bluuebunny/crossref_metadata_2025 huggingface dataset:
Identification and classification of distinct surface markers of T regulatory cells
Authors: Wegrzyn Agnieszka S. , Kedzierska Anna E. , Obojski Andrzej
Published: January 2023

Background

Regulatory T (Treg) cells have emerged as key players in the maintenance of immune homeostasis. Although significant progress has been made in recent years to define the Treg surface markers involved with or identifying their suppressive function, there remains much to be elucidated, and many questions persist. This study determined the expression of surface markers on human peripheral Treg cells and conventional T (Tconv) cells in a steady state and after activation to gain insight into their mechanism of action and more precisely characterize this regulatory population in humans.

Methods

To screen Treg and Tconv cells, peripheral blood mononuclear cells (PBMCs) were isolated from volunteers, stained with a commercially available lyophilized antibody array comprising 371 surface antigens, and analyzed by flow cytometry. To compare Treg cells with activated Tconv cells, PBMCs were stimulated with PMA and further stained similar to freshly isolated cells.

Results

Treg and Tconv cells were positive for 135 and 168 of the 371 antigens, respectively. Based on the frequency distribution, all of the most highly expressed markers identified were shared by both Treg and Tconv cells and participate in T cell activation, act as costimulatory and signaling molecules, or exhibit adhesion and migratory functions. Additionally, we identified several differences in marker expression between Treg and Tconv cells, with most found in the expression of co-stimulatory (ICOS, GITR, 4-1BB) and co-inhibitory (TIGIT, CTLA-4) molecules, as well as chemokine receptors (CXCR4, CXCR5, CCR4, CCR5, CCR7, CCR8, and CXCR7). Furthermore, post-activation expression of surface molecules identified molecules capable of discriminating Treg cells from activated Tconv cells (GITR, 4-1BB, TIGIT, CD120b, and CD39); however, almost all of these markers were also expressed in a small fraction of activated Tconv cells.

Conclusions

These results offer insight into the biology of Tregs and contribute to their accurate identification and characterization in variety of immunological diseases as well as physiological processes
Clinical application and prospect of immune checkpoint inhibitors for CAR-NK cell in tumor immunotherapy
Authors: Yang Kangdi , Zhao Yuze , Sun Guanqun , Zhang Xu , Cao Jinjin , Shao Mingcong , Liang Xijun , Wang Lina
Published: January 2023

Chimeric antigen receptor (CAR) engineering of natural killer (NK) cells is an attractive research field in tumor immunotherapy. While CAR is genetically engineered to express certain molecules, it retains the intrinsic ability to recognize tumor cells through its own receptors. Additionally, NK cells do not depend on T cell receptors for cytotoxic killing. CAR-NK cells exhibit some differences to CAR-T cells in terms of more precise killing, numerous cell sources, and increased effectiveness in solid tumors. However, some problems still exist with CAR-NK cell therapy, such as cytotoxicity, low transfection efficiency, and storage issues. Immune checkpoints inhibit immune cells from performing their normal killing function, and the clinical application of immune checkpoint inhibitors for cancer treatment has become a key therapeutic strategy. The application of CAR-T cells and immune checkpoint inhibitors is being evaluated in numerous ongoing basic research and clinical studies. Immune checkpoints may affect the function of CAR-NK cell therapy. In this review, we describe the combination of existing CAR-NK cell technology with immune checkpoint therapy and discuss the research of CAR-NK cell technology and future clinical treatments. We also summarize the progress of clinical trials of CAR-NK cells and immune checkpoint therapy.
Lysine methyltransferase Kmt2d regulates naive CD8+ T cell activation-induced survival
Authors: Kim Jaekwan , Nguyen Thomas , Cifello Jeffrey , Ahmad Raheel , Zhang Yongqing , Yang Qian , Lee Ji-Eun , Li Xiang , Kai Yan , De Supriyo , Peng Weiqun , Ge Kai , Weng Nan-ping
Published: January 2023

Lysine specific methyltransferase 2D (Kmt2d) catalyzes the mono-methylation of histone 3 lysine 4 (H3K4me1) and plays a critical role in regulatory T cell generation via modulating Foxp3 gene expression. Here we report a role of Kmt2d in naïve CD8+ T cell generation and survival. In the absence of Kmt2d, the number of CD8+ T cells, particularly naïve CD8+ T cells (CD62Lhi/CD44lo), in spleen was greatly decreased and in vitro activation-related death significantly increased from Kmt2dfl/flCD4cre+ (KO) compared to Kmt2dfl/flCD4cre- (WT) mice. Furthermore, analyses by ChIPseq, RNAseq, and scRNAseq showed reduced H3K4me1 levels in enhancers and reduced expression of apoptosis-related genes in activated naïve CD8+ T cells in the absence of Kmt2d. Finally, we confirmed the activation-induced death of antigen-specific naïve CD8+ T cells in vivo in Kmt2d KO mice upon challenge with Listeria monocytogenes infection. These findings reveal that Kmt2d regulates activation-induced naïve CD8+ T cell survival via modulating H3K4me1 levels in enhancer regions of apoptosis and immune function-related genes.
Impact of ankylosing spondylitis on stroke limited to specific subtypes: Evidence from Mendelian randomization study
Authors: Mei Jian , Wei Penghui , Zhang Linjie , Ding Haiqi , Zhang Wenming , Tang Yusen , Fang Xinyu
Published: January 2023

Background

The relationship between Ankylosing Spondylitis (AS) and the risk of stroke is complex. Therefore, we utilized Two-Sample Mendelian randomization to examine the probable causal link between these two features.

Methods

The genetic instruments linked to AS were chosen from a summary-level genetic data set from the FinnGen consortium in people of European ancestry (1462 cases and 164,682 controls). Stroke and its subtypes were selected as outcomes, and the MEGASTROKE consortium population was used to identify the genetic associations of AS on stroke (40,585 cases and 406,111 controls), ischemic stroke (IS) (34,217 cases and 406,111 controls), and its subtypes including large artery stroke (LAS) (4373 cases and 146,392 controls), small vessel stroke (SVS) (5386 cases and 192,662 controls), and cardioembolic stroke (CES) (7193 cases and 204,570 controls). Intracerebral hemorrhage (ICH) (1687 cases and 201,146 controls) data set from the FinnGen consortium was also used. To obtain the casual estimates, the inverse variant weighted (IVW) method was mainly used. By examining the heterogeneity and pleiotropy of particular single nucleotide polymorphisms (SNPs), the robustness of the results was also examined.

Results

There was no evidence found to prove the correlation between genetically predicted AS and stroke (odds ratio [OR] 1.014; 95% confidence interval [CI] 0.999-1.031; P = 0.063), ICH (OR 1.030; 95% CI 0.995-1.067; P = 0.090), and IS (OR 1.013; 95% CI 0. 998-1.030; P = 0.090). In terms of the different subtypes of IS, there was strong evidence of positive causal inferences on CES (OR 1.051; 95% CI 1.022-1.081; P = 0.001), and suggestive evidence of positive causal inferences on LAS (OR 1.042; 95% CI 1.003-1.082; P = 0.033), while it was not significant for SVS (OR 1.010; 95% CI 0.975-1.047; P = 0.563).

Conclusion

This study suggests that the possible causative impact of genetically predicted AS on stroke may be restricted to the CES and LAS subtypes.
The survival outcomes of neoadjuvant sintilimab combined with chemotherapy in patients with locally advanced esophageal squamous cell carcinoma
Authors: Lv Huilai , Huang Chao , Li Jiachen , Zhang Fan , Gai Chunyue , Liu Zhao , Xu Shi , Wang Mingbo , Li Zhenhua , Tian Ziqiang
Published: January 2023

Background

Neoadjuvant programmed death receptor-1 (PD-1) inhibitor combined with chemotherapy has been reported to improve the pathological response of locally advanced esophageal squamous cell carcinoma (ESCC), but the systematic report on survival follow-up is quite few. This study we will report the survival follow-up outcomes after a median follow-up of 21.1 months.

Methods

This was a real-world retrospective study. Locally advanced ESCC patients treated with neoadjuvant sintilimab combined with albumin-bound paclitaxel and nedaplatin followed by surgery and completed at least 1-year follow-up were reviewed. The primary outcome was disease-free survival (DFS) at 24 months. The secondary outcome was overall survival (OS) at 24 months.

Results

Ninety eligible patients were included in the analysis between July 2019 and October 2021. The median number of neoadjuvant cycles was 3 (range 2-4). All patients achieved R0 resection. With a median follow-up of 21.1 months (range 14.0-39.0), the median DFS and median OS had not reached, 2-year DFS rate was 78.3% (95%CI 68.8%-89.1%) and 2-years OS rate was 88.0% (95%CI 80.6%-96.0%). Postoperative pathological stage, pCR, MPR, tumor down-staging were significantly correlated with favorable survival outcome. Univariable and multivariable Cox regression analysis identified cycle number of neoadjuvant treatment as independent predictor of DFS.

Conclusion

Our results preliminarily show a survival benefit of neoadjuvant sintilimab combined with chemotherapy in locally advanced ESCC.
Submesoscale dynamics accompanying the Kuroshio in the East China Sea
Authors: Chen Juntian , Zhu Xiao-Hua , Zheng Hua , Wang Min
Published: January 2023

Submesoscale processes in the ocean are vital for sustaining energy balance across scales. Taking advantage of the high resolution and wide coverage of numerical simulations, which are currently lacking for field observations, we investigated the basic patterns of submesoscale dynamics and mechanisms of corresponding variabilities along with the Kuroshio in the East China Sea. The large-scale western boundary jet serves as a remarkable submesoscale energy reservoir, promoted by steep topographic features. In the discovered hotspots, that is, the continental slope and lee area of the Tokara Strait, long-lasting submesoscale footprints arose in the form of linear patterns of strongly skewed Rossby numbers with maximum values of ~O(1). Their origin may be derived from the high topographically induced strain rate, which shows a consistent distribution and high correlation with the Rossby number. Corresponding to the characteristics of such active submesoscale processes, kinetic energy wavenumber spectra were visibly flatter than previous estimations of typical two-dimensional geostrophic turbulence and were not temporally fixed under the combined effects of multiple factors. The annual cycle of stratification induces seasonality by affecting mixed-layer instabilities, which control the kinetic and potential energy conversion rates. The tidal periods may be due to tides generating inertia-gravity waves that partially overlap in submesoscale ranges. Various other intermediate periods of variability were probably related to the eddy-caused Kuroshio path meander, which implied a closely coupled dynamical system across scales. Uncertainties come from the ascertainment of the specific contribution ratios of each part, which will be studied in the future.
Influence of daily rhythmic light spectra and intensity changes on the growth and physiological status of juvenile steelhead trout (Oncorhynchus mykiss)
Authors: Ma Shisheng , Li Li , Chen Xiaoqun , Chen Shujing , Dong Yunwei , Gao Qinfeng , Zhou Yangen , Dong Shuanglin
Published: January 2023

The objective of this study was to investigate the effects of different rhythmic light spectra and intensities on growth performance and physiological and biochemical parameters of juvenile steelhead trout (Oncorhynchus mykiss). Seven treatments were randomly assigned to 21 tanks using a single-flow system for 13 weeks (N = 3), namely blue–purple–red light (BPR), red–purple–blue light (RPB), blue light (VB), and red light (VR). These light treatments alternated at 300, 900, and 1,200 lx, as well as a constant 900 lx of blue light (CB), red light (CR), and white light (CW). Results showed that the highest feed intake (FI), final body weight (FBW), and specific growth rate (SGR) were observed in the BPR treatment, which were significantly higher than those in the CW, CR, CB, and VB treatments. BPR treatment resulted in higher levels of insulin-like growth factor 1 (IGF-1), free triiodothyronine (FT3) and thyroxine (FT4), superoxide dismutase (SOD), and catalase (CAT), and total antioxidant capacity (T-AOC) activities were found. Fish exposed to BPR showed significantly enhanced lipase (LPS) and trypsin (Trp) activity in the stomach and gut tissues which promoted digestion. Trout exposed to a constant light spectra and intensity environment showed decreased activities of antioxidant and gastrointestinal digestive enzymes. Our results indicate the positive influence of BPR light conditions on the growth, stress response, digestion, and metabolism of juvenile steelhead trout, which is likely related to its similarity to the light rhythm in natural water environments, and can be used to improve growth and physiological status in the aquaculture trout.
Large-scale fire whirl and forest fire disasters: Awareness, implications, and the need for developing preventative methods
Authors: Darwish Ahmad Adnan , Akafuah Nelson K. , Forthofer Jason , Fuchihata Manabu , Hirasawa Taro , Kuwana Kazunori , Nakamura Yuji , Sekimoto Kozo , Saito Kozo , Williams Forman A.
Published: January 2023

The authors are a team of fire whirl researchers who have been actively studying whirls and large-scale wildland fires by directly observing them through fire-fighting efforts and applying theory, scale modeling, and numerical simulations in fire research. This multidisciplinary research-background team previously conducted scale model experiments to reconstruct hazardous large-scale fires in the laboratory, then conducted numerical simulations and developed fundamental theories to translate these findings into a basic understanding of combustion science and fluid dynamics. This article, a mix of reviews of the state of art experiments, theories, numerical modeling and artificial intelligence, and two case studies, is intended to address some safety concerns and raise awareness of large-scale fire whirls and forest fires with knowledge of thermodynamics, chemical kinetics, fluid dynamics, design, and practical fire-fighting experience, offering gaps that should be filled and future research to be conducted in each field, and crucial new observations and insights on large-scale fire incidents. We believe, this timely topic is of interest not only to fire research community but also to general readers, as the frequency and intensity of large-scale forest fires and fire whirls have increased, possibly due to the continuing global warming trend and human-induced changes in fuels. Each section and case study was written by one or two individual researchers based on their field of expertise which allows them to critically review progress made in their section of large-scale fire-whirls and forest-fires. Crucial observations and insights on the historical Great-Kanto-Earthquake-generated Hifukusho-Ato Fire-whirl (HAFW) and the slow rotations observed during recent forest firefighting efforts are presented. The first case study occurred in downtown Tokyo on 1 September 1923, as a result of the Great-Kanto-Earthquake, which claimed over 38,000 deaths within 15 min. The second case study discusses large-scale slow rotations observed during recent forest fires, which might had been responsible for the injuries and deaths of experienced firefighters.
Efficacy of small-incision lenticule extraction surgery in high astigmatism: A meta-analysis
Authors: Cui Ge , Di Yu , Yang Shan , Chen Di , Li Ying
Published: January 2023

Purpose

This study aimed to evaluate the efficacy of small-incision lenticule extraction (SMILE) in improving vision and visual quality and correcting astigmatism for the treatment of high astigmatism.

Methods

Eligible studies and studies comparing the efficacy of SMILE with femtosecond laser-assisted laser in situ keratomileusis (FS-LASIK) or transepithelial photorefractive keratectomy (T-PRK) for high astigmatism (≥2.00 D) were identified in PubMed, Embase, and the Cochrane Central Register of Controlled Trials, searched from their inception to 29 May 2022. The references of all searched studies were checked as supplements. The risk of bias was evaluated for each eligible study. The literature was screened according to the inclusion and exclusion criteria, and relative data were extracted. Data were extracted and analyzed by ReviewManager 5.4. The primary outcome was post-operative uncorrected distance visual acuity (UDVA). The secondary outcomes included corneal aberrations and vector parameters. The weight mean difference (WMD) and their 95% confidence intervals (95% CI) were used to assess the strength of the association.

Results

A total of six studies including 380 astigmatism eyes were involved, with 211 high-astigmatism eyes and 31 low-astigmatism eyes undergoing SMILE surgery, 94 high-astigmatism eyes undergoing FS-LASIK surgery, and 44 high-astigmatism eyes undergoing T-PRK surgery. Compared with non-SMILE, SMILE induced more astigmatism (weighted mean difference [WMD] = −0.07, 95% CI [−0.12 to −0.02], P = 0.005) and fewer sphere aberrations (WMD = −0.12, 95% CI [−0.17 to −0.08], P < 0.00001). The post-operative UDVA, sphere, spherical equivalent (SE), and higher order aberrations in different surgeries were likewise equivalent. The difference vector and index of success were significantly higher, and the surgically induced astigmatism vector, correction index, and magnitude of error were significantly lower in SMILE.

Conclusion

This meta-analysis suggests that SMILE, FS-LASIK, and T-PRK show excellent efficacy, predictability, and safety for myopia. SMILE exhibited less astigmatism refraction predictability and less surgically induced spherical aberrations. There may be more under-correction in SMILE. More randomized, prospective, and large sample-sized studies are needed to confirm these conclusions in the long term.
Thyroid Langerhans cell histiocytosis concurrent with papillary thyroid carcinoma: A case report and literature review
Authors: Mi Bin , Wu Di , Fan Yue , Thong Benjamin Ka Seng , Chen Yudong , Wang Xue , Wang Chaofu
Published: January 2023

Langerhans cell histiocytosis (LCH) is a clonal neoplasm of myeloid dendritic cells, rarely involving the thyroid gland. Papillary thyroid carcinoma (PTC) is the most common histological subtype of thyroid cancer. We report a rare case of a 34-year-old Chinese woman who has LCH with PTC and cervical lymph node metastasis of LCH, with a review of the literature. The patient has thyroid nodules and cervical lymph node enlargement detected by neck ultrasound during physical examination. Fine needle aspiration cytology (FNAC) showed PTC with Hashimoto’s thyroiditis and BRAF V600E mutation after thyroidectomy and lymph node dissection. Histopathological examination suggests that LCH was concurrent with classical PTC, accompanied by LCH cervical lymph node metastasis. No BRAF, HRAS, and TERT promoter mutations were detected in LCH metastatic lesions. The patient is in stable clinical condition currently.
A comprehensive overview of cellular senescence from 1990 to 2021: A machine learning-based bibliometric analysis
Authors: Li Chan , Liu Zhaoya , Shi Ruizheng
Published: January 2023

Background

As a cellular process, senescence functions to prevent the proliferation of damaged, old and tumor-like cells, as well as participate in embryonic development, tissue repair, etc. This study aimed to analyze the themes and topics of the scientific publications related to cellular senescence in the past three decades by machine learning.

Methods

The MeSH term “cellular senescence” was used for searching publications from 1990 to 2021 on the PubMed database, while the R platform was adopted to obtain associated data. A topic network was constructed by latent Dirichlet allocation (LDA) and the Louvain algorithm.

Results

A total of 21,910 publications were finally recruited in this article. Basic studies (15,382, 70.21%) accounted for the most proportion of publications over the past three decades. Physiology, drug effects, and genetics were the most concerned MeSH terms, while cell proliferation was the leading term since 2010. Three senolytics were indexed by MeSH terms, including quercetin, curcumin, and dasatinib, with the accumulated occurrence of 35, 26, and 22, separately. Three clusters were recognized by LDA and network analyses. Telomere length was the top studied topic in the cluster of physiological function, while cancer cell had been a hot topic in the cluster of pathological function, and protein kinase pathway was the most popular topic in the cluster of molecular mechanism. Notably, the cluster of physiological function showed a poor connection with other clusters.

Conclusion

Cellular senescence has obtained increasing attention over the past three decades. While most of the studies focus on the pathological function and molecular mechanism, more researches should be conducted on the physiological function and the clinical translation of cellular senescence, especially the development and application of senotherapeutics.
New onset, transient and stable motoric cognitive risk syndrome: Clinical characteristics and association with incidence of probable dementia in the NuAge cohort
Authors: Beauchet Olivier , Matskiv Jacqueline , Gaudreau Pierrette , Allali Gilles
Published: January 2023

Background

Motoric cognitive risk syndrome (MCR) is a pre-dementia stage. The existence of stable and transient MCR, their related clinical characteristics and their association with incident dementia is a matter of debate.

Objective

This study aims to examine the clinical characteristics and the time course associated with new onset, transient and stable MCR, and their association with incidence of probable dementia in community-dwelling older adults living in the province of Quebec (Canada).

Design

Quebec elderly population-based observational cohort study with 3 years of follow-up.

Setting

Community dwellers.

Subjects

A subset of participants (n = 1,113) from the “Quebec Longitudinal Study on Nutrition and Successful Aging” (NuAge) cohort.

Methods

Participants with MCR were identified at baseline and after 1 year of follow-up. Socio-demographic characteristics, 30-item Geriatric depression scale (GDS) score, cardiovascular risk factors and diseases were recorded at baseline. Incidence of probable dementia was measured at annual follow-up visits over a 3-year period.

Results

Over the period of the first year of follow-up, the prevalence of MCR was 8.5% with 4.3% having new onset MCR, 2.8% transient MCR and 1.4% stable MCR. A higher 30-item GDS score was reported with new onset and transient MCR, and the highest prevalence of cerebrovascular diseases was shown with stable MCR compared to non-MCR participants (p < 0.05). MCR was associated with overall incidence of probable dementia, regardless of its status (Hazard Ratio ≥ 1.86, p ≤ 0.034).

Conclusion

Greater prevalence of depressive symptoms and cerebrovascular diseases were reported, respectively, with new onset and transient MCR, and stable MCR. The association of MCR with incidence of probable dementia remains significant, regardless of MCR subtypes.
Distinct role of the right temporoparietal junction in advantageous and disadvantageous inequity: A tDCS study
Authors: Wu Shijing , Cai Shenggang , Dong Zhiqiang , Zhang Hanqi
Published: January 2023

Fairness is a hallmark of humans' ability to maintain cooperative relationships with large numbers of unrelated others. It influences many aspects of daily life, from how people share their resources with partners to how policymakers shape income distribution policy. The right temporoparietal junction (rTPJ) is a hub of the mentalizing network and it has been proposed to play a key role in guiding human reciprocal behavior; however, its precise functional contribution to fair behavior in situations of advantageous and disadvantageous inequity remains unclear. The purpose of this study was to clarify the role of the rTPJ in relation to fair behavior in situations of advantageous and disadvantageous inequity by modulating the activation of the rTPJ through transcranial direct current stimulation (tDCS). Anodal tDCS at 1.5 mA over the primary visual cortex (VC) or rTPJ was performed and participants subsequently played a binary-choice version of the Dictator Game. We found that anodal tDCS over the rTPJ increased the participants' equity choices in the disadvantageous inequity situation but not in the advantageous inequity situation. The tDCS effect is moderated by sex and, in particular, the tDCS effect increases female equity choices. The results suggest that the rTPJ plays a distinct role in inequity aversion in these two types of inequity situations.
Effect analysis of neural network robot system in music relaxation training to alleviate adverse reactions of chemotherapy in patients with breast cancer
Authors: Teng Yue , Bao Jinlei , Li Yinfeng , Ye Haichun
Published: January 2023

Music therapy is a common method to relieve anxiety and pain in cancer patients after surgery in recent years, but due to the lack of technical and algorithmic support, this therapy is not particularly stable and the therapeutic effect is not good. In this study, a neural network robotic system based on breast cancer patients was designed to analyze the effect of music relaxation training on alleviating adverse reactions after chemotherapy in breast cancer patients. Firstly, this paper introduces the necessity of neural network robot system research under the background of music therapy, and then summarizes the positive effect of music relaxation therapy on alleviating adverse reactions after chemotherapy in breast cancer patients, finally, uses neural network robot system to construct music therapy system. The experimental results show that the new music therapy proposed in this study has a good effect in alleviating the adverse reactions of breast cancer patients after chemotherapy, and the cure rate is increased by 7.84%. The research results of this paper provide reference for the next development of neural network robot system in the medical field.
Protein content of blood-derived extracellular vesicles: An approach to the pathophysiology of cerebral hemorrhage
Authors: Laso-García Fernando , Piniella Dolores , Gómez-de Frutos Mari Carmen , Casado-Fernández Laura , Pérez-Mato María , Alonso-López Elisa , Otero-Ortega Laura , Bravo Susana Belén , Chantada-Vázquez María Del Pilar , Trilla-Fuertes Lucía , Fresno-Vara Juan Ángel , Fuentes Blanca , Díez-Tejedor Exuperio , Gutiérrez-Fernández María , Alonso De Leciñana María
Published: January 2023

Introduction: Extracellular vesicles (EVs) participate in cell-to-cell paracrine signaling and can be biomarkers of the pathophysiological processes underlying disease. In intracerebral hemorrhage, the study of the number and molecular content of circulating EVs may help elucidate the biological mechanisms involved in damage and repair, contributing valuable information to the identification of new therapeutic targets.

Methods: The objective of this study was to describe the number and protein content of blood-derived EVs following an intracerebral hemorrhage (ICH). For this purpose, an experimental ICH was induced in the striatum of Sprague-Dawley rats and EVs were isolated and characterized from blood at baseline, 24 h and 28 days. The protein content in the EVs was analyzed by mass spectrometric data-dependent acquisition; protein quantification was obtained by sequential window acquisition of all theoretical mass spectra data and compared at pre-defined time points.

Results: Although no differences were found in the number of EVs, the proteomic study revealed that proteins related to the response to cellular damage such as deubiquitination, regulation of MAP kinase activity (UCHL1) and signal transduction (NDGR3), were up-expressed at 24 h compared to baseline; and that at 28 days, the protein expression profile was characterized by a higher content of the proteins involved in healing and repair processes such as cytoskeleton organization and response to growth factors (COR1B) and the regulation of autophagy (PI42B).

Discussion: The protein content of circulating EVs at different time points following an ICH may reflect evolutionary changes in the pathophysiology of the disease.
Oligodendrogenesis and myelination tracing in a CRISPR/Cas9-engineered brain microphysiological system
Authors: Romero July Carolina , Berlinicke Cynthia , Chow Sharon , Duan Yukan , Wang Yifei , Chamling Xitiz , Smirnova Lena
Published: January 2023

Introduction

Oligodendrocytes (OLs) are the myelin-forming cells of the central nervous system (CNS). Although OLs can be differentiated from human-induced pluripotent stem cells (hiPSCs), the in vitro modeling of axon myelination in human cells remains challenging. Brain microphysiological systems (bMPS, e.g. organoids) are complex three-dimensional (3D) cultures that offer an ideal system to study this process as OLs differentiate in a more in vivo-like environment; surrounded by neurons and astrocytes, which support the myelination of axons.

Methods

Here, we take advantage of CRISPR/Cas9 technology to generate a hiPSC line in which proteolipid protein 1 (PLP1), an OLs marker, is tagged with super-fold GFP (sfGFP). While generating the PLP1-sfGFP reporter, we used reverse transfection and obtained higher Knock-In (KI) efficiency compared to forward transfection (61–72 vs. 46%).

Results

After validation of the KI and quality control of the PLP1-sfGFP line, selected clones were differentiated into bMPS, and the fidelity, specificity, and function of the tagged PLP protein were verified in this model. We tracked different stages of oligodendrogenesis in the verified lines based on PLP1-sfGFP+ cells’ morphology, and the presence of PLP1-sfGFP surrounding axons during bMPS’ differentiation. Finally, we challenged the bMPS with cuprizone and quantified changes in both the percentage of PLP1-sfGFP expressing cells and the intensity of GFP expression.

Discussion

This work demonstrates an efficient method for generating hiPSC KI lines and the description of a new 3D model to study OL differentiation, migration, and maturation both during in vitro neurodevelopment as well as in response to environmental chemicals or disease-associated stressors.
Treadmill training of rats after sciatic nerve graft does not alter accuracy of muscle reinnervation
Authors: Barham Mohammed , Andermahr Jonas , Majczyński Henryk , Sławińska Urszula , Vogt Johannes , Neiss Wolfram F.
Published: January 2023

Background and purpose

After peripheral nerve lesions, surgical reconstruction facilitates axonal regeneration and motor reinnervation. However, functional recovery is impaired by aberrant reinnervation.

Materials and methods

We tested whether training therapy by treadmill exercise (9 × 250 m/week) before (run–idle), after (idle–run), or both before and after (run–run) sciatic nerve graft improves the accuracy of reinnervation in rats. Female Lewis rats (LEW/SsNHsd) were either trained for 12 weeks (run) or not trained (kept under control conditions, idle). The right sciatic nerves were then excised and reconstructed with 5 mm of a congenic allograft. One week later, training started in the run–run and idle–run groups for another 12 weeks. No further training was conducted in the run–idle and idle–idle groups. Reinnervation was measured using the following parameters: counting of retrogradely labeled motoneurons, walking track analysis, and compound muscle action potential (CMAP) recordings.

Results

In intact rats, the common fibular (peroneal) and the soleus nerve received axons from 549 ± 83 motoneurons. In the run–idle group, 94% of these motoneurons had regenerated 13 weeks after the nerve graft. In the idle–run group, 81% of the normal number of motoneurons had regenerated into the denervated musculature and 87% in both run–run and idle–idle groups. Despite reinnervation, functional outcome was poor: walking tracks indicated no functional improvement of motion in any group. However, in the operated hindlimb of run–idle rats, the CMAP of the soleus muscle reached 11.9 mV (normal 16.3 mV), yet only 6.3–8.1 mV in the other groups.

Conclusion

Treadmill training neither altered the accuracy of reinnervation nor the functional recovery, and pre-operative training (run–idle) led to a higher motor unit activation after regeneration.
Longitudinal association between changes in resting-state network connectivity and cognition trajectories: The moderation role of a healthy diet
Authors: Gaynor Alexandra M. , Varangis Eleanna , Song Suhang , Gazes Yunglin , Habeck Christian , Stern Yaakov , Gu Yian
Published: January 2023

Introduction

Healthy diet has been shown to alter brain structure and function and improve cognitive performance, and prior work from our group showed that Mediterranean diet (MeDi) moderates the effect of between-network resting-state functional connectivity (rsFC) on cognitive function in a cross-sectional sample of healthy adults. The current study aimed to expand on this previous work by testing whether MeDi moderates the effects of changes in between- and within-network rsFC on changes in cognitive performance over an average of 5 years.

Methods

At baseline and 5-year follow up, 124 adults aged 20–80 years underwent resting state fMRI to measure connectivity within and between 10 pre-defined networks, and completed six cognitive tasks to measure each of four cognitive reference abilities (RAs): fluid reasoning (FLUID), episodic memory, processing speed and attention, and vocabulary. Participants were categorized into low, moderate, and high MeDi groups based on food frequency questionnaires (FFQs). Multivariable linear regressions were used to test relationships between MeDi, change in within- and between-network rsFC, and change in cognitive function.

Results

Results showed that MeDi group significantly moderated the effects of change in overall between-network and within-network rsFC on change in memory performance. Exploratory analyses on individual networks revealed that interactions between MeDi and between-network rsFC were significant for nearly all individual networks, whereas the moderating effect of MeDi on the relationship between within-network rsFC change and memory change was limited to a subset of specific functional networks.

Discussion

These findings suggest healthy diet may protect cognitive function by attenuating the negative effects of changes in connectivity over time. Further research is warranted to understand the mechanisms by which MeDi exerts its neuroprotective effects over the lifespan.
Cognitive impairment with Type 2 Diabetes Mellitus among community-dwelling older adults in Chile: Prevalence, risk factors and cognitive characteristics
Authors: Bozanic Agnieszka , Toro Pablo , Bello-Lepe Sebastián , Hurtado-Oliva Javier , Beyle Christian , Valdés Catalina , Formiga Francesc
Published: January 2023

Introduction

The aim of this study is to determine prevalence and risk factors of Cognitive Impairment (CI) and its association with Type 2 Diabetes Mellitus (T2DM) in subjects aged 65 years and above. Additionally, we attempt to provide a cognitive profile for T2DM group.

Methodology

A cross-sectional analytical study to assess CI was carried out. We evaluated a sample of community-dwelling residents from Chile. All participants underwent a general interview, lifestyle questionnaires and a comprehensive neuropsychological battery. Regression analyses were performed to evaluate risk of CI with T2DM and influencing factors. Results between groups in the different domains of the neuropsychological assessment were compared by Student’s t-tests and MANOVA.

Results

Among all 358 subjects, overall T2DM prevalence were 17.3%. The prevalence of CI was higher in T2DM group compared to the healthy participants (30.7%, p < 0.001). The risk of CI was 2.8 times higher in older people with T2DM compared to older people without the diagnosis. Multiple regression analysis, adjusted for age and gender, demonstrated that age, education, presence of dyslipidemia, and T2DM duration were the predictor variables significantly associated with CI. T2DM group performed worse on global cognitive performance, attention, language, verbal memory, visual memory, visual constructional ability, and executive function. After adjusting for significant covariates from multiple regression analysis, a relationship between “cognition” and T2DM is still observed. Amnesic multi-domain impairment was the specific cognitive identified pattern for T2DM group.

Conclusion

The present study confirms the high prevalence of CI with T2DM among Chilean older adults in a community-based population. T2DM is significantly associated with a higher risk of CI, and age, education, presence of dyslipidemia, and duration of T2DM are risk factors. T2DM patients with CI are impaired in multiple cognitive domains, even after adjusting covariables, resulting in an amnesic multi-domain cognitive profile.
Aberrant resting-state regional activity in patients with postpartum depression
Authors: Li Bo , Zhang Shufen , Li Shuyan , Liu Kai , Hou Xiaoming
Published: January 2023

Background

Postpartum depression (PPD) is a common disorder with corresponding cognitive impairments such as depressed mood, memory deficits, poor concentration, and declining executive functions, but little is known about its underlying neuropathology.

Method

A total of 28 patients with PPD and 29 healthy postpartum women were recruited. Resting-state functional magnetic resonance imaging (rs-fMRI) scans were performed in the fourth week after delivery. Individual local activity of PPD patients was observed by regional homogeneity (ReHo) during resting state, and the ReHo value was computed as Kendall's coecient of concordance (KCC) and analyzed for differences between voxel groups. Correlations between ReHo values and clinical variables were also analyzed.

Result

Compared with healthy postpartum women, patients with PPD exhibited significantly higher ReHo values in the left precuneus and right hippocampus. ReHo value was significantly lower in the left dorsolateral prefrontal cortex (dlPFC) and right insula. Furthermore, ReHo values within the dlPFC were negatively correlated with the Edinburgh PPD scale (EPDS) score. The functional connectivity (FC) of the right hippocampus to the left precuneus and left superior frontal gyrus (SFG) was stronger in patients with PPD than that in controls.

Conclusion

The present study provided evidence of aberrant regional functional activity and connectivity within brain regions in PPD, and it may contribute to further understanding of the neuropathology underlying PPD.
Comparing therapeutic modulators of the SOD1 G93A Amyotrophic Lateral Sclerosis mouse pathophysiology
Authors: Lee Albert J. B. , Kittel Tyler E. , Kim Renaid B. , Bach Thao-Nguyen , Zhang Tian , Mitchell Cassie S.
Published: January 2023

Introduction

Amyotrophic Lateral Sclerosis (ALS) is a paralyzing, multifactorial neurodegenerative disease with limited therapeutics and no known cure. The study goal was to determine which pathophysiological treatment targets appear most beneficial.

Methods

A big data approach was used to analyze high copy SOD1 G93A experimental data. The secondary data set comprised 227 published studies and 4,296 data points. Treatments were classified by pathophysiological target: apoptosis, axonal transport, cellular chemistry, energetics, neuron excitability, inflammation, oxidative stress, proteomics, or systemic function. Outcome assessment modalities included onset delay, health status (rotarod performance, body weight, grip strength), and survival duration. Pairwise statistical analysis (two-tailed t-test with Bonferroni correction) of normalized fold change (treatment/control) assessed significant differences in treatment efficacy. Cohen’s d quantified pathophysiological treatment category effect size compared to “all” (e.g., all pathophysiological treatment categories combined).

Results

Inflammation treatments were best at delaying onset (d = 0.42, p > 0.05). Oxidative stress treatments were significantly better for prolonging survival duration (d = 0.18, p < 0.05). Excitability treatments were significantly better for prolonging overall health status (d = 0.22, p < 0.05). However, the absolute best pathophysiological treatment category for prolonging health status varied with disease progression: oxidative stress was best for pre-onset health (d = 0.18, p > 0.05); excitability was best for prolonging function near onset (d = 0.34, p < 0.05); inflammation was best for prolonging post-onset function (d = 0.24, p > 0.05); and apoptosis was best for prolonging end-stage function (d = 0.49, p > 0.05). Finally, combination treatments simultaneously targeting multiple pathophysiological categories (e.g., polytherapy) performed significantly (p < 0.05) better than monotherapies at end-stage.

Discussion

In summary, the most effective pathophysiological treatments change as function of assessment modality and disease progression. Shifting pathophysiological treatment category efficacy with disease progression supports the homeostatic instability theory of ALS disease progression.
Putative cause of seizure-induced cognitive alterations: The oscillatory reconfiguration of seizure network
Authors: Fan Denggui , Qi Lixue , Yang Zecheng , Luan Guoming , Wang Qingyun
Published: January 2023

Introduction

The dynamic reconfiguration of network oscillations is connected with cognitive processes. Changes in how neural networks and signaling pathways work are crucial to how epilepsy and related conditions develop. Specifically, there is evidence that prolonged or recurrent seizures may induce or exacerbate cognitive impairment. However, it still needs to be determined how the seizure brain configures its functional structure to shape the battle of strong local oscillations vs. slow global oscillations in the network to impair cognitive function.

Methods

In this paper, we aim to deduce the network mechanisms underlying seizure-induced cognitive impairment by comparing the evolution of strong local oscillations with slow global oscillations and their link to the resting state of healthy controls. Here, we construct a dynamically efficient network of pathological seizures by calculating the synchrony and directionality of information flow between nine patients’ SEEG signals. Then, using a pattern-based method, we found hierarchical modules in the brain’s functional network and measured the functional balance between the network’s local strong and slow global oscillations.

Results and discussion

According to the findings, a tremendous rise in strong local oscillations during seizures and an increase in slow global oscillations after seizures corresponded to the initiation and recovery of cognitive impairment. Specifically, during the interictal period, local strong and slow global oscillations are in metastable balance, which is the same as a normal cognitive process and can be switched easily. During the pre-ictal period, the two show a bimodal pattern of separate peaks that cannot be easily switched, and some flexibility is lost. During the seizure period, a single-peak pattern with negative peaks is showcased, and the network eventually transitions to a very intense strong local oscillation state. These results shed light on the mechanism behind network oscillations in epilepsy-induced cognitive impairment. On the other hand, the differential (similarity) of oscillatory reorganization between the local (non) epileptogenic network and the global network may be an emergency protective mechanism of the brain, preventing the spread of pathological information flow to more healthy brain regions.
Eighteen years’ experience with tumor treating fields in the treatment of newly diagnosed glioblastoma
Authors: Vymazal Josef , Kazda Tomas , Novak Tomas , Slanina Petr , Sroubek Jan , Klener Jan , Hrbac Tomas , Syrucek Martin , Rulseh Aaron M.
Published: January 2023

Introduction

The prognosis of glioblastoma remains unfavorable. TTFields utilize low intensity electric fields (frequency 150–300 kHz) that disrupt cellular processes critical for cancer cell viability and tumor progression. TTFields are delivered via transducer arrays placed on the patients’ scalp. Methods: Between the years 2004 and 2022, 55 patients (20 female), aged 21.9–77.8 years (mean age 47.3±11.8 years; median 47.6 years) were treated with TTFields for newly-diagnosed GBM, and compared to 54 control patients (20 females), aged 27.0–76.7 years (mean age 51.4±12.2 years; median 51.7 years) (p=0.08). All patients underwent gross total or partial resection of GBM. One patient had biopsy only. When available, MGMT promoter methylation status and IDH mutation was detected.

Results

Patients on TTFields therapy demonstrated improvements in PFS and OS relative to controls (hazard ratio: 0.64, p=0.031; and 0.61, p=0.028 respectively). TTFields average time on therapy was 74.8% (median 82%): median PFS of these patients was 19.75 months. Seven patients with TTFields usage ≤60% (23–60%, mean 46.3%, median 53%) had a median PFS of 7.95 months (p=0.0356). Control patients with no TTFields exposure had a median PFS of 12.45 months. Median OS of TTF patients was 31.67 months compared to 24.80 months for controls.

Discussion

This is the most extensive study on newly-diagnosed GBM patients treated with TTFields, covering a period of 18 years at a single center and presenting not only data from clinical trials but also a group of 36 patients treated with TTFields as a part of routine clinical practice.