bluuebunny/crossref_metadata_2025 huggingface dataset:
YAP/TAZ: Key Players for Rheumatoid Arthritis Severity by Driving Fibroblast Like Synoviocytes Phenotype and Fibro-Inflammatory Response
Authors: Caire Robin , Audoux Estelle , Courbon Guillaume , Michaud Eva , Petit Claudie , Dalix Elisa , Chafchafi Marwa , Thomas Mireille , Vanden-Bossche Arnaud , Navarro Laurent , Linossier Marie-Thérèse , Peyroche Sylvie , Guignandon Alain , Vico Laurence , Paul Stephane , Marotte Hubert
Published: December 2021

Objective

The role of YAP/TAZ, two transcriptional co-activators involved in several cancers, was investigated in rheumatoid arthritis (RA).

Methods

Fibroblast like synoviocytes (FLS) from patients with RA or osteoarthritis were cultured in 2D or into 3D synovial organoids. Arthritis rat model (n=28) and colitis mouse model (n=21) were used. YAP/TAZ transcriptional activity was inhibited by verteporfin (VP). Multiple techniques were used to assess gene and/or protein expression and/or localization, cell phenotype (invasion, proliferation, apoptosis), bone erosion, and synovial stiffness.

Results

YAP/TAZ were transcriptionally active in arthritis (19-fold increase for CTGF expression, a YAP target gene, in RA vs. OA organoids; p<0.05). Stiff support of culture or pro-inflammatory cytokines further enhanced YAP/TAZ transcriptional activity in RA FLS. Inhibiting YAP/TAZ transcriptional activity with VP restored a common phenotype in RA FLS with a decrease in apoptosis resistance, proliferation, invasion, and inflammatory response. Consequently, VP blunted hyperplasic lining layer formation in RA synovial organoids. In vivo, VP treatment strongly reduced arthritis severity (mean arthritic index at 3.1 in arthritic group vs. 2.0 in VP treated group; p<0.01) by restoring synovial homeostasis and decreasing systemic inflammation. YAP/TAZ transcriptional activity also enhanced synovial membrane stiffening in vivo, thus creating a vicious loop with the maintenance of YAP/TAZ activation over time in FLS. YAP/TAZ inhibition was also effective in another inflammatory model of mouse colitis.

Conclusion

Our work reveals that YAP/TAZ were critical factors during arthritis. Thus, their transcriptional inhibition could be relevant to treat inflammatory related diseases.
The cGAS-STING Pathway: A Promising Immunotherapy Target
Authors: Ou Liang , Zhang Ao , Cheng Yuxing , Chen Ying
Published: December 2021

With the continuous development of immunotherapy, researchers have paid more attention to the specific immune regulatory mechanisms of various immune responses in different diseases. As a novel and vital innate immune signal pathway, the cGAS-STING signal pathway activated by nucleic acid substances, interplays with other immune responses, by which it participates in regulating cancer, autoimmune and inflammatory diseases, microbial and parasitic infectious diseases, and other diseases. With the exception of its role in innate immunity, the growing list of researches demonstrated expanding roles of the cGAS-STING signal pathway in bridging the innate immunity (macrophage polarization) with the adaptive immunity (T lymphocytes differentiation). Macrophages and T lymphocytes are the most representative cells of innate immunity and adaptive immunity, respectively. Their polarization or differentiation are involved in the pathogenesis and progression of various diseases. Here we mainly summarized recent advanced discoveries of how the cGAS-STING signal pathway regulated macrophages polarization and T lymphocytes differentiation in various diseases and vaccine applications, providing a promising direction for the development and clinical application of immunotherapeutic strategies for related diseases.
Single-Domain Antibodies for Targeting, Detection, and In Vivo Imaging of Human CD4+ Cells
Authors: Traenkle Bjoern , Kaiser Philipp D. , Pezzana Stefania , Richardson Jennifer , Gramlich Marius , Wagner Teresa R. , Seyfried Dominik , Weldle Melissa , Holz Stefanie , Parfyonova Yana , Nueske Stefan , Scholz Armin M. , Zeck Anne , Jakobi Meike , Schneiderhan-Marra Nicole , Schaller Martin , Maurer Andreas , Gouttefangeas Cécile , Kneilling Manfred , Pichler Bernd J. , Sonanini Dominik , Rothbauer Ulrich
Published: December 2021

The advancement of new immunotherapies necessitates appropriate probes to monitor the presence and distribution of distinct immune cell populations. Considering the key role of CD4+cells in regulating immunological processes, we generated novel single-domain antibodies [nanobodies (Nbs)] that specifically recognize human CD4. After in-depth analysis of their binding properties, recognized epitopes, and effects on T-cell proliferation, activation, and cytokine release, we selected CD4-specific Nbs that did not interfere with crucial T-cell processesin vitroand converted them into immune tracers for noninvasive molecular imaging. By optical imaging, we demonstrated the ability of a high-affinity CD4-Nb to specifically visualize CD4+cellsin vivousing a xenograft model. Furthermore, quantitative high-resolution immune positron emission tomography (immunoPET)/MR of a human CD4 knock-in mouse model showed rapid accumulation of64Cu-radiolabeled CD4-Nb1 in CD4+T cell-rich tissues. We propose that the CD4-Nbs presented here could serve as versatile probes for stratifying patients and monitoring individual immune responses during personalized immunotherapy in both cancer and inflammatory diseases.
Distinct Seasonal Primary Production Patterns in the Sub-Polar Gyre and Surrounding Seas
Authors: Richardson Katherine , Bendtsen Jørgen
Published: December 2021

Primary production (PP) in the sub-polar region appears to be important for ocean carbon uptake but how the different water masses contribute to the PP occurring here has not yet been described. Using two models based on satellite observations of surface chlorophyll, light and temperature, seasonal patterns in the distribution of PP are shown here to differ in the sub-polar gyre south of the Greenland-Scotland Ridge (GSR) and surrounding water masses. Monthly averages of PP (2003–2013) were determined. Total and seasonal PP were similar in both models. Average PP in five of the domains (0.47–0.77 g C m–2 d–1) was well above the global average (0.37 g C m–2 d–1). Over the East Greenland shelf, however, total annual PP was estimated to be only 0.19 g C m–2 d–1. The Norwegian shelf was the most productive of the regions studied. “Spring blooms” appear sporadically as spikes in the annual distribution of PP in some regions/years, but do not emerge as a dominant feature in the average annual development of PP in any of the domains. For all regions, ∼25% of the annual PP takes place in the period January-May. PP peaked over most of the study area at or around maximum insolation or temperature. PP in the study region as a whole appears to be more related to latitude or water masses than to bathymetry. In waters over the East Greenland shelf, the Norwegian shelf, and north of the GSR up to 50% of annual PP had taken place when ∼50% of the annual flux of light has reached the surface. In contrast, only about 35% of annual PP had taken place in the sub-polar gyre and waters over the southern open shelf by this time. Light-use efficiency differences may be explained by differences in mixed layer depth (MLD). Multi-model Earth System model studies have indicated that climate change may decrease the MLD in the sub-polar gyre and suggest this may lead to a decrease in the PP occurring here. The results presented here, however, suggest that a shallower MLD could lead to an increase in PP.
Localized Peptidoglycan Biosynthesis in Chlamydia trachomatis Conforms to the Polarized Division and Cell Size Reduction Developmental Models
Authors: Liechti George W.
Published: December 2021

Cell size regulation in bacteria is a function of two basic cellular processes: the expansion of the cell envelope and its constriction at spatially defined points at what will eventually become the division plane. In most bacterial species, both cell wall expansion and restriction are dependent on peptidoglycan (PG), a structural polymer comprised of sugars and amino acids that imparts strength and rigidity to bacterial membranes. Pathogenic Chlamydia species are unique in that their cell walls contain very little PG, which is restricted almost entirely to the apparent division plane of the microbe’s replicative forms. Very little is known about the degree to which PG affects the size and shape of C. trachomatis during its division process, and recent studies suggest the process is initiated via a polarized mechanism. We conducted an imaging study to ascertain the dimensions, orientation, and relative density of chlamydial PG throughout the organism’s developmental cycle. Our analysis indicates that PG in replicating C. trachomatis can be associated with four, broad structural forms; polar/septal disks, small/thick rings, large rings, and small/thin rings. We found that PG density appeared to be highest in septal disks and small/thick rings, indicating that these structures likely have high PG synthesis to degradation ratios. We also discovered that as C. trachomatis progresses through its developmental cycle PG structures, on average, decrease in total volume, indicating that the average cell volume of chlamydial RBs likely decreases over time. When cells infected with C. trachomatis are treated with inhibitors of critical components of the microbe’s two distinct PG synthases, we observed drastic differences in the ratio of PG synthesis to degradation, as well as the volume and shape of PG-containing structures. Overall, our results suggest that C. trachomatis PG synthases differentially regulate the expansion and contraction of the PG ring during both the expansion and constriction of the microbe’s cell membrane during cell growth and division, respectively.
Multi-Omics Reveal the Efficient Phosphate-Solubilizing Mechanism of Bacteria on Rocky Soil
Authors: Ding Yanqiang , Yi Zhuolin , Fang Yang , He Sulan , Li Yuming , He Kaize , Zhao Hai , Jin Yanling
Published: December 2021

Phosphate-solubilizing bacteria (PSB) can alleviate available phosphorus (AP)-deficiency without causing environmental pollution like chemical phosphate fertilizers. However, the research and application of PSB on the barren rocky soil is very rare. We screened six PSB from sweetpotato rhizosphere rocky soil. Among them, Ochrobactrum haematophilum FP12 showed the highest P-solubilizing ability of 1,085.00 mg/L at 7 days, which was higher than that of the most reported PSB. The assembled genome of PSB FP12 was 4.92 Mb with P-solubilizing and plant growth-promoting genes. In an AP-deficient environment, according to transcriptome and metabolomics analysis, PSB FP12 upregulated genes involved in gluconic acid synthesis and the tricarboxylic acid cycle, and increased the concentration of gluconic acid and malic acid, which would result in the enhanced P-solubilizing ability. Moreover, a series of experiments in the laboratory and field confirmed the efficient role of the screened PSB on significantly increasing AP in the barren rocky soil and promoting sweetpotato yield. So, in this study, we screened highly efficient PSB, especially suitable for the barren rocky soil, and explored the P-solubilizing mechanism. The research will reduce the demand for chemical phosphate fertilizers and promote the environment-friendly agricultural development.
The Importance of Vacuolar Ion Homeostasis and Trafficking in Hyphal Development and Virulence in Candida albicans
Authors: Lv Quanzhen , Yan Lan , Jiang Yuanying
Published: December 2021

The vacuole of Candida albicans plays a significant role in many processes including homeostasis control, cellular trafficking, dimorphic switching, and stress tolerance. Thus, understanding the factors affecting vacuole function is important for the identification of new drug targets needed in response to the world’s increasing levels of invasive infections and the growing issue of fungal drug resistance. Past studies have shown that vacuolar proton-translocating ATPases (V-ATPases) play a central role in pH homeostasis and filamentation. Vacuolar protein sorting components (VPS) regulate V-ATPases assembly and at the same time affect hyphal development. As well, vacuolar calcium exchange systems like Yvc1 and Pmc1 maintain cytosolic calcium levels while being affected by V-ATPases function. All these proteins play a role in the virulence and pathogenesis of C. albicans. This review highlights the relationships among V-ATPases, VPS, and vacuolar calcium exchange proteins while summarizing their importance in C. albicans infections.
Conformational Changes in a Macrolide Antibiotic Binding Protein From Mycobacterium smegmatis Upon ADP Binding
Authors: Zhang Qingqing , Liu Xiang , Liu Huijuan , Zhang Bingjie , Yang Haitao , Mi Kaixia , Guddat Luke W. , Rao Zihe
Published: December 2021

Rv3197 (MABP-1), a non-canonical ABC protein in Mycobacterium tuberculosis, has ATPase activity and confers inducible resistance to the macrolide family of antibiotics. Here we have shown that MSMEG_1954, the homolog of Rv3197 in M. smegmatis, has a similar function of conferring macrolide resistance. Crystal structures of apo-MSMEG_1954 (form1 and form 2) and MSMEG_1954 in complex with ADP have been determined. These three structures show that MSMEG_1954 has at least two different conformations we identify as closed state (MSMEG_1954-form 1) and open state (MSMEG_1954-form 2 and MSMEG_1954-ADP). Structural superimposition shows that the MSMEG_1954-form 2 and MSMEG_1954-ADP complex have similar conformation to that observed for MABP-1 and MABP-1-erythromicin complex structure. However, the antibiotic binding pocket in MSMEG_1954-form 1 is completely blocked by the N-terminal accessory domain. When bound by ADP, the N-terminal accessory domain undergoes conformational change, which results in the open of the antibiotic binding pocket. Because of the degradation of N terminal accessory domain in MSMSG_1954-form 2, it is likely to represent a transitional state between MSMEG_1954-form 1 and MSMEG_1954-ADP complex structure.
Recent Advances in Basic Research for CSF1R-Microglial Encephalopathy
Authors: Wang Yan-Li , Wang Fang-Ze , Li Runzhi , Jiang Jiwei , Liu Xiangrong , Xu Jun
Published: December 2021

Colony-stimulating factor-1 receptor-microglial encephalopathy is a rare rapidly progressive dementia resulting from colony-stimulating factor-1 receptor (CSF1R) mutations, also named pigmentary orthochromatic leukodystrophy (POLD), hereditary diffuse leukoencephalopathy with spheroids (HDLS), adult-onset leukoencephalopathy with axonal spheroids, and pigmented glia (ALSP) and CSF1R-related leukoencephalopathy.CSF1Ris primarily expressed in microglia and mutations normally directly lead to changes in microglial number and function. Many animal models have been constructed to explore pathogenic mechanisms and potential therapeutic strategies, including zebrafish, mice, and rat models which are withCSF1Rmonogenic mutation, biallelic or tri-allelic deletion, orCSF1R-null. Although there is no cure for patients with CSF1R-microglial encephalopathy, microglial replacement therapy has become a topical research area. This review summarizesCSF1R-related pathogenetic mutation sites and mechanisms, especially the feasibility of the microglia-original immunotherapy.
Developmentally Regulated Modulation of Lumbar Motoneurons by Metabotropic Glutamate Receptors: A Cellular and Behavioral Analysis in Newborn Mice
Authors: Quilgars Camille , Cazalets Jean-René , Bertrand Sandrine S.
Published: December 2021

The present study explores the impact of metabotropic glutamate receptor (mGluR) activation on activity-dependent synaptic plasticity (ADSP) and the intrinsic membrane properties of lumbar motoneurons (MNs) using a combination of biochemical, pharmacological, electrophysiological and behavioral techniques. Using spinal cord slices from C57BL/6JRJ mice at two developmental stages, 1-3 and 8-12 postnatal days (P1-P3; P8-P12, respectively), we found that ADSP expressed at glutamatergic synapses between axons conveyed in the ventrolateral funiculus (VLF) and MNs, involved mGluR activation. Using specific agonists of the three groups of mGluRs, we observed that mGluR stimulation causes subtype-specific and developmentally regulated modulation of the ADSP and synaptic transmission at VLF-MN synapses as well as the intrinsic membrane properties of MNs. RT-qPCR analysis revealed a downregulation of mGluR gene expression with age in the ventral part of the lumbar spinal cord. Interestingly, the selective harvest by laser microdissection of MNs innervating the Gastrocnemius and Tibialis anterior muscles unraveled that the level of Grm2 expression is higher in Tibialis MNs compared to Gastrocnemius MNs suggesting a specific mGluR gene expression profile in these two MN pools. Finally, we assessed the functional impact of mGluR modulation on electrically induced bouts of fictive locomotion in the isolated spinal cord preparation of P1-P3 mice, and in vivo during spontaneous episodes of swimming activity in both P1-P3 and P8-P12 mouse pups. We observed that the mGluR agonists induced distinct and specific effects on the motor burst amplitudes and period of the locomotor rhythms tested and that their actions are function of the developmental stage of the animals. Altogether our data show that the metabotropic glutamatergic system exerts a complex neuromodulation in the developing spinal lumbar motor networks and provide new insights into the expression and modulation of ADSP in MNs.
Data Augmentation for EEG-Based Emotion Recognition Using Generative Adversarial Networks
Authors: Bao Guangcheng , Yan Bin , Tong Li , Shu Jun , Wang Linyuan , Yang Kai , Zeng Ying
Published: December 2021

One of the greatest limitations in the field of EEG-based emotion recognition is the lack of training samples, which makes it difficult to establish effective models for emotion recognition. Inspired by the excellent achievements of generative models in image processing, we propose a data augmentation model named VAE-D2GAN for EEG-based emotion recognition using a generative adversarial network. EEG features representing different emotions are extracted as topological maps of differential entropy (DE) under five classical frequency bands. The proposed model is designed to learn the distributions of these features for real EEG signals and generate artificial samples for training. The variational auto-encoder (VAE) architecture can learn the spatial distribution of the actual data through a latent vector, and is introduced into the dual discriminator GAN to improve the diversity of the generated artificial samples. To evaluate the performance of this model, we conduct a systematic test on two public emotion EEG datasets, the SEED and the SEED-IV. The obtained recognition accuracy of the method using data augmentation shows as 92.5 and 82.3%, respectively, on the SEED and SEED-IV datasets, which is 1.5 and 3.5% higher than that of methods without using data augmentation. The experimental results show that the artificial samples generated by our model can effectively enhance the performance of the EEG-based emotion recognition.
The Occurrence of Seizure Clusters in Patients With Epilepsy Is Partly Determined by Epilepsy Severity: A Single-Center Retrospective Observational Study
Authors: Zhong Rui , Chen Qingling , Zhang Xinyue , Lin Weihong
Published: December 2021

Purpose: This retrospective observational study aimed to investigate the self-reported prevalence of seizure clusters (SCs) in patients with epilepsy (PWE) and its relationship with clinical characteristics.

Methods: We retrospectively analyzed data from consecutive PWE from our hospital in northeastern China. Data were collected from the databank of a tertiary epilepsy center. Logistic regression models were employed to investigate the relationships between the individual patient demographic/clinical variables and the occurrence of SC.

Results: In total, 606 consecutive PWE were included in the final analysis, and 268 (44.2%) patients experienced at least one seizure cluster. In multivariate logistic regression models, age (OR: 1.014; 95% CI: 1.002–1.027; p = 0.02), seizure frequency (OR: 2.08; 95% CI: 1.555–2.783; p < 0.001), multiple seizure types (OR: 5.111; 95% CI: 1.737–15.043; p = 0.003), number of current anti-seizure medications (ASM) (OR: 1.533; 95% CI: 1.15–2.042; p = 0.004), drug-resistant epilepsy (OR: 1.987; 95% CI: 1.159–3.407; p = 0.013), and a history of status epilepticus (OR: 1.903; 95% CI: 1.24–2.922; p = 0.003) were independent variables associated with a history of SC in PWE.

Conclusion: Seizure clusters (SCs) are common occurrences at our study center. The occurrence of SC in individuals with epilepsy, to some extent, is determined by the epilepsy severity.
Dissect Relationships Between Gene Co-expression and Functional Connectivity in Human Brain
Authors: Zhang Xue , Xie Yingying , Tang Jie , Qin Wen , Liu Feng , Ding Hao , Ji Yuan , Yang Bingbing , Zhang Peng , Li Wei , Ye Zhaoxiang , Yu Chunshui
Published: December 2021

Although recent evidence indicates an association between gene co-expression and functional connectivity in human brain, specific association patterns remain largely unknown. Here, using neuroimaging-based functional connectivity data of living brains and brain-wide gene expression data of postmortem brains, we performed comprehensive analyses to dissect relationships between gene co-expression and functional connectivity. We identified 125 connectivity-related genes (20 novel genes) enriched for dendrite extension, signaling pathway and schizophrenia, and 179 gene-related functional connections mainly connecting intra-network regions, especially homologous cortical regions. In addition, 51 genes were associated with connectivity in all brain functional networks and enriched for action potential and schizophrenia; in contrast, 51 genes showed network-specific modulatory effects and enriched for ion transportation. These results indicate that functional connectivity is unequally affected by gene expression, and connectivity-related genes with different biological functions are involved in connectivity modulation of different networks.
Investigating the Role of Culture on Negative Emotion Expressions in the Wild
Authors: Hughson Emma , Javadi Roya , Thompson James , Lim Angelica
Published: December 2021

Even though culture has been found to play some role in negative emotion expression, affective computing research primarily takes on a basic emotion approach when analyzing social signals for automatic emotion recognition technologies. Furthermore, automatic negative emotion recognition systems still train data that originates primarily from North America and contains a majority of Caucasian training samples. As such, the current study aims to address this problem by analyzing what the differences are of the underlying social signals by leveraging machine learning models to classify 3 negative emotions, contempt, anger and disgust (CAD) amongst 3 different cultures: North American, Persian, and Filipino. Using a curated data set compiled from YouTube videos, a support vector machine (SVM) was used to predict negative emotions amongst differing cultures. In addition a one-way ANOVA was used to analyse the differences that exist between each culture group in-terms of level of activation of underlying social signal. Our results not only highlighted the significant differences in the associated social signals that were activated for each culture, but also indicated the specific underlying social signals that differ in our cross-cultural data sets. Furthermore, the automatic classification methods showed North American expressions of CAD to be well-recognized, while Filipino and Persian expressions were recognized at near chance levels.
MicroRNA-101 Regulates 6-Hydroxydopamine-Induced Cell Death by Targeting Suppressor/Enhancer Lin-12-Like in SH-SY5Y Cells
Authors: Omura Tomohiro , Nomura Luna , Watanabe Ran , Nishiguchi Hiroki , Yamamoto Kazuhiro , Imai Satoshi , Nakagawa Shunsaku , Itohara Kotaro , Yonezawa Atsushi , Nakagawa Takayuki , Kunimasa Junichi , Yano Ikuko , Matsubara Kazuo
Published: December 2021

Endoplasmic reticulum (ER) stress has been reported as a cause of Parkinson’s disease (PD). We have previously reported that the ubiquitin ligase HMG-CoA reductase degradation 1 (HRD1) and its stabilizing factor suppressor/enhancer lin-12-like (SEL1L) participate in the ER stress. In addition, we recently demonstrated that neuronal cell death is enhanced in the cellular PD model when SEL1L expression is suppressed compared with cell death when HRD1 expression is suppressed. This finding suggests that SEL1L is a critical key molecule in the strategy for PD therapy. Thus, investigation into whether microRNAs (miRNAs) regulate SEL1L expression in neurons should be interesting because relationships between miRNAs and the development of neurological diseases such as PD have been reported in recent years. In this study, using miRNA databases and previous reports, we searched for miRNAs that could regulate SEL1L expression and examined the effects of this regulation on cell death in PD models created by 6-hydroxydopamine (6-OHDA). Five miRNAs were identified as candidate miRNAs that could modulate SEL1L expression. Next, SH-SY5Y cells were exposed to 6-OHDA, following which miR-101 expression was found to be inversely correlated with SEL1L expression. Therefore, we selected miR-101 as a candidate miRNA for SEL1L modulation. We confirmed that miR-101 directly targets the SEL1L 3′ untranslated region, and an miR-101 mimic suppressed the 6-OHDA–induced increase in SEL1L expression and enhanced cell death. Furthermore, an miR-101 inhibitor suppressed this response. These results suggest that miR-101 regulates SEL1L expression and may serve as a new target for PD therapy.
FLRT3 Marks Direction-Selective Retinal Ganglion Cells That Project to the Medial Terminal Nucleus
Authors: Ruff Tobias , Peters Christian , Matsumoto Akihiro , Ihle Stephan J. , Morales Pilar Alcalá , Gaitanos Louise , Yonehara Keisuke , del Toro Daniel , Klein Rüdiger
Published: December 2021

The mammalian retina extracts a multitude of diverse features from the visual scene such as color, contrast, and direction of motion. These features are transmitted separately to the brain by more than 40 different retinal ganglion cell (RGC) subtypes. However, so far only a few genetic markers exist to fully characterize the different RGC subtypes. Here, we present a novel genetic Flrt3-CreERT2 knock-in mouse that labels a small subpopulation of RGCs. Using single-cell injection of fluorescent dyes in Flrt3 positive RGCs, we distinguished four morphological RGC subtypes. Anterograde tracings using a fluorescent Cre-dependent Adeno-associated virus (AAV) revealed that a subgroup of Flrt3 positive RGCs specifically project to the medial terminal nucleus (MTN), which is part of the accessory optic system (AOS) and is essential in driving reflex eye movements for retinal image stabilization. Functional characterization using ex vivo patch-clamp recordings showed that the MTN-projecting Flrt3 RGCs preferentially respond to downward motion in an ON-fashion. These neurons distribute in a regular pattern and most of them are bistratified at the level of the ON and OFF bands of cholinergic starburst amacrine cells where they express the known ON-OFF direction-selective RGC marker CART. Together, our results indicate that MTN-projecting Flrt3 RGCs represent a new functionally homogeneous AOS projecting direction-selective RGC subpopulation.
Human Primary Olfactory Amygdala Subregions Form Distinct Functional Networks, Suggesting Distinct Olfactory Functions
Authors: Noto Torben , Zhou Guangyu , Yang Qiaohan , Lane Gregory , Zelano Christina
Published: December 2021

Three subregions of the amygdala receive monosynaptic projections from the olfactory bulb, making them part of the primary olfactory cortex. These primary olfactory areas are located at the anterior-medial aspect of the amygdala and include the medial amygdala (MeA), cortical amygdala (CoA), and the periamygdaloid complex (PAC). The vast majority of research on the amygdala has focused on the larger basolateral and basomedial subregions, which are known to be involved in implicit learning, threat responses, and emotion. Fewer studies have focused on the MeA, CoA, and PAC, with most conducted in rodents. Therefore, our understanding of the functions of these amygdala subregions is limited, particularly in humans. Here, we first conducted a review of existing literature on the MeA, CoA, and PAC. We then used resting-state fMRI and unbiased k-means clustering techniques to show that the anatomical boundaries of human MeA, CoA, and PAC accurately parcellate based on their whole-brain resting connectivity patterns alone, suggesting that their functional networks are distinct, relative both to each other and to the amygdala subregions that do not receive input from the olfactory bulb. Finally, considering that distinct functional networks are suggestive of distinct functions, we examined the whole-brain resting network of each subregion and speculated on potential roles that each region may play in olfactory processing. Based on these analyses, we speculate that the MeA could potentially be involved in the generation of rapid motor responses to olfactory stimuli (including fight/flight), particularly in approach/avoid contexts. The CoA could potentially be involved in olfactory-related reward processing, including learning and memory of approach/avoid responses. The PAC could potentially be involved in the multisensory integration of olfactory information with other sensory systems. These speculations can be used to form the basis of future studies aimed at clarifying the olfactory functions of these under-studied primary olfactory areas.
Relationship Between Lipodystrophy, Body Composition, Metabolic Profile, and Serum Levels of Adipocytokines
Authors: Sacilotto Lívia Bertazzo , Papini Silvia Justina , Mendes Adriana Lucia , Gatto Mariana , Pereira Paulo Câmara Marques , Corrente José Eduardo , Silva Julhiany de Fátima da
Published: December 2021

Background: Despite the benefits in improving the clinical state of people living with HIV/aids (PLWHA), some side effects associated with the use of antiretroviral therapy (ART) are reported. Redistribution of body fat has been associated with treatment and is characterized by morphological changes, also known as lipodystrophy. The complications of metabolic and morphological changes in these individuals seem to increase the risk of cardiovascular disease. Adipocytokines are proteins that have essential functions in biological processes, in which the levels of these proteins are related to the pathogenesis of metabolic syndrome (MS) and cardiovascular disease. Recent studies have shown that such levels are generally modified in PLWHA, regardless of whether the treatment is established or not. An application of methods for body fat estimation in patients with fat redistribution, as in the case of aids, especially those that quantify body fat by segments, appears to clarify these alterations and plays an important role in the development of multiprofessional treatment.

Objectives: This investigation was carried out to compare and correlate body composition, biochemical metabolic parameters, and levels of adipocytokines and cytokines of PLWHA, with and without lipodystrophy, with individuals with negative HIV serology and stratified by sex.

Material and Methods: This is a cross-sectional study in which body composition, metabolic and anthropometric changes, and levels of adipocytokines of 110 individuals were assessed. These individuals were paired in sex, age, and body mass index (BMI) and subdivided into three groups: PLWHA with and without a clinical diagnosis of lipodystrophy associated with HIV, and a group control.

Results: Collinearity was identified both in the general sample and for genders of the waist-to-height ratio (WHtR) with all anthropometric parameters, except for muscle mass. The results show strong association between IFN-γ and TNF-α both in the general sample and for genders and moderate correlation between leptin and fasting glucose for women; worsening of the triglyceride profile in both women with lipodystrophy compared with the control group and men without lipodystrophy compared with the control group; higher serum TNF-α values among men without lipodystrophy compared to those with HIV-associated lipodystrophy (HALS).

Conclusions: The results of this study underline that, considering the manifestations of the syndrome, these patients have a high-risk endocrine metabolic profile for cardiovascular events.
Ghrelin Enhancer, the Latest Evidence of Rikkunshito
Authors: Yamada Chihiro , Hattori Tomohisa , Ohnishi Shunsuke , Takeda Hiroshi
Published: December 2021

Rikkunshito is a Japanese herbal medicine (Kampo) that has been attracting attention and researched by many researchers not only in Japan but also worldwide. There are 214 rikkunshito articles that can be searched on PubMed by August 2021. The reason why rikkunshito has attracted so much attention is due to an epoch-making report (Gastroenterology, 2008) discovered that rikkunshito promotes the secretion of the orexigenic peptide ghrelin. Since then, many researchers have discovered that rikkunshito has a direct effect on the ghrelin receptor, GHS-R1a, and an effect of enhancing the ghrelin signal to the brain. Additionally, a lot of evidence that rikkunshito is expected to be effective for various gastrointestinal diseases have also been demonstrated. Numerous basic and clinical studies have suggested that rikkunshito affects (i) various discomforts caused by anticancer drugs, gastroesophageal reflux disease, functional dyspepsia, (ii) various stress-induced anorexia, (iii) hypophagia in the elderly, and (iv) healthy lifespan. In this review, as one who discovered the ghrelin enhancer effect of rikkunshito, we will review the research of rikkunshito so far and report on the latest research results.
Imaging Manifestations of Intrahepatic Reactive Lymphoid Hyperplasia: A Case Report and Literature Review
Authors: Zhang Bingqian , Zou Mingyue , Lu Zengxin , Mao Haijia , Huang Ya’nan , Liu Fang , Zhao Zhenhua
Published: December 2021

Reactive lymphoid hyperplasia (RLH) of the liver is a rare benign disease. This article describes a 77-year-old female patient with RLH of the liver. The patient was admitted to the hospital due to atrial fibrillation. A liver tumor was incidentally found during abdominal enhanced CT. Further magnetic resonance imaging (MRI) and PET/CT showed four lesions in the liver. The imaging findings suggested hepatocellular carcinoma (HCC), but it was not consistent that the patient had no history of liver cirrhosis and hepatitis, and a variety of tumor markers were within the normal range. The largest lesion was surgically removed and microscopically diagnosed as RLH of the liver. The pathology included a large number of reactive hyperplastic lymphoid follicles. Immunohistochemical examination showed that the infiltrating lymphocytes were polyclonal. The authors believe that the perinodular enhancement on MRI, the obvious limitation of diffusion on DWI, the insignificant increase of SUVmax on PET-CT delayed phase, and the support of clinical data can help distinguish liver RLH from lymphoma and HCC.
MiRNAs as Anti-Angiogenic Adjuvant Therapy in Cancer: Synopsis and Potential
Authors: Lahooti Behnaz , Poudel Sagun , Mikelis Constantinos M. , Mattheolabakis George
Published: December 2021

Angiogenesis is a key mechanism for tumor growth and metastasis and has been a therapeutic target for anti-cancer treatments. Intensive vascular growth is concomitant with the rapidly proliferating tumor cell population and tumor outgrowth. Current angiogenesis inhibitors targeting either one or a few pro-angiogenic factors or a range of downstream signaling molecules provide clinical benefit, but not without significant side effects. miRNAs are important post-transcriptional regulators of gene expression, and their dysregulation has been associated with tumor progression, metastasis, resistance, and the promotion of tumor-induced angiogenesis. In this mini-review, we provide a brief overview of the current anti-angiogenic approaches, their molecular targets, and side effects, as well as discuss existing literature on the role of miRNAs in angiogenesis. As we highlight specific miRNAs, based on their activity on endothelial or cancer cells, we discuss their potential for anti-angiogenic targeting in cancer as adjuvant therapy and the importance of angiogenesis being evaluated in such combinatorial approaches.
Clinical Significance and Prognostic Value of the Maximum Standardized Uptake Value of 18F-Flurodeoxyglucose Positron Emission Tomography–Computed Tomography in Colorectal Cancer
Authors: Yin Yi-xin , Xie Ming-zhi , Liang Xin-qiang , Ye Meng-ling , Li Ji-lin , Hu Bang-li
Published: December 2021

Background

The role of 18F-flurodeoxyglucose (18F-FDG) positron emission tomography–computed tomography (PET/CT) in colorectal cancer (CRC) remains unclear. This study aimed to explore the association of the maximum standardized uptake value (SUVmax), a parameter of 18F-FDG PET/CT, with KRAS mutation, the Ki-67 index, and survival in patients with CRC.

Methods

Data of 66 patients with CRC who underwent 18F-FDG PET/CT was retrospectively collected in our center. The clinical significance of the SUVmax in CRC and the association of the SUVmax with KRAS mutation and the Ki-67 index were determined. A meta-analysis was conducted by a systematic search of PubMed, Web of Science, and CNKI databases, and the data from published articles were combined with that of our study. The association of the SUVmax with KRAS mutation and the Ki-67 index was determined using the odds ratio to estimate the pooled results. The hazard ratio was used to quantitatively evaluate the prognosis of the SUVmax in CRC.

Results

By analyzing the data of 66 patients with CRC, the SUVmax was found not to be related to the tumor-node-metastasis stage, clinical stage, sex, and KRAS mutation but was related to the tumor location and nerve invasion. The SUVmax had no significant correlation with the tumor biomarkers and the Ki-67 index. Data of 17 studies indicated that the SUVmax was significantly increased in the mutated type compared with the wild type of KRAS in CRC; four studies showed that there was no remarkable difference between patients with a high and low Ki-67 index score regarding the SUVmax. Twelve studies revealed that the SUVmax had no significant association with overall survival and disease-free survival in CRC patients.

Conclusions

Based on the combined data, this study demonstrated that the SUVmax of 18F-FDG PET/CT was different between colon and rectal cancers and associated with KRAS mutation but not the Ki-67 index; there was no significant association between the SUVmax and survival of patients with CRC.
Clinical Features and Prognostic Significance of NOTCH1 Mutations in Diffuse Large B-Cell Lymphoma
Authors: Li Zhongqi , Yu Fang , Ye Wenle , Mao Liping , Huang Jiansong , Shao Yang , Yan Junrong , Yu Wenjuan , Jin Jie , Wang Jinghan
Published: December 2021

Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous group of large lymphoid B cell malignancy with distinct clinical and genetic features. Recently, NOTCH1 mutations were identified in DLBCL cases by Next-generation sequencing (NGS), but the clinical features and prognostic impact were not systematically studied. Here, NOTCH1 genes in 161 DLBCL samples were sequenced by NGS. The prognostic value of NOTCH1 mutations was assessed in the context of clinical and laboratory factors, such as international prognostic index (IPI), cell-of-origin classification, double expression of BCL2 and c-MYC. The combined data from three Western cohorts were used to validate these results. As a result, NOTCH1 mutations were found in 17(10.6%) patients, and three patients had a hotspot mutation of c.7541_7542delCT. The presence of NOTCH1 mutations was significantly associated with poor complete response and progression free survival(PFS), which was independent of established clinical and laboratory parameters. In addition, 30 (1.92%) of 1562 patients treated with R-CHOP regimen in those combined Western cohorts had NOTCH1 mutations. Meta-analysis of the Western cohorts confirmed that NOTCH1 mutations were also associated with poor PFS and OS. In conclusion, DLBCL patients with the NOTCH1 mutations have worse PFS and OS, and the NOTCH1 mutations can be used as an independent predictor for patients with DLBCL.
Circadian Influences on Chemotherapy Efficacy in a Mouse Model of Brain Metastases of Breast Cancer
Authors: Walker William H. , Sprowls Samuel A. , Bumgarner Jacob R. , Liu Jennifer A. , Meléndez-Fernández O. Hecmarie , Walton James C. , Lockman Paul R. , DeVries A. Courtney , Nelson Randy J.
Published: December 2021

Chemotherapy is more effective in the treatment of peripheral tumors than brain metastases, likely reflecting the reduced ability of chemotherapy to cross the blood-brain barrier (BBB) and blood-tumor barrier at efficacious concentrations. Recent studies demonstrate circadian regulation of the BBB. Thus, we predicted that optimally timed chemotherapy would increase anti-tumor efficacy in a model of brain metastases of breast cancer (BMBC). First, we characterized novel daily alterations in BBB permeability to a commonly used chemotherapeutic,14C-paclitaxel, within BMBC following injections given at four time points across the day. Peak and trough14C-paclitaxel concentrations within BMBC occurred during the mid-dark phase and at the beginning of the light phase, respectively. Notably, chemotherapy injections during the dark phase increased cell death within BMBC and delayed onset of neurological symptoms relative to injections during the light phase. These data provide strong evidence for the beneficial effects of chrono-chemotherapy for the treatment of BMBC.
New Frontiers in Functional and Molecular Imaging of the Acutely Injured Lung: Pathophysiological Insights and Research Applications
Authors: Musch Guido
Published: December 2021

This review focuses on the advances in the understanding of the pathophysiology of ventilator-induced and acute lung injury that have been afforded by technological development of imaging methods over the last decades. Examples of such advances include the establishment of regional lung mechanical strain as a determinant of ventilator-induced lung injury, the relationship between alveolar recruitment and overdistension, the regional vs. diffuse nature of pulmonary involvement in acute respiratory distress syndrome (ARDS), the identification of the physiological determinants of the response to recruitment interventions, and the pathophysiological significance of metabolic alterations in the acutely injured lung. Taken together, these advances portray multimodality imaging as the next frontier to both advance knowledge of the pathophysiology of these conditions and to tailor treatment to the individual patient’s condition.
Integration of mRNA and miRNA Analysis Reveals the Molecular Mechanism of Cotton Response to Salt Stress
Authors: Zhan Jingjing , Diao Yangyang , Yin Guo , Sajjad Muhammad , Wei Xi , Lu Zhengying , Wang Ye
Published: December 2021

To identify the regulatory network of known and novel microRNAs (miRNAs) and their targets responding to salt stress, a combined analysis of mRNA libraries, small RNA libraries, and degradome libraries were performed. In this study, we used unique molecular identifiers (UMIs), which are more sensitive, accurate, and reproducible than traditional methods of sequencing, to quantify the number of molecules and correct for amplification bias. We identified a total of 312 cotton miRNAs using seedlings at 0, 1, 3, and 6 h after NaCl treatment, including 80 known ghr-miRNAs and 232 novel miRNAs and found 155 miRNAs that displayed significant differential expression under salt stress. Among them, fifty-nine differentially expressed miRNAs were simultaneously induced in two or three tissues, while 66, 11, and 19 were specifically expressed in the roots, leaves, and stems, respectively. It is indicated there were different populations of miRNAs against salt stress in roots, leaves and stems. 399 candidate targets of salt-induced miRNAs showed significant differential expression before and after salt treatment, and 72 targets of 25 miRNAs were verified by degradome sequencing data. Furthermore, the regulatory relationship of miRNA-target gene was validated experimentally via 5′RLM-RACE, proving our data reliability. Gene ontology and KEGG pathway analysis found that salt-responsive miRNA targets among the differentially expressed genes were significantly enriched, and mainly involved in response to the stimulus process and the plant hormone signal transduction pathway. Furthermore, the expression levels of newly identified miRNA mir1 and known miRNAs miR390 and miR393 gradually decreased when subjected to continuous salt stress, while overexpression of these miRNAs both increased sensitivity to salt stress. Those newly identified miRNAs and mRNA pairs were conducive to genetic engineering and better understanding the mechanisms responding to salt stress in cotton.
Transformation of Teosinte (Zea mays ssp. parviglumis) via Biolistic Bombardment of Seedling-Derived Callus Tissues
Authors: Zobrist Jacob D. , Martin-Ortigosa Susana , Lee Keunsub , Azanu Mercy K. , Ji Q , Wang Kan
Published: December 2021

Modern maize exhibits a significantly different phenotype than its wild progenitor teosinte despite many genetic similarities. Of the many subspecies of Zea mays identified as teosinte, Zea mays ssp. parviglumis is the most closely related to domesticated maize. Understanding teosinte genes and their regulations can provide great insights into the maize domestication process and facilitate breeding for future crop improvement. However, a protocol of genetic transformation, which is essential for gene functional analyses, is not available in teosinte. In this study, we report the establishment of a robust callus induction and regeneration protocol using whorl segments of seedlings germinated from mature seeds of Zea parviglumis. We also report, for the first time, the production of fertile, transgenic teosinte plants using the particle bombardment. Using herbicide resistance genes such as mutant acetolactate synthase (Als) or bialaphos resistance (bar) as selectable markers, we achieved an average transformation frequency of 4.17% (percentage of independent transgenic events in total bombarded explants that produced callus). Expression of visual marker genes of red fluorescent protein tdTomato and β-glucuronidase (gus) could be detected in bombarded callus culture and in T1 and T2 progeny plants. The protocol established in this work provides a major enabling technology for research toward the understanding of this important plant in crop domestication.