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Symbioses between nitrogen (N) 2 —fixing prokaryotes and photosynthetic eukaryotes are important for nitrogen acquisition in N-limited environments. Recently, a widely distributed planktonic uncultured nitrogen-fixing cyanobacterium (UCYN-A) was found to have unprecedented genome reduction, including the lack of oxygen-evolving photosystem II and the tricarboxylic acid cycle, which suggested partnership in a symbiosis. We showed that UCYN-A has a symbiotic association with a unicellular prymnesiophyte, closely related to calcifying taxa present in the fossil record. The partnership is mutualistic, because the prymnesiophyte receives fixed N in exchange for transferring fixed carbon to UCYN-A. This unusual partnership between a cyanobacterium and a unicellular alga is a model for symbiosis and is analogous to plastid and organismal evolution, and if calcifying, may have important implications for past and present oceanic N 2 fixation.

Marine planktonic cyanobacteria capable of fixing molecular nitrogen (termed ‘diazotrophs’) are key in biogeochemical cycling, and the nitrogen fixed is one of the major external sources of nitrogen to the open ocean. Candidatus Atelocyanobacterium thalassa (UCYN-A) is a diazotrophic cyanobacterium known for its widespread geographic distribution in tropical and subtropical oligotrophic oceans, unusually reduced genome and symbiosis with a single-celled prymnesiophyte alga. Recently a novel strain of this organism was also detected in coastal waters sampled from the Scripps Institute of Oceanography pier. We analyzed the metagenome of this UCYN-A2 population by concentrating cells by flow cytometry. Phylogenomic analysis provided strong bootstrap support for the monophyly of UCYN-A (here called UCYN-A1) and UCYN-A2 within the marine Crocosphaera sp. and Cyanothece sp. clade. UCYN-A2 shares 1159 of the 1200 UCYN-A1 protein-coding genes (96.6%) with high synteny, yet the average amino-acid sequence identity between these orthologs is only 86%. UCYN-A2 lacks the same major pathways and proteins that are absent in UCYN-A1, suggesting that both strains can be grouped at the same functional and ecological level. Our results suggest that UCYN-A1 and UCYN-A2 had a common ancestor and diverged after genome reduction. These two variants may reflect adaptation of the host to different niches, which could be coastal and open ocean habitats.

Biological nitrogen (N₂) fixation is important in controlling biological productivity and carbon flux in the oceans. Unicellular N₂-fixing cyanobacteria have only recently been discovered and are widely distributed in tropical and subtropical seas. Metagenomic analysis of flow cytometry-sorted cells shows that unicellular N₂-fixing cyanobacteria in \"group A\" (UCYN-A) lack genes for the oxygen-evolving photosystem II and for carbon fixation, which has implications for oceanic carbon and nitrogen cycling and raises questions regarding the evolution of photosynthesis and N₂ fixation on Earth.

Background We investigated the role of the ETS-1 transcription factor in Head and Neck Squamous Cell Carcinoma (HNSCC) in multiple cisplatin-resistant HNSCC cell lines. Methods We examined its molecular link with SRC and MEK/ERK pathways and determined the efficacy of either MEK/ERK inhibitor PD0325901 or SRC inhibitor Dasatinib on cisplatin-resistant HNSCC inhibition. Results We found that ETS-1 protein expression levels in a majority of cisplatin-resistant HNSCC cell types were higher than those in their parental cisplatin sensitive partners. High ETS-1 expression was also found in patient-derived, cisplatin-resistant HNSCC cells. While ETS-1 knockdown inhibited cell proliferation, migration, and invasion, it could still re-sensitize cells to cisplatin treatment. Interestingly, previous studies have shown that MER/ERK pathways could regulate ETS-1 through its phosphorylation at threonine 38 (T38). Although almost all cisplatin-resistant HNSCC cells we tested showed higher ETS-1 phosphorylation levels at T38, we found that inhibition of MEK/ERK pathways with the MEK inhibitor PD0325901 did not block this phosphorylation. In addition, treatment of cisplatin-resistant HNSCC cells with the MEK inhibitor completely blocked ERK phosphorylation but did not re-sensitize cells to cisplatin treatment. Furthermore, we found that, consistent with ETS-1 increase, SRC phosphorylation dramatically increased in cisplatin-resistant HNSCC, and treatment of cells with the SRC inhibitor, Dasatinib, blocked SRC phosphorylation and decreased ETS-1 expression. Importantly, we showed that Dasatinib, as a single agent, significantly suppressed cell proliferation, migration, and invasion, in addition to survival. Conclusions Our results demonstrate that the SRC/ETS-1 pathway plays a crucial role and could be a key therapeutic target in cisplatin-resistant HNSCC treatment.

Sustaining the organisms, ecosystems and processes that underpin human wellbeing is necessary to achieve sustainable development. Here we define critical natural assets as the natural and semi-natural ecosystems that provide 90% of the total current magnitude of 14 types of nature’s contributions to people (NCP), and we map the global locations of these critical natural assets at 2 km resolution. Critical natural assets for maintaining local-scale NCP (12 of the 14 NCP) account for 30% of total global land area and 24% of national territorial waters, while 44% of land area is required to also maintain two global-scale NCP (carbon storage and moisture recycling). These areas overlap substantially with cultural diversity (areas containing 96% of global languages) and biodiversity (covering area requirements for 73% of birds and 66% of mammals). At least 87% of the world’s population live in the areas benefitting from critical natural assets for local-scale NCP, while only 16% live on the lands containing these assets. Many of the NCP mapped here are left out of international agreements focused on conserving species or mitigating climate change, yet this analysis shows that explicitly prioritizing critical natural assets and the NCP they provide could simultaneously advance development, climate and conservation goals. Bringing together multiple models and databases on nature’s contributions to people, the authors map these contributions globally and determine the critical areas where their magnitude is the highest and where they provide the highest potential human benefit.

Previous studies have revealed that individual T cell receptors (TCRs) can recognize a diverse set of peptide targets displayed by Major Histocompatibility Complexes (MHCs) to enable effective adaptive immune surveillance. However, how TCR sequences encode their cross-reactivity remains poorly understood. Here, we used an assay to characterize the -binding of 19 (~47 million) different TCRs in the context of a single TCR framework for binding to seven related peptides displayed by HLA-A*02:01. We define to be the number of peptide-MHC targets recognized by a TCR within a specific universe of targets. We found a hierarchy of TCR complementarity-determining region 3 (CDR3) alpha and beta chain residue importance that determined -binding for the seven targets. Our machine learning model that embedded TCR sequences using BLOSUM-50 provided an overall F1 score of 0.698 and an AUPRC of 0.745 for predicting TCR-pMHC binding, which was significantly superior to model results from VHSE-8 embedded or one hot encoded sequences. When we used our model to predict observed -binding, we found that experimentally derived sequence motifs do not fully explain the relative importance of different CDR3 residues. We determined CDR3 residue importance by examining the reduction in machine learning model predictive ability by masking individual CDR3 residues. We found that the resulting residue importance ranking was significantly correlated to residue importance determined with a computational alanine scan using Rosetta. Our findings validate past theoretical predictions of TCR cross-reactivity and demonstrate that TCRs used in therapeutics must be carefully evaluated for their specificity.

Diatoms with symbiotic N 2 -fixing cyanobacteria are often abundant in the oligotrophic open ocean gyres. The most abundant cyanobacterial symbionts form heterocysts (specialized cells for N 2 fixation) and provide nitrogen (N) to their hosts, but their morphology, cellular locations and abundances differ depending on the host. Here we show that the location of the symbiont and its dependency on the host are linked to the evolution of the symbiont genome. The genome of Richelia (found inside the siliceous frustule of Hemiaulus ) is reduced and lacks ammonium transporters, nitrate/nitrite reductases and glutamine:2-oxoglutarate aminotransferase. In contrast, the genome of the closely related Calothrix (found outside the frustule of Chaetoceros ) is more similar to those of free-living heterocyst-forming cyanobacteria. The genome of Richelia is an example of metabolic streamlining that has implications for the evolution of N 2 -fixing symbiosis and potentially for manipulating plant–cyanobacterial interactions. Cyanobacterial symbionts of marine diatoms can localize intracellularly or externally to their host partners. Here Hilton et al . describe the genomes of two diazotroph cyanobacterial symbionts of diatoms and show that the location of the symbiont affects expression of nitrogen assimilation genes.

Refractory neonatal seizures do not respond to first-line antiseizure medications like phenobarbital (PB), a positive allosteric modulator for GABAA receptors. GABAA receptor-mediated inhibition is dependent upon electroneutral cation-chloride transporter KCC2, which mediates neuronal chloride extrusion and its age-dependent increase and postnatally shifts GABAergic signaling from depolarizing to hyperpolarizing. Brain-derived neurotropic factor-tyrosine receptor kinase B activation (BDNF-TrkB activation) after excitotoxic injury recruits downstream targets like PLCγ1, leading to KCC2 hypofunction. Here, the antiseizure efficacy of TrkB agonists LM22A-4, HIOC, and deoxygedunin (DG) on PB-refractory seizures and postischemic TrkB pathway activation was investigated in a mouse model (CD-1, P7) of refractory neonatal seizures. LM, a BDNF loop II mimetic, rescued PB-refractory seizures in a sexually dimorphic manner. Efficacy was associated with a substantial reduction in the postischemic phosphorylation of TrkB at Y816, a site known to mediate postischemic KCC2 hypofunction via PLCγ1 activation. LM rescued ischemia-induced phospho-KCC2-S940 dephosphorylation, preserving its membrane stability. Full TrkB agonists HIOC and DG similarly rescued PB refractoriness. Chemogenetic inactivation of TrkB substantially reduced postischemic neonatal seizure burdens at P7. Sex differences identified in developmental expression profiles of TrkB and KCC2 may underlie the sexually dimorphic efficacy of LM. These results support a potentially novel role for the TrkB receptor in the emergence of age-dependent refractory neonatal seizures.

Licensed COVID-19 vaccines ameliorate viral infection by inducing production of neutralizing antibodies that bind the SARS-CoV-2 Spike protein and inhibit viral cellular entry. However, the clinical effectiveness of these vaccines is transitory as viral variants escape antibody neutralization. Effective vaccines that solely rely upon a T cell response to combat SARS-CoV-2 infection could be transformational because they can utilize highly conserved short pan-variant peptide epitopes, but a mRNA-LNP T cell vaccine has not been shown to provide effective anti-SARS-CoV-2 prophylaxis. Here we show a mRNA-LNP vaccine (MIT-T-COVID) based on highly conserved short peptide epitopes activates CD8 + and CD4 + T cell responses that attenuate morbidity and prevent mortality in HLA-A*02:01 transgenic mice infected with SARS-CoV-2 Beta (B.1.351). We found CD8 + T cells in mice immunized with MIT-T-COVID vaccine significantly increased from 1.1% to 24.0% of total pulmonary nucleated cells prior to and at 7 days post infection (dpi), respectively, indicating dynamic recruitment of circulating specific T cells into the infected lungs. Mice immunized with MIT-T-COVID had 2.8 (2 dpi) and 3.3 (7 dpi) times more lung infiltrating CD8 + T cells than unimmunized mice. Mice immunized with MIT-T-COVID had 17.4 times more lung infiltrating CD4 + T cells than unimmunized mice (7 dpi). The undetectable specific antibody response in MIT-T-COVID-immunized mice demonstrates specific T cell responses alone can effectively attenuate the pathogenesis of SARS-CoV-2 infection. Our results suggest further study is merited for pan-variant T cell vaccines, including for individuals that cannot produce neutralizing antibodies or to help mitigate Long COVID.

Because the lung is a mucosal barrier organ with a unique immunologic environment, mechanisms of immunoregulation in lung cancer may differ from those of other malignancies. Consistent with this notion, we found that CD8+ T cells played a paradoxical role in facilitating, rather than ameliorating, the growth of multiple lung adenocarcinoma models. These included spontaneous, carcinogen-induced, and transplantable tumor cell line models. Specifically, we found that CD8+ T cells promoted homing of CD4+Foxp3+ Tregs to the tumor bed by increasing the levels of CCR5 chemokines in the tumor microenvironment in an IFN-γ- and TNF-α-dependent manner. Contrary to their canonical role, these Th1 cytokines contributed to accelerated growth of murine lung adenocarcinomas, while suppressing the growth of other malignancies. Surprisingly, lung cancer cells themselves can serve as a dominant source of IFN-γ, and deletion of this cytokine from cancer cells using CRISPR/Cas9 decreases tumor growth. Importantly for translational applications, in patients with lung cancer, a high level of IFN-γ was also found at both the mRNA and protein levels. Our data outline what we deem a novel and previously undefined lung cancer-specific immunoregulatory pathway that may be harnessed to tailor immune-based therapy specifically for this malignancy.