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Studies evaluating COVID-19 primary vaccination with two vaccines reported a blunt response in Multiple Sclerosis (MS) patients under anti-CD20 and sphingosine-1-phosphate (S1P) modulators. An extended primary vaccination (EPV) was recommended in immunosuppressed MS patients. Data on the effectiveness of the EPV and subsequent booster dose are limited. A prospective cohort study (n = 270) was conducted to evaluate the humoral and cellular immunogenicity of the EPV scheme in immunocompromised MS patients (i.e., treated with anti-CD20, S1P modulators, natalizumab, teriflunomide, or dimethyl fumarate) vs. regular primary vaccination in non-treated patients - primary course (PC) cohort. The effect of a subsequent booster dose was also assessed - first booster (FB) cohort . The seroconversion rates were 55% and 56% in anti-CD20 and 75% and 67% in S1P modulators group in PC and FB cohort, respectively, and 100% in the remaining groups. A positive SARS-CoV-2 Spike T-spot was observed in 22% of patients under S1P modulators in PC cohort and 67% in FB cohort; the remaining groups had 75% or more. Similar rates of breakthrough infection were observed in both groups vs. controls. Compared to non-treated MS patients, immunosuppressed patients under anti-CD20 and S1P modulators drugs receiving EPV scheme or booster dose still present lower protection rates to SARS-CoV-2.

Influenza virus is a prominent cause of respiratory illness in humans. Current influenza vaccines offer strain-specific immunity, while provide limited protection against drifted strains. Broad-spectrum influenza vaccines can induce broad and long-term immunity, and thus are regarded as a future direction for the development of next-generation influenza vaccines. In this study, we have conceptualized a novel mRNA-based multi-antigen influenza vaccine consisting of three conserved antigens of influenza A virus, including the ectodomain of the M2 ion channel (M2e), the long alpha helix of haemagglutinin stalk region (LAH), and nucleoprotein (NP). The vaccine design aims to enhance its potency and promote the development of a future broad-spectrum influenza vaccine. Our mRNA-based vaccine demonstrated potent humoral and cellular responses throughout the time points of the murine model, inducing viral neutralizing antibodies, antibody-dependent cell cytotoxicity effect mediating antibodies and cross-reactive CD8+ T cell immune responses. The vaccine conferred broad protection against H1N1, H3N2, and H9N2 viruses. Moreover, the single-cell transcriptional profiling of T cells in the spleens of vaccinated mice revealed that the mRNA-based vaccine significantly promoted CD8+ T cells and memory T cells by prime-boost immunization. Our results suggest that the mRNA-based influenza vaccine encoding conserved proteins is a promising approach for eliciting broadly protective humoral and cellular immunity against various influenza viruses.

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has undergone multiple mutations since its emergence, and its latest variant, Omicron (B.1.1.529), is the most contagious variant of concern (VOC) which poses a major and imminent threat to public health. Since firstly reported by World Health Organization (WHO) in November 2021, Omicron variant has been spreading rapidly and has become the dominant variant in many countries worldwide. Omicron is the most mutated variant so far, containing 60 mutations in its genome, including 37 mutations in the S-protein. Since all current COVID-19 vaccines in use were developed based on ancestral SARS-CoV-2 strains, whether they are protective against Omicron is a critical question which has been the center of study currently. In this article, we systemically reviewed the studies regarding the effectiveness of 2- or 3-dose vaccines delivered in either homologous or heterologous manner. The humoral and cellular immune responses elicited by various vaccine regimens to protect against Omicron variant are discussed. Current understanding of the molecular basis underlying immune escape of Omicron was also analyzed. These studies indicate that two doses of vaccination are insufficient to elicit neutralizing antibody responses against Omicron variant. Nevertheless, Omicron-specific humoral immune responses can be enhanced by booster dose of almost all type vaccines in certain degree, and heterologous vaccination strategy may represent a better choice than homogenous regimens. Intriguingly, results of studies indicate that all current vaccines are still able to elicit robust T cell response against Omicron. Future focus should be the development of Omicron variant vaccine, which may induce potent humoral as well as cellular immune responses simultaneously against all known variants of the SARS-CoV-2 virus.

Ethanol fermentations can be prematurely halted as Saccharomyces cerevisiae faces adverse conditions, such as acidic pH, presence of acetic acid, and supraoptimal temperatures. The knowledge on yeast responses to these conditions is essential to endowing a tolerant phenotype to another strain by targeted genetic manipulation. In this study, physiological and whole-genome analyses were conducted to obtain insights on molecular responses which potentially render yeast tolerant towards thermoacidic conditions. To this end, we used thermotolerant TTY23, acid tolerant AT22, and thermo-acid tolerant TAT12 strains previously generated by adaptive laboratory evolution (ALE) experiments. The results showed an increase in thermoacidic profiles in the tolerant strains. The whole-genome sequence revealed the importance of genes related to: H+, iron, and glycerol transport (i.e., PMA1, FRE1/2, JEN1, VMA2, VCX1, KHA1, AQY3, and ATO2); transcriptional regulation of stress responses to drugs, reactive oxygen species and heat-shock (i.e., HSF1, SKN7, BAS1, HFI1, and WAR1); and adjustments of fermentative growth and stress responses by glucose signaling pathways (i.e., ACS1, GPA1/2, RAS2, IRA2, and REG1). At 30 °C and pH 5.5, more than a thousand differentially expressed genes (DEGs) were identified in each strain. The integration of results revealed that evolved strains adjust their intracellular pH by H+ and acetic acid transport, modify their metabolism and stress responses via glucose signaling pathways, control of cellular ATP pools by regulating translation and de novo synthesis of nucleotides, and direct the synthesis, folding and rescue of proteins throughout the heat-shock stress response. Moreover, the motifs analysis in mutated transcription factors suggested a significant association of SFP1, YRR1, BAS1, HFI1, HSF1, and SKN7 TFs with DEGs found in thermoacidic tolerant yeast strains.Key points• All the evolved strains overexpressed the plasma membrane H+-ATPase PMA1 at optimal conditions• Tolerant strain TAT12 mutated genes encoding weak acid and heat response TFs HSF1, SKN7, and WAR1• TFs HSF1 and SKN7 likely controlled the transcription of metabolic genes associated to heat and acid tolerance

Dynamic interactions between cells and extracellular matrix (ECM) through integrins influence most cellular functions. Normal cells, but even more, tumor cells are subjected to different forms of stress, including ischemia, radical oxygen species production, starvation, mechanical stress or genotoxic insults due to anti-cancer drugs or irradiation. In these situations, an adaptative cellular response occurs, integrating a complex network of intracellular signaling modules, which, depending on stress intensity, may result to either damage repair followed by complete restitution of cellular functions, or programmed cell death. Because of its implication in oncogenesis and anti-cancer therapy, cellular stress response has been thoroughly investigated. However, most of these studies have been performed in the context of isolated cells without taking into consideration that most cells are part of the tissue within which they interact with ECM through integrin. Few studies have described the influence of stress on cell-to-ECM interaction. However, one can speculate that, in these conditions, cells could functionally interact with protein microenvironment either to create positive interactions to survive (for example by facilitating protective pathways) or negative interaction to die (for example by facilitating detachment). In this review, we summarize the knowledge relative to the influence of different stress modalities on ECM remodeling, integrin expression and/or function modifications, and possible functional consequences, independently from the cellular model as these findings came from a large variety of cells (mesenchymal, endothelial, muscular, epithelial and glandular) and fields of application (cancer, vascular biology and tissue engineering). Most studies support the general notion that non-lethal stress favors ECM stiffness, integrin activation and enhanced survival. This field opens large perspectives not only in tumor biology but also in anti-cancer therapy by targeting one or several steps of the integrin-mediated signaling pathway, including integrin ligation, or activation of integrin-linked enzymes or integrin adaptors.

The cellular homeostatic response (CHR) and cellular stress response (CSR) work together to maintain homeostasis. Studying phylogenetically closely-related species inhabiting different environments can help investigate the interplay between the CHR and CSR. We conducted reciprocal in situ transplant experiments in a natural CO 2 vent (Ischia, Italy), using the sibling annelid species Platynereis cf. . dumerilii and Platynereis cf. . massiliensis which have been shown to have different preferential distributions around the CO 2 vent. Following transplantations, we characterised the response of each individual’s proteome, metabolome, and lipidome, to short or long-term exposure to different p CO 2 regimes (i.e., high and low), and confirmed its genetic identity. Here we show that different components of the CHR and CSR are utilised at different rates when Platynereis spp. are exposed to different p CO 2 regimes, with cellular responses shown to be conserved across species. Metabolome and lipidome responses were dependent on regime of origin, and changed relatively slowly, whereas proteome responses were dependent on transplant type and changed more rapidly. Our results provide new insights to improve our understanding of the interplay between different cellular physiological responses involved in defining the functional phenotype of marine species, and their ability to acclimatise to future projected high p CO 2 conditions.

The aim of this study was to test the hypothesis that mechanical ventilation (MV) during cancer surgery induces lung stroma/tissue milieu changes, creating a favorable microenvironment for postoperative lung metastatic tumor establishment. In Protocol A, female BALB/c mice were divided into an MV group and a control (no MV) group, both of which were anesthetized and subjected to intravenous injection of green fluorescent protein (GFP)-labeled mouse mammary carcinoma cell line (4T1) cells. After 24 h, the lung tissue was removed and the number of GFP-labeled 4T1 cells was calculated. In Protocol B, the clinically relevant mouse model of spontaneous breast cancer lung metastasis was used with surgical resection of the primary tumor to investigate the MV event that dictates postoperative lung metastasis. Female BALB/c mice were inoculated in the mammary fat pad with 4T1 cells. After 14-d growth, mice were anesthetized and divided into an MV group and a control (no MV) group during surgical procedures (mastectomy). Metastatic tumor burden was assessed two weeks after mastectomy by both macroscopic metastatic nodule count, hematoxylin-eosin histology, immunohistochemistry for the macrophage marker (CD68), and epithelial cell adhesion molecule (EpCAM). MV was associated with a significant increase in the number of circulating breast tumor cells (GFP-labeled 4T1 cells) remaining in the microvasculature of the lung ( <0.01). Immunohistochemical results showed increased infiltration of CD68-positive macrophages within injured lung parenchyma and metastatic tumor as well as increased expression of EpCAM in metastatic nodules. Postoperative metastases were more prevalent in the mechanically ventilated mice group compared to the non-ventilated group ( <0.05). MV-induced lung metastasis occurs by attracting circulating tumor cells to the site of the lung injury and by accelerating the proliferation of preexisting micro-metastases in the lung. These observations indicate that the metastasis-enhancing effect of MV should be considered in general anesthesia during cancer surgery.

Hypoxia arises in tumor regions with insufficient oxygen supply and is a major barrier in cancer treatment. The distribution of hypoxia levels is highly heterogeneous, ranging from mild, almost non-hypoxic, to severe and anoxic levels. The individual hypoxia levels induce a variety of biological responses that impair the treatment effect. A stronger focus on hypoxia levels rather than the absence or presence of hypoxia in our investigations will help development of improved strategies to treat patients with hypoxic tumors. Current knowledge on how hypoxia levels are sensed by cancer cells and mediate cellular responses that promote treatment resistance is comprehensive. Recently, it has become evident that hypoxia also has an important, more unexplored role in the interaction between cancer cells, stroma and immune cells, influencing the composition and structure of the tumor microenvironment. Establishment of how such processes depend on the hypoxia level requires more advanced tumor models and methodology. In this review, we describe promising model systems and tools for investigations of hypoxia levels in tumors. We further present current knowledge and emerging research on cellular responses to individual levels, and discuss their impact in novel therapeutic approaches to overcome the hypoxia barrier.

Live-attenuated rubella vaccine strain RA27/3 has been demonstrated to be safe and immunogenic in millions of children. The vaccine strain was used to insert SIV gag sequences and the resulting rubella vectors were tested in rhesus macaques alone and together with SIV gag DNA in different vaccine prime-boost combinations. We previously reported that such rubella vectors induce robust and durable SIV-specific humoral immune responses in macaques. Here, we report that recombinant rubella vectors elicit robust de novo SIV-specific cellular immune responses detectable for >10 months even after a single vaccination. The antigen-specific responses induced by the rubella vector include central and effector memory CD4+ and CD8+ T cells with cytotoxic potential. Rubella vectors can be administered repeatedly even after vaccination with the rubella vaccine strain RA27/3. Vaccine regimens including rubella vector and SIV gag DNA in different prime-boost combinations resulted in robust long-lasting cellular responses with significant increase of cellular responses upon boost. Rubella vectors provide a potent platform for inducing HIV-specific immunity that can be combined with DNA in a prime-boost regimen to elicit durable cellular immunity.

Antimicrobial efficacy, which is central to many aspects of medicine, is being rapidly eroded by bacterial resistance. Since new resistance can be induced by antimicrobial action, highly lethal agents that rapidly reduce bacterial burden during infection should help restrict the emergence of resistance. To improve lethal activity, recent work has focused on toxic reactive oxygen species (ROS) as part of the bactericidal activity of diverse antimicrobials. We report that when Escherichia coli was subjected to antimicrobial stress and the stressor was subsequently removed, both ROS accumulation and cell death continued to occur. Blocking ROS accumulation by exogenous mitigating agents slowed or inhibited poststressor death. Similar results were obtained with a temperature-sensitive mutational inhibition of DNA replication. Thus, bacteria exposed to lethal stressors may not die during treatment, as has long been thought; instead, death can occur after plating on drug-free agar due to poststress ROS-mediated toxicity. Examples are described in which (i) primary stress-mediated damage was insufficient to kill bacteria due to repair; (ii) ROS over-came repair (i.e., protection from anti-ROS agents was reduced by repair deficiencies); and (iii) killing was reduced by anti-oxidative stress genes acting before stress exposure. Enzymatic suppression of poststress ROS-mediated lethality by exogenous catalase supports a causal rather than a coincidental role for ROS in stress-mediated lethality, thereby countering challenges to ROS involvement in anti-microbial killing. We conclude that for a variety of stressors, lethal action derives, at least in part, from stimulation of a self-amplifying accumulation of ROS that overwhelms the repair of primary damage.