, the genes cydA and cydB related to electron transport were continuously downregulated as the Cr(VI) concentration increased. Our results provide clues to the molecular mechanism of Cr(VI) reduction by microorganisms in MFCs systems.
Genomic epidemiology of nosocomial carbapenemase-producing Citrobacter freundii in sewerage systems in the Helsinki metropolitan area, Finland
Authors: Heljanko Viivi , Johansson Venla , Räisänen Kati , Anttila Veli-Jukka , Lyytikäinen Outi , Jalava Jari , Weijo Irma , Lehtinen Jaana-Marija , Lehto Kirsi-Maarit , Lipponen Anssi , Oikarinen Sami , Pitkänen Tarja , Heikinheimo Annamari ,   WastPan Study Group
Published: May 2023

Multi-drug resistance is emerging in Citrobacter freundii, which is the third most common carbapenemase-producing (CP) Enterobacteriaceae in humans in Finland due to recent outbreaks. The objective of this study was to determine if wastewater surveillance (WWS) could detect CP C. freundii strains causing infections in humans. Selective culturing was used to isolate CP C. freundii from the hospital environment, hospital wastewater, and untreated municipal wastewater in Helsinki, Finland, between 2019 and 2022. Species were identified using MALDI-TOF, and presumptive CP C. freundii isolates were subjected to antimicrobial susceptibility testing and further characterized by whole genome sequencing. A genomic comparison was conducted to compare isolates collected from the hospital environment, untreated municipal wastewater, and a selection of isolates from human specimens from two hospitals in the same city. We also examined the persistence of CP C. freundii in the hospital environment and the impact of our attempts to eradicate it. Overall, 27 blaKPC − 2-carrying C. freundii were detected in the hospital environment (ST18; n = 23 and ST8; n = 4), while 13 blaKPC − 2-carrying C. freundii (ST8) and five blaVIM − 1-carrying (ST421) C. freundii were identified in untreated municipal wastewater. CP C. freundii was not identified in hospital wastewater. We found three clusters (cluster distance threshold ≤ 10 allelic difference) after comparing the recovered isolates and a selection of isolates from human specimens. The first cluster consisted of ST18 isolates from the hospital environment (n = 23) and human specimens (n = 4), the second consisted of ST8 isolates from the hospital environment (n = 4), untreated municipal wastewater (n = 6), and human specimens (n = 2), and the third consisted of ST421 isolates from the untreated municipal wastewater (n = 5). Our results support previous studies suggesting that the hospital environment could act as a source of transmission of CP C. freundii in clinical settings. Furthermore, the eradication of CP Enterobacteriaceae from the hospital environment is challenging. Our findings also showed that CP C. freundii is persistent throughout the sewerage system and demonstrate the potential of WWS for detecting CP C. freundii.
Coptischinensis Franch root rot infection disrupts microecological balance of rhizosphere soil and endophytic microbiomes
Authors: Tang Tao , Wang Fanfan , Fang Guobin , Mao Ting , Guo Jie , Kuang Hui , Sun Guangzhong , Guo Xiaoliang , Duan Yuanyuan , You Jingmao
Published: May 2023

Introduction

The ecological balance of the plant microbiome, as a barrier against pathogens, is very important for host health. Coptis chinensis is one of the important medicinal plants in China. In recent years, Illumina Miseq high-throughput sequencing technology was frequently used to analyze root rot pathogens and the effects of root rot on rhizosphere microorganisms of C. chinensis. But the effects of root rot infection on rhizosphere microecological balance of C. chinensis have received little attention.

Methods

In this study, Illumina Miseq high-throughput sequencing technology was applied to analyze the impact on microbial composition and diversity of C. chinensis by root rot.

Results

The results showed that root rot infection had significant impact on bacterial α-diversity in rhizome samples, but had no significant effect on that in leaf samples and rhizosphere soil samples, while root rot infection exhibited significant impact on the fungal α-diversity in leaf samples and rhizosphere soil samples, and no significant impact on that in rhizome samples. PCoA analysis showed that the root rot infection had a greater impact on the fungal community structure in the rhizosphere soil, rhizome, and leaf samples of C. chinensis than on the bacterial community structure. Root rot infection destroyed the microecological balance of the original microbiomes in the rhizosphere soil, rhizome, and leaf samples of C. chinensis, which may also be one of the reasons for the serious root rot of C. chinensis.

Discussion

In conclusion, our findings suggested that root rot infection with C. chinensis disrupts microecological balance of rhizosphere soil and endophytic microbiomes. The results of this study can provide theoretical basis for the prevention and control of C. chinensis root rot by microecological regulation.
Monosomes buffer translational stress to allow for active ribosome elongation
Authors: Schieweck Rico , Ciccopiedi Giuliana , Klau Kenneth , Popper Bastian
Published: May 2023

Introduction: The synthesis of proteins is a fundamental process in the life-span of all cells. The activation of ribosomes on transcripts is the starting signal for elongation and, in turn, the translation of an mRNA. Thereby, most mRNAs circulate between single (monosomes) and multi ribosomal particles (polysomes), a process that defines their translational activity. The interplay between monosomes and polysomes is thought to crucially impact translation rate. How monosomes and polysomes are balanced during stress remains, however, elusive.

Methods: Here, we set out to investigate the monosome and polysome levels as well as their kinetics under different translational stress conditions including mTOR inhibition, downregulation of the eukaryotic elongation factor 2 (eEF2) and amino acid depletion.

Results: By using a timed ribosome runoff approach in combination with polysome profiling, we found that the used translational stressors show very distinct effects on translation. However, they all had in common that the activity of monosomes was preferentially affected. This adaptation seems to be needed for sufficient translation elongation. Even under harsh conditions such as amino acid starvation, we detected active polysomes while monosomes were mostly inactive. Hence, it is plausible that cells compensate the reduced availability of essential factors during stress by adapting the levels of active monosomes to favor sufficient elongation.

Discussion: These results suggest that monosome and polysome levels are balanced under stress conditions. Together, our data argue for the existence of translational plasticity that ensure sufficient protein synthesis under stress conditions, a process that is necessary for cell survival and recovery.
Altered gut microbiota in older adults with mild cognitive impairment: a case-control study
Authors: Fan Kang-Chen , Lin Chen-Ching , Liu Yi-Chien , Chao Yi-Ping , Lai Yen-Jun , Chiu Yen-Ling , Chuang Yi-Fang
Published: May 2023

Introduction

The microbiota-gut-brain axis is implicated in Alzheimer’s disease. Gut microbiota alterations in mild cognitive impairment (MCI) are inconsistent and remain to be understood. This study aims to investigate the gut microbial composition associated with MCI, cognitive functions, and structural brain differences.

Methods

A nested case-control study was conducted in a community-based prospective cohort where detailed cognitive functions and structural brain images were collected. Thirty-one individuals with MCI were matched to sixty-five cognitively normal controls by age strata, gender, and urban/rural area. Fecal samples were examined using 16S ribosomal RNA (rRNA) V3–V4 sequencing. Compositional differences between the two groups were identified and correlated with the cognitive functions and volumes/thickness of brain structures.

Results

There was no significant difference in alpha and beta diversity between MCIs and cognitively normal older adults. However, the abundance of the genus Ruminococcus, Butyricimonas, and Oxalobacter decreased in MCI patients, while an increased abundance of nine other genera, such as Flavonifractor, were found in MCIs. Altered genera discriminated MCI patients well from controls (AUC = 84.0%) and were associated with attention and executive function.

Conclusion

This study provides insights into the role of gut microbiota in the neurodegenerative process.
The ANeED study – ambroxol in new and early dementia with Lewy bodies (DLB): protocol for a phase IIa multicentre, randomised, double-blinded and placebo-controlled trial
Authors: Chwiszczuk Luiza Jadwiga , Breitve Monica Haraldseid , Kirsebom Bjørn-Eivind Bordewick , Selnes Per , Fløvig John Chr. , Knapskog Anne-Brita , Skogseth Ragnhild E. , Hubbers Jessica , Holst-Larsen Elin , Rongve Arvid
Published: May 2023

Background

Currently, there are no disease-modifying pharmacological treatment options for dementia with Lewy bodies (DLB). The hallmark of DLB is pathological alpha-synuclein (aS) deposition. There are growing amounts of data suggesting that reduced aS clearance is caused by failure in endolysosomal and authophagic pathways, as well as and glucocerebrosidase (GCase) dysfunction and mutations in the GCase gene (GBA). The population’s studies demonstrated that the incidence of GBA mutations is higher among Parkinson’s disease (PD) patients, and carriers of such mutations have a higher risk of developing PD. The incidence of GBA mutations is even higher in DLB and a genome-wide association study (GWAS) confirmed the correlation between GBA mutations and DLB. In vivo experiments have shown that ambroxol (ABX) may increase GCase activity and GCase levels and therefore enhance aS autophagy-lysosome degradation pathways. Moreover, there is an emerging hypothesis that ABX may have an effect as a DLB modifying drug. The aims of the study “Ambroxol in new and early Dementia with Lewy Bodies (ANeED) are to investigate the tolerability, safety and effects of ABX in patients with DLB.

Methods

This is a multicentre, phase IIa, double-blinded, randomised and placebo-controlled clinical trial, using a parallel arm design for 18 months’ follow-up. The allocation ratio is 1:1 (treatment:placebo).

Discussion

The ANeED study is an ongoing clinical drug trial with ABX. The unique, but not fully understood mechanism of ABX on the enhancement of lysosomal aS clearance may be promising as a possible modifying treatment in DLB.

Trial Registration

The clinical trial is registered in the international trials register – clinicaltrials.com (NCT0458825) and nationally at the Current Research Information System in Norway (CRISTIN 2235504).
Functional and technical outcomes in acute ischemic stroke patients with hyperdense middle cerebral artery sign treated with endovascular thrombectomy
Authors: Chen Yimin , Diana Francesco , Mofatteh Mohammad , Zhou Sijie , Chen Juanmei , Huang Zhou , Wu Weijuan , Yang Yajie , Zeng Zhiyi , Zhang Weijian , Ouyang Ziqi , Nguyen Thanh N. , Yang Shuiquan , Baizabal-Carvallo José Fidel , Liao Xuxing
Published: May 2023

Background and objective

The hyperdense middle cerebral artery sign (HMCAS) is observed in a proportion of patients with acute ischemic stroke (AIS). This sign reflects the presence of an intravascular thrombus rich in red blood cells. Several studies have demonstrated that HMCAS increases the risk of poor outcomes in AIS patients treated with IV thrombolysis or no reperfusion therapy; however, whether HMCAS predicts a poor outcome in patients treated with endovascular thrombectomy (EVT) is less clear. We aimed to evaluate the functional outcome by the modified Rankin scale (mRS) at 90 days and technical challenges in patients with HMCAS undergoing EVT.

Methods

We studied 143 consecutive AIS patients with middle cerebral artery M1 segment or internal carotid artery + M1 occlusions who underwent EVT.

Results

There were 73 patients (51%) with HMCAS. Patients with HMCAS had a higher frequency of cardioembolic stroke (p = 0.038); otherwise, no other baseline difference was observed. No differences in functional outcomes (mRS) at 90  days (p = 0.698), unfavorable outcomes (mRS > 2) (p = 0.929), frequency of symptomatic intracranial hemorrhage (p = 0.924), and mortality (mRS-6) (p = 0.736) were observed between patients with and without HMCAS. In patients with HMCAS, EVT procedures were 9  min longer, requiring a higher number of passes (p = 0.073); however, optimal recanalization scores (modified thrombolysis in cerebral infarction: 2b-3) were equally achieved by both groups.

Conclusion

Patients with HMCAS treated with EVT do not have a worse outcome at 3  months compared with no-HMCAS patients. Patients with HMCAS required a greater number of thrombus passes and longer procedure times.
Effects of altered excitation–inhibition imbalance by repetitive transcranial magnetic stimulation for self-limited epilepsy with centrotemporal spikes
Authors: Yang Yujiao , Han Yixian , Wang Jing , Zhou Yongkang , Chen Dong , Wang Mengyang , Li Tianfu
Published: May 2023

Objectives

Patients with self-limited epilepsy with centrotemporal spikes (SeLECTS) with electrical status epilepticus in sleep (ESES) have generalized cognitive impairment, yet treatment options are limited. Our study aimed to examine the therapeutic effects of repetitive transcranial magnetic stimulation (rTMS) on SeLECTS with ESES. In addition, we applied electroencephalography (EEG) aperiodic components (offset and slope) to investigate the improvement of rTMS on the excitation–inhibition imbalance (E-I imbalance) in the brain of this group of children.

Methods

Eight SeLECTS patients with ESES were included in this study. Low-frequency rTMS (≤1 Hz) was applied for 10 weekdays in each patient. To assess the clinical efficacy and changes in E-I imbalance, EEG recordings were performed both before and after rTMS. Seizure-reduction rate and spike-wave index (SWI) were measured to investigate the clinical effects of rTMS. The aperiodic offset and slope were calculated to explore the effect of rTMS on E-I imbalance.

Results

Five of the eight patients (62.5%) were seizure-free within 3 months after stimulation, with treatment effects decreasing with longer follow-ups. The SWI decreased significantly at 3 and 6 months after rTMS compared with the baseline (P = 0.0157 and P = 0.0060, respectively). The offset and slope were compared before rTMS and within 3 months after stimulation. The results showed a significant reduction in the offset after stimulation (P < 0.0001). There was a remarkable increase in slope after the stimulation (P < 0.0001).

Conclusion

Patients achieved favorable outcomes in the first 3 months after rTMS. The ameliorative effect of rTMS on SWI may last up to 6 months. Low-frequency rTMS could reduce firing rates in neuronal populations throughout the brain, which was most pronounced at the site of stimulation. A significant reduction in the slope after rTMS treatment suggested an improvement in the E-I imbalance in the SeLECTS.
Conduction treatment of temporal lobe epilepsy in rats: the dose-effect relationship between current resistance and therapeutic effect
Authors: Zhang Shaohui , Yuan Liu , Liu Chunxiu , Kuang Suhui , Wang Jiaqi , Liang Shuli , Cong Ming
Published: May 2023

Objective

To investigate the effect of current resistance on therapeutic outcomes, and the mechanism of current conduction treatment in a rat model of temporal lobe epilepsy (TLE).

Methods

Rats were randomly divided into four groups: normal control, epileptic group, low-resistance conduction (LRC) and high-resistance conduction (HRC) group. The content of glutamate (Glu) and gamma-amino butyric acid (GABA) in the hippocampus was determined using a neurotransmitter analyzer. mRNA and protein expression of interleukin 1β (IL-1β) /IL-1 receptor 1(IL-1R1) and high mobility group protein B1 (HMGB-1)/toll-like receptor-4 (TLR-4) in hippocampal neurons were tested. Video electroencephalogram monitoring was used to record seizures and EEG discharges. Cognitive function in the rats was tested using the Morris water maze.

Results

Glu/GABA ratio in the epileptic control and HRC groups was significant differences from LRC group. The levels of HMGB1/TLR4 and IL-1β/IL-1R1 in the LRC group and normal control group were significantly lower than those in epileptic control group (p < 0.01) and the HRC group. The mRNA levels of HMGB1/TLR4 and IL-1β/IL-1R1 in the LRC group and normal control group were significantly lower than those in epileptic control group. The frequency of total and propagated seizures was lower in the LRC group than in the epileptic control and HRC groups (p < 0.01). The numbers of platform crossings in the LRC group and normal control group were significantly higher than those in the epileptic control and HRC groups in the space exploration experiment.

Conclusion

Current resistance affected seizure control and cognitive protection in rats with TLE treated by current conduction. The lower current resistance, the better seizure control and cognitive protection in rats with TLE treated by current conduction. Glu/GABA, IL-1β/IL-1R1, and HMGB1/TLR-4 may participate in the anti-seizure mechanism of current conduction treatment.
Excess cerebellar granule neurons induced by the absence of p75NTR during development elicit social behavior deficits in mice
Authors: Zanin Juan Pablo , Pandya Mansi A. , Espinoza Diego , Friedman Wilma J. , Shiflett Michael W.
Published: May 2023

Introduction

Recently, the cerebellum has been implicated with non-motor functions, including cognitive and emotional behavior. Anatomical and functional studies demonstrate bidirectional cerebellar connections with brain regions involved in social cognition. Cerebellar developmental abnormalities and injury are often associated with several psychiatric and mental disorders including autism spectrum disorders and anxiety. The cerebellar granule neurons (CGN) are essential for cerebellar function since they provide sensorimotor, proprioceptive, and contextual information to Purkinje cells to modify behavior in different contexts. Therefore, alterations to the CGN population are likely to compromise cerebellar processing and function. Previously we demonstrated that the p75 neurotrophin receptor (p75NTR) was fundamental for the development of the CGN. In the absence of p75NTR, we observed increased proliferation of the granule cell precursors (GCPs), followed by increased GCP migration toward the internal granule layer. The excess granule cells were incorporated into the cerebellar network, inducing alterations in cerebellar circuit processing.

Methods

In the present study, we used two conditional mouse lines to specifically delete the expression of p75NTR in CGN. In both mouse lines, deletion of the target gene was under the control of the transcription factor Atoh-1 promotor, however, one of the lines was also tamoxifen-inducible.

Results

We observed a loss of p75NTR expression from the GCPs in all cerebellar lobes. Compared to control animals, both mouse lines exhibited a reduced preference for social interactions when presented with a choice to interact with a mouse or an object. Open-field locomotor behavior and operant reward learning were unaffected in both lines. Lack of preference for social novelty and increased anxiety-related behavior was present in mice with constitutive p75NTR deletion; however, these effects were not present in the tamoxifen-inducible mice with p75NTR deletion that more specifically targeted the GCPs.

Discussion

Our findings demonstrate that alterations to CGN development by loss of p75NTR alter social behavior, and contribute to the increasing evidence that the cerebellum plays a role in non-motor-related behaviors, including social behavior.
Therapeutic effects of phlorotannins in the treatment of neurodegenerative disorders
Authors: Kwon Yoon Ji , Kwon Oh Ig , Hwang Hye Jeong , Shin Hyeon-Cheol , Yang Sungchil
Published: May 2023

Phlorotannins are natural polyphenolic compounds produced by brown marine algae and are currently found in nutritional supplements. Although they are known to cross the blood–brain barrier, their neuropharmacological actions remain unclear. Here we review the potential therapeutic benefits of phlorotannins in the treatment of neurodegenerative diseases. In mouse models of Alzheimer’s disease, ethanol intoxication and fear stress, the phlorotannin monomer phloroglucinol and the compounds eckol, dieckol and phlorofucofuroeckol A have been shown to improve cognitive function. In a mouse model of Parkinson’s disease, phloroglucinol treatment led to improved motor performance. Additional neurological benefits associated with phlorotannin intake have been demonstrated in stroke, sleep disorders, and pain response. These effects may stem from the inhibition of disease-inducing plaque synthesis and aggregation, suppression of microglial activation, modulation of pro-inflammatory signaling, reduction of glutamate-induced excitotoxicity, and scavenging of reactive oxygen species. Clinical trials of phlorotannins have not reported significant adverse effects, suggesting these compounds to be promising bioactive agents in the treatment of neurological diseases. We therefore propose a putative biophysical mechanism of phlorotannin action in addition to future directions for phlorotannin research.
From molecule to oblivion: dedicated brain circuitry underlies anesthetic loss of consciousness permitting pain-free surgery
Authors: Baron Mark , Devor Marshall
Published: May 2023

The canonical view of how general anesthetics induce loss-of-consciousness (LOC) permitting pain-free surgery posits that anesthetic molecules, distributed throughout the CNS, suppress neural activity globally to levels at which the cerebral cortex can no longer sustain conscious experience. We support an alternative view that LOC, in the context of GABAergic anesthesia at least, results from anesthetic exposure of a small number of neurons in a focal brainstem nucleus, the mesopontine tegmental anesthesia area (MPTA). The various sub-components of anesthesia, in turn, are effected in distant locations, driven by dedicated axonal pathways. This proposal is based on the observations that microinjection of infinitesimal amounts of GABAergic agents into the MPTA, and only there, rapidly induces LOC, and that lesioning the MPTA renders animals relatively insensitive to these agents delivered systemically. Recently, using chemogenetics, we identified a subpopulation of MPTA “effector-neurons” which, when excited (not inhibited), induce anesthesia. These neurons contribute to well-defined ascending and descending axonal pathways each of which accesses a target region associated with a key anesthetic endpoint: atonia, anti-nociception, amnesia and LOC (by electroencephalographic criteria). Interestingly, the effector-neurons do not themselves express GABAA-receptors. Rather, the target receptors reside on a separate sub-population of presumed inhibitory interneurons. These are thought to excite the effectors by disinhibition, thus triggering anesthetic LOC.
Effects of Ganoderma lucidum polysaccharide peptide ameliorating cyclophosphamide-induced immune dysfunctions based on metabolomics analysis
Authors: Xie Jing , Lin Dongmei , Li Jing , Zhou Tonghui , Lin Shuqian , Lin Zhanxi
Published: May 2023

Ganoderma lucidum polysaccharide peptide (GLPP) is one of the most abundant constituents of Ganoderma lucidum (G. lucidum), with a wide range of functional activities. The present study investigated the immunomodulatory effects of GLPP in cyclophosphamide (CTX)-induced immunosuppressive mice. The results showed that 100 mg/kg/day of GLPP administration significantly alleviated CTX-induced immune damage by improving immune organ indexes, earlap swelling rate, the index of carbon phagocytosis and clearance value, secretion of cytokines (TNF-α, IFN-γ, and IL-2), and immunoglobulin A(IgA) in the mice. Furthermore, ultra-performance liquid chromatography with mass/mass spectrometry (UPLC-MS/MS) was conducted to identify the metabolites, followed by biomarker and pathway analysis. The results showed that GLPP treatment alleviated CTX-induced alterations in the fecal metabolome profile, including arachidonic acid (AA), leukotriene D4 (LTD4), indole-3-ethanol, and formyltetrahydrofolate (CF), by reversing citric acid, malic acid, cortisol, and oleic acid. These results support the concept that GLPP exhibits immunomodulatory activity via the folate cycle, methionine cycle, TCA cycle, fatty acid biosynthesis and metabolism, glycerophospholipid metabolism, AA metabolism, and cAMP pathways. In conclusion, the results could be helpful to understand the use of GLPP to clarify the immunomodulatory mechanism and be used as immunostimulants to prevent CTX-induced side effects in the immune system.
Attenuated glucose uptake promotes catabolic metabolism through activated AMPK signaling and impaired insulin signaling in zebrafish
Authors: Xi Longwei , Zhai Gang , Liu Yulong , Gong Yulong , Lu Qisheng , Zhang Zhimin , Liu Haokun , Jin Junyan , Zhu Xiaoming , Yin Zhan , Xie Shouqi , Han Dong
Published: May 2023

Glucose metabolism in fish remains a controversial area of research as many fish species are traditionally considered glucose-intolerant. Although energy homeostasis remodeling has been observed in fish with inhibited fatty acid β-oxidation (FAO), the effects and mechanism of the remodeling caused by blocked glucose uptake remain poorly understood. In this study, we blocked glucose uptake by knocking out glut2 in zebrafish. Intriguingly, the complete lethality, found in Glut2-null mice, was not observed in glut2−/− zebrafish. Approxiamately 30% of glut2−/− fish survived to adulthood and could reproduce. The maternal zygotic mutant glut2 (MZglut2) fish exhibited growth retardation, decreased blood and tissue glucose levels, and low locomotion activity. The decreased pancreatic β-cell numbers and insulin expression, as well as liver insulin receptor a (insra), fatty acid synthesis (chrebp, srebf1, fasn, fads2, and scd), triglyceride synthesis (dgat1a), and muscle mechanistic target of rapamycin kinase (mtor) of MZglut2 zebrafish, suggest impaired insulin-dependent anabolic metabolism. Upregulated expression of lipolysis (atgl and lpl) and FAO genes (cpt1aa and cpt1ab) in the liver and proteolysis genes (bckdk, glud1b, and murf1a) in muscle were observed in the MZglut2 zebrafish, as well as elevated levels of P-AMPK proteins in both the liver and muscle, indicating enhanced catabolic metabolism associated with AMPK signaling. In addition, decreased amino acids and elevated carnitines of the MZglut2 zebrafish supported the decreased protein and lipid content of the whole fish. In summary, we found that blocked glucose uptake impaired insulin signaling-mediated anabolism via β-cell loss, while AMPK signaling-mediated catabolism was enhanced. These findings reveal the mechanism of energy homeostasis remodeling caused by blocked glucose uptake, which may be a potential strategy for adapting to low glucose levels.