bluuebunny/crossref_metadata_2025 huggingface dataset:
Immune dysfunctions affecting bone marrow Vγ9Vδ2 T cells in multiple myeloma: Role of immune checkpoints and disease status
Authors: Giannotta Claudia , Castella Barbara , Tripoli Ezio , Grimaldi Daniele , Avonto Ilaria , D’Agostino Mattia , Larocca Alessandra , Kopecka Joanna , Grasso Mariella , Riganti Chiara , Massaia Massimo
Published: December 2022

Introduction

Bone marrow (BM) Vγ9Vδ2 T cells are intrinsically predisposed to sense the immune fitness of the tumor microenvironment (TME) in multiple myeloma (MM) and monoclonal gammopathy of undetermined significance (MGUS).

Methods

In this work, we have used BM Vγ9Vδ2 T cells to interrogate the role of the immune checkpoint/immune checkpoint-ligand (ICP/ICP-L) network in the immune suppressive TME of MM patients.

Results

PD-1+ BM MM Vγ9Vδ2 T cells combine phenotypic, functional, and TCR-associated alterations consistent with chronic exhaustion and immune senescence. When challenged by zoledronic acid (ZA) as a surrogate assay to interrogate the reactivity to their natural ligands, BM MM Vγ9Vδ2 T cells further up-regulate PD-1 and TIM-3 and worsen TCR-associated alterations. BM MM Vγ9Vδ2 T cells up-regulate TIM-3 after stimulation with ZA in combination with αPD-1, whereas PD-1 is not up-regulated after ZA stimulation with αTIM-3, indicating a hierarchical regulation of inducible ICP expression. Dual αPD-1/αTIM-3 blockade improves the immune functions of BM Vγ9Vδ2 T cells in MM at diagnosis (MM-dia), whereas single PD-1 blockade is sufficient to rescue BM Vγ9Vδ2 T cells in MM in remission (MM-rem). By contrast, ZA stimulation induces LAG-3 up-regulation in BM Vγ9Vδ2 T cells from MM in relapse (MM-rel) and dual PD-1/LAG-3 blockade is the most effective combination in this setting.

Discussion

These data indicate that: 1) inappropriate immune interventions can exacerbate Vγ9Vδ2 T-cell dysfunction 2) ICP blockade should be tailored to the disease status to get the most of its beneficial effect.
Anti-PD-1 immune-related adverse events are associated with high therapeutic antibody fixation on T cells
Authors: Gazzano Marianne , Parizot Christophe , Psimaras Dimitri , Vozy Aurore , Baron Marine , Abbar Baptiste , Fallet Vincent , Litvinova Elena , Canellas Anthony , Birzu Cristina , Pourcher Valérie , Touat Mehdi , Weiss Nicolas , Demeret Sophie , Roos-Weil Damien , Spano Jean-Philippe , Lebbe Celeste , Salem Joe-Elie , Cadranel Jacques , Hervier Baptiste , Gorochov Guy , Guihot Amélie
Published: December 2022

Immune checkpoint inhibitors (ICI) widely improved the treatment of solid and hematologic malignancies. Yet, a remarkable proportion of patients receiving ICI develop immune related adverse events (irAEs) which are difficult to define as treatment-related. This underlines the need to develop a biomarker to guide irAE diagnosis. We developed a novel flow cytometry assay combining measurement of anti-PD-1 (programmed cell death protein-1) occupancy and evaluation of remaining PD-1 receptor availability with anti-IgG4 PE and anti-PD-1 BV421. We prospectively collected blood and biological fluids samples from patients treated by IgG4 anti-PD-1 therapy (nivolumab or pembrolizumab), with (n=18) or without (n=12) current irAE. We analyzed PD-1+ and IgG4+ staining pattern and MFI values of these parameters on CD4 and CD8 T cells, and IgG4+/PD-1+ MFI ratios are calculated. A higher mean fluorescence intensity IgG4+/PD-1+ ratio was measured on peripheral CD4+ T cells of irAE cases, when compared to controls (p=0.003). ICI-related toxicity is therefore associated with increased therapeutic antibody occupancy of PD-1 receptors on CD4+ T cells. Furthermore, in one case of ICI-related pneumonitis, binding of therapeutic antibody was stronger on lung CD4+ T cell than in blood. In another case of ICI-related encephalitis, the PD-1 receptor occupancy was total on CSF CD4 T cells, but only partial on peripherical CD4 T cells. Our results suggest that flow cytometry monitoring of ICI occupancy can be used in patients treated with monoclonal ICI to guide irAE diagnosis.
Systematic analysis of brain and skull ischemic injury expression profiles reveals associations of the tumor immune microenvironment and cell death with ischemic stroke
Authors: Zhang Chao , Wang Lisi , Guo Yunmiao , Feng Wei
Published: December 2022

Background

Previous studies have shown that stroke is a potential first sign of neoplasia, but the relationship between stroke and cancer remains unclear. As a complex brain disease, ischemic stroke involves cell death and immunity. Thus, it is necessary to investigate the association of the tumor immune microenvironment and cell death with ischemic stroke.

Methods

We established a photothrombosis-induced ischemic injury model in mouse brain and skull. Subsequently, we sequenced the whole transcriptome of the injured mouse brain and skull and analyzed the expression profiles. To investigate the association of stroke with cell death and cancer, we systematically performed gene set enrichment analysis in pan-cell death (i.e., apoptosis, cuproptosis, ferroptosis, necroptosis, and pyroptosis) and the cancer hallmark pathways. The time-dependent immune cell abundance variations after ischemic injury were estimated. Furthermore, pan-cancer genomic and prognostic analyses of the ischemic injury-related gene sets were also performed.

Results

In this study, we found that there exist temporal and spatial differences in the gene expression patterns of both the brain and skull with ischemic injury. The skull ischemic injury-induced changes in the brain transcriptome were particularly great, but could recover in a short period, while the skull transcriptome variation resulting from brain ischemic injury was long-lasting. In addition, the expression of the genes related to ischemic injury was also associated with pan-cell death and the cancer hallmark pathways. The changes in the abundance of immune cells indicate that brain ischemic injury may disrupt the immune microenvironment for a longer time, while the skull can balance the stability of the immune microenvironment better. Moreover, the brain ischemic injury-related gene sets were highly correlated with a variety of tumors, particularly glioblastoma multiforme (GBM), kidney renal clear cell carcinoma (KIRC), brain lower grade glioma (LGG), and uveal melanoma (UVM), which carry a greater mortality risk after stroke.

Conclusion

This systematic analysis not only helps in the understanding of the changes in the gene expression profiles of both the brain and skull with ischemic injury but also reveals the association of the tumor immune microenvironment and cell death with ischemic stroke.
Precision-cut rat placental slices as a model to study sex-dependent inflammatory response to LPS and Poly I:C
Authors: Anandam Kasin Yadunandam , Abad Cilia , Synova Tetiana , Vinas-Noguera Mireia , Bolboli Bahareh , Vokral Ivan , Karahoda Rona , Staud Frantisek
Published: December 2022

Introduction

Maternal inflammation in pregnancy represents a major hallmark of several pregnancy complications and a significant risk factor for neurodevelopmental and neuropsychiatric disorders in the offspring. As the interface between the mother and the fetus, the placenta plays a crucial role in fetal development and programming. Moreover, studies have suggested that the placenta responds to an inflammatory environment in a sex-biased fashion. However, placenta-mediated immunoregulatory mechanisms are still poorly understood.

Methods

Therefore, we have developed a model of ex vivo precision-cut placental slices from the rat term placenta to study acute inflammatory response. Rat placental slices with a precise thickness of 200 µm were generated separately from male and female placentas. Inflammation was stimulated by exposing the slices to various concentrations of LPS or Poly I:C for 4 and 18 hours.

Results

Treatment of placental slices with LPS significantly induced the expression and release of proinflammatory cytokines TNF-α, IL-6, and IL-1β. In contrast, Poly I:C treatment resulted in a less-pronounced inflammatory response. Interestingly, the female placenta showed higher sensitivity to LPS than male placenta. Anti-inflammatory agents, curcumin, 1α,25- dihydroxyvitamin D3, and progesterone attenuated the LPS-induced proinflammatory cytokine response at both mRNA and protein levels.

Discussion

We conclude that rat placental slices represent a novel alternative model to study the role of sexual dimorphism in the acute inflammatory response and immune activation in pregnancy.
Multi-omics pan-cancer study of cuproptosis core gene FDX1 and its role in kidney renal clear cell carcinoma
Authors: Xu Jiahao , Hu Zhengang , Cao Hui , Zhang Hao , Luo Peng , Zhang Jian , Wang Xiaoyan , Cheng Quan , Li Jingbo
Published: December 2022

Background

The mechanism of copper-induced cellular death was newly discovered and termed cuproptosis. Inducing cuproptosis in cancer cells is well anticipated for its curative potential in treating tumor diseases. However, ferredoxin 1 (FDX1), the core regulatory gene in cuproptosis, is rarely studied, and the regulation of FDX1 in tumor biology remains obscure. A comprehensive pan-cancer analysis of FDX1 is needed.

Methods

Thirty-three types of tumors were included with paired normal tissues in The Cancer Genome Atlas (TCGA) and the Genotype-Tissue Expression (GTEx) datasets. The interaction between transcription, protein, phosphorylation, and promoter methylation levels was analyzed. Survival, immune infiltration, single-cell FDX1 expression, FDX1-related tumor mutational burden (TMB), microsatellite instability (MSI), stemness, tumor immune dysfunction and exclusion (TIDE), and immunotherapy-related analyses were performed. FDX1 protein expression was assessed by kidney renal clear cell carcinoma (KIRC) tissue microarray immunohistochemistry. The function of FDX1 in KIRC was further explored by experiments in 786-O cell lines in vitro.

Results

FDX1 is highly expressed in 15 tumor types and lowly expressed in 11 tumor types. The corresponding changes in protein expression, phosphorylation, and promoter methylation level of FDX1 have been described in several tumors. Survival analysis showed that FDX1 was related to favorable or poor overall survival in eight tumors and progression-free survival in nine tumors. Immune infiltration and single-cell analysis indicated the indispensable role of FDX1 expression in macrophages and monocytes. Multiple established immunotherapy cohorts suggested that FDX1 may be a potential predictor of treatment effects for tumor patients. Tissue microarray analysis showed decreased FDX1 expression in KIRC patients’ tumor tissues. Knockdown of FDX1 resulted in the downregulation of cuproptosis in kidney renal clear tumor cells. Mechanistically, the FDX1-associated gene expression signature in KIRC is related to the enrichment of genes involved in the tricarboxylic acid (TCA) cycle, NOTCH pathway, etc. Several NOTCH pathway genes were differentially expressed in the high- and low-FDX1 groups in KIRC.

Conclusion

Our analysis showed that the central regulatory gene of cuproptosis, FDX1, has differential expression and modification levels in various tumors, which is associated with cellular function, immune modulation, and disease prognosis. Thus, FDX1-dependent cuproptosis may serve as a brand-new target in future therapeutic approaches against tumors.
The role of marine and diving authorities in workforce development in the blue economy
Authors: Nisa Zahidah Afrin
Published: December 2022

Island governments have made decent work and social protection their highest policy priority, aiming to link them to the so-called blue economy sectors such as fisheries. The development of small-scale commercial fishing is primarily driven by transnational fisheries trade and depends on dive fisher labour force facing issues with deficits in decent work, health and safety, and safety at sea provisions. Given the macro-policy priorities for decent work in the transition of small island developing states (SIDS) to blue economy, this paper examines the development interventions in small-scale commercial fisheries trade that have exacerbated unsafe marine working conditions of dive fishers. Despite significant investments in developing commercial fisheries trade, the mismatch between macro-level decisions and micro-level labour needs has hardly been exploredviathe blue economy and sustainable development goal interlinkages. This study used a qualitative research approach to examine the unsafe working conditions of dive fishers and examined why dive-related accidents and fatalities occur in commercial fisheries in the first place. A systematic approach in the analysis of diving accidents helps the study to, firstly, highlight the gaps between macro policy and practice at the national and global levels. Secondly, the approach helps explore the need for a coherent approach to policy integration that bridges the gap between the macro and operational levels of small-scale fisheries labour force. The study analyses the International Labour Organization’s decent work instruments with SIDS sustainable development priorities for fisheries workforce and points out that governments must be responsible at the macro level for managing accidents at sea and building a safe diving workforce through competent marine and diving authorities.
Deep submerged speleothems in the Sansha Yongle Blue Hole (South China Sea) as determination of low sea levels during the Last Glacial Maximum
Authors: Yu Xiaoxiao , Duan Baichuan , Zhao Jingyao , Gu Dongqi , Feng Aiping , Liu Yanxiong , Li Tiegang
Published: December 2022

Although Last Glacial Maximum (LGM) sea levels have been the focus of much attention in climate and marine sciences, the timing, duration, and magnitude need further research. Here we present observations and analyses of the deepest speleothems (-116 m) collected from the deepest known blue hole on a global scale, the Sansha Yongle Blue Hole, Xisha Islands, South China Sea. The field investigations illustrate that submerged speleothems are irregular cauliflower-like coatings on the downward cave ceiling from water depths of ~90 to 120 m. The downward growth direction and negative stable carbon and oxygen stable isotopes of submerged speleothems suggest that they may deposit in an air-filled condition through gravity drip, indicating the maximum LGM sea level. The deep submerged speleothems were dated, indicating two U–Th ages of 29.16 ± 0.17 and 26.04 ± 0.18 ka BP and one radiocarbon age of 18.64 ± 0.12 ka BP, respectively. The investigated deep submerged speleothems therefore clearly determine the minimum onset and maximum termination times for LGM terms of sea level. The results show that LGM began at ~29 ka BP and ended at ~18.5 ka BP. This study therefore provides initial evidence for the use of deep speleothems to determine LGM sea levels and emphasizes the importance of deep submerged speleothems in the reconstruction of Pleistocene low sea levels.
Effects of varying types and amounts of herbivory and nutrient enrichment on a tropicalizing seagrass meadow
Authors: Rodriguez Alexandra R. , Marco-Méndez Candela , Campbell Justin , Heck Kenneth L.
Published: December 2022

Climate change is impacting marine ecosystem community dynamics on a global scale. While many have assessed direct effects of climate change, indirect effects on marine ecosystems produced by biotic interactions remain poorly understood. For example, warming-induced range expansions and increased consumption rates of herbivores can lead to significant and unexpected changes in seagrass-dominated ecosystems. To better understand the threats tropicalization presents for the functioning of turtlegrass (Thalassia testudinum) meadows, we focused on the extensive turtlegrass beds of St. Joseph Bay, Florida in the northern Gulf of Mexico, a location with increasing numbers of tropically-associated green turtles. Our goals were to investigate experimentally how different grazing rates (natural and simulated),including high levels reflective of green turtle herbivory, coupled with nutrient supply, might alter turtlegrass structure and functioning in a higher latitude, subtropical turtlegrass meadow. We found that 4 months of varying levels of herbivory did not affect turtlegrass productivity, while 7 months of herbivory reduced percent cover, and 10 months reduced shoot density. Nutrient additions had few important effects. Ten months into the study, a massive recruitment of the herbivorous sea urchin (Lytechinus variegatus), whose densities reached 19 urchins/m2 completely overgrazed our study area and a large portion of the lush turtlegrass meadows of St. Joseph Bay. While local turtlegrass overgrazing had been previously noted at these urchin densities, a total loss of seagrass in such a large area has rarely ever been recorded. Overgrazing of the kind we observed, likely a result of both urchin and increasing green turtle grazing, can result in the loss of many key ecosystem services. As tropicalization continues, understanding how changes in biotic interactions, such as increased herbivory, affect higher latitude seagrass meadows will be necessary for their proper management and conservation.
Estimating abundance of an elusive cetacean in a complex environment: Harbor porpoises (Phocoena phocoena) in inland waters of Southeast Alaska
Authors: Zerbini Alexandre N. , Goetz Kimberly T. , Forney Karin A. , Boyd Charlotte
Published: December 2022

The harbor porpoise (Phocoena phocoena) is common in temperate waters of the eastern North Pacific Ocean, including Southeast Alaska inland waters, a complex environment comprised of open waterways, narrow channels, and inlets. Two demographically independent populations are currently recognized in this region. Bycatch of porpoises in the salmon drift gillnet fisheries is suspected to occur regularly. In this study, we apply distance sampling to estimate abundance of harbor porpoise during ship surveys carried out in the summer of 2019. A stratified survey design was implemented to sample different harbor porpoise habitats. Survey tracklines were allocated following a randomized survey design with uniform coverage probability. Density and abundance for the northern and southern Southeast Alaska inland water populations were computed using a combination of design-based line- and strip-transect methods. A total of 2,893 km was surveyed in sea state conditions ranging from Beaufort 0 to 3 and 194 harbor porpoise groups (301 individuals) were detected. An independent sighting dataset from surveys conducted between 1991 and 2012 were used to calculate the probability of missing porpoise groups on the survey trackline (g[0]=0.53, CV=0.11). Abundance of the northern and southern populations were estimated at 1,619 (CV=0.26) and 890 (CV=0.37) porpoises, respectively. Bycatch estimates, which were only obtained for a portion of the drift gillnet fishery, suggest that mortality within the range of the southern population may be unsustainable. Harbor porpoises are highly vulnerable to mortality in gillnets, therefore monitoring abundance and bycatch is important for evaluating the potential impact of fisheries on this species in Southeast Alaska.
“Nothing works without the doctor:” Physicians’ perception of clinical decision-making and artificial intelligence
Authors: Samhammer David , Roller Roland , Hummel Patrik , Osmanodja Bilgin , Burchardt Aljoscha , Mayrdorfer Manuel , Duettmann Wiebke , Dabrock Peter
Published: December 2022

Introduction

Artificial intelligence–driven decision support systems (AI–DSS) have the potential to help physicians analyze data and facilitate the search for a correct diagnosis or suitable intervention. The potential of such systems is often emphasized. However, implementation in clinical practice deserves continuous attention. This article aims to shed light on the needs and challenges arising from the use of AI-DSS from physicians’ perspectives.

Methods

The basis for this study is a qualitative content analysis of expert interviews with experienced nephrologists after testing an AI-DSS in a straightforward usage scenario.

Results

The results provide insights on the basics of clinical decision-making, expected challenges when using AI-DSS as well as a reflection on the test run.

Discussion

While we can confirm the somewhat expectable demand for better explainability and control, other insights highlight the need to uphold classical strengths of the medical profession when using AI-DSS as well as the importance of broadening the view of AI-related challenges to the clinical environment, especially during treatment. Our results stress the necessity for adjusting AI-DSS to shared decision-making. We conclude that explainability must be context-specific while fostering meaningful interaction with the systems available.
A cautionary tale for health education initiatives in vulnerable populations: Improving nutrition in Haiti prisons
Authors: Mainous Arch G. , Bernard Jean , Auguste Stephanie , Louis Jacques R. , Dieufort Danove J. , Duverger Karine , Beau de Rochars Madsen , May John
Published: December 2022

Introduction

Prisons in low-income countries have barriers to providing adequate nutrition to the incarcerated. This perspective discusses a quality improvement program with health education to improve nutrition provided to men in two prisons in Haiti.

Methods

Incarcerated men in the National Penitentiary in Port Au Prince and the prison in Mirebalais were the focus of the program. A culturally competent educational intervention was delivered to the prison cooks. Program evaluation included a baseline and a follow-up assessment in 2021 and 2022 in both prisons. Calories, body composition, and nutrition were assessed at both time points.

Results

Among 1,060 men assessed in the baseline time period, the mean number of calories per day was 571. Further, 62.5% had a vitamin C intake insufficient to prevent scurvy and 91.6% had vitamin B1 insufficient to prevent beriberi. In the follow-up period, caloric intake decreased to a mean of 454 per day (p < 0.001). The proportion of incarcerated men who had insufficient vitamin C and vitamin B1 to prevent disease increased in the follow-up period.

Discussion

The caloric and nutritional intake of incarcerated men in Haitian prisons is poor and is getting worse. The educational intervention with the cooks was not successful due to civil and political strife in the low-income country of Haiti. Standard interventions to improve nutrition need to consider the social context for accessing food.
Gut microbiota and calcium balance
Authors: Wang Jiali , Wu Shuang , Zhang Yinshan , Yang Jiao , Hu Zhongliang
Published: December 2022

Microorganisms living on the surface and inside the human body play an important role in the physiological activities of the human body. The largest microecosystem in the human body is the gut microbiome. Calcium disorders are found in many diseases. For example, patients with chronic renal insufficiency present with secondary hyperparathyroidism, which is caused by a calcium imbalance in the body. In addition, calcium dysregulation may affect lipid metabolism in the liver through the calmodulator pathway, leading to cirrhosis, etc. Currently, a considerable number of probiotics have been proven to enhance the body’s absorption of calcium. This paper reviews the effects of intestinal flora and related factors such as short-chain fatty acids, estrogen, immune factors and vitamin D on calcium balance.
Heterologous expression and activity verification of ornithine decarboxylase from a wild strain of Shewanella xiamenensis
Authors: Liu Chang , Wang Guiyuan , Han Xiangning , Cao Limin , Wang Kaiqiang , Lin Hong , Sui Jianxin
Published: December 2022

Shewanella xiamenensis is widely found in spoilage fish, shrimp and other seafoods. Under suitable conditions, ornithine can be synthesized into putrescine, which may spoil food or endanger health. Our research used a wild strain of Shewanella xiamenensis isolated from “Yi Lu Xian” salted fish (a salting method for sea bass) as a research object. According to the database of National Center of Biotechnology Information (NCBI), the target ornithine decarboxylase (ODC) gene SpeF was successfully amplified using the wild strain of Shewanella xiamenensis as the template. Sequencing alignment showed that the SpeF of the wild strain had more than 98% homology compared with the standard strain. The amino acid substitution occurred in the residues of 343, 618, 705, and 708 in the wild strain. After optimizing the expression conditions, a heterologous expression system of ODC was constructed to achieve a high yield of expression. The amount of 253.38 mg of ODC per liter of LB broth was finally expressed. High performance liquid chromatography (HPLC) and subsequent ODC activity verification experiments showed that hetero-expressed ODC showed a certain enzyme activity for about 11.91 ± 0.38 U/mg. Our study gives a new way to the development of a low-cost and high-yield strategy to produce ODC, providing experimental materials for further research and elimination of putrescine in food hazards.
Comprehensive molecular analyses of an autoimmune-related gene predictive model and immune infiltrations using machine learning methods in moyamoya disease
Authors: Li Shifu , Han Ying , Zhang Qian , Tang Dong , Li Jian , Weng Ling
Published: December 2022

Background: Growing evidence suggests the links between moyamoya disease (MMD) and autoimmune diseases. However, the molecular mechanism from genetic perspective remains unclear. This study aims to clarify the potential roles of autoimmune-related genes (ARGs) in the pathogenesis of MMD.

Methods: Two transcription profiles (GSE157628 and GSE141025) of MMD were downloaded from GEO databases. ARGs were obtained from the Gene and Autoimmune Disease Association Database (GAAD) and DisGeNET databases. Differentially expressed ARGs (DEARGs) were identified using “limma” R packages. GO, KEGG, GSVA, and GSEA analyses were conducted to elucidate the underlying molecular function. There machine learning methods (LASSO logistic regression, random forest (RF), support vector machine-recursive feature elimination (SVM-RFE)) were used to screen out important genes. An artificial neural network was applied to construct an autoimmune-related signature predictive model of MMD. The immune characteristics, including immune cell infiltration, immune responses, and HLA gene expression in MMD, were explored using ssGSEA. The miRNA-gene regulatory network and the potential therapeutic drugs for hub genes were predicted.

Results: A total of 260 DEARGs were identified in GSE157628 dataset. These genes were involved in immune-related pathways, infectious diseases, and autoimmune diseases. We identified six diagnostic genes by overlapping the three machine learning algorithms: CD38, PTPN11, NOTCH1, TLR7, KAT2B, and ISG15. A predictive neural network model was constructed based on the six genes and presented with great diagnostic ability with area under the curve (AUC) = 1 in the GSE157628 dataset and further validated by GSE141025 dataset. Immune infiltration analysis showed that the abundance of eosinophils, natural killer T (NKT) cells, Th2 cells were significant different between MMD and controls. The expression levels of HLA-A, HLA-B, HLA-C, HLA-DMA, HLA-DRB6, HLA-F, and HLA-G were significantly upregulated in MMD. Four miRNAs (mir-26a-5p, mir-1343-3p, mir-129-2-3p, and mir-124-3p) were identified because of their interaction at least with four hub DEARGs.

Conclusion: Machine learning was used to develop a reliable predictive model for the diagnosis of MMD based on ARGs. The uncovered immune infiltration and gene-miRNA and gene-drugs regulatory network may provide new insight into the pathogenesis and treatment of MMD.
Interaction learning control with movement primitives for lower limb exoskeleton
Authors: Wang Jiaqi , Wu Dongmei , Gao Yongzhuo , Dong Wei
Published: December 2022

Research on robotic exoskeletons both in the military and medical fields has rapidly expanded over the previous decade. As a human–robot interaction system, it is a challenge to develop an assistive strategy that makes the exoskeleton supply efficient and natural assistance following the user's intention. This paper proposed a novel interaction learning control strategy for the lower extremity exoskeleton. A powerful representative tool probabilistic movement primitives (ProMPs) is adopted to model the motion and generate the desired trajectory in real-time. To adjust the trajectory by the user's real-time intention, a compensation term based on human–robot interaction force is designed and merged into the ProMPs model. Then, compliant impedance control is adopted as a low-level control where the desired trajectory is put into. Moreover, the model will be dynamically adapted online by penalizing both the interaction force and trajectory mismatch, with all the parameters that can be further learned by learning algorithm PIBB. The experimental results verified the effectiveness of the proposed control framework.
Different subtypes of motor cortex pyramidal tract neurons projects to red and pontine nuclei
Authors: Lopez-Virgen Veronica , Olivares-Moreno Rafael , de Lafuente Victor , Concha Luis , Rojas-Piloni Gerardo
Published: December 2022

Introduction

Pyramidal tract neurons (PTNs) are fundamental elements for motor control. However, it is largely unknown if PTNs are segregated into different subtypes with distinct characteristics.

Methods

Using anatomical and electrophysiological tools, we analyzed in mice motor cortex PTNs projecting to red and pontine midbrain nuclei, which are important hubs connecting cerebral cortex and cerebellum playing a critical role in the regulation of movement.

Results

We reveal that the vast majority of M1 neurons projecting to the red and pontine nuclei constitutes different populations. Corticopontine neurons have higher conduction velocities and morphologically, a most homogeneous dendritic and spine distributions along cortical layers.

Discussion

The results indicate that cortical neurons projecting to the red and pontine nuclei constitute distinct anatomical and functional pathways which may contribute differently to sensorimotor integration.
Perspectives on the basis of seizure-induced respiratory dysfunction
Authors: Mulkey Daniel K. , Milla Brenda M.
Published: December 2022

Epilepsy is an umbrella term used to define a wide variety of seizure disorders and sudden unexpected death in epilepsy (SUDEP) is the leading cause of death in epilepsy. Although some SUDEP risk factors have been identified, it remains largely unpredictable, and underlying mechanisms remain poorly understood. Most seizures start in the cortex, but the high mortality rate associated with certain types of epilepsy indicates brainstem involvement. Therefore, to help understand SUDEP we discuss mechanisms by which seizure activity propagates to the brainstem. Specifically, we highlight clinical and pre-clinical evidence suggesting how seizure activation of: (i) descending inhibitory drive or (ii) spreading depolarization might contribute to brainstem dysfunction. Furthermore, since epilepsy is a highly heterogenous disorder, we also considered factors expected to favor or oppose mechanisms of seizure propagation. We also consider whether epilepsy-associated genetic variants directly impact brainstem function. Because respiratory failure is a leading cause of SUDEP, our discussion of brainstem dysfunction focuses on respiratory control.
Comprehensive profile and natural history of pediatric patients with spinal muscular atrophy: A large retrospective study from China
Authors: Hu Chaoping , Li Xihua , Shi Yiyun , Zhu Xiaomei , Zhao Lei , Li Wenhui , Zhou Shuizhen , Wang Yi
Published: December 2022

Background

There is a large population of people with spinal muscular atrophy (SMA) in China, and new disease-modifying therapies have become available recently. However, comprehensive data on the management and profile of treatment-naive SMA patients in China are still lacking.

Methods

As a retrospective study, a large cohort of treatment-naive patients with clinical and genetic diagnoses of 5q SMA were enrolled, ranging from neonatal to 18 years old, from the Neurology Department of Children's Hospital of Fudan University between January 2013 and December 2020. The data regarding their clinical presentations, genetic defects, motor function assessment results, and follow ups were reviewed.

Results

We enrolled 392 SMA patients (male: female = 189: 203): 1a = 46, 1b = 44, 1c = 31, 2a = 119, 2b = 56, 3a = 52, 3b = 14, from 27 of the 34 administrative districts in China, and 389 patients harbored homozygous deletion of exon 7 in the SMN1 gene (99.2%). The median age of onset was 0.08 (range: 0–0.30), 0.25 (0.06–0.60), 0.42 (0.08–1.50), 0.67 (0.07–5.08), 1.0 (0.40–1.83), 1.5 (1.00–3.00), and 4.04 (1.80–12.00) years old for SMA 1a, 1b, 1c, 2a, 2b, 3a, and 3b patients, while the median age of first assessment was 0.25 (0.08–2.60), 0.42 (0.17–1.90), 0.80 (0.17–4.5), 2.50 (0.5–15.83), 2.92 (1.08–13.42), 4.25 (1.58–17.33), and 7.34 (3.67–14.00) years old, respectively. Patients were followed up with for up to 15.8 years. The median event-free survival time was 7 months, 15 months, and indeterminate in SMA 1a, 1b, and 1c patients (p < 0.0001), with a better survival situation for higher SMN2 copies (p = 0.0171). The median age of sitting loss was 5.75 years and 13.5 years in SMA 2a and 2b (p = 0.0214) and that of ambulation loss was 9.0 years and undefined in SMA 3a and 3b (p = 0.0072). Cox regression analysis showed that higher SMN2 copies indicated better remaining ambulation in SMA 3. The median time to develop orthopedic deformities was 4.5, 5.2, and 10.1 years in SMAs 1c, 2, and 3, respectively (p < 0.0001), with a possible trend of better preservation of joint function for patients under regular rehabilitation (p = 0.8668).

Conclusion

Our study elucidated insight into the comprehensive management and profile of different types of SMA patients in China, providing a clinical basis for assessing the efficacy of new therapies.
Long-term neurorehabilitation outcomes of pediatric vs. adult onset acquired brain injury
Authors: Johnson Spring Flores , Klonoff Pamela S. , Perumparaichallai Ramaswamy Kavitha
Published: December 2022

Background

Functional outcomes of intensive neurorehabilitation for pediatric onset acquired brain injury (ABI) are understudied. The extent and pervasiveness of impairments are often uncovered years after an ABI and can worsen over time, leading to a cascade of academic, functional, and psychosocial difficulties.

Objective

To examine the long-term outcomes of survivors with pediatric onset vs. adult onset ABI who completed holistic milieu-oriented neurorehabilitation up to 30 years ago.

Methods

One hundred twenty-three survivors of ABI including a pediatric onset group (n = 22) and an adult onset group (n = 101) with heterogeneous neurological etiologies who attended holistic, milieu-oriented neurorehabilitation. Productivity, driving, and functional outcomes were evaluated using the Mayo-Portland Adaptability Inventory-4 (MPAI-4) and a psychosocial outcome questionnaire. Treatment for the pediatric onset group started much later than onset.

Results

A one-way analysis of covariance revealed no significant differences between the two groups on the MPAI-4. At the follow-up survey, there was no significant difference between age at onset of injury and productivity status. The average follow-up time was ~8 years (SD = 6.28) from time of discharge to the time of the survey. Although there was no significant difference between the two groups for driving at the time of admission, the adult onset group was significantly more likely to return to driving after treatment.

Conclusions

This study demonstrates the positive and enduring benefits of holistic, milieu-oriented neurorehabilitation for survivors of pediatric onset ABI regardless of the time between initial injury and engagement in rehabilitative therapies.
Surface electromyography analysis of mirror movements under unilateral movement in stroke patients: A retrospective study
Authors: Dai Jie , Wu Fangchao , Li Jianhua , Yu Mengjie , Liao Chen , Shou Yiqun
Published: December 2022

Objective

Mirror movements (MMs) are common abnormal motor performance in patients with poststroke hemiparesis. The study aimed to utilize the Electromyography (EMG) characterization of MMs in stroke patients and explore the relationship between MMs and the motor function of affected limbs.

Methods

Sixty patients with stroke who had used to undergo clinical assessment and surface Electromyography (sEMG) were selected in this study. We investigated the standardized net excitation (SNE) and overflow percentage (OF) as a measure of mirror activities on bilateral muscles of stroke patients.

Results

In stroke patients, mirror activities occurred in both affected and unaffected muscles during maximal contractions. We found that OF at unilateral contraction on the affected side (UCA) was significantly greater than that at unilateral contraction on the unaffected side (UCU). Additionally, a negative correlation between OF at UCA and Brunnstrom stages on admission and discharge. However, there were no significant correlations between OF and disease duration, Barthel Index, or the degree of improvement in all clinical evaluations. We still found a positive correlation between SNE at UCA and the improvement of the Brunnstrom stage of the hand. But we could not find any significant correlation between SNE and other clinical evaluation scores.

Conclusion

In conclusion, the study found mirror activities in both affected and unaffected muscles, confirming an asymmetry between them. Although the mechanisms are still unclear, we confirmed a significant correlation between MMs at UCA and the motor function of the affected upper extremity, which might provide further evidences for understanding MMs in stroke patients and a new research direction on evaluation for motor function and outcomes of stroke patients.
Functional MRI study of feedback-based reinforcement learning in depression
Authors: Kustubayeva Almira M. , Nelson Erik B. , Smith Michael L. , Allendorfer Jane B. , Eliassen James C.
Published: December 2022

Reinforcement learning depends upon the integrity of emotional circuitry to establish associations between environmental cues, decisions, and positive or negative outcomes in order to guide behavior through experience. The emotional dysregulation characteristic of major depressive disorder (MDD) may alter activity in frontal and limbic structures that are key to learning. Although reward and decision-making have been examined in MDD, the effects of depression on associative learning is less well studied. We investigated whether depressive symptoms would be related to abnormalities in learning-related brain activity as measured by functional magnetic resonance imaging (fMRI). Also, we explored whether melancholic and atypical features were associated with altered brain activity. We conducted MRI scans on a 4T Varian MRI system in 10 individuals with MDD and 10 healthy subjects. We examined event-related brain activation during feedback-based learning task using Analysis of Functional NeuroImages (AFNI) for image processing and statistical analysis. We observed that MDD patients exhibited reduced activation in visual cortex but increased activation in cingulate and insular regions compared to healthy participants. Also, in relation to features of depressive subtypes, we observed that levels of activation in striatal, thalamic, and precuneus regions were negatively correlated with atypical characteristics. These results suggest that the effects of MDD change the neural circuitry underlying associative learning, and these effects may depend upon subtype features of MDD.
Mechanism of extracellular space changes in cryptococcal brain granuloma revealed by MRI tracer
Authors: Abulikemu Nuerbiyemu , Gao Xin , Wang Wei , He Qingyuan , Wang Gang , Jiang Tao , Wang Xiaodong , Cheng Yumeng , Chen Min , Li Yanran , Liu Lulu , Zhao Jingjing , Li Jin , Jiang Chunhui , Wang Yunling , Han Hongbin , Wang Jian
Published: December 2022

Purpose

This study aimed to investigate the changes in extracellular space (ECS) in cryptococcal brain granuloma and its pathological mechanism.

Materials and methods

The animal model of cryptococcal brain granuloma was established by injecting 1 × 106 CFU/ml of Cryptococcus neoformans type A suspension into the caudate nucleus of Sprague–Dawley rats with stereotactic technology. The infection in the brain was observed by conventional MRI scanning on days 14, 21, and 28 of modeling. The tracer-based MRI with a gadolinium-diethylenetriamine pentaacetic acid (Gd-DTPA) as a magnetic tracer was performed on the rats with cryptococcal granuloma and the rats in the control group. The parameters of ECS in each area of cryptococcal brain granuloma were measured. The parameters of ECS in the two groups were compared by independent sample t-test, and the changes in ECS and its mechanism were analyzed.

Results

Up to 28 days of modeling, the success rate of establishing the brain cryptococcal granuloma model with 1 × 106 CFU/ml Cryptococcus neoformans suspension was 60%. In the internal area of cryptococcal granuloma, the effective diffusion coefficient D* was significantly higher than that of the control group (t = 2.76, P < 0.05), and the same trend showed in the volume ratio α (t = 3.71, P < 0.05), the clearance rate constant k (t = 3.137, P < 0.05), and the tracer half-life T1/2 (t = 3.837, P < 0.05). The tortuosity λ decreased compared with the control group (t = −2.70, P < 0.05). At the edge of the cryptococcal granuloma, the D* and α decreased, while the λ increased compared with the control group (D*:t = −6.05, P < 0.05; α: t = −4.988, P < 0.05; λ: t = 6.222, P < 0.05).

Conclusion

The internal area of the lesion demonstrated a quicker, broader, and more extended distribution of the tracer, while the edge of the lesion exhibited a slower and narrower distribution. MRI tracer method can monitor morphological and functional changes of ECS in pathological conditions and provide a theoretical basis for the treatment via ECS.
Enhanced sweet taste perception in obesity: Joint analysis of gustatory data from multiple studies
Authors: Ribeiro Gabriela , Torres Sandra , Fernandes Ana B. , Camacho Marta , Branco Teresa L. , Martins Sandra S. , Raimundo Armando , Oliveira-Maia Albino J. ,   Food Reward in Bariatric Surgery Portuguese Study Group
Published: December 2022

Introduction

While sweet taste perception is a potential determinant of feeding behavior in obesity, the supporting evidence is inconsistent and is typically associated with methodological limitations. Notably, possible associations between sweet taste perception and measures of food reward remain undetermined.

Materials and methods

We conducted a cross-sectional analysis comparing 246 individuals with severe obesity and 174 healthy volunteers using a validated method for taste perception assessment. We included gustatory variables, namely intensity and pleasantness ratings of sour, salt, sweet, and bitter tastants, and taste thresholds assessed by electrogustometry. Reward-related feeding behavior, including hedonic hunger, food addiction, feeding behavior traits, and acceptance of foods and alcohol, was evaluated using self-rated scales for comparison with gustatory measures.

Result

In logistic regressions adjusted for age, gender, educational level, and research center, we found that a greater likelihood of belonging to the obesity group was associated with higher sweet intensity ratings (OR = 1.4, P = 0.01), hedonic hunger, food addiction symptoms, restrained and emotional eating (1.7 < OR ≤ 4.6, all P ≤ 0.001), and lower alcohol acceptance (OR = 0.6, P = 0.0002). Using principal component analysis, we found that while hedonic hunger, food addiction, and emotional eating were strongly interrelated, they were not associated with sweet intensity perception that, in turn, had a closer relationship with alcohol acceptance and restrained eating.

Conclusion

We found that individuals with obesity report higher sweet taste intensity ratings than healthy controls. Furthermore, while psychological measures of reward-related feeding behavior assess a common construct, sweet intensity perception may represent a different obesity-related dimension.
The role of lymphoid tissue SPARC in the pathogenesis and response to treatment of multiple myeloma
Authors: Aly Nesreen Amer Ramadan , Rizk Samia , Aboul Enein Azza , El Desoukey Nermeen , Zawam Hamdy , Ahmed Manzoor , El Shikh Mohey Eldin , Pitzalis Costantino
Published: December 2022

Background

Despite the significant progress in the treatment of multiple myeloma (MM), the disease remains untreatable and its cure is still an unmet clinical need. Neoplastic transformation in MM is initiated in the germinal centers (GCs) of secondary lymphoid tissue (SLT) where B cells experience extensive somatic hypermutation induced by follicular dendritic cells (FDCs) and T-cell signals.

Objective

We reason that secreted protein acidic and rich in cysteine (SPARC), a common stromal motif expressed by FDCs at the origin (SLTs) and the destination (BM) of MM, plays a role in the pathogenesis of MM, and, here, we sought to investigate this role.

Methods

There were 107 BM biopsies from 57 MM patients (taken at different time points) together with 13 control specimens assessed for SPARC gene and protein expression and compared with tonsillar tissues. In addition, regulation of myeloma-promoting genes by SPARC-secreting FDCs was assessed in in vitro GC reactions (GCRs).

Results

SPARC gene expression was confirmed in both human primary (BM) and secondary (tonsils) lymphoid tissues, and the expression was significantly higher in the BM. Sparc was detectable in the BM and tonsillar lysates, co-localized with the FDC markers in both tissues, and stimulation of FDCs in vitro induced significantly higher levels of SPARC expression than unstimulated controls. In addition, SPARC inversely correlated with BM PC infiltration, ISS staging, and ECOG performance of the MM patients, and in vitro addition of FDCs to lymphocytes inhibited the expression of several oncogenes associated with malignant transformation of PCs.

Conclusion

FDC-SPARC inhibits several myelomagenic gene expression and inversely correlates with PC infiltration and MM progression. Therapeutic induction of SPARC expression through combinations of the current MM drugs, repositioning of non-MM drugs, or novel drug discovery could pave the way to better control MM in clinically severe and drug-resistant patients.