Mind the gap: Increased inter-letter spacing as a means of improving reading performance.

Theeffects of text display, specificallywithin-word spacing, on children's reading at different developmental levels has barely been investigated.This study explored the influence of manipulating inter-letter spacing on reading performance (accuracy and rate) of beginner Hebrew readers compared with older readers and of low-achieving readers compared with age-matched high-achieving readers.A computer-based isolated word reading task was performed by 132 first and third graders. Words were displayed under two spacing conditions: standard spacing (100%) and increased spacing (150%). Words were balanced for length and frequency across conditions. Results indicated that increased spacing contributed to reading accuracy without affecting reading rate. Interestingly, all first graders benefitted fromthe spaced condition. Thiseffect was found only in long words but not in short words. Among third graders, only low-achieving readers gained in accuracy fromthespaced condition. Thetheoretical and clinical effects ofthefindings are discussed.

The role of IL-1ß in the early tumor cell-induced angiogenic response.

In this study, we assessed the involvement of IL-1ß in early angiogenic responses induced by malignant cells using Matrigel plugs supplemented with B16 melanoma cells. We found that during the angiogenic response, IL-1ß and vascular endothelial growth factor (VEGF) interact in a newly described autoinduction circuit, in which each of these cytokines induces the other. The IL-1ß and VEGF circuit acts through interactions between bone marrow-derived VEGF receptor 1(+)/IL-1R1(+) immature myeloid cells and tissue endothelial cells. Myeloid cells produce IL-1ß and additional proinflammatory cytokines, which subsequently activate endothelial cells to produce VEGF and other proangiogenic factors and provide the inflammatory microenvironment for angiogenesis and tumor progression. These mechanisms were also observed in a nontumor early angiogenic response elicited in Matrigel plugs by either rIL-1ß or recombinant VEGF. We have shown that IL-1ß inhibition stably reduces tumor growth by limiting inflammation and inducing the maturation of immature myeloid cells into M1 macrophages. In sharp contrast, only transient inhibition of tumor growth was observed after VEGF neutralization, followed by tumor recurrence mediated by rebound angiogenesis. This occurs via the reprogramming of VEGF receptor 1(+)/IL-1R1(+) cells to express hypoxia inducible factor-1α, VEGF, and other angiogenic factors, thereby directly supporting proliferation of endothelial cells and blood vessel formation in a paracrine manner. We suggest using IL-1ß inhibition as an effective antitumor therapy and are currently optimizing the conditions for its application in the clinic.

Non-redundant properties of IL-1α and IL-1ß during acute colon inflammation in mice.

OBJECTIVE: The differential role of the IL-1 agonists, IL-1α, which is mainly cell-associated versus IL-1ß, which is mostly secreted, was studied in colon inflammation. DESIGN: Dextran sodium sulfate (DSS) colitis was induced in mice globally deficient in either IL-1α or IL-1ß, and in wild-type mice, or in mice with conditional deletion of IL-1α in intestinal epithelial cells (IECs). Bone marrow transplantation experiments were performed to assess the role of IL-1α or IL-1ß of myeloid versus colon non-hematopoietic cells in inflammation and repair in acute colitis. RESULTS: IL-1α released from damaged IECs acts as an alarmin by initiating and propagating colon inflammation, as IL-1α deficient mice exhibited mild disease symptoms with improved recovery. IL-1ß is involved in repair of IECs and reconstitution of the epithelial barrier during the resolution of colitis; its deficiency correlates with disease exacerbation. Neutralisation of IL-1α in control mice during acute colitis led to alleviation of clinical and histological manifestations, whereas treatment with rIL-1Ra or anti-IL-1ß antibodies was not effective. Repair after colitis correlated with accumulation of CD8 and regulatory T cells in damaged crypts. CONCLUSIONS: The role of IL-1α and IL-1ß differs in DSS-induced colitis in that IL-1α, mainly of colon epithelial cells is inflammatory, whereas IL-1ß, mainly of myeloid cell origin, promotes healing and repair. Given the dissimilar functions of each IL-1 agonistic molecule, an IL-1 receptor blockade would not be as therapeutically effective as specific neutralising of IL-1α, which leaves IL-1ß function intact.

The impact of school closures during the COVID-19 pandemic on reading fluency among second grade students: socioeconomic and gender perspectives.

Introduction: The acquisition of reading skills is a crucial milestone in early education, with formal instruction and practice playing pivotal roles. The outbreak of COVID-19 led to widespread school closures and a shift to remote learning. Methods: This study aimed to investigate the effects of school closures on reading acquisition and fluency among a large sample of second-grade children, considering socioeconomic status (SES) and gender differences. In 2019, a cohort of 2228 second-grade students from 34 schools was assessed for word reading fluency and comprehension. In 2020, during the pandemic, 765 students from a subsample of 20 original schools were re-evaluated using the same measures. The study also collected school-related data. Results: The findings from the entire sample indicated no significant differences in fluency and comprehension scores between children in the second grade in 2019 and 2020. However, a significant interaction emerged when analyzing low SES versus high SES children. Children from low SES backgrounds exhibited notably lower reading scores after a year of remote learning due to the COVID-19 outbreak. Moreover, the disparity in reading scores between low SES and high SES children nearly doubled in 2020. Gender differences were also detected. Discussion: These results underscore the impact of remote learning during the COVID-19 crisis on exacerbating gaps in reading fluency and comprehension between children from high and low SES backgrounds. The implications of these findings highlight the critical role of in-person schooling and targeted support for disadvantaged students, especially during pivotal stages of reading development.

Microenvironment-derived IL-1 and IL-17 interact in the control of lung metastasis.

Inflammatory cytokines modulate immune responses in the tumor microenvironment during progression/metastasis. In this study, we have assessed the role of IL-1 and IL-17 in the control of antitumor immunity versus progression in a model of experimental lung metastasis, using 3LL and B16 epithelial tumor cells. The absence of IL-1 signaling or its excess in the lung microenvironment (in IL-1ß and IL-1R antagonist knockout [KO] mice, respectively) resulted in a poor prognosis and reduced T cell activity, compared with WT mice. In IL-1ß KO mice, enhanced T regulatory cell development/function, due to a favorable in situ cytokine network and impairment in APC maturation, resulted in suppressed antitumor immunity, whereas in IL-1R antagonist KO mice, enhanced accumulation and activity of myeloid-derived suppressor cells were found. Reduced tumor progression along with improved T cell function was found in IL-17 KO mice, compared with WT mice. In the microenvironment of lung tumors, IL-1 induces IL-17 through recruitment of γ/δ T cells and their activation for IL-17 production, with no involvement of Th17 cells. These interactions were specific to the microenvironment of lung tumors, as in intrafootpad tumors in IL-1/IL-17 KO mice, different patterns of invasiveness were observed and no IL-17 could be locally detected. The results highlight the critical and unique role of IL-1, and cytokines induced by it such as IL-17, in determining the balance between inflammation and antitumor immunity in specific tumor microenvironments. Also, we suggest that intervention in IL-1/IL-17 production could be therapeutically used to tilt this balance toward enhanced antitumor immunity.

Differential release of chromatin-bound IL-1alpha discriminates between necrotic and apoptotic cell death by the ability to induce sterile inflammation.

IL-1alpha, like IL-1beta, possesses multiple inflammatory and immune properties. However, unlike IL-1beta, the cytokine is present intracellularly in healthy tissues and is not actively secreted. Rather, IL-1alpha translocates to the nucleus and participates in transcription. Here we show that intracellular IL-1alpha is a chromatin-associated cytokine and highly dynamic in the nucleus of living cells. During apoptosis, IL-1alpha concentrates in dense nuclear foci, which markedly reduces its mobile nature. In apoptotic cells, IL-1alpha is retained within the chromatin fraction and is not released along with the cytoplasmic contents. To simulate the in vivo inflammatory response to cells undergoing different mechanisms of death, lysates of cells were embedded in Matrigel plugs and implanted into mice. Lysates from cells undergoing necrosis recruited cells of the myeloid lineage into the Matrigel, whereas lysates of necrotic cells lacking IL-1alpha failed to recruit an infiltrate. In contrast, lysates of cells undergoing apoptotic death were inactive. Cells infiltrating the Matrigel were due to low concentrations (20-50 pg) of the IL-1alpha precursor containing the receptor interacting C-terminal, whereas the N-terminal propiece containing the nuclear localization site failed to do so. When normal keratinocytes were subjected to hypoxia, the constitutive IL-1alpha precursor was released into the supernatant. Thus, after an ischemic event, the IL-1alpha precursor is released by hypoxic cells and incites an inflammatory response by recruiting myeloid cells into the area. Tissues surrounding the necrotic site also sustain damage from the myeloid cells. Nuclear trafficking and differential release during necrosis vs. apoptosis demonstrate that inflammation by IL-1alpha is tightly controlled.

T Cells Expressing a Modified FcγRI Exert Antibody-Dependent Cytotoxicity and Overcome the Limitations of CAR T-cell Therapy against Solid Tumors.

The pioneering design of chimeric antigen receptor (CAR) T-cell therapy demonstrated the potential of reprogramming the immune system. Nonetheless, T-cell exhaustion, toxicity, and suppressive microenvironments limit their efficacy in solid tumors. We previously characterized a subset of tumor-infiltrating CD4+ T cells expressing the FcγRI receptor. Herein, we detail engineering of a receptor, based on the FcγRI structure, allowing T cells to target tumor cells using antibody intermediates. These T cells showed effective and specific cytotoxicity only when an appropriate antibody was added. Only target-bound antibodies activated these cells, while free antibodies were internalized without activation. Their cytotoxic activity was correlated to target protein density, therefore targeting tumor cells with high antigen density while sparing normal cells with low or no expression. This activation mechanism prevented premature exhaustion. Furthermore, during antibody-dependent cytotoxicity these cells secreted attenuated cytokine levels compared with CAR T cells, thereby enhancing their safety profile. These cells eradicated established melanomas, infiltrated the tumor microenvironment, and facilitated host immune cell recruitment in immunocompetent mice. In NOD/SCID gamma mice the cells infiltrate, persist, and eradicate tumors. As opposed to CAR T-cell therapies, which require changing the receptor across different types of cancer, our engineered T cells remain the same across tumor types, while only the injected antibody changes. Overall, we generated a highly flexible T-cell therapy capable of binding a wide range of tumor cells with high affinity, while preserving the cytotoxic specificity only to cells expressing high density of tumor-associated antigens and using a single manufacturing process.

Lack of interleukin-1α or interleukin-1ß inhibits transformation of steatosis to steatohepatitis and liver fibrosis in hypercholesterolemic mice.

BACKGROUND & AIMS: The identification of the cellular and molecular pathways that mediate the development of non-alcoholic steatohepatitis is of crucial importance. Cytokines produced by liver-resident and infiltrating inflammatory cells, play a pivotal role in liver inflammation. The role of the proinflammatory cytokines IL-1α and IL-1ß in steatohepatitis remains elusive. METHODS: We employed IL-1α and IL-1ß-deficient mice and transplanted marrow cells to study the role of liver-resident and bone marrow-derived IL-1 in steatosis and its progression to steatohepatitis. RESULTS: Atherogenic diet-induced steatohepatitis in wild-type mice was associated with 16 and 4.6 fold-elevations in mRNA levels of hepatic IL-1α and IL-1ß, respectively. In mice deficient in either IL-1α or IL-1ß the transformation of steatosis to steatohepatitis and liver fibrosis was markedly reduced. This protective effect in IL-1α-deficient mice was noted despite increased liver cholesterol levels. Deficiency of IL-1α markedly reduced plasma serum amyloid A and steady-state levels of mRNA coding for inflammatory genes (P-selectin, CXCL1, IL-6, and TNFα) as well as pro-fibrotic genes (MMP-9 and Collagen) and particularly a 50% decrease in TGFß levels (p = 0.004). IL-1α mRNA levels were two-folds lower in IL-1ß-deficient mice, and IL-1ß transcripts were three-folds lower in IL-1α-deficient compared to wild-type mice. Hepatic cell derived IL-1α rather than from recruited bone marrow-derived cells was required for steatohepatitis development. CONCLUSIONS: These data demonstrate the critical role of IL-1α and IL-1ß in the transformation of steatosis to steatohepatitis and liver fibrosis in hypercholesterolemic mice. Therefore, the potential of neutralizing IL-1α and/or IL-1ß to inhibit the development of steatohepatitis should be explored.

Reduced atherosclerosis and inflammatory cytokines in apolipoprotein-E-deficient mice lacking bone marrow-derived interleukin-1α.

OBJECTIVE: Interleukin (IL)-1α and IL-1ß are products of macrophages, endothelial cells and vascular smooth muscle cells; moreover, each of these cell types is affected by the pro-inflammatory properties of both IL-1's. Whereas several studies demonstrate the proatherogenic properties of IL-1ß, the role of IL-1α in atherogenesis remains unclear. We assessed whether IL-1α and IL-1ß from tissue resident vascular cells or emigrating bone marrow-derived cells promote the development of atherosclerosis in apoE-/- mice and determined the effect of selective macrophage IL-1α or IL-1ß deficiency on degradation of LDL and cytokine production. METHODS: We generated strains of double knock-out (KO) mice (apoE-/-/IL-1α-/- and apoE-/-/IL-1ß-/-) and created chimeras consisting of apoE-/- mice reconstituted with bone marrow-derived cells from apoE-/-/IL-1+/+, apoE-/-/IL-1α-/- and apoE-/-/IL-1ß-/-. RESULTS: The areas of aortic sinus lesions were lower in either double KO mice compared to solely apoE-/- mice, despite higher non-HDL cholesterol levels. Importantly, selective deficiency of IL-1α or IL-1ß in bone marrow-derived cells inhibited atherogenesis to the same extent as in double KO mice without affecting plasma lipids. Aortic sinus lesions in apoE-/- mice transplanted with IL-1ß-/- or IL-1α-/- cells were 32% and 52% lower, respectively, than in IL-1+/+ transplanted mice. Ex vivo, isolated IL-1α-/- macrophages from atherosclerotic mice degraded LDL and secreted IL-6, TNFα and IL-12 similarly to IL-1+/+ macrophages; however, IL-1α deficient macrophages secreted reduced levels of IL-1ß (-50%) and 2-3-fold higher levels of the anti-inflammatory cytokine IL-10. CONCLUSION: We show for the first time that it is IL-1α from bone marrow-derived cells that accelerates atherogenesis in apoE-deficient mice rather than constitutive IL-1α in vascular cells, possibly by increasing the inflammatory cytokine profile of macrophages.

IL-1-induced inflammation promotes development of leishmaniasis in susceptible BALB/c mice.

The role of host-derived IL-1 on the course of Leishmania major infection in susceptible BALB/c mice was assessed. Manifestations of the disease were more severe in mice deficient in the physiological inhibitor of IL-1, the IL-1 receptor antagonist (IL-1Ra) in comparison with control mice. In mice lacking one of the IL-1 genes (IL-1alpha or IL-1beta), there was delayed development of the disease and more attenuated systemic inflammatory responses. IL-1alpha-deficient mice were slightly more resistant to L. major infection compared with IL-1beta-knockout mice. During disease progression in IL-1Ra KO and control mice, myeloid-derived suppressor cells invaded the spleen, concomitant to suppression of T cell-mediated immunity and expression of systemic high levels of pro-inflammatory cytokines. In IL-1-deficient mice, T(h)1 responses were still apparent, even at late stages of the disease. Thus, dose-dependent effects of IL-1 were shown to influence the pathogenesis of murine leishamaniasis in susceptible BALB/c mice. Physiological and supra-physiological levels of IL-1 in the microenvironment promoted an exacerbated form of disease, whereas sub-physiological doses of IL-1 induced a less progressive disease. Thus, manipulation of IL-1 levels in the host, using the IL-1Ra or specific antibodies, has the potential to alleviate symptoms of visceral manifestations of leishmaniasis.

Host-derived interleukin-1alpha is important in determining the immunogenicity of 3-methylcholantrene tumor cells.

Using IL-1/IL-1Ra knockout BALB/c mice, we showed that 3-methylcholatrene (3-MCA)-induced carcinogenesis is dependent on IL-1beta-induced inflammatory responses. Patterns of local inflammation and tumorigenicity were similar in wild-type (WT) and IL-1alpha(-/-) mice, while in IL-1beta(-/-) mice, tumorigenicity was attenuated and in IL-1Ra(-/-) mice accentuated. 3-MCA-induced fibrosarcoma cell lines from WT mice developed into progressive tumors in WT mice, while surprisingly, lines from IL-1alpha(-/-) mice formed tumors only in immunocompromized mice. 3-MCA-induced fibrosarcoma cell lines from IL-1alpha(-/-) mice, compared with lines from WT mice, manifested higher expression levels of "global" surface molecules related to Ag presentation and interactions with immune surveillance cells (MHC class I, B7.1, B7.2, L-selectin, and NKG2D ligands) and were eradicated mainly by CD4(+)- and CD8(+)-dependent T cell responses. Concomitantly, at the injection site of 3-MCA-induced fibrosarcoma cells derived from IL-1alpha(-/-) mice, a leukocyte infiltrate, subsequently replaced by a scar-like tissue, was observed. Immune aberrations in NK cell maturation, antitumor specific immunity and killing capacity of effector cells were observed in IL-1alpha(-/-) mice, in contrast to WT mice. Thus, we demonstrate in this study the significance of host-derived IL-1alpha in cancer immunoediting, by affecting innate and specific immunosurveillance mechanisms. Overall, the results presented in this study, together with our previous studies, attest to differential involvement of IL-1alpha and IL-1beta in tumorigenesis; host-derived IL-1beta mainly controls inflammation, while concomitantly, IL-1alpha controls immunosurveillance of the arising malignant cells. Elucidation of the involvement of the IL-1 molecules in the malignant process will hopefully lead to the development of novel approaches for chemoprevention and immunotherapy.

The role of macrophage-derived IL-1 in induction and maintenance of angiogenesis.

Inflammation and angiogenesis are pivotal processes in the progression of many diseases, including malignancies. A hypoxic microenvironment often results in a milieu of proinflammatory and proangiogenic cytokines produced by infiltrating cells. We assessed the role of macrophage-derived hypoxia-associated cytokines in promoting inflammation and angiogenesis. Supernatants of macrophages, stimulated under hypoxia with or without an inflammatory stimulus (LPS), promoted angiogenesis when incorporated into Matrigel plugs. However, neutralization of IL-1 in the supernatants, particularly IL-1beta, completely abrogated cell infiltration and angiogenesis in Matrigel plugs and reduced vascular endothelial growth factor (VEGF) levels by 85%. Similarly, supernatants from macrophages of IL-1beta knockout mice did not induce inflammatory or angiogenic responses. The importance of IL-1 signaling in the host was demonstrated by the dramatic reduction of inflammatory and angiogenic responses in Matrigel plugs that contained macrophage supernatants from control mice which had been implanted in IL-1 receptor type I knockout mice. Myeloid cells infiltrating into Matrigel plugs were of bone marrow origin and represented the major source of IL-1 and other cytokines/chemokines in the plugs. Cells of endothelial lineage were the main source of VEGF and were recruited mainly from neighboring tissues, rather than from the bone marrow. Using the aortic ring sprouting assay, it was shown that in this experimental system, IL-1 does not directly activate endothelial cell migration, proliferation and organization into blood vessel-like structures, but rather activates infiltrating cells to produce endothelial cell activating factors, such as VEGF. Thus, targeting IL-1beta has the potential to inhibit angiogenesis in pathological situations and may be of considerable clinical value.

Differences in the sialylation patterns of membrane stress proteins in chemical carcinogen-induced tumors developed in BALB/c and IL-1alpha deficient mice.

We evaluated the patterns of sialylation on fibrosarcoma cell lines arising following 3-methylcholanthrene treatments of wild-type and IL-1alpha-deficient mice; the former induced progressive tumors, whereas the latter cell lines induced regressing tumors or failed to develop into tumors in mice due to immune rejection. In regressing tumors, terminating alpha2-6-Neu5Ac residues were present at lower levels than in progressively growing tumors. In both tumor cells, the amount of alpha2-6-Neu5Ac residues was higher by an order of magnitude relative to the amount expressed in primary fibroblasts harvested from IL-1alpha-deficient and wild-type mice. We focused on membrane proteins, which may interact with the immune system. Interestingly, HSP65, grp75, and gp96 were found on the surfaces of malignant cells and were shown to possess sialylated N-glycans. The amount of trisialylated glycans on gp96 and HSP65 and monosialylated glycans on grp75 of regressing cells was significantly lower than in progressively growing cells, suggesting a dependency of these specific glycoforms on anti-tumor immunity.

Interleukin-1beta-driven inflammation promotes the development and invasiveness of chemical carcinogen-induced tumors.

The role of microenvironment interleukin 1 (IL-1) on 3-methylcholanthrene (3-MCA)-induced carcinogenesis was assessed in IL-1-deficient mice, i.e., IL-1beta(-/-), IL-1alpha(-/-), IL-1alpha/beta(-/-) (double knockout), and mice deficient in the naturally occurring inhibitor of IL-1, the IL-1 receptor antagonist (IL-1Ra). Tumors developed in all wild-type (WT) mice, whereas in IL-1beta-deficient mice, tumors developed slower and only in some of the mice. In IL-1Ra-deficient mice, tumor development was the most rapid. Tumor incidence was similar in WT and IL-1alpha-deficient mice. Histologic analyses revealed fibrotic structures forming a capsule surrounding droplets of the carcinogen in olive oil, resembling foreign body-like granulomas, which appeared 10 days after injection of 3-MCA and persisted until the development of local tumors. A sparse leukocyte infiltrate was found at the site of carcinogen injection in IL-1beta-deficient mice, whereas in IL-1Ra-deficient mice, a dense neutrophilic infiltrate was observed. Treatment of IL-1Ra-deficient mice with recombinant IL-1Ra but not with an inhibitor of tumor necrosis factor abrogated the early leukocytic infiltrate. The late leukocyte infiltrate (day 70), which was dominated by macrophages, was also apparent in WT and IL-1alpha-deficient mice, but was nearly absent in IL-1beta-deficient mice. Fibrosarcoma cell lines, established from 3-MCA-induced tumors from IL-1Ra-deficient mice, were more aggressive and metastatic than lines from WT mice; cell lines from IL-1-deficient mice were the least invasive. These observations show the crucial role of microenvironment-derived IL-1beta, rather than IL-1alpha, in chemical carcinogenesis and in determining the invasive potential of malignant cells.

Production of WW males lacking the masculine Z chromosome and mining the Macrobrachium rosenbergii genome for sex-chromosomes.

The cultivation of monosex populations is common in animal husbandry. However, preselecting the desired gender remains a major biotechnological and ethical challenge. To achieve an efficient biotechnology for all-female aquaculture in the economically important prawn (Macrobrachium rosenbergii), we achieved - for the first time - WW males using androgenic gland cells transplantation which caused full sex-reversal of WW females to functional males. Crossing the WW males with WW females yielded all-female progeny lacking the Z chromosome. We now have the ability to manipulate - by non-genomic means - all possible genotype combinations (ZZ, WZ and WW) to retain either male or female phenotypes and hence to produce monosex populations of either gender. This calls for a study of the genomic basis underlying this striking sexual plasticity, questioning the content of the W and Z chromosomes. Here, we report on the sequencing of a high-quality genome exhibiting distinguishable paternal and maternal sequences. This assembly covers ~ 87.5% of the genome and yielded a remarkable N50 value of ~ 20 × 106 bp. Genomic sex markers were used to initiate the identification and validation of parts of the W and Z chromosomes for the first time in arthropods.

Streptococcus pneumoniae Cell Wall-Localized Trigger Factor Elicits a Protective Immune Response and Contributes to Bacterial Adhesion to the Host.

Trigger factor (TF) has a known cytoplasmic function as a chaperone. In a previous study we showed that pneumococcal TF is also cell-wall localized and this finding combined with the immunogenic characteristic of TF, has led us to determine the vaccine potential of TF and decipher its involvement in pneumococcal pathogenesis. Bioinformatic analysis revealed that TF is conserved among pneumococci and has no human homologue. Immunization of mice with recombinant (r)TF elicited a protective immune response against a pneumococcal challenge, suggesting that TF contributes to pneumococcal pathogenesis. Indeed, rTF and an anti-rTF antiserum inhibited bacterial adhesion to human lung derived epithelial cells, indicating that TF contributes to the bacterial adhesion to the host. Moreover, bacteria lacking TF demonstrated reduced adhesion, in vitro, to lung-derived epithelial cells, neural cells and glial cells. The reduced adhesion could be restored by chromosomal complementation. Furthermore, bacteria lacking TF demonstrated significantly reduced virulence in a mouse model. Taken together, the ability of rTF to elicit a protective immune response, involvement of TF in bacterial adhesion, conservation of the protein among pneumococcal strains and the lack of human homologue, all suggest that rTF can be considered as a future candidate vaccine with a much broader coverage as compared to the currently available pneumococcal vaccines.

Reading Self-Concept and Reading Anxiety in Second Grade Children: The Roles of Word Reading, Emergent Literacy Skills, Working Memory and Gender.

Background: Most studies in the field of reading have focused on the linguistic and cognitive factors. Less is known about the affective aspects of reading in young readers, such as self-perceptions of reading, and reading anxiety. Aims: This study aimed to shed light on the direct and indirect relations between reading and related skills (working memory, emergent literacy skills, word reading accuracy and rate, and gender) as sources of reading affect (reading self-concept and anxiety). Sample: A total of 115 Hebrew speaking second graders participated in this study. Methods: A set of measures assessing reading accuracy and rate, emergent literacy skills (phonological fluency, rapid automatized naming and working memory) and reading affect questionnaires (reading self-concept and reading anxiety) were administered to the participants. Results: Path analysis was used as the primary analytic approach. Results indicated a negative moderate relation between reading self-concept and reading anxiety. The relations of working memory and emergent literacy to reading self-concept and reading anxiety were indirect via word reading accuracy and reading rate. Girls reported higher reading anxiety and lower reading self-concept, despite higher performance in reading accuracy and no difference in reading rate. Conclusion: The current results support the importance of examining reading affect and potential sources of reading affect. Results suggest that reading self-concept and reading anxiety and their related skills should be considered in designing reading intervention and instructions.

Flavin Reductase Contributes to Pneumococcal Virulence by Protecting from Oxidative Stress and Mediating Adhesion and Elicits Protection Against Pneumococcal Challenge.

Pneumococcal flavin reductase (FlaR) is known to be cell-wall associated and possess age dependent antigenicity in children. This study aimed at characterizing FlaR and elucidating its involvement in pneumococcal physiology and virulence. Bioinformatic analysis of FlaR sequence identified three-conserved cysteine residues, suggesting a transition metal-binding capacity. Recombinant FlaR (rFlaR) bound Fe2+ and exhibited FAD-dependent NADP-reductase activity, which increased in the presence of cysteine or excess Fe2+ and inhibited by divalent-chelating agents. flaR mutant was highly susceptible to H2O2 compared to its wild type (WT) and complemented strains, suggesting a role for FlaR in pneumococcal oxidative stress resistance. Additionally, flaR mutant demonstrated significantly decreased mice mortality following intraperitoneal infection. Interestingly, lack of FlaR did not affect the extent of phagocytosis by primary mouse peritoneal macrophages but reduced adhesion to A549 cells compared to the WT and complemented strains. Noteworthy are the findings that immunization with rFlaR elicited protection in mice against intraperitoneal lethal challenge and anti-FlaR antisera neutralized bacterial virulence. Taken together, FlaR's roles in pneumococcal physiology and virulence, combined with its lack of significant homology to human proteins, point towards rFlaR as a vaccine candidate.

Effects of micro-environment- and malignant cell-derived interleukin-1 in carcinogenesis, tumour invasiveness and tumour-host interactions.

Interleukin-1 (IL-1) comprises a family of closely related genes; the two major agonistic proteins, IL-1alpha and IL-1beta, are pleiotropic and affect mainly inflammation, immunity and haemopoiesis. IL-1beta is active solely in its secreted form, whereas IL-1alpha is active mainly as an intracellular precursor. IL-1 is abundant at tumour sites, where it may affect the process of carcinogenesis, tumour growth and invasiveness and the patterns of tumour-host interactions. Here, we review the effects of micro-environment- and tumour cell-derived IL-1 on malignant processes in experimental tumour models. We propose that membrane-associated IL-1alpha expressed on malignant cells stimulates anti-tumour immunity, while secretable IL-1beta derived from the micro-environment or the malignant cells, activates inflammation that promotes invasiveness and induces tumour-mediated suppression. Inhibition of the function of IL-1 by the inhibitor of IL-1, interleukin-1 receptor antagonist (IL-1Ra), reduces tumour invasiveness and alleviates tumour-mediated suppression, pointing to its feasible use in cancer therapy. Differential manipulation of IL-1alpha and IL-1beta in malignant cells or in the tumour's micro-environment may open new possibilities for using IL-1 in cancer immunotherapy.

Streptococcus pneumoniae fructose-1,6-bisphosphate aldolase, a protein vaccine candidate, elicits Th1/Th2/Th17-type cytokine responses in mice.

Streptococcus pneumoniae (S. pneumoniae) is a major pathogen worldwide. The currently available polysaccharide-based vaccines significantly reduce morbidity and mortality. However, the inherent disadvantages of the currently available polysaccharide-based vaccines have motivated the search for other bacterial immunogens capable of eliciting a protective immune response against S. pneumoniae. Fructose-1,6-bisphosphate aldolase (FBA) is a glycolytic enzyme, which was found to localize to the bacterial surface, where it functions as an adhesin. Previously, immunizing mice with recombinant FBA (rFBA) in the presence of alum elicited a protective immune response against a lethal challenge with S. pneumoniae. Thus, the aim of the present study was to determine the cytokine responses that are indicative of protective immunity following immunization with rFBA. The protective effects against pneumococcal challenge in mice immunized with rFBA with complete Freund's adjuvant (CFA) in the initial immunization and with incomplete Freund's adjuvant (IFA) in booster immunizations surpassed the protective effects observed following immunization with either rFBA + alum or pVACfba. CD4+ T-cells obtained from the rFBA/CFA/IFA/IFA-immunized mice co-cultured with rFBA-pulsed antigen-presenting cells (APCs), exhibited a significantly greater proliferative ability than CD4+ T-cells obtained from the adjuvant-immunized mice co-cultured with rFBA­pulsed APCs. The levels of the Th1-type cytokines, interferon (IFN)-γ, interleukin (IL)-2, tumor necrosis factor (TNF)-α and IL-12, the Th2-type cytokines, IL-4, IL-5 and IL-10, and the Th17-type cytokine, IL-17A, significantly increased within 72 h of the initiation of co-culture with CD4+ T-cells obtained from the rFBA­immunized mice, in comparison with the co-cultures with CD4+ T-cells obtained from the adjuvant-immunized mice. Immunizing mice with rFBA resulted in an IgG1/IgG2 ratio of 41, indicating a Th2 response with substantial Th1 involvement. In addition, rabbit and mouse anti-rFBA antisera significantly protected the mice against a lethal S. pneumoniae challenge in comparison with preimmune sera. Our results emphasize the mixed involvement of the Th1, Th2 and Th17 arms of the immune system in response to immunization with pneumococcal rFBA, a potential vaccine candidate.