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Introduction: Alzheimer’s disease (AD) and Type 2 diabetes (T2D) are both ageassociated diseases. Identification of shared genes could help develop early diagnosis and preventive strategies. Although genetic background plays a crucial role in these diseases, we noticed an underrepresentation tendency of North African populations in omics studies. Materials and methods: First, we conducted a comprehensive review of genes and pathways shared between T2D and AD through PubMed. Then, the function of the identified genes and variants was investigated using annotation tools including PolyPhen2, RegulomeDB, and miRdSNP. Pathways enrichment analyses were performed with g:Profiler and EnrichmentMap. Next, we analyzed variant distributions in 16 worldwide populations using PLINK2, R, and STRUCTURE software. Finally, we performed an inter-ethnic comparison based on the minor allele frequency of T2D-AD common variants. Results: A total of 59 eligible papers were included in our study. We found 231 variants and 363 genes shared between T2D and AD. Variant annotation revealed six single nucleotide polymorphisms (SNP) with a high pathogenic score, three SNPs with regulatory effects on the brain, and six SNPs with potential effects on miRNA-binding sites. The miRNAs affected were implicated in T2D, insulin signaling pathways, and AD. Moreover, replicated genes were significantly enriched in pathways related to plasma protein binding, positive regulation of amyloid fibril deposition, microglia activation, and cholesterol metabolism. Multidimensional screening performed based on the 363 shared genes showed that main North African populations are clustered together and are divergent from other worldwide populations. Interestingly, our results showed that 49 SNP associated with T2D and AD were present in North African populations. Among them, 11 variants located in DNM3, CFH, PPARG, ROHA, AGER, CLU, BDNF1, CST9, and PLCG1 genes display significant differences in risk allele frequencies between North African and other populations. Conclusion: Our study highlighted the complexity and the unique molecular architecture of North African populations regarding T2D-AD shared genes. In conclusion, we emphasize the importance of T2D-AD shared genes and ethnicity-specific investigation studies for a better understanding of the link behind these diseases and to develop accurate diagnoses using personalized genetic biomarkers. [ABSTRACT FROM AUTHOR]

Vibrio parahaemolyticus is a significant seafood-borne pathogen, leading to serious acute gastrointestinal diseases worldwide. In this study, a reliable 4-plex droplet digital PCR (ddPCR) was successfully established and evaluated for the simultaneous detection of V. parahaemolyticus based on tlh , tdh , ureR , and orf8 in food samples using single intact cells. The targets tlh and ureR were labeled with 6-Carboxyfluorescein (FAM), and the targets tdh and orf8 were labeled with 5'-Hexachlorofluorescein (HEX). Due to reasonable proration of primers and probes corresponding into the two fluorescence channels of the ddPCR detecting platforms, the clearly separated 16 (24) clusters based on fluorescence amplitude were obtained. For better results, the sample hot lysis time and the cycle number were optimized. The results showed that the minimum number of "rain" and maximum fluorescence amplification were presented for precise detection in the condition of 25 min of the sample hot lysis time and 55 cycles. The sensitivity of this 4-plex ddPCR assay was 39 CFU/mL, which was in accordance with that of the conventional plate counting and was 10-fold sensitive than that of qPCR. In conclusion, the 4-plex ddPCR assay presented in this paper was a rapid, specific, sensitive, and accurate tool for the detection of V. parahaemolyticus including pandemic group strains and could be applied in the differentiation of V. parahaemolyticus in a wide variety of samples. [ABSTRACT FROM AUTHOR]

In the present paper, the Layer by Layer (LbL) method using β-lactoglobulin and sodium alginate was performed to individually encapsulate Saccharomyces cerevisiae cells in microorganized shells in order to protect them against stresses during dehydration. Higher survival (∼1 log) for encapsulated yeast cells was effectively observed after air dehydration at 45°C. For the first time, the potentiality of Synchrotron-Fourier Transform InfraRed microspectroscopy (S-FTIR) was used at the single-cell level in order to analyze the contribution of the biochemical composition of non-encapsulated vs. encapsulated cells in response to dehydration. The microspectroscopy measurements clearly differentiated between non-encapsulated and encapsulated yeast cells in the amide band region. In the spectral region specific to lipids, the S-FTIR results indicated probably the decrease in membrane fluidity of yeast after dehydration without significant distinction between the two samples. These data suggested minor apparent chemical changes in cell attributable to the LbL system upon dehydration. More insights are expected regarding the lower mortality among encapsulated cells. Indeed the hypothesis that the biopolymeric layers could induce less damage in cell by affecting the transfer kinetics during dehydration-rehydration cycle, should be verified in further work. [ABSTRACT FROM AUTHOR]

Background: Alzheimer's disease (AD) is the predominant cause of dementia on a global scale, significantly impacting the health of the elderly population. The pathogenesis of AD is closely linked to neuroinflammation. The present study employs a bibliometric analysis to examine research pertaining to neuroinflammation and AD within the last decade, with the objective of providing a comprehensive overview of the current research profile, hotspots and trends. Methods: This research conducted a comprehensive review of publications within the Science Citation Index Expanded of the Web of Science Core Collection Database spanning the years 2014 to 2024. Bibliometric analyses were performed using VOSviewer (version 1.6.19) and CiteSpace (version 6.3.R1) software to visualize data on countries, institutions, authors, journals, keywords, and references. Results: A total of 3,833 publications on neuroinflammation and AD were included from January 2014 to January 2024. Publications were mainly from the United States and China. Zetterberg, Henrik emerged as the author with the highest publication output, while Edison, Paul was identified as the most cited author. The most productive journal was Journal of Alzheimers Disease, and the most co-cited was Journal of Neuroinflammation. Research hotspot focused on microglia, mouse models, oxidative stress, and amyloid-beta through keyword analysis. Additionally, keywords such as blood-brain barrier and tau protein exhibited prolonged citation bursts from 2022 to 2024. Conclusion: This study provides a comprehensive review of the last 10 years of research on neuroinflammation and AD, including the number and impact of research findings, research hotspots, and future trends. The quantity of publications in this field is increasing, mainly in the United States and China, and there is a need to further strengthen close cooperation with different countries and institutions worldwide. Presently, research hotspots are primarily concentrated on microglia, with a focus on inhibiting their pro-inflammatory responses and promoting their anti-inflammatory functions as a potential direction for future investigations. [ABSTRACT FROM AUTHOR]

Introduction: Cultivated meat has received growing attention since claims were made that cultivated meat can be produced more ethically and sustainably than the current meat production. However, there are still major challenges in the development of cell lines, scaffolding, growth media, and bioprocess, which need to be overcome to reach industrial production levels. Numerous technological innovations have been proposed to overcome these challenges but they have rarely been evaluated with regard to their social sustainability. Consequently, it remains unclear if and how cultivated meat would contribute towards creating inclusive food systems. Methods: To bring more clarity, the study identifies different technological solutions that are used or developed for production of cultivated meat and identifies the positive and negative claims about the expected contributions of these technological solutions to social inclusion in food systems, using evidence from the literature review and 11 expert interviews. An innovation radar for cultivated meat is proposed to visualise the variety of technological innovations and the claims about their expected contributions to social sustainability. Results: The technologies in the areas cell line development, scaffolding, growth media, and bioprocess are expected to have an impact on inclusion in consumption of cultivated meat. Some cell innovations are expected to raise cognitive barriers due to complex technologies that might be difficult for the consumer to understand. Cultural barriers are expected to be raised by cell innovation entailing genetic engineering and medium innovation using FBS or animal components, which is considered to harm animals. Further, regulatory barriers are expected in the EU if genetic modification is used in the production process, which concerns the areas cells, media, and scaffolding. The innovations for scaffolds are expected to mainly lower cost and cultural barriers since most technologies are already used in the food industry. Bioprocess innovations promise to lower cost barriers, however it must be considered, that most of the collected data for innovations in the bioprocess domain are based on assumptions. Discussion: The study concludes that at this point in time, the most socially sustainable approach to cultivated meat production is not obvious. Under the current technological state of the art, it is not thinkable that production and consumption of cultivated meat could be socially inclusive. As it remains poorly understood if technologies for cultivated meat production could raise or lower barriers to inclusive consumption and production, further research is needed. [ABSTRACT FROM AUTHOR]

Background: It is beneficial to evaluate changes in neuroscience research field regarding research directions and topics over a defined period. Such information enables stakeholders to quickly identify the most influential research and incorporate latest evidence into research-informed education. To our knowledge, no study reported changes in neuroscience literature over the last decade. Therefore, the current study determined research terms with highest citation scores, compared publication shares of research areas and contributing countries in this field from 2006 to 2015 and identified the most productive journals. Methods: Data were extracted fromWeb of Science and Journal Citation Reports (JCR). Only articles and reviews published in journals classified under the JCR "Neurosciences" category over the period of interest were included. Title and abstract fields of each included publication were extracted and analyzed via VOSviewer to identify recurring terms with high relative citation scores. Two term maps were produced for publications over the study period to illustrate the extent of co-occurrence, and the impact of terms was evaluated based on their relative citation scores. To further describe the recent research priority or "hot spots," 10 terms with the highest relative citation scores were identified annually. In addition, by applying Bradford's law, we identified 10 journals being the most productive journals per annum over the survey period and evaluated their bilbiometric performances. Results: From 2006 to 2015, there were 47 terms involved in the annual lists of top 10 terms with highest relative citation scores. The most frequently recurring terms were autism (8), meta-analysis (7), functional connectivity (6), default mode network (4) and neuroimaging (4). Neuroscience research related to psychology and behavioral sciences showed an increase in publication share over the survey period, and China has become one of the major contributors to neuroscience research. Ten journals were frequently identified (≥8 years) as core journals within the survey period. Discussion: The landscape of neuroscience research has changed recently, and this paper provides contemporary overview for researchers and health care workers interested in this field's research and developments. Brain imaging and brain connectivity terms had high relative citation scores. [ABSTRACT FROM AUTHOR]

Local Field Potentials (LFPs) are population signals generated by complex spatiotemporal interaction of current sources and dipoles. Mathematical computations of LFPs allow the study of circuit functions and dysfunctions via simulations. This paper introduces LFPsim, a NEURON-based tool for computing population LFP activity and single neuron extracellular potentials. LFPsim was developed to be used on existing cable compartmental neuron and network models. Point source, line source, and RC based filter approximations can be used to compute extracellular activity. As a demonstration of efficient implementation, we showcase LFPs from mathematical models of electrotonically compact cerebellum granule neurons and morphologically complex neurons of the neocortical column. LFPsim reproduced neocortical LFP at 8, 32, and 56 Hz via current injection, in vitro post-synaptic N2a, N2b waves and in vivo T-C waves in cerebellum granular layer. LFPsim also includes a simulation of multi-electrode array of LFPs in network populations to aid computational inference between biophysical activity in neural networks and corresponding multi-unit activity resulting in extracellular and evoked LFP signals. [ABSTRACT FROM AUTHOR]

The visual cortex's hierarchical, multi-level organization is captured in many biologically inspired computational vision models, the general idea being that progressively larger scale (spatially/temporally) and more complex visual features are represented in progressively higher areas. However, most earlier models use localist representations (codes) in each representational field (which we equate with the cortical macrocolumn, "mac"), at each level. In localism, each represented feature/concept/event (hereinafter "item") is coded by a single unit. The model we describe, Sparsey, is hierarchical as well but crucially, it uses sparse distributed coding (SDC) in every mac in all levels. In SDC, each represented item is coded by a small subset of the mac's units. The SDCs of different items can overlap and the size of overlap between items can be used to represent their similarity. The difference between localism and SDC is crucial because SDC allows the two essential operations of associative memory, storing a new item and retrieving the best-matching stored item, to be done in fixed time for the life of the model. Since the model's core algorithm, which does both storage and retrieval (inference), makes a single pass over all macs on each time step, the overall model's storage/retrieval operation is also fixed-time, a criterion we consider essential for scalability to the huge ("Big Data") problems. A 2010 paper described a nonhierarchical version of this model in the context of purely spatial pattern processing. Here, we elaborate a fully hierarchical model (arbitrary numbers of levels and macs per level), describing novel model principles like progressive critical periods, dynamic modulation of principal cells' activation functions based on a mac-level familiarity measure, representation of multiple simultaneously active hypotheses, a novel method of time warp invariant recognition, and we report results showing learning/recognition of spatiotemporal patterns. [ABSTRACT FROM AUTHOR]

Background: Although clinically, Alzheimer's disease (AD) and vascular dementia (VaD) are the two major types of dementia, it is unclear whether the biophotonic activities associated with cognitive impairments in these diseases share common pathological features. Methods: We used the ultraweak biophoton imaging system (UBIS) and synaptosomes prepared by modified percoll method to directly evaluate the functional changes in synapses and neural circuits in AD and VaD model animals. Results: We found that biophotonic activities induced by glutamate were significantly reduced and spectral blueshifted in synaptosomes and brain slices. These changes could be partially reversed by pre-perfusion of the ifenprodil, a specific antagonist of the GluN2B subunit of N-methyl-D-aspartate receptors (NMDARs). Conclusion: Our findings suggest that AD and VaD pathology present similar but complex changes in biophotonic activities and transmission at synapses and neural circuits, implying that communications and information processing of biophotonic signals in the brain are crucial for advanced cognitive functions. [ABSTRACT FROM AUTHOR]

Rheumatoid arthritis (RA) is a systemic autoimmune disease accompanied with joint destruction. Serious joint destruction will eventually lead to disability and the decline of life quality in RA patients. At present, the therapeutic effect of drugs to alleviate joint destruction in RA is limited. Recently, accumulating evidences have shown that long non-coding RNAs (lncRNAs) play an important role in the pathogenesis of joint diseases. Therefore, this paper reviews the expression change and the action mechanism of lncRNAs in joint destruction of RA in recent years. A more comprehensive understanding of the role of lncRNAs in joint destruction will help the treatment of RA.

Traumatic brain injury (TBI) is a serious disease that threatens life and health of people. It poses a great economic burden on the healthcare system. Thus, seeking effective therapy to cure a patient with TBI is a matter of great urgency. Microglia are macrophages in the central nervous system (CNS) and play an important role in neuroinflammation. When TBI occurs, the human body environment changes dramatically and microglia polarize to one of two different phenotypes: M1 and M2. M1 microglia play a role in promoting the development of inflammation, while M2 microglia play a role in inhibiting inflammation. How to regulate the polarization direction of microglia is of great significance for the treatment of patients with TBI. The polarization of microglia involves many cellular signal transduction pathways, such as the TLR-4/NF-kB, JAK/STAT, HMGB1, MAPK, and PPAR-g pathways. These provide a theoretical basis for us to seek therapeutic drugs for the patient with TBI. There are several drugs that target these pathways, including fingolimod, minocycline, Tak-242 and erythropoietin (EPO), and CSF-1. In this study, we will review signaling pathways involved inmicroglial polarization and medications that influence this process. [ABSTRACT FROM AUTHOR]

Osteoarthritis (OA) is a chronic, debilitating joint disease characterized by progressive destruction of articular cartilage. For a long time, OA has been considered as a degenerative disease, while recent observations indicate the mechanisms responsible for the pathogenesis of OA are multifaceted. Aging is a key factor in its development. Current treatments are palliative and no disease modifying anti-osteoarthritis drugs (DMOADs) are available. In addition to articular cartilage degradation, cellular senescence, synovial inflammation, and epigenetic alterations may all have a role in its formation. Accumulating data demonstrate a clear relationship between the senescence of articular chondrocytes and OA formation and progression. Inhibition of cell senescence may help identify new agents with the properties of DMOADs. Several anti-cellular senescence strategies have been proposed and these include sirtuin-activating compounds (STACs), senolytics, and senomorphics drugs. These agents may selectively remove senescent cells or ameliorate their harmful effects. The results from preclinical experiments and clinical trials are inspiring. However, more studies are warranted to confirm their efficacy, safety profiles and adverse effects of these agents. [ABSTRACT FROM AUTHOR]

The hippocampal place cell system in rodents has provided a major paradigm for the scientific investigation of memory function and dysfunction. Place cells have been observed in area CA1 of the hippocampus of both freely moving animals, and of head-fixed animals navigating in virtual reality environments. However, spatial coding in virtual reality preparations has been observed to be impaired. Here we show that the use of a real-world environment system for head-fixed mice, consisting of an air-floating track with proximal cues, provides some advantages over virtual reality systems for the study of spatial memory. We imaged the hippocampus of head-fixed mice injected with the genetically encoded calcium indicator GCaMP6s while they navigated circularly constrained or open environments on the floating platform. We observed consistent place tuning in a substantial fraction of cells despite the absence of distal visual cues. Place fields remapped when animals entered a different environment. When animals re-entered the same environment, place fields typically remapped over a time period of multiple days, faster than in freely moving preparations, but comparable with virtual reality. Spatial information rates were within the range observed in freely moving mice. Manifold analysis indicated that spatial information could be extracted from a low-dimensional subspace of the neural population dynamics. This is the first demonstration of place cells in head-fixed mice navigating on an air-lifted real-world platform, validating its use for the study of brain circuits involved in memory and affected by neurodegenerative disorders. [ABSTRACT FROM AUTHOR]

Asymptomatic/subclinical gonococcal infections in females continue to be prevalent within the general population, thus emerging as a global health problem. However, the reasons for these clinical manifestations are unknown. Our group had previously found out that in females, asymptomatic gonococcal infections correlate with higher serum progesterone (P4) levels and lower IL-1β levels in cervical secretions. We used murine infection model and THP-1 cells to determine whether P4 exerts anti-inflammatory effects on gonococcal infections. In the murine infection model, P4 (1 mg/day) inhibited the inflammatory effects induced by gonococcal infections which led to decreased neutrophil infiltration, reduced polymorphonuclear neutrophils (PMNs) numbers, IL-1β, TNF-α, and IL-6 levels in vaginal secretions. In addition, P4 down-regulated the mRNA and protein levels of NLRP3, associated with lower mRNA levels of pro-IL-1β, repressed caspase-1 activity in genital tissues and THP-1 cells. Moreover, P4 suppressed the phosphorylation levels of NF-κB and attenuated Neisseria gonorrhoeae (N. gonorrhoeae , gonococci or GC)-induced ROS generation. This is consistent with the two signals required for activation of the NLRP3 (NOD-, LRR-, and pyrin domain-containing protein 3) inflammasome. In conclusion, our result shows that P4 suppresses the gonococci induced-inflammation, especially through the NLRP3 inflammasome pathway, and partially explains the pathogenesis of asymptomatic GC infection in women. [ABSTRACT FROM AUTHOR]

Networks of oscillating processes are a common occurrence in living systems. This is as true as anywhere in the energy metabolism of individual cells. Exchanges of molecules and common regulation operate throughout the metabolic processes of glycolysis and oxidative phosphorylation, making the consideration of each of these as a network a natural step. Oscillations are similarly ubiquitous within these processes, and the frequencies of these oscillations are never truly constant. These features make this system an ideal example with which to discuss an alternative approach to modeling living systems, which focuses on their thermodynamically open, oscillating, non-linear and non-autonomous nature. We implement this approach in developing a model of non-autonomous Kuramoto oscillators in two all-to-all weighted networks coupled to one another, and themselves driven by non-autonomous oscillators. Each component represents a metabolic process, the networks acting as the glycolytic and oxidative phosphorylative processes, and the drivers as glucose and oxygen supply. We analyse the effect of these features on the synchronization dynamics within the model, and present a comparison between this model, experimental data on the glycolysis of HeLa cells, and a comparatively mainstream model of this experiment. In the former, we find that the introduction of oscillator networks significantly increases the proportion of the model's parameter space that features some form of synchronization, indicating a greater ability of the processes to resist external perturbations, a crucial behavior in biological settings. For the latter, we analyse the oscillations of the experiment, finding a characteristic frequency of 0.01–0.02 Hz. We further demonstrate that an output of the model comparable to the measurements of the experiment oscillates in a manner similar to the measured data, achieving this with fewer parameters and greater flexibility than the comparable model. [ABSTRACT FROM AUTHOR]

Genome-wide association studies (GWASs) have identified and replicated many genetic variants that are associated with diseases and disease-related complex traits. However, the biological mechanisms underlying these identified associations remain largely elusive. Exploring the biological mechanisms underlying these associations requires identifying trait-relevant tissues and cell types, as genetic variants likely influence complex traits in a tissue- and cell type-specific manner. Recently, several statistical methods have been developed to integrate genomic data with GWASs for identifying trait-relevant tissues and cell types. These methods often rely on different genomic information and use different statistical models for trait-tissue relevance inference. Here, we present a comprehensive technical review to summarize ten existing methods for trait-tissue relevance inference. These methods make use of different genomic information that include functional annotation information, expression quantitative trait loci information, genetically regulated gene expression information, as well as gene co-expression network information. These methods also use different statistical models that range from linear mixed models to covariance network models. We hope that this review can serve as a useful reference both for methodologists who develop methods and for applied analysts who apply these methods for identifying trait relevant tissues and cell types. [ABSTRACT FROM AUTHOR]

Dim light at night (dLAN) has become a pervasive part of the modern world, and growing evidence shows its association with increased health risks. Though this link is attributed to a disturbed circadian clock, the underlying mechanisms that can explain how circadian disruption from dLAN causes negative health effects remain unclear. Here, we exposed rats to a light–dark cycle (12:12 h) with low-intensity light at night (~2 lx) for 2 and 5 weeks and explored the steady-state pattern of circulating immune cells and renal immune-related markers, which are well controlled by the circadian clock. After 5 weeks, dLAN impaired the daily variation in several types of white blood cells, especially monocytes and T cells. Two-week dLAN caused a reduction in blood monocytes and altered gene expression of macrophage marker Cd68 and monocyte-attracting chemokine Ccl2 in the kidney. Interestingly, dLAN decreased renal 3-nitrotyrosine levels and resulted in up-regulation of the main endogenous antioxidant pathways, indicating a disturbance in the renal redox balance and an activation of compensatory mechanisms. These effects paralleled the altered renal expression of the molecular clock components and increased plasma corticosterone levels. Together, our results show that chronic exposure to dLAN weakened the circadian control of daily variation of circulating immune cells and disturbed renal immune and redox homeostasis. Consequences of this dLAN-disturbed immune balance on the ability of the immune system to cope with other challenges should by clarified in further studies. [ABSTRACT FROM AUTHOR]

During endoplasmic reticulum (ER)-associated degradation, free N -glycans (FNGs) are produced from misfolded nascent glycoproteins via the combination of the cytosolic peptide N -glycanase (cPNGase) and endo-β- N -acetylglucosaminidase (ENGase) in the plant cytosol. The resulting high-mannose type (HMT)-FNGs, which carry one GlcNAc residue at the reducing end (GN1-FNGs), are ubiquitously found in developing plant cells. In a previous study, we found that HMT-FNGs assisted in protein folding and inhibited β-amyloid fibril formation, suggesting a possible biofunction of FNGs involved in the protein folding system. However, whether these HMT-FNGs occur in the ER, an organelle involved in protein folding, remained unclear. On the contrary, we also reported the presence of plant complex type (PCT)-GN1-FNGs, which carry the Lewisa epitope at the non-reducing end, indicating that these FNGs had been fully processed in the Golgi apparatus. Since plant ENGase was active toward HMT- N -glycans but not PCT- N -glycans that carry β1-2xylosyl and/or α1-3 fucosyl residue(s), these PCT-GN1-FNGs did not appear to be produced from fully processed glycoproteins that harbored PCT- N -glycans via ENGase activity. Interestingly, PCT-GN1-FNGs were found in the extracellular space, suggesting that HMT-GN1-FNGs formed in the cytosol might be transported back to the ER and processed in the Golgi apparatus through the protein secretion pathway. As the first step in elucidating the production mechanism of PCT-GN1-FNGs, we analyzed the structures of free oligosaccharides in plant microsomes and proved that HMT-FNGs (Man9-7GlcNAc1 and Man9-8GlcNAc2) could be found in microsomes, which almost consist of the ER compartments. [ABSTRACT FROM AUTHOR]

Place recognition is naturally informed by the mosaic of sensations we remember from previously visiting a location and general knowledge of our location in the world. Neurons in the mammalian brain (specifically in the hippocampus formation) named "place cells" are thought to reflect this recognition of place and are involved in implementing a spatial map that can be used for path planning and memory recall. In this research, we use bat-inspired sonar to mimic how bats might sense objects in the environment and recognize the views associated with different places. These "echo view cells" may contribute (along with odometry) to the creation of place cell representations observed in bats. Although detailed sensory template matching is straightforward, it is quite unlikely that a flying animal or robot will return to the exact 3-D position and pose where the original memory was captured. Instead, we strive to recognize views over extended regions that are many body lengths in size, reducing the number of places to be remembered for a map. We have successfully demonstrated some of this spatial invariance by training feed-forward neural networks (traditional neural networks and spiking neural networks) to recognize 66 distinct places in a laboratory environment over a limited range of translations and rotations. We further show how the echo view cells respond between known views and how their outputs can be combined over time for continuity. [ABSTRACT FROM AUTHOR]

Fibroblastic reticular cells (FRCs) are the specialized lymphoid stromal cells initially identified as triggering T-cell recruitment and dynamic motion in secondary lymphoid organs. Interestingly, FRCs also display antigen presentation capacities and support lymphocyte survival. CXCR5+CD4+ follicular T cells are important players of B-cell maturation and antibody response. Our study reported that in vitro -differentiated FRC-like cells enhanced the growth of the whole CXCR5+CD4+ T-cell compartment, while enhancing IL-4 secretion specifically by the PD1dimCXCR5+CD4+ cell subset, in a Notch- and ICAM1/LFA1-dependent manner. In addition, we revealed that in follicular lymphoma (FL) tissues, previously identified as enriched for PD1hiCXCR5hiCD4+ mature follicular helper T cells, PD1dimCXCR5+CD4+ T cells displayed an enrichment for Notch and integrin gene signatures, and a Notch and ICAM-1-dependent overexpression of IL-4 compared to their non-malignant counterparts. These findings suggest that the crosstalk between FRCs and CXCR5+PD1dimCD4+ T cells may contribute to the FL IL-4 rich environment, thus providing new insights in FL lymphomagenesis. [ABSTRACT FROM AUTHOR]

Determining biophysical details of spatially extended neurons is a challenge that needs to be overcome if we are to understand the dynamics of brain function from cellular perspectives. Moreover, we now know that we should not average across recordings from many cells of a given cell type to obtain quantitative measures such as conductance since measures can vary multiple-fold for a given cell type. In this work we examine whether a tight combination of experimental and computational work can address this challenge. The oriens-lacunosum/moleculare (OLM) interneuron operates as a "gate" that controls incoming sensory and ongoing contextual information in the CA1 of the hippocampus, making it essential to understand how its biophysical properties contribute to memory function. OLM cells fire phase-locked to the prominent hippocampal theta rhythms, and we previously used computational models to show that OLM cells exhibit high or low theta spiking resonance frequencies that depend respectively on whether their dendrites have hyperpolarization-activated cation channels (h-channels) or not. However, whether OLM cells actually possess dendritic h-channels is unknown at present. We performed a set of whole-cell recordings of OLM cells from mouse hippocampus and constructed three multi-compartment models using morphological and electrophysiological parameters extracted from the same OLM cell, including per-cell pharmacologically isolated h-channel currents. We found that the models best matched experiments when h-channels were present in the dendrites of each of the three model cells created. This strongly suggests that h-channels must be present in OLM cell dendrites and are not localized to their somata. Importantly, this work shows that a tight integration of model and experiment can help tackle the challenge of characterizing biophysical details and distributions in spatially extended neurons. Full spiking models were built for two of the OLM cells, matching their current clamp cell-specific electrophysiological recordings. Overall, our work presents a technical advancement in modeling OLM cells. Our models are available to the community to use to gain insight into cellular dynamics underlying hippocampal function. [ABSTRACT FROM AUTHOR]

MR1-restricted T (MR1T) cells are defined by their recognition of metabolite antigens presented by the monomorphic MHC class 1-related molecule, MR1, the most highly conserved MHC class I related molecule in mammalian species. Mucosal-associated invariant T (MAIT) cells are the predominant subset of MR1T cells expressing an invariant TCR α-chain, TRAV1-2. These cells comprise a T cell subset that recognizes and mediates host immune responses to a broad array of microbial pathogens, including Mycobacterium tuberculosis. Here, we sought to characterize development of circulating human MR1T cells as defined by MR1-5-OP-RU tetramer labeling and of the TRAV1-2+ MAIT cells defined by expression of TRAV1-2 and high expression of CD26 and CD161 (TRAV1-2+CD161++CD26++ cells). We analyzed postnatal expansion, maturation, and functionality of peripheral blood MR1-5-OP-RU tetramer+ MR1T cells in cohorts from three different geographic settings with different tuberculosis (TB) vaccination practices, levels of exposure to and infection with M. tuberculosis. Early after birth, frequencies of MR1-5-OP-RU tetramer+ MR1T cells increased rapidly by several fold. This coincided with the transition from a predominantly CD4+ and TRAV1-2− population in neonates, to a predominantly TRAV1-2+CD161++CD26++ CD8+ population. We also observed that tetramer+ MR1T cells that expressed TNF upon mycobacterial stimulation were very low in neonates, but increased ~10-fold in the first year of life. These functional MR1T cells in all age groups were MR1-5-OP-RU tetramer+TRAV1-2+ and highly expressed CD161 and CD26, markers that appeared to signal phenotypic and functional maturation of this cell subset. This age-associated maturation was also marked by the loss of naïve T cell markers on tetramer+ TRAV1-2+ MR1T cells more rapidly than tetramer+TRAV1-2− MR1T cells and non-MR1T cells. These data suggest that neonates have infrequent populations of MR1T cells with diverse phenotypic attributes; and that exposure to the environment rapidly and preferentially expands the MR1-5-OP-RU tetramer+TRAV1-2+ population of MR1T cells, which becomes the predominant population of functional MR1T cells early during childhood. [ABSTRACT FROM AUTHOR]

Background: The clinical management of pancreatic and other periampullary neoplasms remains challenging. In contrast to other cancer types, immunotherapies are largely ineffective, and the reason for the deprived immune response and the immune inhibiting cellular composition is only fragmentarily understood. The aim of this study was to comprehensively map the abundance, topographic distribution and spatial interaction of innate and innate-like immune cells in the tumor microenvironment of periampullary adenocarcinoma. Methods: Multiplexed immunofluorescent imaging was performed on tissue microarrays with tumors from a consecutive cohort of 175 patients with resected periampullary adenocarcinoma. To obtain a detailed spatial analysis of immune cell infiltration, two multiplex immune panels including antibodies against CD3, NKp46, CD56, CD68, CD163 and CD1a, CD208, CD123, CD15, CD68 and pan-cytokeratin were applied. Results: The infiltration of natural killer (NK) and NK-like T (NKT) cells was lower in malignant compared to benign tissue. NKT cells were more abundant in intestinal type compared to pancreatobiliary type tumors, and were associated with more favorable clinicopathological features and a prolonged survival. The interaction of NKp46+ NKT cells with macrophages was also associated with a prolonged survival. Conclusions: This study provides a comprehensive map of the innate immune landscape in periampullary adenocarcinoma. NK cells, and even more so NKT cells, are revealed to be central players in the local immune response in a clinically relevant context. [ABSTRACT FROM AUTHOR]

The mechanisms that mediate plasticity in pituitary function have long been a subject of vigorous investigation. Early studies overcame technical barriers and challenged conceptual barriers to identify multipotential and multihormonal cell populations that contribute to diverse pituitary stress responses. Decades of intensive study have challenged the standard model of dedicated, cell type-specific hormone production and have revealed the malleable cellular fates that mediate pituitary responses. Ongoing studies at all levels, from animal physiology to molecular analyses, are identifying the mechanisms underlying this cellular plasticity. This review describes the findings from these studies that utilized state-of-the-art tools and techniques to identify mechanisms of plasticity throughout the pituitary and focuses on the insights brought to our understanding of pituitary function. [ABSTRACT FROM AUTHOR]

Mucosal-associated invariant T (MAIT) cells constitute a highly conserved subset of effector T cells with innate-like recognition of a wide array of bacteria and fungi in humans. Harnessing the potential of these cells could represent a major advance as a new immunotherapy approach to fight difficult-to-treat bacterial infections. However, despite recent advances in the design of potent agonistic ligands for MAIT cells, it has become increasingly evident that adjuvants are required to elicit potent antimicrobial effector functions by these cells, such as IFNγ production and cytotoxicity. Indeed, TCR triggering alone elicits mostly barrier repair functions in MAIT cells, whereas an inflammatory milieu is required to drive the antibacterial functions. Cytokines such as IL-7, IL-12 and IL-18, IL-15 or more recently type 1 IFN all display an apparently similar ability to synergize with TCR stimulation to induce IFNγ production and/or cytotoxic functions in vitro , but their mechanisms of action are not well established. Herein, we show that MAIT cells feature a build-in mechanism to respond to IFNα. We confirm that IFNα acts directly and specifically on MAIT cells and synergizes with TCR/CD3 triggering to induce maximum cytokine production and cytotoxic functions. We provide evidences suggesting that the preferential activation of the Stat4 pathway is involved in the high sensitivity of MAIT cells to IFNα stimulation. Finally, gene expression data confirm the specific responsiveness of MAIT cells to IFNα and pinpoints specific pathways that could be the target of this cytokine. Altogether, these data highlight the potential of IFNα-inducing adjuvants to maximize MAIT cells responsiveness to purified ligands in order to induce potent anti-infectious responses. [ABSTRACT FROM AUTHOR]

Summary: Intestinal grafts carry large donor lymphoid load that is replaced by recipient cells. The dynamics of this process may influence the tolerance, rejection or graft‐versus‐host disease. We analysed distribution and turnover of T and B (Lin+) lymphocytes, natural killer (NK) and helper innate lymphoid cells (hILC) in intestinal epithelium (IEp) and lamina propia (LP) from a long‐term cohort of eight intestinal recipients and from a single patient monitored deeply during the first 8 months post‐transplant (posTx). Long‐term intestinal grafts showed significantly higher %hILC than native bowels in IEp and LP until 10 years posTx and recovery to normal levels was observed afterwards. We also observed an imbalance between hILC subsets in IEp [increase of type 1 (ILC1) and decrease in type 3 (ILC3) innate lymphoid cells] that persisted along posTx time even when %hILC was similar to native bowels. Regarding hILC origin, we still detected the presence of donor cells at 13 years posTx. However, this chimerism was significantly lower than in Lin+ and NK populations. According to these findings, observation from the patient monitored in early posTx period showed that recipient hILC repopulate earlier and faster than Lin+ cells, with increase in ILC1 related to rejection and infection episodes. [ABSTRACT FROM AUTHOR]

Purposes: To measure expression levels of CD47 during endometrial carcinoma development, and to determine specific modulatory effects. Methods: CD47 expression levels in endometrial carcinoma tissues and adjacent tissues were analyzed using qRT-PCR. CD47-overexpressed or downregulated cell models were established using CD47 plasmid or CD47 shRNA. The effects of CD47 on HEC-1A and Ishikawa cell growth were evaluated using CCK-8 assays. Migration ability of transfected HEC-1A and Ishikawa cells were examined using wound healing assays. Flow cytometry was used to measure the effects of CD47 on apoptosis and the cell cycle in HEC-1A and Ishikawa cells. Western blot was used to analyze the correlation between CD47 expression level and PI3K/Akt/mTOR signaling pathway. Results: Highly expressed CD47 was observed in endometrial carcinoma tissues, with higher levels in more advanced tissues than in early tissues. Upregulation of CD47 enhanced cell viability and migration ability in HEC-1A and Ishikawa cells, while silencing CD47 caused the opposite results. CD47 overexpression suppressed apoptosis and inhibited cell cycle arrest in HEC-1A and Ishikawa cells. CD47 upregulation contributes to the activation of PI3K/Akt/mTOR signaling pathway in endometrial carcinoma cells. Conclusion: CD47 exerts oncogenic functions in endometrial carcinoma by activating PI3K/Akt/mTOR signaling, suggesting it may be a novel immunotherapeutic target for therapeutic interventions. [ABSTRACT FROM AUTHOR]

S100A8 and S100A9 function as essential factors in inflammation and also exert antitumor or tumorigenic activity depending on the type of cancer. Chronic eosinophilic leukemia (CEL) is a rare hematological malignancy having elevated levels of eosinophils and characterized by the presence of the FIP1L1-PDGFRA fusion gene. In this study, we examined the pro-apoptotic mechanisms of S100A8 and S100A9 in FIP1L1-PDGFRα+ eosinophilic cells and hypereosinophilic patient cells. S100A8 and S100A9 induce apoptosis of the FIP1L1-PDGFRα+ EoL-1 cells via TLR4. The surface TLR4 expression increased after exposure to S100A8 and S100A9 although total TLR4 expression decreased. S100A8 and S100A9 suppressed the FIP1L1-PDGFRα-mediated signaling pathway by downregulating FIP1L1-PDGFRα mRNA and protein expression and triggered cell apoptosis by regulating caspase 9/3 pathway and Bcl family proteins. S100A8 and S100A9 also induced apoptosis of imatinib-resistant EoL-1 cells (EoL-1-IR). S100A8 and S100A9 blocked tumor progression of xenografted EoL-1 and EoL-1-IR cells in NOD-SCID mice and evoked apoptosis of eosinophils derived from hypereosinophilic syndrome as well as chronic eosinophilic leukemia. These findings may contribute to a progressive understanding of S100A8 and S100A9 in the pathogenic and therapeutic mechanism of hematological malignancy. [ABSTRACT FROM AUTHOR]

Glioblastoma (GBM) often recurs after radio- and chemotherapies leading to poor prognosis. Glioma stem-like cells (GSCs) contribute to drug resistance and recurrence. Thus, understanding cellular mechanism underlying the growth of GSCs is critical for the treatment of GBM. Here GSCs were isolated from human U87 GBM cells with magnetic-activated cell sorting (MACS) using CD133 as a marker. The CD133+ cells highly expressed sonic hedgehog (Shh) and were capable of forming tumor spheroids in vitro and tumor in vivo. Athymic mice received intracranial injection of luciferase transduced parental and CD133+ GBM cells was utilized as orthotopic GBM model. Inhibited Shh by LDE225 delayed GBM growth in vivo , and downregulated Ptch1 and Gli1. CD133+ cell proliferation was more sensitive to inhibition by LDE225 than that of CD133− cells. Treatment with LDE225 significantly reduced CD133+-derived tumor spheroid formation. Large membranous vacuoles appeared in the LDE225-treated cells concomitant with the conversion of LC3-I to LC3-II. In addition, LDE225-induced cell death was mitigated in the presence of autophagy inhibitor 3-methyladenine (3-MA). Tumor growth was much slower in Shh shRNA-knockdown mice than in control RNA-transfected mice. Conversely, tumor growth was faster in Shh overexpressed mice. Furthermore, combination of LDE225 and rapamycin treatment resulted in additive effect on LC3-I to LC3-II conversion and reduction in cell viability. However, LDE225 did not affect the phosphorylated level of mTOR. Similarly, amiodarone, an mTOR-independent autophagy enhancer, reduced CD133+ cell viability and tumor spheroid formation in vitro and exhibited anti-tumor activity in vivo. These results suggest that Shh inhibitor induces autophagy of CD133+ cells likely through mTOR independent pathway. Targeting Shh signal pathway may overcome chemoresistance and provide a therapeutic strategy for patients with malignant gliomas. [ABSTRACT FROM AUTHOR]

In the present work, we used a double cell screening approach based on phenanthrene (phe) epifluorescence histochemical localization and oxygen radical detection to generate new data about how some specialized cells are involved in tolerance to organic xenobiotics. Thereby, we bring new insights about phe [a common Polycyclic Aromatic Hydrocarbon (PAH)] cell specific detoxification, in two contrasting plant lineages thriving in different ecosystems. Our data suggest that in higher plants, detoxification may occur in specialized cells such as trichomes and pavement cells in Arabidopsis , and in the basal cells of salt glands in Spartina species. Such features were supported by a survey from the literature, and complementary data correlating the size of basal salt gland cells and tolerance abilities to PAHs previously reported between Spartina species. Furthermore, we conducted functional validation in two independent Arabidopsis trichomeless glabrous T-DNA mutant lines (GLABRA1 mutants). These mutants showed a sensitive phenotype under phe-induced stress in comparison with their background ecotypes without the mutation, indicating that trichomes are key structures involved in the detoxification of organic xenobiotics. Interestingly, trichomes and pavement cells are known to endoreduplicate, and we discussed the putative advantages given by endopolyploidy in xenobiotic detoxification abilities. The same feature concerning basal salt gland cells in Spartina has been raised. This similarity with detoxification in the endopolyploid liver cells of the animal system is included. [ABSTRACT FROM AUTHOR]

Antibodies mediate a broad array of non-neutralizing Fc-mediated functions against HIV-1 including antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP). Accordingly, ADCC and ADCP induced by anti-HIV envelope gp120 IgG have been correlated to the limited success of the HIV-1 phase III vaccine trial RV144. It remains elusive whether ADCP can also be triggered by IgA, the isotype predominant at mucosal surfaces through which HIV-1 is mainly transmitted. Yet, we have previously shown that the HIV envelope subunit gp41-specific broadly neutralizing antibody 2F5 under the IgA isotype (2F5-IgA) triggers ADCC and cooperates with 2F5-IgG to increase HIV-1-infected cell lysis. Here, we now demonstrate that 2F5-IgA, more efficiently than 2F5-IgG, induces ADCP not only of gp41-coated beads but also of primary HIV-1-infected cells in a FcαRI-dependent manner. Both primary monocytes and neutrophils can act as effector cells of 2F5-IgA-mediated ADCP, although with different kinetics with faster neutrophil phagocytosis. However, unlike for ADCC, 2F5-IgA and 2F5-IgG do not cooperate to increase ADCP. Altogether, our results reveal that gp41-specific IgA mediate the efficient phagocytosis of HIV-1-infected cells. Inducing such ADCC and ADCP-prone IgA response by vaccination in addition to anti-HIV envelope IgG, might increase the protection against HIV acquisition at mucosal level. [ABSTRACT FROM AUTHOR]

Among all T and NK cell subsets, regulatory T (Treg) cells typically respond to the lowest concentrations of IL-2 due to elevated surface expression of the IL-2R alpha chain (IL2RA; CD25) and the high affinity IL-2 receptor (IL-2R) complex. This enhanced sensitivity forms the basis for low-dose (LD) IL-2 therapy for the treatment of inflammatory diseases, where efficacy correlates with increased Treg cell number and expression of functional markers. Despite strong preclinical support for this approach, moderate and variable clinical efficacy has raised concerns that adequate Treg selectivity still cannot be achieved with LD IL-2, and/or that doses are too low to stimulate effective Treg-mediated suppression within tissues. This has prompted development of IL-2 variants with greater Treg selectivity, achieved through attenuated affinity for the signaling chains of the IL-2R complex (IL2RB or CD122 and IL2RG or CD132) and, consequently, greater reliance on high CD25 levels for full receptor binding and signaling. While certain IL-2 variants have advanced to the clinic, it remains unknown if the full range of IL-2R signaling potency and Treg-selectivity observed with low concentrations of wildtype IL-2 can be sufficiently recapitulated with attenuated IL-2 muteins at high concentrations. Using a panel of engineered IL-2 muteins, we investigated how a range of IL-2R signaling intensity, benchmarked by the degree of STAT5 phosphorylation, relates to biologically relevant Treg cell responses such as proliferation, lineage and phenotypic marker expression, and suppressor function. Our results demonstrate that a surprisingly wide dynamic range of IL-2R signaling intensity leads to productive biological responses in Treg cells, with negligible STAT5 phosphorylation associating with nearly complete downstream effects such as Treg proliferation and suppressor activity. Furthermore, we show with both in vitro and humanized mouse in vivo systems that different biological responses in Treg cells require different minimal IL-2R signaling thresholds. Our findings suggest that more than minimal IL-2R signaling, beyond that capable of driving Treg cell proliferation, may be required to fully enhance Treg cell stability and suppressor function in vivo. [ABSTRACT FROM AUTHOR]

The rapid development of single-cell transcriptome sequencing technology has provided us with a cell-level perspective to study biological problems. Identification of cell types is one of the fundamental issues in computational analysis of single-cell data. Due to the large amount of noise from single-cell technologies and high dimension of expression profiles, traditional clustering methods are not so applicable to solve it. To address the problem, we have designed an adaptive sparse subspace clustering method, called AdaptiveSSC, to identify cell types. AdaptiveSSC is based on the assumption that the expression of cells with the same type lies in the same subspace; one cell can be expressed as a linear combination of the other cells. Moreover, it uses a data-driven adaptive sparse constraint to construct the similarity matrix. The comparison results of 10 scRNA-seq datasets show that AdaptiveSSC outperforms original subspace clustering and other state-of-art methods in most cases. Moreover, the learned similarity matrix can also be integrated with a modified t-SNE to obtain an improved visualization result. [ABSTRACT FROM AUTHOR]

Recent research using chromatin conformation capture technologies, such as Hi-C, has demonstrated the importance of topologically associated domains (TADs) and smaller chromatin loops, collectively referred hereafter as "interacting domains." Many such domains change during development or disease, and exhibit cell- and condition-specific differences. Quantification of the dynamic behavior of interacting domains will help to better understand genome regulation. Methods for comparing interacting domains between cells and conditions are highly limited. We developed TADCompare, a method for differential analysis of boundaries of interacting domains between two or more Hi-C datasets. TADCompare is based on a spectral clustering-derived measure called the eigenvector gap, which enables a loci-by-loci comparison of boundary differences. Using this measure, we introduce methods for identifying differential and consensus boundaries of interacting domains and tracking boundary changes over time. We further propose a novel framework for the systematic classification of boundary changes. Colocalization- and gene enrichment analysis of different types of boundary changes demonstrated distinct biological functionality associated with them. TADCompare is available on https://github.com/dozmorovlab/TADCompare and Bioconductor (submitted). [ABSTRACT FROM AUTHOR]

Microcystin-leucine arginine (MC-LR) is a potent tumor initiator that can induce malignant cell transformation. Cellular mechanical characteristics are pivotal parameters that are closely related to cell invasion. The aim of this study is to determine the effect of MC-LR on mechanical parameters, microfilament, and cell invasion in DU145 and WPMY cells. Firstly, 10 μM MC-LR was selected as the appropriate concentration via cell viability assay. Subsequently, after MC-LR treatment, the cellular deformability and viscoelastic parameters were tested using the micropipette aspiration technique. The results showed that MC-LR increased the cellular deformability, reduced the cellular viscoelastic parameter values, and caused the cells to become softer. Furthermore, microfilament and microfilament-associated proteins were examined by immunofluorescence and Western blot, respectively. Our results showed that MC-LR induced microfilament reorganization and increased the expression of p-VASP and p-ezrin. Finally, the impact of MC-LR on cell invasion was evaluated. The results revealed that MC-LR promoted cell invasion. Taken together, our results suggested that mechanical changes and microfilament reorganization were involved in MC-LR-promoted cell invasion in DU145 and WPMY cells. Our data provide novel information to explain the toxicological mechanism of MC-LR. [ABSTRACT FROM AUTHOR]

Insulin receptor substrate (IRS)-1 is a major substrate of insulin-like growth factor (IGF)-I receptors. It is well-known that IGF-I and II play essential roles in myogenesis progression. Herein, we report an unexpected phenomenon that IRS-1-overexpressing L6 myoblasts are eliminated from normal cell layers at the beginning of differentiation. Initially, the IRS protein level and apoptosis were examined during myogenic differentiation in L6 myoblasts. We found that the IRS-1 protein level decreased, whereas active caspase 3 increased around 1 day after induction of differentiation. The addition of a pan-caspase inhibitor, Z-VAD-FMK, inhibited differentiation-induced suppression of the IRS-1 protein level. Apoptosis was not enhanced in L6 myoblasts stably expressing high levels of IRS-1 (L6-IRS-1). However, when L6-IRS-1 was cultured with control cells (L6-mock), we observed that L6-IRS-1 was eliminated from the cell layer. We have recently reported that, in L6-IRS-1, internalization of the IGF-I receptor was delayed and IGF signal activation was sustained for a longer period than in L6-mock. When cells stably expressing IRS-1 3YA mutant, which could not maintain the IGF signals, were cultured with normal cells, elimination from the cell layer was not detected. These data suggested that the high level of IRS-1 in myoblasts induces elimination from the cell layer due to abnormal sustainment of IGF-I receptor activation. [ABSTRACT FROM AUTHOR]

Sufficient uterine remodeling is essential for fetal survival and development. Pathologies related to poor remodeling have a negative impact on maternal and fetal health even years after birth. Research of the last decades yielded excellent studies demonstrating the key role of immune cells in the remodeling processes. This review summarizes the current knowledge about the relevance of immune cells for uterine remodeling during pregnancy and further discusses immunomodulatory effects of man-made endocrine disrupting chemicals on immune cells. [ABSTRACT FROM AUTHOR]

The interest in pancreatic stellate cells (PSCs) has been steadily growing over the past two decades due mainly to the central role these cells have in the desmoplastic reaction associated with diseases of the pancreas, such as pancreatitis or pancreatic cancer. In recent years, the scientific community has devoted substantial efforts to understanding the signaling pathways that govern PSC activation and interactions with neoplastic cells. This mini review aims to summarize some very recent findings on signaling in PSCs and highlight their impact to the field. [ABSTRACT FROM AUTHOR]

DivIVA plays multifaceted roles in Gram-positive organisms through its association with various cell division and non-cell division proteins. We report a novel DivIVA interacting protein in Enterococcus faecalis , named EF1025 (encoded by EF1025), which is conserved in Gram-positive bacteria. The interaction of EF1025 with DivIVAEf was confirmed by Bacterial Two-Hybrid, Glutathione S-Transferase pull-down, and co-immunoprecipitation assays. EF1025, which contains a DNA binding domain and two Cystathionine β-Synthase (CBS) domains, forms a decamer mediated by the two CBS domains. Viable cells were recovered after insertional inactivation or deletion of EF1025 only through complementation of EF1025 in trans. These cells were longer than the average length of E. faecalis cells and had distorted shapes. Overexpression of EF1025 also resulted in cell elongation. Immuno-staining revealed comparable localization patterns of EF1025 and DivIVAEf in the later stages of division in E. faecalis cells. In summary, EF1025 is a novel DivIVA interacting protein influencing cell length and morphology in E. faecalis. [ABSTRACT FROM AUTHOR]

Recent investigations on the regulatory action of extracellular vesicles (EVs) on immune cells in vitro and in vivo have sparked interest on the subject. As commonly known, EVs are subcellular components secreted by a paracellular mechanism and are essentially a group of nanoparticles containing exosomes, microvesicles, and apoptotic bodies. They are double-layer membrane-bound vesicles enriched with proteins, nucleic acids, and other active compounds. EVs are recognized as a novel apparatus for intercellular communication that acts through delivery of signal molecules. EVs are secreted by almost all cell types, including stem/progenitor cells. The EVs derived from stem/progenitor cells are analogous to the parental cells and inhibit or enhance immune response. This review aims to provide its readers a comprehensive overview of the possible mechanisms underlying the immunomodulatory effects exerted by stem/progenitor cell-derived EVs upon natural killer (NK) cells, dendritic cells (DCs), monocytes/macrophages, microglia, T cells, and B cells. [ABSTRACT FROM AUTHOR]

B-1 cells are an innate-like population of B lymphocytes that are subdivided into B-1a and B-1b distinguished by the presence or absence of CD5, respectively. B-1 cells can act as regulatory B cells, are able to present antigen and produce IL-10. Leishmaniasis in humans is a complex of diseases caused by parasites of the genus Leishmania. More than 20 species can infect humans, with each species causing the development of different immunological responses in the host. Susceptibility is usually related to the production of anti-inflammatory cytokines while the production of Th1 cytokines is indicative of resistance. However, few studies have attempted to evaluate the role of B-1 cells during either the in vivo infection or in vitro interaction with Leishmania parasites. In vivo studies were performed using XID mice model, BALB/Xid mice have a mutation in the Bruton's tyrosine kinase, which is an important enzyme for developing B-1 and maturing B-2 lymphocytes leading to the presence of immature B-2 cells. Here, we compile these studies and assess the influence of B-1 cells on disease progression with different Leishmania species. [ABSTRACT FROM AUTHOR]

Monocyte chemoattractant protein-1 (MCP-1/CCL2) is renowned for its ability to drive the chemotaxis of myeloid and lymphoid cells. It orchestrates the migration of these cell types both during physiological immune defense and in pathological circumstances, such as autoimmune diseases including rheumatoid arthritis and multiple sclerosis, inflammatory diseases including atherosclerosis, as well as infectious diseases, obesity, diabetes, and various types of cancer. However, new data suggest that the scope of CCL2's functions may extend beyond its original characterization as a chemoattractant. Emerging evidence shows that it can impact leukocyte behavior, influencing adhesion, polarization, effector molecule secretion, autophagy, killing, and survival. The direction of these CCL2-induced responses is context dependent and, in some cases, synergistic with other inflammatory stimuli. The involvement of CCL2 signaling in multiple diseases renders it an interesting therapeutic target, although current targeting strategies have not met early expectations in the clinic. A better understanding of how CCL2 affects immune cells will be pivotal to the improvement of existing therapeutic approaches and the development of new drugs. Here, we provide an overview of the pleiotropic effects of CCL2 signaling on cells of the myeloid lineage, beyond chemotaxis, and highlight how these actions might help to shape immune cell behavior and tumor immunity. [ABSTRACT FROM AUTHOR]

Head direction (HD) cells, which fire action potentials whenever an animal points its head in a particular direction, are thought to subserve the animal's sense of spatial orientation. HD cells are found prominently in several thalamo-cortical regions including anterior thalamic nuclei, postsubiculum, medial entorhinal cortex, parasubiculum, and the parietal cortex. While a number of methods in neural decoding have been developed to assess the dynamics of spatial signals within thalamo-cortical regions, studies conducting a quantitative comparison of machine learning and statistical model-based decoding methods on HD cell activity are currently lacking. Here, we compare statistical model-based and machine learning approaches by assessing decoding accuracy and evaluate variables that contribute to population coding across thalamo-cortical HD cells. [ABSTRACT FROM AUTHOR]

Previous studies showed that chidamide enhances the cytotoxicity of drugs in acute myeloid leukemia (AML) cells. Therefore, we examined whether chidamide enhanced the cytotoxicity of drugs in AML cells by affecting H3K9me3 and autophagy levels. AML cells (THP-1 and MV4-11 cells) were treated with chidamide, cytarabine (Ara-c), or sorafenib alone or in combination. Cell proliferation and survival rates were analyzed by MTT, flow cytometry, and Western blotting assays. The results showed that a low dose of chidamide enhanced the cytotoxicity of Ara-c or sorafenib in AML cells, decreasing proliferation and increasing apoptosis. H3K9me3 levels as assessed by Western blotting were upregulated by chidamide treatment. Chromatin immunoprecipitation sequencing, which was used to investigate potential signaling pathways, indicated that the autophagy pathway might play a role in the effects of chidamide. The level of autophagy induced in AML cells upon treatment with Ara-c or sorafenib was inhibited by chidamide, and autophagy markers (LC3, P62) were tested by Western blotting. SIRT1 messenger RNA (mRNA) and protein levels were lower in AML cells treated with Ara-c or sorafenib in combination with chidamide than those in cells treated with these drugs alone. Additionally, the Integrative Genomics Viewer results indicate that the H3K9me3 changes were related to SIRT1-binding sites. Together, these results show that chidamide enhances the cytotoxicity of two chemotherapy drugs in AML cells by increasing the H3K9me3 level and inhibiting autophagy via decreasing the expression of SIRT1. Chidamide may be a potential treatment strategy for AML in the future, especially for refractory AML patients. [ABSTRACT FROM AUTHOR]

In acute vulvovaginal candidiasis (VVC), the fungus Candida albicans activates inflammasome receptors of vaginal epithelial cells through the production of virulence and immuno-inflammatory factors. Here, we show that in VVC patients, genes encoding some of the above factors (SAP2 , SAP5 , SAP6 , ECE1 , and HWP1) are expressed in a correlated fashion. Cytological observations pointed out that pseudohyphal filaments with yeast cells are dominant at the acidic vaginal pH, and this is coupled with co-expression, at roughly similar level, of SAP2 , a typical yeast and ECE1 , a typical hyphae-associated genes. In contrast, vigorous hyphal growth dominated at the neutral vaginal pH of mice experimentally infected with C. albicans isolates from VVC subjects, and this is coupled with a high ratio of ECE1 to SAP2 expression. We suggest that the pseudohyphal rather than true hyphal cells of C. albicans play a critical role in VVC, possibly through the activity of multiple inflammasome inducers. [ABSTRACT FROM AUTHOR]

The endogenous spinal cord ependymal cells (SCECs), which form the central canal (CC), are critically involved in proliferation, differentiation and migration after spinal cord injury (SCI) and represents a repair cell source in treating SCI. Previously, we reported that BAF45D is expressed in the SCECs and the spinal cord neurons in adult mice and knockdown of BAF45D fail to induce expression of PAX6, a neurogenic fate determinant, during early neural differentiation of human embryonic stem cells. However, the effects of SCI on expression of BAF45D have not been reported. The aim of this study is to explore the expression and potential role of BAF45D in rat SCI model. In this study, adult rats were randomly divided into intact, sham, and SCI groups. We first explored expression of BAF45D in the SCECs in intact adult rats. We then explored SCI-induced loss of motor neurons and lesion of neurites in the anterior horns induced by the SCI. We also investigated whether the SCI-induced lesions in SCECs are accompanied by the motor neuron lesions. Finally, we examined the effect of BAF45D knockdown on cell growth in neuro2a cells. Our data showed that BAF45D is expressed in SCECs, neurons, and oligodendrocytes but not astrocytes in the spinal cords of intact adult rats. After SCI, the structure of CC was disrupted and the BAF45D-positive SCEC-derivatives were decreased. During the early stages of SCI, when shape of CC was affected but there was no disruption in circular structure of the SCECs, it was evident that there was a significant reduction in the number of neurites and motor neurons in the anterior horns compared with those of intact rats. In comparison, a complete loss of SCECs accompanied by further loss of motor neurons but not neurites was observed at the later stage. BAF45D knockdown was also found to inhibit cell growth in neuro2a cells. These results highlight the decreased expression of BAF45D in SCI-injured SCECs and the potential role of BAF45D downregulation in development of neuronal lesion after SCI in adult rats. [ABSTRACT FROM AUTHOR]

Despite efficient combination of the antiretroviral therapy (cART), which significantly decreased mortality and morbidity of HIV-1 infection, a definitive HIV cure has not been achieved. Hidden HIV-1 in cellular and anatomic reservoirs is the major hurdle toward a functional cure. Microglial cells, the Central Nervous system (CNS) resident macrophages, are one of the major cellular reservoirs of latent HIV-1. These cells are believed to be involved in the emergence of drugs resistance and reseeding peripheral tissues. Moreover, these long-life reservoirs are also involved in the development of HIV-1-associated neurocognitive diseases (HAND). Clearing these infected cells from the brain is therefore crucial to achieve a cure. However, many characteristics of microglial cells and the CNS hinder the eradication of these brain reservoirs. Better understandings of the specific molecular mechanisms of HIV-1 latency in microglial cells should help to design new molecules and new strategies preventing HAND and achieving HIV cure. Moreover, new strategies are needed to circumvent the limitations associated to anatomical sanctuaries with barriers such as the blood brain barrier (BBB) that reduce the access of drugs. [ABSTRACT FROM AUTHOR]

Therapy with alloantigen-specific CD4+CD25+ T regulatory cells (Treg) for induction of transplant tolerance is desirable, as naïve thymic Treg (tTreg) are not alloantigen-specific and are weak suppressor cells. Naïve tTreg from DA rats cultured with fully allogeneic PVG stimulator cells in the presence of rIL-2 express IFN-gamma receptor (IFNGR) and IL-12 receptor beta2 (IL-12Rβ2) and are more potent alloantigen-specific regulators that we call Ts1 cells. This study examined additional markers that could identify the activated alloantigen-specific Treg as a subpopulation within the CD4+CD25+Foxp3+Treg. After culture of naïve DA CD4+CD8−CD25+T cells with rIL-2 and PVG alloantigen, or rIL-2 without alloantigen, CD8α was expressed on 10–20% and CD8β on <5% of these cells. These cells expressed ifngr and Il12rb2. CD8α+ cells had increased Ifngr that characterizes Ts1 cells as well was Irf4 , a transcription factor induced by TCR activation. Proliferation induced by re-culture with rIL-12 and alloantigen was greater with CD4+CD8α+CD25+Treg consistent with the CD8α+ cells expressing IL-12R. In MLC, the CD8α+ fraction suppressed responses against allogeneic stimulators more than the mixed Ts1 population, whereas the CD4+CD8−CD25+T cells were less potent. In an adoptive transfer assay, rIL-2 and alloantigen activated Treg suppress rejection at a ratio of 1:10 with naïve effector cells, whereas alloantigen and rIL-2 activated tTreg depleted of the CD8α+ cells were much less effective. This study demonstrated that expression of CD8α by rIL-2 and alloantigen activation of CD4+CD8−CD25+Foxp3+T cells was a marker of activated and potent Treg that included alloantigen-specific Treg. [ABSTRACT FROM AUTHOR]

Background: Psoriasis is a chronic immune-mediated inflammatory skin disease, with over-activated interleukin (IL)-17-producing CD4+ T cells (Th17) and repressed regulatory T (Treg) cells. IL-21 is a Th17-related cytokine and plays an important role in the pathogenesis of psoriasis. However, the mechanism by which IL-21 affects the pathogenic progress of psoriasis remains poorly understood. Methods: IL-21 and IL-21 receptor (IL-21R) expression in normal and psoriatic lesional skin were determined by immumohistochemical staining, immunofluorescence staining, and western blotting. The levels of IL-21, IL-17A, and IL-22 in the culture supernatants were measured by enzyme-linked immunosorbent assay (ELISA). The level of IL-10 in the culture supernatants was measured by cytometric bead array (CBA). The mRNA expression levels were assessed by quantitative polymerase chain reaction (qPCR). CD4+ T cells were isolated from the peripheral blood mononuclear cells (PBMCs) from the psoriasis patients and healthy individuals and then treated with or without IL-21 for 3 days. The proportions of Th17 and Treg cells were determined by flow cytometric analysis. Results: IL-21 and IL-21R were highly expressed in the lesional skin and peripheral blood of psoriasis patients. IL-21 promoted CD4+ T cells proliferation and Th17 cells differentiation and inhibiting Treg cells differentiation by upregulating RORγt expression and downregulating Foxp3 expression, with increased expression and secretion of IL-17A and IL-22. The proportion of Treg cells was negatively correlated with that of Th17 cells in psoriasis patients. Conclusion: Our results suggest that IL-21 may promote psoriatic inflammation by inducing imbalance in Th17 and Treg cell populations. [ABSTRACT FROM AUTHOR]