Titin N2A Domain and Its Interactions at the Sarcomere

Titin is a giant protein in the sarcomere that plays an essential role in muscle contraction with actin and myosin filaments. However, its utility goes beyond mechanical functions, extending to versatile and complex roles in sarcomere organization and maintenance, passive force, mechanosensing, and signaling. Titin’s multiple functions are in part attributed to its large size and modular structures that interact with a myriad of protein partners. Among titin’s domains, the N2A element is one of titin’s unique segments that contributes to titin’s functions in compliance, contraction, structural stability, and signaling via protein–protein interactions with actin filament, chaperones, stress-sensing proteins, and proteases. Considering the significance of N2A, this review highlights structural conformations of N2A, its predisposition for protein–protein interactions, and its multiple interacting protein partners that allow the modulation of titin’s biological effects. Lastly, the nature of N2A for interactions with chaperones and proteases is included, presenting it as an important node that impacts titin’s structural and functional integrity.     

Electrostatic complexation of polyelectrolyte and magnetic nanoparticles: from wild clustering to controllable magnetic wires

We present the electrostatic complexation between polyelectrolytes and charged nanoparticles. The nanoparticles in solution are γ-Fe₂O₃ (maghemite) spheres with 8.3 nm diameter and anionic surface charges. The complexation was monitored using three different formulation pathways such as direct mixing, dilution, and dialysis. In the first process, the hybrids were obtained by mixing stock solutions of polymers and nanoparticles. A ‘destabilization state’ with sharp and intense maximum aggregation was found at charges stoichiometry (isoelectric point). While on the two sides of the isoelectric point, ‘long-lived stable clusters state’ (arrested states) were observed. Dilution and dialysis processes were based on controlled desalting kinetics according to methods developed in molecular biology. Under an external magnetic field (B = 0.3 T), from dialysis at isoelectric point and at arrested states, cationic polyelectrolytes can ‘paste’ these magnetic nanoparticles (NPs) together to yield irregular aggregates (size of 100 μm) and regular rod-like aggregates, respectively. These straight magnetic wires were fabricated with diameters around 200 nm and lengths comprised between 1 μm and 0.5 mm. The wires can have either positive or negative charges on their surface. After analyzing their orientational behavior under an external rotating field, we also showed that the wires made from different polyelectrolytes have the same magnetic property. The recipe used a wide range of polyelectrolytes thereby enhancing the versatility and applied potentialities of the method. This simple and general approach presents significant perspective for the fabrication of hybrid functional materials.     

Insulin Diminishes Superoxide Increase in Cytosol and Mitochondria of Cultured Cortical Neurons Treated with Toxic Glutamate

Glutamate excitotoxicity is involved in the pathogenesis of many disorders, including stroke, traumatic brain injury, and Alzheimer’s disease, for which central insulin resistance is a comorbid condition. Neurotoxicity of glutamate (Glu) is primarily associated with hyperactivation of the ionotropic N-methyl-D-aspartate receptors (NMDARs), causing a sustained increase in intracellular free calcium concentration ([Ca²⁺]_i) and synchronous mitochondrial depolarization and an increase in intracellular superoxide anion radical (O₂^–•) production. Recently, we found that insulin protects neurons against excitotoxicity by decreasing the delayed calcium deregulation (DCD). However, the role of insulin in O₂^–• production in excitotoxicity still needs to be clarified. The present study aims to investigate insulin’s effects on glutamate-evoked O₂^–• generation and DCD using the fluorescent indicators dihydroethidium, MitoSOX Red, and Fura-FF in cortical neurons. We found a linear correlation between [Ca²⁺]_i and [O₂^–•] in primary cultures of the rat neuron exposed to Glu, with insulin significantly reducing the production of intracellular and mitochondrial O₂^–• in the primary cultures of the rat neuron. MK 801, an inhibitor of NMDAR-gated Ca²⁺ influx, completely abrogated the glutamate effects in both the presence and absence of insulin. In experiments in sister cultures, insulin diminished neuronal death and O₂ consumption rate (OCR).     

Cystine/Glutamate Antiporter in Schizophrenia: From Molecular Mechanism to Novel Biomarker and Treatment

Glutamate, a crucial excitatory neurotransmitter, plays a major role in the modulation of schizophrenia’s pathogenesis. New drug developments for schizophrenia have been prompted by the hypoglutamatergic hypothesis of schizophrenia. The cystine/glutamate antiporter system x_c⁻ is related to glutamate-release regulation. Patients with schizophrenia were recently discovered to exhibit downregulation of x_c⁻ subunits—the solute carrier (SLC) family 3 member 2 and the SLC family 7 member 11. We searched for relevant studies from 1980, when Bannai and Kitamura first identified the protein subunit system x_c⁻ in lung fibroblasts, with the aim of compiling the biological, functional, and pharmacological characteristics of antiporter x_c⁻, which consists of several subunits. Some of them can significantly stimulate the human brain through the glutamate pathway. Initially, extracellular cysteine activates neuronal x_c⁻, causing glutamate efflux. Next, excitatory amino acid transporters enhance the unidirectional transportation of glutamate and sodium. These two biochemical pathways are also crucial to the production of glutathione, a protective agent for neural and glial cells and astrocytes. Investigation of the expression of system x_c⁻ genes in the peripheral white blood cells of patients with schizophrenia can facilitate better understanding of the mental disorder and future development of novel biomarkers and treatments for schizophrenia. In addition, the findings further support the hypoglutamatergic hypothesis of schizophrenia.     

The Effect of Sera from Children with Obstructive Sleep Apnea Syndrome (OSAS) on Human Cardiomyocytes Differentiated from Human Embryonic Stem Cells

Obstructive sleep apnea syndrome (OSAS) patients suffer from cardiovascular morbidity, which is the leading cause of death in this disease. Based on our previous work with transformed cell lines and primary rat cardiomyocytes, we determined that upon incubation with sera from pediatric OSAS patients, the cell’s morphology changes, NF-κB pathway is activated, and their beating rate and viability decreases. These results suggest an important link between OSAS, systemic inflammatory signals and end-organ cardiovascular diseases. In this work, we confirmed and expanded these observations on a new in vitro system of beating human cardiomyocytes (CM) differentiated from human embryonic stem cells (hES). Our results show that incubation with pediatric OSAS sera, in contrast to sera from healthy children, induces over-expression of NF-κB p50 and p65 subunits, marked reduction in CMs beating rate, contraction amplitude and a strong reduction in intracellular calcium signal. The use of human CM cells derived from embryonic stem cells has not been previously reported in OSAS research. The results further support the hypothesis that NF-κB dependent inflammatory pathways play an important role in the evolution of cardiovascular morbidity in OSAS. This study uncovers a new model to investigate molecular and functional aspects of cardiovascular pathology in OSAS.     

The situ preparation of silica nanoparticles on the surface of functionalized graphene nanoplatelets

A method for situ preparing a hybrid material consisting of silica nanoparticles (SiO₂) attached onto the surface of functionalized graphene nanoplatelets (f-GNPs) is proposed. Firstly, polyacrylic acid (PAA) was grafted to the surface of f-GNPs to increase reacting sites, and then 3-aminopropyltriethoxysilane (APTES) KH550 reacted with abovementioned product PAA-GNPs to obtain siloxane-GNPs, thus providing reaction sites for the growth of SiO₂ on the surface of GNPs. Finally, the SiO₂/graphene nanoplatelets (SiO₂/GNPs) hybrid material is obtained through introducing siloxane-GNPs into a solution of tetraethyl orthosilicate, ammonia and ethanol for hours'' reaction. The results from Fourier transform infrared spectroscopy (FTIR) showed that SiO₂ particles have situ grown on the surface of GNPs through chemical bonds as Si-O-Si. And the nanostructure of hybrid materials was characterized by scanning electron microscopy (SEM) and transmission electron microscopy (TEM). All the images indicated that SiO₂ particles with similar sizes were grafted on the surface of graphene nanoplatelets successfully. And TEM images also showed the whole growth process of SiO₂ particles on the surface of graphene as time grows. Moreover, TGA traces suggested the SiO₂/GNPs hybrid material had stable thermal stability. And at 900°C, the residual weight fraction of polymer on siloxane-GNPs was about 94.2% and that of SiO₂ particles on hybrid materials was about 75.0%. However, the result of Raman spectroscopy showed that carbon atoms of graphene nanoplatelets became much more disordered, due to the destroyed carbon domains during the process of chemical drafting. Through orthogonal experiments, hybrid materials with various sizes of SiO₂ particles were prepared, thus achieving the particle sizes controllable. And the factors’ level of significance is as follows: the quantity of ammonia > the quantity of tetraethyl orthosilicate (TEOS) > the reaction time.     

Magnetic Resonance Imaging in Animal Models of Alzheimer’s Disease Amyloidosis

Amyloid-beta (Aβ) plays an important role in the pathogenesis of Alzheimer’s disease. Aberrant Aβ accumulation induces neuroinflammation, cerebrovascular alterations, and synaptic deficits, leading to cognitive impairment. Animal models recapitulating the Aβ pathology, such as transgenic, knock-in mouse and rat models, have facilitated the understanding of disease mechanisms and the development of therapeutics targeting Aβ. There is a rapid advance in high-field MRI in small animals. Versatile high-field magnetic resonance imaging (MRI) sequences, such as diffusion tensor imaging, arterial spin labeling, resting-state functional MRI, anatomical MRI, and MR spectroscopy, as well as contrast agents, have been developed for preclinical imaging in animal models. These tools have enabled high-resolution in vivo structural, functional, and molecular readouts with a whole-brain field of view. MRI has been used to visualize non-invasively the Aβ deposits, synaptic deficits, regional brain atrophy, impairment in white matter integrity, functional connectivity, and cerebrovascular and glymphatic system in animal models of Alzheimer’s disease amyloidosis. Many of the readouts are translational toward clinical MRI applications in patients with Alzheimer’s disease. In this review, we summarize the recent advances in MRI for visualizing the pathophysiology in amyloidosis animal models. We discuss the outstanding challenges in brain imaging using MRI in small animals and propose future outlook in visualizing Aβ-related alterations in the brains of animal models.     

[β-Glu2]TRH Is a Functional Antagonist of Thyrotropin-Releasing Hormone (TRH) in the Rodent Brain

Selective antagonists of thyrotropin-releasing hormone (TRH; pGlu-His-Pro-NH₂), in order to enable a better understanding of this peptide’s central functions, have not been identified. Using pGlu-Glu-Pro-NH₂ ([Glu²]TRH) as a lead peptide and with modification at its central residue, our studies focused on some of its analogues synthesized as potential functional antagonists of TRH in the rodent brain. Among the peptides studied, the novel isomeric analogue [β-Glu²]TRH was found to suppress the analeptic and antidepressant-like pharmacological activities of TRH without eliciting intrinsic effects in these paradigms. [β-Glu²]TRH also completely reversed TRH’s stimulation of acetylcholine turnover in the rat hippocampus without a cholinergic activity of its own, which was demonstrated through in vivo microdialysis experiments. Altogether, [β-Glu²]TRH emerged as the first selective functional antagonist of TRH’s prominent cholinergic actions, by which this endogenous peptide elicits a vast array of central effects.     

Collagen Mimetic Peptides Promote Adherence and Migration of ARPE-19 Cells While Reducing Inflammatory and Oxidative Stress

Epithelial cells of multiple types produce and interact with the extracellular matrix to maintain structural integrity and promote healthy function within diverse endogenous tissues. Collagen is a critical component of the matrix, and challenges to collagen’s stability in aging, disease, and injury influence survival of adherent epithelial cells. The retinal pigment epithelium (RPE) is important for maintaining proper function of the light-sensitive photoreceptors in the neural retina, in part through synergy with the collagen-rich Bruch’s membrane that promotes RPE adherence. Degradation of Bruch’s is associated with RPE degeneration, which is implicated early in age-related macular degeneration, a leading cause of irreversible vision loss worldwide. Collagen mimetic peptides (CMPs) effectively repair damage to collagen helices, which are present in all collagens. Our previous work indicates that in doing so, CMPs promote survival and integrity of affected cells and tissues in models of ocular injury and disease, including wounding of corneal epithelial cells. Here, we show that CMPs increase adherence and migration of the ARPE-19 line of human RPE cells challenged by digestion of their collagen substrate. Application of CMPs also reduced both ARPE-19 secretion of pro-inflammatory cytokines (interleukins 6 and 8) and production of reactive oxygen species. Taken together, these results suggest that repairing collagen damaged by aging or other pathogenic processes in the posterior eye could improve RPE adherence and survival and, in doing so, reduce the inflammatory and oxidative stress that perpetuates the cycle of destruction at the root of age-related diseases of the outer retina.     

In situ growth of CuInS2 nanocrystals on nanoporous TiO2 film for constructing inorganic/organic heterojunction solar cells

Inorganic/organic heterojunction solar cells (HSCs) have attracted increasing attention as a cost-effective alternative to conventional solar cells. This work presents an HSC by in situ growth of CuInS₂(CIS) layer as the photoabsorption material on nanoporous TiO₂ film with the use of poly(3-hexylthiophene) (P3HT) as hole-transport material. The in situ growth of CIS nanocrystals has been realized by solvothermally treating nanoporous TiO₂ film in ethanol solution containing InCl₃ · 4H₂O, CuSO₄ · 5H₂O, and thioacetamide with a constant concentration ratio of 1:1:2. InCl₃ concentration plays a significant role in controlling the surface morphology of CIS layer. When InCl₃ concentration is 0.1 M, there is a layer of CIS flower-shaped superstructures on TiO₂ film, and CIS superstructures are in fact composed of ultrathin nanoplates as ‘petals’ with plenty of nanopores. In addition, the nanopores of TiO₂ film are filled by CIS nanocrystals, as confirmed using scanning electron microscopy image and by energy dispersive spectroscopy line scan analysis. Subsequently, HSC with a structure of FTO/TiO₂/CIS/P3HT/PEDOT:PSS/Au has been fabricated, and it yields a power conversion efficiency of 1.4%. Further improvement of the efficiency can be expected by the optimization of the morphology and thickness of CIS layer and the device structure.     

The β2-Subunit (AMOG) of Human Na+, K+-ATPase Is a Homophilic Adhesion Molecule

The β₂ subunit of Na⁺, K⁺-ATPase was originally identified as the adhesion molecule on glia (AMOG) that mediates the adhesion of astrocytes to neurons in the central nervous system and that is implicated in the regulation of neurite outgrowth and neuronal migration. While β₁ isoform have been shown to trans-interact in a species-specific mode with the β₁ subunit on the epithelial neighboring cell, the β₂ subunit has been shown to act as a recognition molecule on the glia. Nevertheless, none of the works have identified the binding partner of β₂ or described its adhesion mechanism. Until now, the interactions pronounced for β₂/AMOG are heterophilic cis-interactions. In the present report we designed experiments that would clarify whether β₂ is a cell–cell homophilic adhesion molecule. For this purpose, we performed protein docking analysis, cell–cell aggregation, and protein–protein interaction assays. We observed that the glycosylated extracellular domain of β₂/AMOG can make an energetically stable trans-interacting dimer. We show that CHO (Chinese Hamster Ovary) fibroblasts transfected with the human β₂ subunit become more adhesive and make large aggregates. The treatment with Tunicamycin in vivo reduced cell aggregation, suggesting the participation of N-glycans in that process. Protein–protein interaction assay in vivo with MDCK (Madin-Darby canine kidney) or CHO cells expressing a recombinant β₂ subunit show that the β₂ subunits on the cell surface of the transfected cell lines interact with each other. Overall, our results suggest that the human β₂ subunit can form trans-dimers between neighboring cells when expressed in non-astrocytic cells, such as fibroblasts (CHO) and epithelial cells (MDCK).     

Self-compliance RRAM characteristics using a novel W/TaO x /TiN structure

Self-compliance resistive random access memory (RRAM) characteristics using a W/TaO _x /TiN structure are reported for the first time. A high-resolution transmission electron microscope (HRTEM) image shows an amorphous TaO _x layer with a thickness of 7 nm. A thin layer of TiO _x N _y with a thickness of 3 nm is formed at the TaO _x /TiN interface, owing to the oxygen accumulation nature of Ti. This memory device shows 100 consecutive switching cycles with excellent uniformity, 100 randomly picked device-to-device good uniformity, and program/erase endurance of >10³ cycles. It is observed that the 0.6-μm devices show better switching uniformity as compared to the 4-μm devices, which is due to the thinner tungsten (W) electrode as well as higher series resistance. The oxygen-rich TaO _x layer at the W/TaO _x interface also plays an important role in getting self-compliance resistive switching phenomena and non-linear current-voltage (I-V) curve at low resistance state (LRS). Switching mechanism is attributed to the formation and rupture of oxygen vacancy conducting path in the TaO _x switching material. The memory device also exhibits long read endurance of >10⁶ cycles. It is found that after 400,000 cycles, the high resistance state (HRS) is decreased, which may be due to some defects creation (or oxygen moves away) by frequent stress on the switching material. Good data retention of >10⁴ s is also obtained.     

Refinement and Neutralization Evaluation of the F(ab’)2 Type of Antivenom against the Deadly Jellyfish Nemopilema nomurai Toxins

Jellyfish stings threaten people’s health and even life in coastal areas worldwide. Nemopilema nomurai is one of the most dangerous jellyfish in the East Asian Marginal Seas, which not only stings hundreds of thousands of people every year but also is assumed to be responsible for most deaths by jellyfish stings in China. However, there is no effective first-aid drug, such as antivenoms, for the treatment of severe stings by N. nomurai to date. In this study, we prepared a N. nomurai antiserum from rabbits using inactivated N. nomurai toxins (NnTXs) and isolated the IgG type of antivenom (IgG-AntiNnTXs) from the antiserum. Subsequently, IgG-AntiNnTXs were refined with multiple optimizations to remove Fc fragments. Finally, the F(ab’)₂ type of antivenom (F(ab’)₂-AntiNnTXs) was purified using Superdex 200 and protein A columns. The neutralization efficacy of both types of antivenom was analyzed in vitro and in vivo, and the results showed that both IgG and F(ab’)₂ types of antivenom have some neutralization effect on the metalloproteinase activity of NnTXs in vitro and could also decrease the mortality of mice in the first 4 h after injection. This study provides some useful information for the development of an effective antivenom for N. nomurai stings in the future.     

Identification of Novel GSK-3β Hits Using Competitive Biophysical Assays

Glycogen synthase kinase 3 beta (GSK-3β) is an evolutionarily conserved serine-threonine kinase dysregulated in numerous pathologies, such as Alzheimer’s disease and cancer. Even though GSK-3β is a validated pharmacological target most of its inhibitors have two main limitations: the lack of selectivity due to the high homology that characterizes the ATP binding site of most kinases, and the toxicity that emerges from GSK-3β complete inhibition which translates into the impairment of the plethora of pathways GSK-3β is involved in. Starting from a 1D ¹⁹F NMR fragment screening, we set up several biophysical assays for the identification of GSK-3β inhibitors capable of binding protein hotspots other than the ATP binding pocket or to the ATP binding pocket, but with an affinity able of competing with a reference binder. A phosphorylation activity assay on a panel of several kinases provided selectivity data that were further rationalized and corroborated by structural information on GSK-3β in complex with the hit compounds. In this study, we identified promising fragments, inhibitors of GSK-3β, while proposing an alternative screening workflow that allows facing the flaws that characterize the most common GSK-3β inhibitors through the identification of selective inhibitors and/or inhibitors able to modulate GSK-3β activity without leading to its complete inhibition.     

Effect of ZnO:Cs2CO3 on the performance of organic photovoltaics

We demonstrate a new solution-processed electron transport layer (ETL), zinc oxide doped with cesium carbonate (ZnO:Cs₂CO₃), for achieving organic photovoltaics (OPVs) with good operational stability at ambient air. An OPV employing the ZnO:Cs₂CO₃ ETL exhibits a fill factor of 62%, an open circuit voltage of 0.90 V, and a short circuit current density of −6.14 mA/cm² along with 3.43% power conversion efficiency. The device demonstrated air stability for a period over 4 weeks. In addition, we also studied the device structure dependence on the performance of organic photovoltaics. Thus, we conclude that ZnO:Cs₂CO₃ ETL could be employed in a suitable architecture to achieve high-performance OPV.     

Genome-Wide Identification and Expression Analysis of AMT and NRT Gene Family in Pecan (Carya illinoinensis) Seedlings Revealed a Preference for NH4+-N

Nitrogen (N) is a major limiting factor for plant growth and crop production. The use of N fertilizer in forestry production is increasing each year, but the loss is substantial. Mastering the regulatory mechanisms of N uptake and transport is a key way to improve plant nitrogen use efficiency (NUE). However, this has rarely been studied in pecans. In this study, 10 AMT and 69 NRT gene family members were identified and systematically analyzed from the whole pecan genome using a bioinformatics approach, and the expression patterns of AMT and NRT genes and the uptake characteristics of NH₄⁺ and NO₃⁻ in pecan were analyzed by aeroponic cultivation at varying NH₄⁺/NO₃⁻ ratios (0/0, 0/100,25/75, 50/50, 75/25,100/0 as CK, T1, T2, T3, T4, and T5). The results showed that gene duplication was the main reason for the amplification of the AMT and NRT gene families in pecan, both of which experienced purifying selection. Based on qRT-PCR results, CiAMTs were primarily expressed in roots, and CiNRTs were majorly expressed in leaves, which were consistent with the distribution of pecan NH₄⁺ and NO₃⁻ concentrations in the organs. The expression levels of CiAMTs and CiNRTs were mainly significantly upregulated under N deficiency and T4 treatment. Meanwhile, T4 treatment significantly increased the NH₄⁺, NO₃⁻, and NO₂⁻ concentrations as well as the Vmax and Km values of NH₄⁺ and NO₃⁻ in pecans, and Vmax/Km indicated that pecan seedlings preferred to absorb NH₄⁺. In summary, considering the single N source of T5, we suggested that the NH₄⁺/NO₃⁻ ratio of 75:25 was more beneficial to improve the NUE of pecan, thus increasing pecan yield, which provides a theoretical basis for promoting the scale development of pecan and provides a basis for further identification of the functions of AMT and NRT genes in the N uptake and transport process of pecan.     

Heavy Metal Complexation of Thiol-Containing Peptides from Soy Glycinin Hydrolysates

Many thiol-containing molecules show heavy metal complexation ability and are used as antidotes. In this study, the potential function associated with thiol-containing peptides (TCPs) from soy protein hydrolysates as natural detoxicants for heavy metals is reported. TCPs enriched by Thiopropyl-Sepharose 6B covalent chromatography had different molecular weight distributions as well as different numbers of proton dissociable groups, depending on the proteases and degree of hydrolysis. The major contribution of sulfhydryl groups was confirmed by the largest pH decrease between 8.0 and 8.5 of the pH titration curves. The complexation of TCPs with heavy metalswas evaluated by stability constants (β_n) of TCP-metal complexes whose stoichiometry was found to be 1:1 (ML) and 1:2 (ML₂). TCPs from degree of hydrolysis of 25% hydrolysates gave high affinities towards Hg²⁺, Cd²⁺, and Pb²⁺ (giving similar or even bigger lgβ values than that of glutathione). A significantly positive correlation was found between the logarithm of stability constants for ML₂ (lgβ₂) and the sulfhydryl group content. Molecular weight distribution of TCPs affected the complexation with Pb²⁺ notably more than Hg²⁺ and Cd²⁺. These results suggest that soy TCPs have the potential to be used in the formulation of functional foods to counteract heavy metal accumulation in humans.     

Changing Microspatial Patterns of Sulfate-Reducing Microorganisms (SRM) during Cycling of Marine Stromatolite Mats

Microspatial arrangements of sulfate-reducing microorganisms (SRM) in surface microbial mats (~1.5 mm) forming open marine stromatolites were investigated. Previous research revealed three different mat types associated with these stromatolites, each with a unique petrographic signature. Here we focused on comparing “non-lithifying” (Type-1) and “lithifying” (Type-2) mats. Our results revealed three major trends: (1) Molecular typing using the dsrA probe revealed a shift in the SRM community composition between Type-1 and Type-2 mats. Fluorescence in-situ hybridization (FISH) coupled to confocal scanning-laser microscopy (CSLM)-based image analyses, and ³⁵SO₄ ²⁻-silver foil patterns showed that SRM were present in surfaces of both mat types, but in significantly (p < 0.05) higher abundances in Type-2 mats. Over 85% of SRM cells in the top 0.5 mm of Type-2 mats were contained in a dense 130 μm thick horizontal layer comprised of clusters of varying sizes; (2) Microspatial mapping revealed that locations of SRM and CaCO₃ precipitation were significantly correlated (p < 0.05); (3) Extracts from Type-2 mats contained acylhomoserine-lactones (C4-, C6-, oxo-C6 C7-, C8-, C10-, C12-, C14-AHLs) involved in cell-cell communication. Similar AHLs were produced by SRM mat-isolates. These trends suggest that development of a microspatially-organized SRM community is closely-associated with the hallmark transition of stromatolite surface mats from a non-lithifying to a lithifying state.     

CD4+ T-Cell Plasticity in Non-Infectious Retinal Inflammatory Disease

Non-infectious uveitis (NIU) is a potentially sight-threatening disease. Effector CD4⁺ T cells, especially interferon-γ-(IFNγ) producing Th1 cells and interleukin-17-(IL-17) producing Th17 cells, are the major immunopathogenic cells, as demonstrated by adoptive transfer of disease in a model of experimental autoimmune uveitis (EAU). CD4⁺FoxP3⁺CD25⁺ regulatory T cells (Tregs) were known to suppress function of effector CD4⁺ T cells and contribute to resolution of disease. It has been recently reported that some CD4⁺ T-cell subsets demonstrate shared phenotypes with another CD4⁺ T-cell subset, offering the potential for dual function. For example, Th17/Th1 (co-expressing IFNγ and IL-17) cells and Th17/Treg (co-expressing IL-17 and FoxP3) cells have been identified in NIU and EAU. In this review, we have investigated the evidence as to whether these ‘plastic CD4⁺ T cells’ are functionally active in uveitis. We conclude that Th17/Th1 cells are generated locally, are resistant to the immunosuppressive effects of steroids, and contribute to early development of EAU. Th17/Treg cells produce IL-17, not IL-10, and act similar to Th17 cells. These cells were considered pathogenic in uveitis. Future studies are needed to better clarify their function, and in the future, these cell subsets may in need to be taken into consideration for designing treatment strategies for disease.