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Where to buy zithromax online

A still unanswered question is what drives the small fraction of where to buy zithromax online activated germinal center (GC) B cells to become long-lived quiescent memory B cells. We found here that a small population of GC-derived CD38intBcl6hi/intEfnb1+ cells with lower mTORC1 activity favored the memory B cell fate. Constitutively high mTORC1 where to buy zithromax online activity led to defects in formation of the CD38intBcl6hi/intEfnb1+ cells.

Conversely, decreasing mTORC1 activity resulted in relative enrichment of this memory-prone population over the recycling-prone one. Furthermore, the CD38intBcl6hi/intEfnb1+ cells had higher levels of Bcl2 and surface BCR where to buy zithromax online that, in turn, contributed to their survival and development. We also found that downregulation of Bcl6 resulted in increased expression of both Bcl2 and BCR.

Given the positive correlation between the strength of where to buy zithromax online T cell help and mTORC1 activity, our data suggest a model in which weak help from T cells together with provision of an increased survival signal are key for GC B cells to adopt a memory B cell fate. Memory B cells and long-lived plasma cells are responsible for effective long-term immunity against pathogens. The majority where to buy zithromax online of these cells responding to T cell–dependent antigens are generated from the germinal center (GC) reaction.

Indeed, memory B cells emerge from the GC as recirculating cells and, upon secondary antigen challenge, they are primed to elicit rapid antibody responses. GCs are divided into two anatomical structures where to buy zithromax online. The light zone (LZ) and the dark zone (DZ.

Allen et where to buy zithromax online al., 2007. Victora and Nussenzweig, 2012). B cells where to buy zithromax online proliferate and undergo somatic hypermutation in the DZ before entering the LZ, where they exit the cell cycle.

In the LZ, GC B cells expressing newly mutated B cell receptors (BCRs) capture antigen presented on follicular dendritic cells and internalize it for presentation to follicular helper T cells. Subsequently, antigen- and where to buy zithromax online T cell–dependent selection takes place, whereby the “choice” of recycling to the DZ for further affinity maturation or of exiting the GC as plasma or memory B cells is made. In regard to the selection mechanism, it has been postulated that precursor cells destined to become recycling GC, plasma, or memory B cells already become committed in the LZ, at least to some extent, thereafter entering the recycling DZ, plasma, or memory B cell pools (Inoue et al., 2018).

For instance, it has been demonstrated that a small fraction of LZ where to buy zithromax online B cells expressing c-Myc, a key cell-cycle regulator, corresponds to precursor cells for the recycling GC fate. C-Myc+ cells are enriched for high-affinity BCRs and ablation of c-Myc affects DZ reentry (Calado et al., 2012. Dominguez-Sola et al., 2012 where to buy zithromax online.

Finkin et al., 2019). Bcl6loCD69hi LZ B cells expressing IRF4, a critical transcription factor for plasma cell differentiation, were recently shown where to buy zithromax online to be the precursors of plasma cells (Ise et al., 2018). In contrast to these insights into the precursor cells for recycling and plasma cell fates, studies of the memory fate decision have been hampered by the lack of a known master transcription factor for differentiation of memory B cells.

Hence, surrogate markers such as an S1PR2 reporter, CCR6 expression, or a cell cycle reporter have been recently employed for identification where to buy zithromax online of memory precursor cells (Laidlaw et al., 2017. Suan et al., 2017. Wang et al., 2017).

Although informative, these studies have not where to buy zithromax online identified key features for development of the GC-derived precursor cells committed to the long-lived memory B cell fate, or what signals regulate these key features. Here, after identifying a memory-prone population (CD38intBcl6hi/int Ephrin-B1 [Efnb1+]), we found that this small population exhibited lower mTORC1 activity than the recycling-prone population. Constitutive high mTORC1 activity led to defective development of CD38intBcl6hi/intEfnb1+ cells, where to buy zithromax online whereas decreasing mTORC1 activity resulted in relative enrichment in this memory-prone cell population versus the recycling-prone one.

Moreover, the CD38intBcl6hi/intEfnb1+ cells had higher levels of Bcl2 and surface BCR, thereby contributing to their survival and development. We also found where to buy zithromax online that downregulation of Bcl6 resulted in increased expression of both Bcl2 and BCR. Given the positive correlation between the strength of T cell help and mTORC1 activity (Ersching et al., 2017), our data suggest a model in which weak help from T cells together with provision of an increased survival signal are key for GC cells to assume the memory B cell fate.

To clarify the initiating process for memory B cell differentiation occurring in the GC, we wished to identify GC B cells destined to the where to buy zithromax online memory fate. For this, we used Bcl6 protein reporter mice (Kitano et al., 2011). We immunized these mice with 4-hydroxy-3-nitrophenylacetyl (NP)–chicken γ-globulin (CGG) where to buy zithromax online in alum i.p.

And analyzed NP-specific IgG1+ splenic B cells at day 10. Since CD38 upregulation takes place during the transition from GC to memory B cells (Ridderstad and Tarlinton, 1998), we examined such CD38+ B cells that still maintained GC identity to some extent, i.e., were Bcl6+, together with conventional CD38− where to buy zithromax online GC B cells. By using a fractionation method described previously (Fig.

S1 A where to buy zithromax online. Ise et al., 2018), the LZ B cells were further separated based on their Bcl6 and CD69 expression pattern (upper right panel in Fig. 1 A) where to buy zithromax online.

Fraction (Fr.) 1 (CD38−Bcl6loCD69hi) and Fr.2 (CD38−Bcl6hiCD69hi) cells are plasma and recycling GC precursor cells, respectively (Ise et al., 2018). Characterization of Fr.3 (CD38−Bcl6hiCD69lo) where to buy zithromax online cells is described below. Efnb1 is expressed at a high level by almost all Fas+GL7+ cells, but is barely detectable on naive B cells (Laidlaw et al., 2017.

Lu et where to buy zithromax online al., 2017. Wang et al., 2017), allowing us to identify transitional populations between GC and memory B cells. Hence, for CD38+ cells, by using Efnb1 and Bcl6, we where to buy zithromax online further separated the NP+ IgG1+CD38+GL7−CD138− cells into Bcl6+Efnb1+ (Fr.5), Bcl6loEfnb1+ (Fr.6), and Bcl6−Efnb1− (Fr.7.

Lower right panel in Fig. 1 A) where to buy zithromax online. Since expression level of Bcl6 in Fr.5 cells was slightly but significantly lower than that of Fr.3 cells, as shown by the left panel in Fig.

1 B, where to buy zithromax online herein, we designated Bcl6hi/int for Fr.5. CD38 expression levels on Fr.5, Fr.6, and Fr.7 cells were increased in that order (middle panel in Fig. 1 B.

Herein, indicated as CD38int, and CD38+ for Fr.5 where to buy zithromax online and 6/7, respectively). During the time course of the GC response, Fr.5 and Fr.6 cell numbers peaked at day 10 before declining, whereas Fr.7 cells peaked at day 12 and then slowly declined (Fig. S1 B) where to buy zithromax online.

These kinetic data suggest that Fr.5 and Fr.6 contain cells that are transient and intermediate, and that once cells enter the Fr.7 pool, they are stably maintained. The Fr.7 cells displayed a where to buy zithromax online typical CD38+Bcl6−Efnb1− mature memory phenotype (Fig. 1 B).

To assess the relationship between overall LZ B cells and Fr.5/6/7 cells, we performed where to buy zithromax online RNA sequencing (RNA-seq) analysis (Fig. S2 A). To obtain sufficient where to buy zithromax online amounts of RNA for this analysis, we used transferred B1-8hi B cells instead of non-BCR transgenic mice.

These NP-specific transgenic GC B cells were present in similar proportions in each fraction as in non-BCR transgenic mice (Fig. S1 C) where to buy zithromax online. The principal component analysis (PCA) for each fraction indicated that memory B cells (Fr.7) clustered most tightly with CD38+Bcl6loEfnb1+ (Fr.6) cells but differed greatly from total LZ GC B cells (Fig.

1 C) where to buy zithromax online. Fr.5 cells were intermediate between Fr.6 and LZ GC B cells. Fr.6 cells expressed lower levels of S1pr2 and higher levels of Gpr183 where to buy zithromax online (EBI2) mRNA compared with LZ B cells (Fig.

S1 D), implying that they are a cell population in the process of exiting the GC. Herein, we call Fr.6 “pre-memory B cells.” In contrast where to buy zithromax online to Fr.6 and mature memory B cells (Fr.7), Fr.5 cells seem to start the process of downregulating Bcl6. Fr.6 cells are most likely to correspond to the already identified GC-derived pre-memory B cells (“Efnb1+S1pr2lo [Pop 4]”.

Laidlaw et al., 2017), “LZ CCR6+” (Suan et al., 2017), where to buy zithromax online and “mKO2hi” (Wang et al., 2017) in that, like those cells, Fr.6 cells are Bcl6int/loBach2int (Fig. S3, A and B). The above data prompted where to buy zithromax online us to consider that, among Fr.2, Fr.3, and Fr.5 cells, the CD38intBcl6hi/intEfnb1+ cells (Fr.5) could be potential GC-derived precursors of the pre-memory B cells (Fr.6).

To test this possibility, we took the following three approaches. First, PCA where to buy zithromax online of the RNA-seq data was performed, indicating that CD38intBcl6hi/intEfnb1+ cells (Fr.5) and pre-memory B cells (Fr.6) clustered most closely together (Fig. 1 D).

Second, to monitor cellular quiescence, we employed mVenus-p27K− transgenic mice, in which mainly G0 phase cells are labeled (Oki et al., 2014), demonstrating that in contrast to Fr.2 and Fr.3 cells, Fr.5 and Fr.6 cells had more mVenus-p27K− where to buy zithromax online probe–positive, i.e., quiescent cells (Fig. 1 E). Finally, in order to assess the memory recall potential of the Fr.5 cells, we used a previously described adoptive transfer method (Wang et al., 2017).

As illustrated where to buy zithromax online in Fig. 1 F, Fr.2, Fr.3, Fr.5, or Fr.6 cells were isolated from NP-CGG/alum immunized mice and adoptively transferred (2 × 104 cells per mouse) into sublethally irradiated recipient mice together with CD4+ T cells isolated from CGG-immunized mice. The recipient mice were where to buy zithromax online then challenged with NP-CGG and analyzed on day 6 for NP-specific plasma cells.

Although less proficient than pre-memory B cells (Fr.6), the ability of the adoptively transferred CD38intBcl6hi/intEfnb1+ (Fr.5) cells to give rise to plasma cells was significantly superior to Fr.2 and Fr.3 cells (Fig. 1 G) where to buy zithromax online. To rule out the possibility that Fr.5 cells were cells that had reentered the GC reaction from already generated memory B cells, we stained them for Ki67 and observed lower expression in Fr.5 than in the pre-GC B cells, which are in the process of entering the GC (Fig.

S1 E) where to buy zithromax online. Together, CD38intBcl6hi/intEfnb1+ (Fr.5) cells are likely to be a precursor of pre-memory B cells, herein called Fr.5 “pro-memory B cells,” and to represent a precursor population of previously identified pre-memory B cells (“Efnb1+S1pr2lo [Pop 4]”. Laidlaw et al., 2017), “LZ CCR6+” (Suan et al., 2017), and “mKO2hi” (Wang et where to buy zithromax online al., 2017.

Fig. S3, A where to buy zithromax online and B). However, we do not exclude the possibility that the pro-memory B cell population (Fr.5) is heterogeneous in its origins and properties.

For instance, Fr.5 cells appear to overlap, to some where to buy zithromax online extent, with LZ CCR6+ cells in that they are beginning to express Ccr6 (Fig. S3 C). To gain insight into the specific features of CD38intBcl6hi/intEfnb1+ (Fr.5) cells that promote their potential development and/or differentiation into memory cells, we compared their RNA-seq profile to that of the other LZ B cells (Fr.2 where to buy zithromax online and Fr.3.

Fig. 2 A where to buy zithromax online and Fig. S2 A).

CD38−Bcl6hiCD69hi (Fr.2) cells are destined to the recycling GC fate (Ise where to buy zithromax online et al., 2018). Gene set enrichment analysis (GSEA) of Hallmark gene sets (Liberzon et al., 2015) revealed a strong enrichment in Fr.2 cells of c-Myc targets, E2F targets, and mTORC1 signaling genes (Fig. S4 A) where to buy zithromax online.

Consistent with the mRNA analysis, expression of c-Myc protein, mTORC1 activity (assessed by phospho-S6), and E2F activity (assessed by phospho-Rb) were significantly decreased in Fr.5 cells (Fig. S4 B) where to buy zithromax online. In support of this, when we produced anti-NP IgHV186.2 Igλ monoclonal antibodies cloned from single cell-sorted Fr.2 and Fr.5 NP+IgG1+ B cells and measured their relative affinity for NP29- or NP1-BSA, we found a significant overrepresentation of lower-affinity antibodies in CD38intBcl6hi/intEfnb1+ (Fr.5) cells (Fig.

2 B). Consistently, the frequency of canonical affinity–improving mutation (replacement of Trp33 with where to buy zithromax online Leu33. W33L+) was lower in Fr.5 cells (Fig.

2 C) where to buy zithromax online. Hence, we conclude that, in contrast to CD38−Bcl6hiCD69hi (Fr.2) cells, most of the Fr.5 cells possess lower-affinity BCRs, an indication that they received less T cell help in the LZ (Victora et al., 2010). We next compared the RNA-seq profile of Fr.3 to Fr.5 cells (Fig where to buy zithromax online.

2 A and Fig. S2 A) where to buy zithromax online. Some differences were observed between these two fractions.

Particularly, expression of some of mTORC1 signaling genes was higher in Fr.3 than Fr.5 where to buy zithromax online cells (Fig. 2 D). Myc expression in Fr.3 cells was somewhat higher compared where to buy zithromax online with Fr.5 cells (Fig.

2 D). Reflecting these differences, GSEA showed an enrichment in Fr.3 of c-Myc targets and mTORC1 signaling where to buy zithromax online genes (Fig. 2 E), although the enrichment extent of Fr.3 to Fr.5 was much smaller than Fr.2 to Fr.5 cells (Fig.

S4 C) where to buy zithromax online. By flow cytometry analysis of c-Myc and pS6, however, we could not detect significant differences in both c-Myc protein expression and mTORC1 activity between Fr.3 and Fr.5 cells (Fig. S5 A) where to buy zithromax online.

These data suggest that our flow cytometry analysis might not have sufficed to detect small changes induced by differential mRNA levels between Fr.3 and Fr.5 cells. An alternative possibility is that, in addition to mRNA level, where to buy zithromax online changes in translational/posttranslational regulation might take place between Fr.3 and Fr.5 cells. The potential reason why Fr.5 but not Fr.3 cells can become pro-memory B cells, despite relatively small differences in RNA-seq profiles between these two populations, is described below.

To identify key properties for the development of Fr.5 cells and/or their activity, we where to buy zithromax online considered that Bach2/Blimp1 double-deficient GC B cells could provide a clue, since these mutant cells are defective in generating GC-derived memory B cells (Shinnakasu et al., 2016). To this end, we transferred B cells of three genotypes (Bach2f/fPrdm1f/fERT2cre B1-8hi, Bach2+/+Prdm1f/fERT2cre B1-8hi, and Bach2+/+Prdm1+/+ERT2cre B1-8hi) into recipient mice, treated them with tamoxifen, and then immunized them with NP-CGG/alum (Fig. 3 A) where to buy zithromax online.

In contrast to the control wild-type and Blimp1 single-deficient B cells, Bach2/Blimp1 double-deficient GC B cells showed an enrichment in DZ cells (Fig. 3 B) where to buy zithromax online. Moreover, the relatively small proportion of LZ B cells still contained Fr.2 and Fr.3 cells, whereas the numbers of Fr.5 and Fr.7 cells were robustly decreased in Bach2/Blimp1 double-deficient B cells (Fig.

3 B). Since Blimp1 single knockout did where to buy zithromax online not significantly affect the numbers of pro-memory (Fr.5) and mature memory B cells (Fr.7. Fig.

3 B), we conclude that Bach2 plays an important where to buy zithromax online role in development of pro-memory cells and subsequent mature memory B cells. To determine how Bach2 participates in this process, we performed RNA profiling of Bach2/Blimp1 double-deficient LZ B cells, together with Blimp1-deficient LZ B cells as a control (Fig. S2 B) where to buy zithromax online.

In Bach2/Blimp1 double-deficient LZ B cells, GSEA revealed a significant enrichment of c-Myc target genes, E2F target genes, and mTORC1 signaling genes, in that order (Fig. 3 C) where to buy zithromax online. This was also demonstrated by flow cytometry analysis (expression levels of c-Myc, pRb, and pS6.

Fig. 3 D). Moreover, as expected, the mutant GC B cells were hyperproliferative, as assessed by 5-ethynyl-2′-deoxyuridine (EdU) pulse labeling (Fig.

3 E). These results, considering the previous demonstration that c-Myc–overexpressing and hyper-mTORC1 GC B cells manifest a bias toward the DZ (Ersching et al., 2017. Finkin et al., 2019), like Bach2/Blimp1 double-deficient GC B cells, allowed us to hypothesize that the defective pro-memory in the mutant GC cells 5could result from anomalies of the mTORC1 and/or c-Myc pathways.

Here, we focused our analysis on the mTORC1 pathway. To test this hypothesis, we first asked whether normalizing mTORC1 activity in Bach2/Blimp1 double-deficient GC cells could rescue development of pro-memory B cells and subsequent memory B cells. We transferred Bach2f/fPrdm1f/fERT2cre B1-8hi B cells into rapamycin-resistant (MtorF2108L/F2108L) hosts (Ersching et al., 2017), deleted Bach2 and Prdm1 with tamoxifen, and then immunized the mice with NP-CGG/alum (Fig.

4 A). After immunization, the mice were treated with rapamycin to decrease mTORC1 activity in a transferred B cell–intrinsic manner. As shown in Fig.

4 B, the dose of rapamycin used nearly normalized pS6 levels in the Bach2/Blimp1 double-deficient LZ B cells. The rapamycin treatment partially corrected the c-Myc overexpression and hyperproliferation observed in the Bach2/Blimp1 double-deficient B1-8hi B cells (Fig. 4 B), suggesting coexistence of mTORC1-dependent and -independent pathways to regulate c-Myc activities.

In contrast to control vehicle treatment of Bach2/Blimp1 double-deficient B1-8hi B cells, upon rapamycin treatment, those mutant cells generated threefold higher numbers of IgG1+ memory B cells. The numbers of IgG1+CD73+ memory B cells were similarly increased (Fig. 4 C, right).

Furthermore, the Fr.5:Fr.2 ratio was also increased upon rapamycin treatment (Fig. 4 D). However, the memory B cells number upon rapamycin treatment did not reach those from wild-type B1-8hi B cells upon control vehicle injection (Fig.

4 C). Hence, we conclude that hyper-mTORC1 activity in Bach2/Blimp1 double-deficient GC B cells is one of the mechanisms that cause defective development of memory B cells, although there must be other, currently unknown ones, as well. In regard to GC B cells, the numbers were not significantly changed upon rapamycin treatment of Bach2/Blimp1 double-deficient B1-8hi B cells.

Skewing of Bach2/Blimp1 double-deficient GC B cells toward the DZ was decreased upon rapamycin treatment, although a small enrichment was still observed (Fig. 4 C). To further examine whether, in a wild-type setting, restraining mTORC1 activity could indeed facilitate differentiation of GC B cells to memory cells, we performed adoptive transfer experiments.

For this, we conducted experiments in which two types of congenically marked B cells, rapamycin-sensitive (Mtor+/+) and rapamycin-resistant (MtorF2108L/F2108L) B1-8ge B cells, were cotransferred as a 1:1 mixture into rapamycin-resistant hosts (MtorF2108L/F2108L), which were immunized with NP-CGG/alum and then administered with rapamycin. As expected, rapamycin treatment led to a decrease in S6 phosphorylation in the transferred rapamycin-sensitive, but not rapamycin-resistant, B1-8ge GC B cells (Fig. 5 A).

Upon rapamycin treatment, the number of rapamycin-sensitive NP+ GC B cells was decreased while the number of NP+ memory B cells was increased compared with their rapamycin-resistant counterparts, assessed by conventional flow cytometry analysis (Fig. 5 B). To more directly demonstrate the transition from GC B cells to Fr.7 cells, we treated the immunized mice with EdU for 3 d (days 10–13) before analysis.

In this setting, incorporation of EdU marks GC cells that divided during the treatment period and the resultant quiescent memory B cells (Fig. 5 C). We previously confirmed that during this period, the majority of proliferating cells (>95%) are GC B cells and plasmablasts (Shinnakasu et al., 2016).

Upon rapamycin treatment, the frequency of EdU+IgG1+ Fr.7 cells compared with GC cells was higher among the rapamycin-sensitive B1-8ge cells than the rapamycin-resistant ones, demonstrating rapamycin-mediated facilitation of the transition from GC to Fr.7 cells (Fig. 5 D). Moreover, upon rapamycin treatment, the numbers of CD38−Bcl6hiCD69hi (Fr.2) and CD38intBcl6hi/intEfnb1+ (Fr.5) rapamycin-sensitive B1-8ge IgG1+ B cells were decreased and maintained, respectively.

Thus, the ratio of Fr.5 to Fr.2 was increased (Fig. 5 E). Together, we conclude that a relative enrichment in Fr.5 over Fr.2 cells is induced by rapamycin treatment, thereby facilitating the overall transition from GC B cells to memory B cells.

The memory B cells generated in the presence of rapamycin were able to induce similar recall antibody responses to those generated in the absence of rapamycin, as assessed by adoptive transfer experiments (Fig. 5 F). We next wished to examine why Fr.5, but not Fr.3 cells, can become pro-memory B cells.

Since there were almost no differences in mTORC1 activity between Fr.5 and Fr.3 cells (Fig. S5 A), it appears that an mTORC1lo state is necessary but not sufficient for development of pro-memory B cells (Fr.5). Thus, additional key properties must be required for development of these cells.

Since one of crucial features of mature memory B cells is longevity, one straightforward possibility is that Fr.5 cells begin to acquire more survival activity. Supporting this idea, CD38intBcl6hi/intEfnb1+ (Fr.5) cells were less apoptotic compared with CD38−Bcl6hiCD69lo (Fr.3) cells as assessed by active caspase-3 staining (Fig. 6 A).

Transcript data (Fig. 6 B) together with protein expression data (Fig. 6 C) demonstrated that Bcl2 expression was upregulated in Fr.5 cells compared with Fr.3 cells, and even more in pre-memory B cells (Fr.6).

Similarly, we found that the cell surface BCR expression level was increased stepwise from Fr.3 to Fr.6 cells (Fig. 6 D). We also observed a slight increase of IgG1 and Igα/β mRNA expression in Fr.5 over Fr.3 cells.

Thus, regulation of both mRNA and protein levels seems to be operative. To examine whether Bcl2 family protein–mediated survival activity could impact the development of Fr.5 cells, we employed GC B cells with haploinsufficiency of Bim (Bcl2l11. See Materials and methods), a counteracting factor against anti-apoptotic Bcl2-family members (O’Connor et al., 1998).

Bcl2l11+/+ ERT2cre B1-8ge B cells and Bcl2l11f/+ERT2cre B1-8ge B cells were cotransferred as a 1:1 mixture into wild-type recipient mice, which were then immunized with NP-CGG/alum and treated with tamoxifen on day 8 (Fig. 6 E). Bim mRNA expression was decreased to almost 50% of control levels after tamoxifen treatment in Bcl2l11f/+ GC B cells (Fig.

6 F). In this competitive setting, among the Fr.2/3/5/6 cells, the frequency was most significantly increased in Fr.5 and Fr.6 cells upon Bim haploinsufficiency (Fig. 6 G), although there was also a modest increase of Fr.3 cells.

Consequently, the frequency of Bcl2l11f/+ NP+IgG1+CD73+ memory B cells was also increased (Fig. S5 B). To examine the effects of surface BCR expression on survival, B1-8ge-flox/+ ERT2cre B cells were employed.

For these particular experiments, we mixed these B cells and control B1-8ge/+ ERT2cre B cells at a 7:3 ratio and adoptively cotransferred them into recipient mice, which were then immunized with NP-CGG/alum (Fig. 6 H). We injected tamoxifen on day 10 and examined surface BCR expression on day 12, demonstrating a significant decrease on Fr.5 cells derived from B1-8ge-flox/+ ERT2cre B cells (Fig.

6 I). To detect apoptotic cells in this experiment, we analyzed mixtures of Fr.5 and Fr.6 cells (CD38+Efnb1+) to acquire a sufficient number of cells for the assay. As demonstrated in Fig.

6 J, concomitant with decreased surface BCR expression, there was a higher frequency of apoptotic (aCasp3+) cells among pro/pre-memory cells derived from B1-8ge-flox/+ ERT2cre B cells. Similarly, frequency of apoptotic cells among total LZ GC cells was enhanced upon BCR downregulation (Fig. S5 C).

A control experiment using Prdm1f/+B1-8ge/+ ERT2cre B cells showed that a nonspecific effect on apoptosis induced simply by Cre-mediated double-strand breaks was negligible (Fig. S5 D). Together, stepwise increases of Bcl2 and surface BCR expression from pro-memory (Fr.5) cells to pre-memory (Fr.6) toward mature memory B cells are likely to contribute to their survival.

It is still unclear what signals and processes in LZ GC cells initiate their differentiation toward long-lived memory B cells. Here, by focusing on key features for development of GC-derived memory precursors, we show that an mTORC1lo state is necessary to develop pro-memory B cells. Since mTORC1lo LZ B cells receive weak T cell help and, as a result, have been thought to undergo apoptosis, this raises the question of how such pro-memory B cells are prevented from dying and able to differentiate into mature memory B cells.

Our experiments suggest that the memory precursor B cells express higher levels of Bcl2 and surface BCR, thereby acquiring a survival advantage. We have already shown that Bach2hi LZ GC B cells are predisposed to differentiate into memory B cells (Shinnakasu et al., 2016), indicating that memory cell commitment already begins in a subset of GC B cells. This memory-prone subset most likely corresponds to the Fr.5 (CD38intBcl6hi/intEfnb1+ pro-memory) cells.

Indeed, expression of Bach2 in Fr.5 is higher than in Fr.2 cells (Fig. 2 A and Fig. S3 B).

Fr.6 (pre-memory B) cells appear to be undergoing a further developmental step toward mature memory B cells, manifested by further downregulation of Bcl6 (Fig. 1 B). We found that mTORC1 has a marked effect on the ratio of memory-prone (Fr.5) to recycling-prone (Fr.2) GC B cell formation.

Rapamycin treatment increased the proportion of Fr.5 cells and, conversely, hyperactivation of mTORC1 in the Bach2/Blimp1 double-deficient setting led to a relative increase in Fr.2 cells. Several nonmutually exclusive possibilities can be envisaged to explain why lower mTORC1 activity contributes to development of memory-prone cells. Decay in mTORC1 activity as GC B cells proliferate in the DZ appears to be required for their timely return to the LZ (Ersching et al., 2017).

Given the importance of LZ residency for memory differentiation (Bannard et al., 2013), one possibility is that LZ residency imposed by mTORC1lo could allow development of pro-memory B cells. Second, apart from this spatial requirement mediated through modulation of mTORC1, inhibition of mTORC1, as is seen during the generation of natural killer cell memory (O’Sullivan et al., 2015), may stimulate autophagy, thereby enhancing pro-memory B cell survival. Finally, it is also well known that mTORC1 activity is suppressed in memory B cells (Boothby and Rickert, 2017).

Such metabolic changes as the cells progress toward mature memory B cells thus appear to be initiated already in pro-memory cells, and this might be a necessary first step for generating mature memory B cells. The partial restoration of memory B cells by rapamycin treatment in Bach2/Blimp1 double-deficient GC cells suggests that, in addition to hyper-mTORC1 activity, other anomalies occur in mutant GC B cells in regard to memory differentiation. One of them is likely the c-Myc overexpression, because of the following.

First, indeed, in rapamycin-treated Bach2/Blimp1 double-deficient GC cells, overexpression of c-Myc and hyperproliferation were still observed to a significant extent (Fig. 4 B). Second, c-Myc–overexpressing GC cells were reported to have a significant bias toward the DZ (Finkin et al., 2019).

Considering the importance of LZ residency for memory differentiation (Bannard et al., 2013), overexpression of c-Myc is assumed to be detrimental to memory differentiation. Hence, we would propose that restraining both mTORC1-mediated metabolism and c-Myc–mediated cell-cycle progression is required to develop pro-memory B cells and that Bach2 is one of the critical regulators for suppressing both pathways. Functionally, Bach2 is well known to act as a repressive guardian transcription factor (Igarashi et al., 2017).

In regard to relationship between signaling and Bach2 expression, the mTORC1 activity and Bach2 expression appear to be mutually exclusive, because the BCR-induced AKT-mTORC1 inhibits Bach2 expression (Kometani et al., 2013), and Bach2 represses transcription of mTORC1 signaling molecules. Such a negative feedback loop is characteristic of “bistable” signal transduction circuits, which can operate in two stable formats. This might take place between Fr.5 and Fr.2 cells.

It should be mentioned that, from mTORC1 signaling molecule side, Bach2 is one of the transcription factors, and probably additional factors participate in transcriptional regulation on mTORC1 signaling genes. In addition to the connection between BCR signal and Bach2, considering the T cell data showing that ICOS and integrin αE are upregulated in Bach2lo T cells (Grant et al., 2020. Sidwell et al., 2020), Bach2 might be involved in connecting the BCR signal to T cell help.

For instance, Bach2lo LZ GC cells with high-affinity BCRs might modulate T/B interactions through adhesion status and coreceptor expression and affect the strength of T cell help. This might further downregulate Bach2, because we previously showed that strong T cell help depresses Bach2 expression (Shinnakasu et al., 2016). After moving back into the LZ, apoptosis is generally thought to be the default pathway for LZ GC B cells.

However, high-affinity cells are spared and positively selected after they encounter sufficient cognate T cell help (Allen et al., 2007. Victora and Nussenzweig, 2012). These spared high-affinity cells correspond to Fr.2 cells, whereas the defaulting apoptotic LZ cells are likely to be Fr.3 cells.

Indeed, among LZ GC cells, Fr.3 cells were most apoptotic. Here, we show that a small population of pro-memory B cells exists in the LZ and, despite apparently receiving weak T cell help, they are relatively resistant to apoptosis. The inability of prior studies to detect such apoptosis-resistant LZ B cells is most likely due to the fact that the numbers of pro-memory cells are so limited (Mayer et al., 2017).

Previous data using B cell–specific Bcl2-tg mice (Smith et al., 1994) or Bim knockout mice (Fischer et al., 2007) showed that such mice develop an enlarged memory B cell compartment. Recently, more detailed analysis using the same Bcl2-tg mice (Stewart et al., 2018) provided mechanistic insights into the above phenomenon. First, in these mice, aberrant populations of seemingly quiescent cells arise that express markers of memory precursor cells.

Second, overexpression of Bcl2 is not sufficient for DZ GC B cells with damaged BCRs to reach the LZ. Hence, in a physiological setting, it is reasonable to speculate that, after returning to the LZ in a Bcl2-independent manner, if Bcl2 expression is upregulated in some of the LZ GC B cells, they are better able to be rescued from apoptosis in the late G1 phase and to begin to differentiate into memory B cells. Supporting this idea, we show here that among LZ GC cells, small numbers of pro-memory B cells (Fr.5), but not Fr.3 cells, begin to upregulate Bcl2, and that development of pro-memory B cells is facilitated by Bim haploinsufficiency.

Because Bach2 expression in Fr.5 cells is similar to Fr.3 cells (Fig. S3 B), Bach2 appears not to be involved in such differential survival activity between Fr.5 and Fr.3 cells. Rather, a Bach2-independent mechanism such as Bcl6 downregulation (discussed below) is likely to be operated, thereby allowing Fr.5 cells to survive enough to begin to differentiate into memory precursor cells.

In contrast to Fr.5 cells (pro-memory), Fr.6 cells (pre-memory) apparently possess more survival activity (Fig. 6 A), possibly explaining the generation kinetics between Fr.5 and Fr.6 cells. Fr.6 cells were more accumulated at later phases (days 14 and 20) during immune responses (Fig.

S1 B). Induced downregulation of surface BCR expression in pro/pre-memory B cells resulted in increased apoptosis in the pro-memory B cells. These results, together with the evidence that pro-memory B cells express higher surface BCR levels, lead us to propose that the BCR-mediated survival signal also plays a role in the development of pro-memory B cells.

Based on the previous report that BCR ablation leads to cell death, which can be delayed by constitutive Bcl2 expression (Lam et al., 1997), we considered the possibility that downregulation of the BCR might decrease Bcl2 expression in pro/pre-memory B cells. However, we could not detect such a connection (data not shown). In naive B cells, the constitutive PI3 kinase–Foxo1 pathway is known to replace the missing BCR-mediated survival signals (Srinivasan et al., 2009).

Therefore, a question arises of how pro-memory B cells, despite being mTORC1lo (reflecting lower Akt activity), generate such a survival signal. Given that there is no enlarged GC phenotype in PTEN or Foxo1 knockout mice (Dominguez-Sola et al., 2015. Inoue et al., 2017.

Sander et al., 2015. Suzuki et al., 2003), one straightforward explanation might be that the quality and/or quantity of BCR-mediated survival signals differ between naive B cells and GC-derived memory B cells. We provide evidence that downregulation of Bcl6 in pro-memory B cells could be one of the mechanisms for upregulation of Bcl2 and surface BCR.

However, since the extent of Bcl6 downregulation in pro-memory B cells is small, such a slight change might not account for the observed upregulation of Bcl2 and surface BCR. Hence, our data cannot completely exclude the possibility that, particularly at the pro-memory B cell stage, other mechanisms might operate to initiate upregulation of Bcl2 and BCR. In this case, it is likely that downregulation of Bcl6 acts as an amplification pathway for further upregulation of Bcl2 and surface BCR during differentiation toward mature memory B cells.

In regard to this differentiation pathway, our data using Bcl6 haploinsufficiency are highly complementary to previous in vitro data that ectopic expression of Bcl6 in B cell cultures blocks the GC B cells from differentiating into memory B cells (Kuo et al., 2007). Together, it is likely that stepwise decreases in Bcl6 expression (pro-memory >. Pre-memory >.

Mature memory B cells) play a key role in memory B cell development. This raises the question of how is Bcl6 downregulated. Three possibilities have already been reported.

(1) upon strong BCR engagement, Erk-mediated degradation of Bcl6 (Niu et al., 1998). (2) transcriptional downregulation of Bcl6, mediated by CD40-activated IRF4 (Saito et al., 2007). And (3) downregulation of Bcl6 by defective IL-21 signaling (Linterman et al., 2010).

Among these, in regard to differentiation from GC to memory B cells, the final possibility seems to best fit with our observation that pro-memory B cells possess lower-affinity BCRs, thereby receiving less T cell help. In addition, as a transcriptional circuit–type regulation, the transcription factor Hhex, critical for memory B cell differentiation, has been recently reported to participate in downregulation of Bcl6 (Laidlaw et al., 2020). In summary, this study provides important insights into the initial events for the fate decisions from GC to memory B cells.

The modulation of cellular metabolism and survival play fundamental roles. Given the importance of GC-derived memory B cells for protection against heterologous zithromax re (Leach et al., 2019. Purtha et al., 2011), our findings may contribute to the development of efficient vaccination strategies.

Single-cell suspensions of splenocytes were analyzed and sorted on a FACSCanto II (BD Biosciences) or a FACSAria II (BD Biosciences). Alexa647-active caspase-3, V500-B220, V450-Bcl6, BV786-CD138, BV510-CD38, V500-CD45.2, BV510-IgG1, PE-IgG1 antibodies, and BV786-streptavidin were purchased from BD Biosciences. APC-eFluor780-B220, FITC-CD45.1, PE-CD45.1, APC-eFluor780-CD45.1, FITC-CD45.2, APC-eFluor780-CD45.2, APC-CD69, APC-eFluor780-CD69, eFluor450-CD73, PE-CD86, PerCP-Cy5.5-GL7 antibodies, PerCP-Cy5.5-streptavidin, PE-streptavidin, and APC-eFluor780-streptavidin were purchased from eBioscience.

PE-B220, PE-Cy7-CD138, PE-Cy7-CD38, PacificBlue-CD45.1, PE-CD45.2, biotin-CD69, PerCP-Cy5.5-CD86, BV421-CXCR4, V450-Ki67 antibodies, and BV510-streptavidin were purchased from BioLegend. PE-pRb and PE-pS6 antibodies were purchased from Cell Signaling. C-Myc antibody was purchased from Abcam.

PE-Bcl2 antibody was purchased from Miltenyi Biotec. Biotin-Efnb1 antibody was purchased from R&D Systems. Alexa488-goat anti-rabbit IgG antibody was purchased from Thermo Fisher Scientific.

For intracellular staining, the cells were fixed and permeabilized using a Foxp3 staining kit (eBioscience) for Bcl6, Bcl2, and pRb, a BD Cytofix/Cytoperm solution (BD Biosciences) for pS6 and active caspase-3, or a True-Nuclear Transcription Factor Staining Buffer Set (BioLegend) for c-Myc. APC-conjugated NP was prepared as described previously (Shinnakasu et al., 2016). Incorporation of EdU was detected using a Click-iT Plus EdU Flow Cytometry Assay Kit (Thermo Fisher Scientific) according to the manufacturer’s instructions.

We thank M.C. Nussenzweig (The Rockefeller University, New York, NY) for B1-8hi mice, T. Okada (RIKEN Center for Integrative Medical Sciences, Kanagawa, Japan) for Bcl6-YFP mice, G.D.

Victora (The Rockefeller University) for MtorF2108L mice, and P.D. Burrows for critical reading of the manuscript. This work was supported by grants from JSPS KAKENHI (JP17K08882 to T.

Inoue. JP26221306 and JP19H01028 to T. Kurosaki), the SENSHIN Medical Research Foundation (to T.

Inoue), the Mochida Memorial Foundation for Medical and Pharmaceutical Research (to T. Inoue), and a research grant from Astellas Foundation for Research on Metabolic Disorders (to T. Inoue).

Kawai performed the experiments. T. Inoue and T.

Kurosaki designed the experiments. R. Shinnakasu, W.

Fukuyama provided essential reagents. E. Kawakami, N.

Sax, and K. Yamashita performed bioinformatics analyses. T.

Inoue and T. Kurosaki wrote the manuscript.GRIP1 is a broadly acting transcriptional coregulator whose role in MS/EAE or in MG at any state has never been investigated. To begin to identify the GRIP1-dependent transcriptome changes leading to neuroinflammation, we performed bulk RNAseq analysis on CD45+Cd11b+ myeloid cells isolated from spinal cords of WT and GRIP1-cKO mice.

Consistent with a lack of overt phenotype in our conditional GRIP1-deficient mice (Coppo et al., 2016. Rollins et al., 2017), at homeostasis, a CD45+Cd11b+ CNS myeloid cell population composed principally of MG displayed no significant transcriptomic differences between WT and GRIP1-cKO mice (Fig. 5 A, upper panel.

GRIP1 deletion efficiency is shown on the right as normalized read counts across “floxed” exon 11 of the Ncoa2 gene). In contrast, more heterogeneous activated CD45+Cd11b+ cells during EAE (Fig. S2 C and Fig.

2 C) presented distinct transcriptomic signatures in WT versus GRIP1-cKO mice. Indeed, genes upregulated in WT (Fig. 5 A, lower panel, and Fig.

5 B), such as chemokines and chemokine receptors (Ccl22, Ccr7), antigen presentation molecule (H2-q10), components of complement (C3, C1ra), and type I IFN (Trim12c, Oas3) pathways, are indicative of inflammation and EAE pathogenesis (Belikan et al., 2018. Salter and Stevens, 2017. Scheu et al., 2017).

Interestingly, a pool of genes downregulated in WT mice during EAE but persisting in GRIP1-cKO mice (e.g., Gpr34, P2ry12. Fig. 5 A, lower panel, and Fig.

5 B) are homeostatic genes referred to as the MG “sensome” (Hickman et al., 2013), which controls chemotaxis and tissue repair (Lou et al., 2016). To identify physiologically relevant pathways differentially active in myeloid cells from WT and GRIP1-cKO spinal cords during EAE, we performed quantitative set analysis of gene expression (QuSAGE. Yaari et al., 2013), a gene set enrichment analysis–like Bayesian method that provides better accounts for intergene correlations than classic gene set enrichment analysis.

QuSAGE determines pathway-wide expression (pathway activity) by combining probability density functions for individual gene expression using numerical convolution. Several pathways were expressed at higher levels in the WT CNS myeloid cells, including NODE-like receptor signaling pathways (Kyoto Encyclopedia of Genes and Genomes) and a nuclear receptor transcription pathway (REACTOME), including Nr4a2 (Nurr1) and Nr4a3 (Nor-1. Fig.

5 C). Remarkably, several key genes of the IFN axis (IFN signaling pathway [REACTOME]), including Irf4, Irf1, Ifng, Ifitm1, Gbp5, and Oas3, were also expressed at higher levels in the WT (Fig. 5 C), in accord with whole-brain and spinal cord quantitative PCR (qPCR) data (Fig.

3 A and Fig. S5 A) and with a demonstrated coactivator role for GRIP1 in type I IFN network in MФ (Flammer et al., 2010. Reily et al., 2006).

Collectively, these data demonstrate a failure to upregulate inflammatory and type I IFN pathways and persistence of homeostatic signature in GRIP1-cKO myeloid cells. However, it could potentially stem from the role of GRIP1 in MG, MФ, or both. To dissect the contribution of resident versus infiltrating myeloid cells to EAE pathogenesis, we performed single-cell RNAseq (scRNAseq) analysis of all myeloid CD45+CD11b+ cells from WT and GRIP1-cKO spinal cords at the peak of EAE (DPI20).

After filtering out low-quality barcodes (see Materials and methods), we analyzed 20,376 cells (6,427 WT and 11,949 cKO) expressing 11,093 genes. Automated cell type assignment with singleR yielded four major clusters—“monocytes,” “MФ,” “dendritic cells,” and “neutrophils” (Fig. 6 A and Table S1)—and a large number of minor clusters composed predominately of lymphoid cell impurities that were collected during the cell sorting and had the same location in uniform manifold approximation and projection (UMAP) coordinates (Fig.

6 A). Because of an unbalanced group size, we performed a bootstrapping analysis to determine the associations between genotype and singleR cell types. We counted cell types of 2,000 cells that were sampled with the replacement from each genotype with 500 repeats (Fig.

6 B and Fig. S4 A). This analysis indicated that singleR monocytes and neutrophils were more common in the cKO, whereas MФ were overrepresented in the WT.

There was a substantial overlap between singleR cell types, suggesting either the presence of cell subpopulations or different differentiation/activation states. To separate these states, we performed Louvain graph–based community clustering that yielded nine clusters (Fig. 6 C and Table S2).

Cluster 8 corresponded to singleR lymphoid cell–enriched group (Fig. 6 A. €œOthers,” “T cells”), whereas cluster 6 was highly enriched with canonical neutrophilic markers (Fig.

6, A, D, and E). Cluster 3 is enriched in proliferation markers (Fig. 6 E, Fig.

S4 B, and Table S4). Slingshot trajectory analyses anchored on cluster 3 (see Materials and methods) identified two main trajectories (3-5-9-7-1 and 3-5-9-2-4-6) bifurcating at cluster 9 (Fig. 6 C and Fig.

S4 C). The analysis of genes differentially expressed along trajectories suggested that the 3-5-9-7-1 trajectory likely corresponds to monocyte-to-MФ transitions. Conversely, clusters 2-4-6 exhibit an increasing gradient of expression of neutrophilic markers (Fig.

6 E. S100a8, S100a9), suggesting that clusters 4 and 2 contain a decreasing admixture of neutrophils from cluster 6. Cluster 3 expresses monocytic markers at high levels (Fig.

6 F. Ly6c2, F13a1, Stmn1) and activated MФ/MG markers at low levels (Fig. 6, F and G.

Cd74, Fth1, Fcgr2b, H2-Aa, Il1b) that reciprocally change along the trajectories. MФ-like clusters (1, 7, and 2) contain either different proportions of MФ/MG, different activation states, or an admixture of other cell types (e.g., oligodendrocyte precursors. Table S3).

Although expression distributions for activated MФ/MG markers are broadly comparable in these clusters (Fig. S4 D), differential expression analysis between WT and cKO stratified by Louvain clusters revealed that clusters 1, 7, 2, and 4 expressed markers of homeostatic MG at higher levels in the cells from cKO mice (Fig. 6 H, Fig.

S4 E, and Table S5. Sparc, Siglech, Olfml3, and Tmem119). Cluster 2 contained the largest percentage of cells expressing homeostatic MG markers.

Conversely, many markers of activated inflammatory MФ were upregulated in these clusters in the WT cells including Il1a, Il1r2, Il7r, Ifng, Ctla2s, and Nos2 (Fig. 6 I and Table S5)..

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€˜None of us will where to buy zithromax online be safe until everyone is safe. Global access to antibiotics treatments, tests and treatments for everyone who needs them, where to buy zithromax online anywhere, is the only way out’. This statement by Dr Tedros Adhanom Ghebreyesus, Director-General of the WHO and Ursula von der Leyen, President of the European Commission1 has become the rallying call for buy antibiotics vaccination. The success of a safe and efficacious buy antibiotics treatment depends just not only on production and availability but also crucially on uptake.In countries such as the where to buy zithromax online UK where buy antibiotics treatment prioritisation and rollout are proceeding quickly, attitudes to vaccination have rapidly become a priority.2 treatment hesitancy (‘behavioural delay in acceptance or refusal of treatments despite availability of treatment services’)3 is not a single entity.

Reasons vary and there is a continuum from complete where to buy zithromax online acceptance to refusal of all treatments, with treatment hesitancy lying between the two poles. Factors involved include confidence (trusting or not the treatment or provider), complacency (seeing the need or value of a treatment) and convenience (easy, convenient access to the treatment).3 4 Importantly, attitudes to vaccination can change and people who are initially hesitant can still come to see a treatment’s safety, efficacy and necessity.5Developing strategies to address hesitancy is key.6 The expedited development and relative novelty of the buy antibiotics treatments have led to public uncertainty.4 In addition, efforts to explain the mode of action of these treatments involve a degree of complexity (eg, immune response and genetic mechanisms), which is difficult to communicate quickly and simply. There are genuine knowledge voids (eg, long-term safety data), which in some cases have where to buy zithromax online been filled with misinformation.7 Recent studies have assessed potential acceptance rates specifically for the buy antibiotics treatment. A UK study of more than 5000 adults using a validated scale found 71.7% were willing to be vaccinated, 16.6% were very unsure and 11.7% were strongly hesitant, with where to buy zithromax online hesitancy relatively evenly spread across the population.8 Willingness to take a treatment was closely bound to recognition of the collective importance of this decision as well as beliefs about the likelihood of buy antibiotics , the efficacy, speed of development and side effects of the treatment.

This implies that public information emphasising social benefits may be especially effective, at least in a majority of a population, and information that encourages mistrust or undermines social cohesion will lower treatment uptake.We also need to consider more focused strategies about treatment hesitancy for particular groups, including those groups who are most at risk of hesitancy and severe course of illness. As mental health clinicians, we assessed the impact of mental health conditions on buy antibiotics treatment hesitancy and searched for current guidance in this area using a validated approach.9 We found that there is where to buy zithromax online currently no specific guidance in addressing treatment hesitancy in those with mental health difficulties,10 although it is recognised that this is a high-risk group who should be monitored. People with mental health issues, particularly with severe mental illness (SMI), are at particular risk both for with buy antibiotics where to buy zithromax online and for more severe complications and higher mortality.11 Historically, the uptake of similar treatments such as the influenza treatment in those with SMI can be as low as 25%,12 and so, similar to other low uptake groups, focused efforts are needed to increase this. Suggestions for change include offering specific discussions from mental health professionals and peer workers, treatment education and awareness focused for those with SMI, vaccination programmes within mental health services (with coexistent organisational change to facilitate this), alignment with other preventative health strategies (such as influenza vaccination, smoking cessation, metabolic monitoring), focused outreach and monitoring uptake.13Monitoring of vulnerable groups treatment uptake itself presents problems.

In the example of the UK, where to buy zithromax online monitoring of treatment coverage of most routine immunisation programmes relies on data extracted from primary care systems. To monitor where to buy zithromax online vulnerable groups, the data need to be specifically recorded. For example, Public Health England’s national immunisation equity audit in 2019 identified inequalities in uptake by a number of important variables (such as age, geography, ethnicity) but could not assess others including mental illness due to a lack of systematically collected data.14 Inequalities that were assessed by the audit were not only in overall coverage but also in timing of treatments and completion of treatment schedules. In addition, the extent of a particular inequality varies when where to buy zithromax online it intersects with one or more other factors.

In the case of mental illness, multiple long-term conditions across mental and physical health domains as well as where to buy zithromax online socio-economic factors means that both vulnerability and inequality are likely to be additive.11 However, treatment impact may be greater among the most vulnerable despite lower treatment uptake because the baseline absolute risk is so high.15 Therefore, in the context of a buy antibiotics treatment programme, even if treatment uptake falls short in some high-risk groups, even small increases in treatment uptake will still have significant health benefits.14Uptake of vaccination is crucial both for the individual and protection of others. It is in everyone’s interests to ensure that groups where a low uptake is predicted have extra care and input. At the moment there is little formal guidance on how to support those with mental health where to buy zithromax online issues to access clear and reliable information, and practical and easy access to vaccination for those who are willing. If we are to ensure that ‘everyone is safe’, we need a concerted and global effort16 to guide and focus strategies to support and inform those who are both potentially most hesitant and most vulnerable, including and prioritising those with mental health difficulties..

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N/A 2013-12-02 2019-12-02 N/A 2021-12-02 lixisenatide 193862 Adlyxine Sanofi-aventis Canada Inc. Soliqua 2017-05-25 2023-05-25 N/A 2025-05-25 lomitapide mesylate 160385 Juxtapid Aegerion Pharmaceuticals Canada Ltd. N/A 2014-02-04 2020-02-04 N/A 2022-02-04 lorlatinib 215733 Lorbrena Pfizer zithromax 250mg cost Canada ULC N/A 2019-02-22 2025-02-22 N/A 2027-02-22 lubiprostone 179333 Amitiza Sucampo Pharma Americas LLC N/A 2015-10-14 2021-10-14 N/A 2023-10-14 lumacaftor 181715 Orkambi Vertex Pharmaceuticals (Canada) Incorporated N/A 2016-01-26 2022-01-26 Yes 2024-07-26 luspatercept 236441 Reblozyl Celgene Inc. N/A 2020-09-25 2026-09-25 N/A 2028-09-25 lutetium177 Lu oxodotreotide 217184 Lutathera Advanced Accelerator Applications USA, Inc. N/A 2019-01-09 2025-01-09 N/A 2027-01-09 macitentan 161372 Opsumit Janssen Inc zithromax 250mg cost.

N/A 2013-11-06 2019-11-06 Yes 2022-05-06 mecasermin 235023 Increlex Ipsen Biopharmaceuticals Canada Inc. N/A 2020-12-17 2026-12-17 Yes 2029-06-17 mepolizumab 179850 Nucala GlaxoSmithKline Inc. N/A 2015-12-03 2021-12-03 Yes 2024-06-03 midostaurin 201101 Rydapt Novartis Pharmaceuticals zithromax 250mg cost Canada Inc. N/A 2017-07-21 2023-07-21 Yes 2026-01-21 mifepristone 160063 Mifegymiso Linepharma International Limited N/A 2015-07-29 2021-07-29 Yes 2024-01-29 migalastat hydrochloride 196956 Galafold Amicus Therapeutics UK LTD N/A 2017-09-05 2023-09-05 N/A 2025-09-05 modified vaccinia zithromax (ankara-bavarian nordic) 144762 Imvamune Bavarian Nordic A/S N/A 2013-11-21 2019-11-21 N/A 2021-11-21 naloxegol oxalate 167790 Movantik Knight Therapeutics Inc. N/A 2015-06-02 2021-06-02 N/A 2023-06-02 necitumumab 193689 Portrazza Eli Lilly Canada Inc.

N/A 2017-03-16 2023-03-16 N/A 2025-03-16 neisseria meningitidis serogroup A polysaccharide, neisseria meningitidis serogroup zithromax 250mg cost C polysaccharide, neisseria meningitidis serogroup W-135 polysaccharide, neisseria meningitidis serogroup Y polysaccharide, conjugated to tetanus toxoid carrier protein 154290 Nimenrix Pfizer Canada Inc. N/A 2013-03-05 2019-03-05 Yes 2021-09-05 neisseria meningitidis serogroup B recombinant lipoprotein 2086 (rLP2086) subfamily A and Neisseria meningitidis serogroup B recombinant lipoprotein 2086 (rLP2086) subfamily B 195550 Trumenba Pfizer Canada Inc. N/A 2017-10-05 2023-10-05 Yes 2026-04-05 neratinib maleate 218224 Nerlynx Knight Therapeutics Inc. N/A 2019-07-16 2025-07-16 N/A 2027-07-16 netupitant 196495 Akynzeo Elvium Life Sciences N/A 2017-09-28 2023-09-28 N/A 2025-09-28 nintedanib (supplied as nintedanib esilate) 176043 Ofev zithromax 250mg cost Boehringer Ingelheim (Canada) Ltd N/A 2015-06-25 2021-06-25 N/A 2023-06-25 niraparib 216792 Zejula GlaxoSmithKline Inc. N/A 2019-06-27 2025-06-27 N/A 2027-06-27 nivolumab 180828 Opdivo Bristol-Myers-Squibb Canada N/A 2015-09-25 2021-09-25 Yes 2024-03-25 nusinersen 200070 Spinraza Biogen Canada Inc.

N/A 2017-06-29 2023-06-29 Yes 2025-12-29 obeticholic acid 198418 Ocaliva Intercept Pharmaceuticals Inc. N/A 2017-05-24 2023-05-24 N/A 2025-05-24 obiltoxaximab zithromax 250mg cost 230825 Anthim Elusys Therapeutics, Inc. N/A 2020-07-30 2026-07-30 N/A 2028-07-30 obinutuzumab 168227 Gazyva Hoffmann-La Roche Limited N/A 2014-11-25 2020-11-25 N/A 2022-11-25 ocrelizumab 198094 Ocrevus Hoffmann-La Roche Limited N/A 2017-08-14 2023-08-14 N/A 2025-08-14 ocriplasmin 161356 Jetrea ThromboGenics N.V. N/A 2013-08-13 2019-08-13 N/A 2021-08-13 olaparib 182823 Lynparza AstraZeneca Canada zithromax 250mg cost Inc. N/A 2016-04-29 2022-04-29 N/A 2024-04-29 olaratumab 203478 Lartruvo Eli Lilly Canada Inc.

N/A 2017-11-23 2023-11-23 N/A 2025-11-23 ombitasvir, paritaprevir, dasabuvir sodium 174739 Holkira Pak Abbvie Corporation Technivie 2014-12-22 2020-12-22 N/A 2022-12-22 onasemnogene abeparvovec 239719 Zolgensma Novartis Pharmaceuticals Canada Inc. N/A 2020-12-15 2026-12-15 Yes 2029-06-15 osimertinib mesylate 188171 zithromax 250mg cost Tagrisso AstraZeneca Canada Inc. N/A 2016-07-05 2022-07-05 N/A 2024-07-05 ospemifene 222001 Osphena Duchesnay Inc. N/A 2021-07-16 2027-07-16 N/A 2029-07-16 ozanimod (supplied as ozanimod hydrochloride) 232761 Zeposia Celgene Inc. N/A 2020-10-02 2026-10-02 N/A 2028-10-02 ozenoxacin 192925 zithromax 250mg cost Ozanex Ferrer Internacional, S.A.

N/A 2017-05-01 2023-05-01 Yes 2025-11-01 palbociclib 182048 Ibrance Pfizer Canada Inc. N/A 2016-03-16 2022-03-16 Yes 2024-09-16 pasireotide diaspartate 145005 Signifor Novartis Pharmaceuticals Canada Inc. Signifor Lar 2013-09-23 2019-09-23 N/A 2021-09-23 patiromer sorbitex calcium 210368 Veltassa Vifor zithromax 250mg cost Fresenius Medical Care Renal Pharma Ltd. N/A 2018-10-03 2024-10-03 N/A 2026-10-03 patisiran (as patisiran sodium) 221896 Onpattro Alnylam Netherlands B.V. N/A 2019-06-07 2025-06-07 N/A 2027-06-07 peginterferon beta-1a 166974 Plegridy Biogen Idec Canada Inc.

N/A 2015-08-10 2021-08-10 N/A 2023-08-10 pembrolizumab 175884 Keytruda Merck zithromax 250mg cost Canada Inc. N/A 2015-05-19 2021-05-19 Yes 2023-11-19 peramivir 191280 Rapivab BioCryst Pharmaceuticals Inc. N/A 2017-01-05 2023-01-05 N/A 2025-01-05 perampanel 153747 Fycompa Eisai Limited N/A zithromax 250mg cost 2013-04-04 2019-04-04 Yes 2021-10-04 pitolisant hydrochloride 238175 Wakik Endo Ventures Ltd. N/A 2021-05-25 2027-05-25 N/A 2029-05-25 plecanatide 215288 Trulance Bausch Health, Canada Inc. N/A 2019-10-10 2025-10-10 N/A 2027-10-10 polatuzumab vedotin 232303 Polivy Hoffmann-La Roche Limited N/A 2020-07-09 2026-07-09 N/A 2028-07-09 polidocanol 177359 Varithena Provensis Ltd.

N/A 2015-08-04 2021-08-04 zithromax 250mg cost N/A 2023-08-04 pomalidomide 165891 Pomalyst Celgene Inc. N/A 2014-01-20 2020-01-20 Yes 2022-07-20 pralatrexate 207545 Folotyn Servier Canada Inc. N/A 2018-10-26 2024-10-26 N/A 2026-10-26 pralsetinib 243731 Gavreto Hoffmann-La Roche Limited N/A 2021-06-30 2027-06-30 N/A 2029-06-30 prasterone 198822 Intrarosa Endoceutics Inc. N/A 2019-11-01 2025-11-01 N/A 2027-11-01 ponatinib hydrochloride 165121 Iclusig zithromax 250mg cost Ariad Pharmaceuticals Inc. N/A 2015-04-02 2021-04-02 N/A 2023-04-02 ponesimod 239537 Ponvory Janssen Inc.

N/A 2021-04-28 2027-04-28 N/A 2029-04-28 propiverine hydrochloride 188323 Mictoryl / Mictoryl Pediatric Duchesnay Inc. N/A 2017-01-05 2023-01-05 zithromax 250mg cost Yes 2025-07-05 radium - 223 dichloride 161312 Xofigo Bayer Inc. N/A 2013-12-12 2019-12-12 N/A 2021-12-12 ramucirumab 176810 Cyramza Eli Lilly Canada Inc. N/A 2015-07-16 2021-07-16 N/A 2023-07-16 ravulizumab 217955 Ultomiris Alexion Pharma GmbH N/A 2019-08-28 2025-08-28 N/A 2027-08-28 recombinant haemagglutinin protein-strain A (H1N1) recombinant haemagglutinin protein-strain A (H3N2) recombinant haemagglutinin protein-strain B (Victoria) recombinant haemagglutinin protein-strain B (Yamagata) 235672 Supemtek Sanofi Pasteur Limited N/A 2021-01-14 2027-01-14 N/A 2029-01-14 recombinant human papillomazithromax types 31, 33, 45, 52 and 58 170006 Gardasil 9 Merck Canada Inc. N/A 2015-02-05 2021-02-05 Yes 2023-08-05 recombinant neisseria meningitidis group B NHBA fusion protein, recombinant neisseria meningitidis group B NadA protein, recombinant zithromax 250mg cost neisseria meningitidis group B FHBP fusion protein, outer membrane vesicle (neisseria meningitidis group B NZ98/254 strain) 147275 Bexsero GlaxoSmithKline Inc.

N/A 2013-12-06 2019-12-06 Yes 2022-06-06 recombinant porcine factor VIII (antihemophilic factor (recombinant), porcine sequence) 177290 Obizur Takeda Canada Inc. N/A 2015-10-14 2021-10-14 N/A 2023-10-14 zithromax 250mg cost regorafenib monohydrate 157970 Stivarga Bayer Inc. N/A 2013-03-11 2019-03-11 Yes 2021-09-11 remdesivir 240551 Veklury Gilead Sciences Canada, Inc. N/A 2020-07-27 2026-07-27 N/A 2028-07-27 reslizumab 185873 Cinqair Teva Canada Limited N/A 2016-07-20 2022-07-20 Yes 2025-01-20 ribociclib (supplied as ribociclib succinate) 203884 Kisqali Novartis Pharmaceuticals Canada Inc. N/A 2018-03-02 2024-03-02 N/A 2026-03-02 rifaximin 161256 Zaxine Salix zithromax 250mg cost Pharmaceuticals Inc.

N/A 2013-08-13 2019-08-13 N/A 2021-08-13 riociguat 162761 Adempas Bayer Inc. N/A 2013-09-19 2019-09-19 N/A 2021-09-19 ripretinib 234688 Qinlock Deciphera Pharmaceuticals, LLC N/A 2020-06-19 2026-06-19 N/A 2028-06-19 risankizumab 215753 Skyrizi AbbVie Corporation N/A 2019-04-17 2025-04-17 N/A 2027-04-17 risdiplam 242373 Evrysdi Hoffman-La Roche Limited N/A 2021-04-14 2027-04-14 Yes 2029-10-14 romidepsin 152293 Istodax Celgene Inc. N/A 2013-10-16 2019-10-16 N/A 2021-10-16 romosozumab 197713 Evenity Amgen zithromax 250mg cost Canada Inc. N/A 2019-06-17 2025-06-17 N/A 2027-06-17 rupatadine (supplied as rupatadine fumarate) 186488 Rupall Medexus Pharmaceuticals Inc. N/A 2016-07-20 2022-07-20 Yes 2025-01-20 sacubitril 182734 Entresto Novartis Pharmaceuticals Canada Inc.

N/A 2015-10-02 2021-10-02 Yes 2024-04-02 safinamide zithromax 250mg cost (as safinamide mesylate) 207115 Onstryv Valeo Pharma Inc. N/A 2019-01-10 2025-01-10 N/A 2027-01-10 sarilumab 191745 Kevzara Sanofi-aventis Canada Inc. N/A 2017-01-12 2023-01-12 N/A 2025-01-12 satralizumab 233642 Enspryng Hoffmann-La Roche Limited N/A 2020-06-01 2026-06-01 Yes 2028-12-01 sebelipase alfa 204085 Kanuma Alexion Pharma GmbH N/A 2017-12-15 2023-12-15 Yes 2026-06-15 secukinumab 170732 Cosentyx Novartis Pharmaceuticals Canada Inc. N/A 2015-02-27 2021-02-27 Yes 2023-08-27 selexipag 182114 Uptravi zithromax 250mg cost Janssen Inc. N/A 2016-01-20 2022-01-20 N/A 2024-01-20 selpercatinib 243748 Retevmo Loxo Oncology Inc.

N/A 2021-06-15 2027-06-15 Yes 2029-12-15 semaglutide 202059 Ozempic Novo zithromax 250mg cost Nordisk Canada Inc. Rybelsus 2018-01-04 2024-01-04 N/A 2026-01-04 siltuximab 174291 Sylvant EUSA Pharma (UK) Limited N/A 2014-12-03 2020-12-03 N/A 2022-12-03 simeprevir 164021 Galexos Janssen Inc. N/A 2013-11-18 2019-11-18 N/A 2021-11-18 siponimod 223225 Mayzent Novartis Pharmaceuticals Canada Inc. N/A 2020-02-20 2026-02-20 N/A zithromax 250mg cost 2028-02-20 sodium zirconium cyclosilicate 218799 Lokelma AstraZeneca Canada Inc. N/A 2019-07-25 2025-07-25 N/A 2027-07-25 sofosbuvir 165043 Sovaldi Gilead Sciences Canada Inc.

HarvoniEpclusaVosevi 2013-12-13 2019-12-13 N/A 2021-12-13 solriamfetol hydrochloride 237511 Sunosi Jazz Pharmaceuticals Ireland Ltd. N/A 2021-05-13 2027-05-13 N/A 2029-11-13 sonidegib phosphate 229407 Odomzo Sun Pharma Global FZE N/A 2020-06-12 2026-06-12 zithromax 250mg cost N/A 2028-06-12 sucroferric oxyhydroxide 201492 Velphoro Vifor Fresenius Medical Care Renal Pharma Ltd. N/A 2018-01-05 2024-01-05 N/A 2026-01-05 sugammadex sodium 180385 Bridion Merck Canada Inc. N/A 2016-02-05 2022-02-05 N/A 2024-02-05 suvorexant 196367 Belsomra Merck Canada Inc. N/A 2018-11-29 2024-11-29 N/A 2026-11-29 tafamidis meglumine 228368 Vyndaqel Pfizer Canada ULC Vyndamax 2020-01-20 2026-01-20 N/A 2028-01-20 tafluprost 165596 Saflutan Purdue Pharma N/A 2014-05-26 2020-05-26 N/A 2022-05-26 talazoparib (supplied as talazoparib zithromax 250mg cost tosylate) 220584 Talzenna Pfizer Canada ULC N/A 2019-09-06 2025-09-06 N/A 2027-09-06 taliglucerase alfa 140854 Elelyso Pfizer Canada Inc.

N/A 2014-05-29 2020-05-29 Yes 2022-11-29 tedizolid phosphate 173603 Sivextro Merck Canada Inc. N/A 2015-03-17 2021-03-17 N/A 2023-03-17 teduglutide 180223 Revestive Takeda Canada Inc. N/A 2015-09-04 2021-09-04 Yes 2024-03-04 telotristat ethyl (as telotristat etiprate) 208730 Xermelo Ipsen Biopharmaceuticals Canada Inc zithromax 250mg cost. N/A 2018-10-10 2024-10-10 N/A 2026-10-10 tenapanor hydrochloride 224850 Ibsrela Knight Therapeutics Inc. N/A 2020-04-15 2026-04-15 N/A 2028-04-15 tenofovir alafenamide hemifumarate 181399 Genvoya zithromax 250mg cost Gilead Sciences Canada Inc.

DescovyOdefseyVemlidySymtuzaBiktarvy 2015-11-27 2021-11-27 Yes 2024-05-27 tepotinib (supplied as tepotinib hydrochloride) 242300 Tepmetko EMD Serono, a Division of EMD Inc., Canada N/A 2021-05-27 2027-05-27 N/A 2029-05-27 teriflunomide 160646 Aubagio Genzyme Canada a division of Sanofi-aventis Canada Inc. N/A 2013-11-14 2019-11-14 Yes 2022-05-14 tesamorelin 131836 Egrifta Theratechnologies Inc. N/A 2014-04-29 2020-04-29 N/A 2022-04-29 tezacaftor 211292 Symdeko Vertex Pharmaceuticals (Canada) Incorporated N/A 2018-06-27 2024-06-27 Yes 2026-12-27 tildrakizumab 224036 Ilumya Sun Pharma Global FZE N/A 2021-05-19 2027-05-19 N/A 2029-05-19 tisagenlecleucel 213547 / 213698 Kymriah Novartis Pharmaceuticals Canada Inc. N/A 2018-09-05 2024-09-05 Yes 2027-03-05 tofacitinib 154642 Xeljanz Pfizer Canada Inc. N/A 2014-04-17 2020-04-17 Yes 2022-10-17 trastuzumab deruxtecan 242104 Enhertu AstraZeneca Canada Inc.

N/A 2021-04-15 2027-04-15 N/A 2029-04-15 trastuzumab emtansine 162414 Kadcyla Hoffmann-La Roche Limited N/A 2013-09-11 2019-09-11 N/A 2021-09-11 trifarotene 221945 Aklief Galderma Canada Inc. N/A 2019-11-25 2025-11-25 Yes 2028-05-25 tipiracil hydrochloride 205852 Lonsurf Taiho Pharma Canada Inc. N/A 2018-01-25 2024-01-25 N/A 2026-01-25 triheptanoin 242196 Dojolvi Uagenyx Pharmaceutical Inc. N/A 2021-02-15 2027-02-15 Yes 2029-08-15 tucatinib 235295 Tukysa Seagen Inc. N/A 2020-06-05 2026-06-05 N/A 2028-06-05 turoctocog alfa 170796 Zonovate Novo Nordisk Canada Inc.

N/A 2014-12-08 2020-12-08 Yes 2023-06-08 umeclidinium bromide 161585 Anoro Ellipta GlaxoSmithKline Inc. Incruse Ellipta 2013-12-23 2019-12-23 N/A 2021-12-23 upadacitinib 223734 Rinvoq AbbVie Corporation N/A 2019-12-23 2025-12-23 N/A 2027-12-23 varicella-zoster zithromax glycoprotein E (gE) 200244 Shingrix GlaxoSmithKline Inc. N/A 2017-10-13 2023-10-13 N/A 2025-10-13 vedolizumab 169414 Entyvio Takeda Canada Inc. N/A 2015-01-29 2021-01-29 Yes 2023-07-29 velpatasvir 190521 Epclusa Gilead Sciences Canada Inc. Vosevi 2016-07-11 2022-07-11 Yes 2025-01-11 venetoclax 190761 Venclexta AbbVie Corporation N/A 2016-09-30 2022-09-30 N/A 2024-09-30 vernakalant hydrochloride 190817 Brinavess Cipher Pharmaceuticals Inc.

N/A 2017-03-13 2023-03-13 N/A 2025-03-13 vilanterol trifenatate 157301 Breo Ellipta GlaxoSmithKline Inc. Anoro ElliptaTrelegy Ellipta 2013-07-03 2019-07-03 Yes 2022-01-03 vilazodone hydrochloride 176820 Viibryd Allergan Inc. N/A 2015-07-16 2021-07-16 Yes 2024-01-16 von willebrand factor (recombinant) (vonicog alfa) 213188 Vonvendi Takeda Canada Inc. N/A 2019-01-10 2025-01-10 N/A 2027-01-10 vorapaxar sulfate 179320 Zontivity Toprol Acquisition LLC N/A 2016-05-13 2022-05-13 N/A 2024-05-13 voretigene neparvovec 233097 Luxturna Novartis Pharmaceuticals Canada Inc. N/A 2020-10-13 2026-10-13 Yes 2029-04-13 vortioxetine hydrobromide 159019 Trintellix Lundbeck Canada Inc.

N/A 2014-10-22 2020-10-22 Yes 2023-04-22 voxilaprevir 202324 Vosevi Gilead Sciences Canada Inc. N/A 2017-08-16 2023-08-16 N/A 2025-08-16 zanubrutinib 242748 Brukinsa BeiGene Switzerland GmbH N/A 2021-03-01 2027-03-01 N/A 2029-03-01The fee as of April 1, 2021 is $9,756 Register of Certificates of Supplementary Protection and Applications Guidance Document. Certificate of Supplementary Protection Regulations - summary Notice. Publication of update to the Guidance Document. Certificate of Supplementary Protection Regulations CSP Application Form (effective January 6, 2021) CSP Application Form (effective April 1, 2020 to January 5, 2021) CSP Application Form (effective May 15, 2019 to March 31, 2020) CSP Application Form (effective September 22, 2018 to May 14, 2019) CSP Application Form (from September 21, 2017 to September 21, 2018) Advance Payment Details for Master Files for Human and Disinfectant Drugs, and Certificate of Supplementary Protection Applications How to Pay Fees to Health Products and Food Branch (HPFB) BackgroundRegister of Certificates of Supplementary Protection and Applications Certificates of Supplementary Protection and Applications - Human Use Certificate of Supplementary Protection (CSP) and/or Application Number Medicinal Ingredient(s) New Drug Submission (NDS) Number Patent Number Patent Expiry Dateyyyy-mm-dd Application Status CSP Term Beginsyyyy-mm-dd CSP Term Endsyyyy-mm-dd 900039 abemaciclib 215268 2747055 2029-12-15 Issued 2029-12-16 2031-12-15 900045 acalabrutinib 214504 2841886 2032-07-11 Issued 2032-07-12 2034-07-11 900056 alpelisib 226941 2734819 2029-09-08 Issued 2029-09-09 2031-09-08 900035 antihemophilic factor (recombinant, B-domain deleted, pegylated) (also known as damoctocog alfa pegol) 210935 2586379 2025-11-14 Issued 2025-11-15 2027-11-14 900027 apalutamide 211942 2875767 2033-06-04 Issued 2033-06-05 2033-07-04 900026 baricitinib 193687 2718271 2029-03-10 Issued 2029-03-11 2031-03-10 900012 benralizumab 204008 2685222 2028-05-14 Issued 2028-05-15 2030-05-14 900028 bictegravir sodium / emtricitabine / tenofovir alafenamide hemifumarate 203718 2416757 2021-07-20 Refused 900020 brigatinib 210369 2723961 2029-05-21 Issued 2029-05-22 2031-05-21 900015 brodalumab 195317 2663537 2027-10-01 Issued 2027-10-02 2029-10-01 900060 brolucizumab 226224 2727839 2029-06-25 Issued 2029-06-26 2031-06-25 900057 cabotegravir (cabotegravir sodium) 227315 2606282 2026-04-28 Issued 2026-04-29 2028-04-28 900063 cedazuridine / decitabine 234610 2702274 2028-10-16 Issued 2028-10-17 2030-10-16 900022 cenegermin 218145 2346257 2019-10-11 Refused 900083 ciclesonide 200882 2888428 2033-12-18 Pending 900011 coagulation factor IX (recombinant), pegylated 201114 2462930 2022-10-09 Refused 900052 coagulation factor IX (recombinant), pegylated 201114 2665480 2027-10-04 Refused 900019 crisaborole 206906 2597982 2026-02-16 Issued 2026-02-17 2028-02-16 900041 dacomitinib 214572 2565812 2025-04-25 Issued 2025-04-26 2027-04-25 900058 darolutamide 226146 2777896 2030-10-27 Issued 2030-10-28 2032-10-27 900017 darunavir ethanolate / cobicistat / emtricitabine / tenofovir alafenamide hemifumarate 199705 2678907 2028-02-22 Issued 2028-02-23 2030-02-22 900051 dolutegravir (dolutegravir sodium) / lamivudine 220275 3003988 2031-01-24 Issued 2031-01-25 2033-01-24 900021 dolutegravir (dolutegravir sodium) / rilpivirine (rilpivirine hydrochloride) 206402 2606282 2026-04-28 Refused 900034 doravirine 211293 2794377 2031-03-28 Issued 2031-03-29 2033-03-28 900004 dupilumab 201285 2737044 2029-10-27 Issued 2029-10-28 2031-10-27 900010 durvalumab 202953 2778714 2030-11-24 Issued 2030-11-25 2032-11-04 900024 emicizumab 212635 2817964 2031-11-17 Issued 2031-11-18 2033-08-03 900053 entrectinib 227517 2693901 2028-07-08 Issued 2028-07-09 2030-07-08 900074 eptinezumab 233288 2836649 2032-05-21 Issued 2032-05-22 2034-05-21 900070 erdafitinib 224529 2796204 2031-04-28 Issued 2031-04-29 2033-04-28 900025 erenumab 208607 2746858 2029-12-18 Issued 2029-12-19 2031-12-18 900018 ertugliflozin 204724 2733795 2029-08-17 Issued 2029-08-18 2031-08-17 900076 estetrol monohydrate / drospirenone 236197 2448278 2022-05-23 Pending 900033 fluticasone furoate, umeclidinium (as bromide), vilanterol (as trifenatate) 204880 2781487 2030-11-29 Issued 2030-11-30 2032-11-29 900044 galcanezumab 219521 2802102 2031-06-07 Issued 2031-06-08 2033-06-07 900055 gilteritinib fumarate 227918 2760061 2030-05-06 Issued 2030-05-07 2032-05-06 900062 glasdegib 225793 2690953 2028-06-16 Issued 2028-06-17 2030-06-16 900001 glecaprevir / pibrentasvir 202233 2807847 2031-10-12 Refused 900014 glycopyrronium (as bromide) / formoterol fumarate dihydrate 201306 2763936 2030-05-28 Refused 900003 guselkumab 200590 2635692 2026-12-28 Issued 2026-12-29 2028-12-28 900032 inotersen (inotersen sodium) 214274 2797792 2031-04-29 Issued 2031-04-30 2033-04-29 900023 insulin glargine / lixisenatide 207006 2740685 2029-10-09 Issued 2029-10-10 2031-10-09 900029 lanadelumab 213920 2786019 2031-01-06 Issued 2031-01-07 2033-01-06 900043 larotrectinib (larotrectinib sulfate) 219998 2741313 2029-10-21 Issued 2029-10-22 2031-10-21 900066 lefamulin (supplied as lefamulin acetate) 233292 2678795 2028-03-19 Issued 2028-03-20 2030-03-19 900069 lemborexant 231286 2811895 2031-09-20 Issued 2031-09-21 2033-09-20 900007 letermovir 204165 2524069 2024-04-17 Issued 2024-04-18 2026-04-17 900009 lifitegrast 199810 2609053 2026-05-17 Issued 2026-05-18 2028-05-17 900040 lorlatinib 215733 2863892 2033-02-20 Issued 2033-02-21 2034-02-23 900071 luspatercept 236441 2733911 2029-08-13 Issued 2029-08-14 2031-08-13 900002 neisseria meningitidis grp B recombinant lipoprotein 2086 subfamily A / neisseria meningitidis grp B recombinant lipoprotein 2086 subfamily B 195550 2463476 2022-10-11 Issued 2022-10-12 2024-10-11 900008 olaratumab 203478 2680945 2026-06-19 Issued 2026-06-20 2028-06-19 900072 ozanimod (ozanimod hydrochloride) 232761 2723904 2029-05-14 Issued 2029-05-15 2031-05-14 900073 ozanimod (ozanimod hydrochloride) 232761 2780772 2030-11-15 Withdrawn 900080 pertuzumab, trastuzumab 237402 2788253 2032-08-29 Pending 900067 polatuzumab vedotin 232303 2693255 2028-07-15 Issued 2028-07-16 2030-07-15 900079 ponesimod 239537 2968180 2035-12-10 Pending 900050 prasterone 198822 2696127 2028-08-08 Withdrawn 900068 remdesivir 240551 2804840 2031-07-22 Issued 2031-07-23 2033-07-22 900016 ribociclib (ribociclib succinate) 203884 2734802 2029-08-20 Issued 2029-08-21 2031-08-20 900065 ripretinib 234688 2875970 2032-06-07 Issued 2032-06-08 2034-06-07 900042 risankizumab 215753 2816950 2031-11-02 Issued 2031-11-03 2033-11-02 900078 risdiplam 242373 2948561 2035-05-11 Pending 900031 rivaroxaban 211611 2451258 2022-06-07 Pending 900046 romosozumab 197713 2607197 2026-04-28 Issued 2026-04-29 2028-04-28 900061 satralizumab 233642 2699834 2029-09-25 Issued 2029-09-26 2031-09-25 900005 semaglutide 202059 2601784 2026-03-20 Issued 2026-03-21 2028-03-20 900054 siponimod 223225 2747437 2029-12-16 Withdrawn 900059 siponimod 223225 2747992 2029-12-21 Issued 2029-12-22 2031-12-21 900038 suvorexant 160233 2670892 2027-11-30 Refused 900048 talazoparib (talazoparib tosylate) 220584 2732797 2029-07-27 Issued 2029-07-28 2031-07-27 900082 tepotinib hydrochloride 242300 2693600 2028-04-29 Pending 900036 tezacaftor / Ivacaftor 211292 2742821 2028-11-12 Issued 2028-11-13 2030-11-12 900030 tisagenlecleucel 213547 2820681 2031-12-09 Issued 2031-12-10 2033-12-09 900081 trastuzumab / deruxtecan 242104 2928794 2035-01-28 Pending 900064 tucatinib 235295 2632194 2026-11-15 Issued 2026-11-16 2028-11-15 900049 upadacitinib 223734 2781891 2030-12-01 Issued 2030-12-02 2032-12-01 900006 varicella-zoster zithromax glycoprotein E (gE) 200244 2600905 2026-03-01 Refused 900075 zanubrutinib 242748 2902686 2034-04-22 Issued 2034-04-23 2036-03-02 Certificates of Supplementary Protection and Applications - Veterinary Use Certificate of Supplementary Protection (CSP) and/orApplication Number Medicinal Ingredient(s) New Drug Submission (NDS) Number Patent Number Patent Expiry Dateyyyy-mm-dd Application Status CSP Term Beginsyyyy-mm-dd CSP Term Endsyyyy-mm-dd 900077 esafoxolaner / eprinomectin / praziquantel 234676 2848317 2032-09-12 Pending 900013 lotilaner 193712 2747354 2029-12-17 Issued 2029-12-18 2031-12-17 900047 sarolaner/moxidectin/pyrantel (as pyrantel pamoate) 210868 2882200 2033-09-04 Issued 2033-09-05 2034-09-27 900037 sarolaner / selamectin 190913 2828397 2032-02-23 Issued 2032-02-24 2033-11-07 BackgroundThe Register of Certificates of Supplementary Protection (CSP) and Applications is maintained pursuant to the Certificate of Supplementary Protection Regulations and the Patent Act.

The register includes information from CSPs and CSP applications. Under the subsection 115(1) of the Patent Act, the issuance of a CSP grants the certificate's holder and their legal representatives the same legal rights, privileges and liberties that are granted by the patent set out in the certificate, but only with respect to the making, constructing, using and selling of any drug that contains the medicinal ingredient, or combination of medicinal ingredients.The format of the register is an electronic table. The register lists, in alphabetical order, the medicinal ingredient(s) in the CSPs and CSP applications.Information regarding the patent set out in the CSP or CSP application is available at the Canadian Intellectual Property Office.For comments or questions, or to obtain a copy of a CSP or CSP application details, please contact the Office of Patented Medicines and Liaison by email at hc.opml-bmbl.sc@canada.ca or by telephone at 613-941-7281..

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Publication of update to the Guidance Document. Certificate of Supplementary Protection Regulations CSP Application Form (effective January 6, 2021) CSP Application Form (effective April 1, 2020 to January 5, 2021) CSP Application Form (effective May 15, 2019 to March 31, 2020) CSP Application Form (effective September 22, 2018 to May 14, 2019) CSP Application Form (from September 21, 2017 to September 21, 2018) Advance Payment Details for Master Files for Human and Disinfectant Drugs, and Certificate of Supplementary Protection Applications How to Pay Fees to Health Products and Food Branch (HPFB) BackgroundRegister of Certificates of Supplementary Protection and Applications Certificates of Supplementary Protection and Applications - Human Use Certificate of Supplementary Protection (CSP) and/or Application Number Medicinal Ingredient(s) New Drug Submission (NDS) Number Patent Number Patent Expiry Dateyyyy-mm-dd Application Status CSP Term Beginsyyyy-mm-dd CSP Term Endsyyyy-mm-dd 900039 abemaciclib 215268 2747055 2029-12-15 Issued 2029-12-16 2031-12-15 900045 acalabrutinib 214504 2841886 2032-07-11 Issued 2032-07-12 2034-07-11 900056 alpelisib 226941 2734819 2029-09-08 Issued 2029-09-09 2031-09-08 900035 antihemophilic factor (recombinant, B-domain deleted, pegylated) (also known as damoctocog alfa pegol) 210935 2586379 2025-11-14 Issued 2025-11-15 2027-11-14 900027 apalutamide 211942 2875767 2033-06-04 Issued 2033-06-05 2033-07-04 900026 baricitinib 193687 2718271 2029-03-10 Issued 2029-03-11 2031-03-10 900012 benralizumab 204008 2685222 2028-05-14 Issued 2028-05-15 2030-05-14 900028 bictegravir sodium / emtricitabine / tenofovir alafenamide hemifumarate 203718 2416757 2021-07-20 Refused 900020 brigatinib 210369 2723961 2029-05-21 Issued 2029-05-22 2031-05-21 900015 brodalumab 195317 2663537 2027-10-01 Issued 2027-10-02 2029-10-01 900060 brolucizumab 226224 2727839 2029-06-25 Issued 2029-06-26 2031-06-25 900057 cabotegravir (cabotegravir sodium) 227315 2606282 2026-04-28 Issued 2026-04-29 2028-04-28 900063 cedazuridine / decitabine 234610 2702274 2028-10-16 Issued 2028-10-17 2030-10-16 900022 cenegermin 218145 2346257 2019-10-11 Refused 900083 ciclesonide 200882 2888428 2033-12-18 Pending 900011 coagulation factor IX (recombinant), pegylated 201114 2462930 2022-10-09 Refused 900052 coagulation factor IX (recombinant), pegylated 201114 2665480 2027-10-04 Refused 900019 crisaborole 206906 2597982 2026-02-16 Issued 2026-02-17 2028-02-16 900041 dacomitinib 214572 2565812 2025-04-25 Issued 2025-04-26 2027-04-25 900058 darolutamide 226146 2777896 2030-10-27 Issued 2030-10-28 2032-10-27 900017 darunavir ethanolate / cobicistat / emtricitabine / tenofovir alafenamide hemifumarate 199705 2678907 2028-02-22 Issued 2028-02-23 2030-02-22 900051 dolutegravir (dolutegravir sodium) / lamivudine 220275 3003988 2031-01-24 Issued 2031-01-25 2033-01-24 900021 dolutegravir (dolutegravir sodium) / rilpivirine (rilpivirine hydrochloride) 206402 2606282 2026-04-28 Refused 900034 doravirine 211293 2794377 2031-03-28 Issued 2031-03-29 2033-03-28 900004 dupilumab 201285 2737044 2029-10-27 Issued 2029-10-28 2031-10-27 900010 durvalumab 202953 2778714 2030-11-24 Issued 2030-11-25 2032-11-04 900024 emicizumab 212635 2817964 2031-11-17 Issued 2031-11-18 2033-08-03 900053 entrectinib 227517 2693901 2028-07-08 Issued 2028-07-09 2030-07-08 900074 eptinezumab 233288 2836649 2032-05-21 Issued 2032-05-22 2034-05-21 900070 erdafitinib 224529 2796204 2031-04-28 Issued 2031-04-29 2033-04-28 900025 erenumab 208607 2746858 2029-12-18 Issued 2029-12-19 2031-12-18 900018 ertugliflozin 204724 2733795 2029-08-17 Issued 2029-08-18 2031-08-17 900076 estetrol monohydrate / drospirenone 236197 2448278 2022-05-23 Pending 900033 fluticasone furoate, umeclidinium (as bromide), vilanterol (as trifenatate) 204880 2781487 2030-11-29 Issued 2030-11-30 2032-11-29 900044 galcanezumab 219521 2802102 2031-06-07 Issued 2031-06-08 2033-06-07 900055 gilteritinib fumarate 227918 2760061 2030-05-06 Issued 2030-05-07 2032-05-06 900062 glasdegib 225793 2690953 2028-06-16 Issued 2028-06-17 2030-06-16 900001 glecaprevir / pibrentasvir 202233 2807847 2031-10-12 Refused 900014 glycopyrronium (as bromide) / formoterol fumarate dihydrate 201306 2763936 2030-05-28 Refused 900003 guselkumab 200590 2635692 2026-12-28 Issued 2026-12-29 2028-12-28 900032 inotersen (inotersen sodium) 214274 2797792 2031-04-29 Issued 2031-04-30 2033-04-29 900023 insulin glargine / lixisenatide 207006 2740685 2029-10-09 Issued 2029-10-10 2031-10-09 900029 lanadelumab 213920 2786019 2031-01-06 Issued 2031-01-07 2033-01-06 900043 larotrectinib (larotrectinib sulfate) 219998 2741313 2029-10-21 Issued 2029-10-22 2031-10-21 900066 lefamulin (supplied as lefamulin acetate) 233292 2678795 2028-03-19 Issued 2028-03-20 2030-03-19 900069 lemborexant 231286 2811895 2031-09-20 Issued 2031-09-21 2033-09-20 900007 letermovir 204165 2524069 2024-04-17 Issued 2024-04-18 2026-04-17 900009 lifitegrast 199810 2609053 2026-05-17 Issued 2026-05-18 2028-05-17 900040 lorlatinib 215733 2863892 2033-02-20 Issued 2033-02-21 2034-02-23 900071 luspatercept 236441 2733911 2029-08-13 Issued 2029-08-14 2031-08-13 900002 neisseria meningitidis grp B recombinant lipoprotein 2086 subfamily A / neisseria meningitidis grp B recombinant lipoprotein 2086 subfamily B 195550 2463476 2022-10-11 Issued 2022-10-12 2024-10-11 900008 olaratumab 203478 2680945 2026-06-19 Issued 2026-06-20 2028-06-19 900072 ozanimod (ozanimod hydrochloride) 232761 2723904 2029-05-14 Issued 2029-05-15 2031-05-14 900073 ozanimod (ozanimod hydrochloride) 232761 2780772 2030-11-15 Withdrawn 900080 pertuzumab, trastuzumab 237402 2788253 2032-08-29 Pending 900067 polatuzumab vedotin 232303 2693255 2028-07-15 Issued 2028-07-16 2030-07-15 900079 ponesimod 239537 2968180 2035-12-10 Pending 900050 prasterone 198822 2696127 2028-08-08 Withdrawn 900068 remdesivir 240551 2804840 2031-07-22 Issued 2031-07-23 2033-07-22 900016 ribociclib (ribociclib succinate) 203884 2734802 2029-08-20 Issued 2029-08-21 2031-08-20 900065 ripretinib 234688 2875970 2032-06-07 Issued 2032-06-08 2034-06-07 900042 risankizumab 215753 2816950 2031-11-02 Issued 2031-11-03 2033-11-02 900078 risdiplam 242373 2948561 2035-05-11 Pending 900031 rivaroxaban 211611 2451258 2022-06-07 Pending 900046 romosozumab 197713 2607197 2026-04-28 Issued 2026-04-29 2028-04-28 900061 satralizumab 233642 2699834 2029-09-25 Issued 2029-09-26 2031-09-25 900005 semaglutide 202059 2601784 2026-03-20 Issued 2026-03-21 2028-03-20 900054 siponimod 223225 2747437 2029-12-16 Withdrawn 900059 siponimod 223225 2747992 2029-12-21 Issued 2029-12-22 2031-12-21 900038 suvorexant 160233 2670892 2027-11-30 Refused 900048 talazoparib (talazoparib tosylate) 220584 2732797 2029-07-27 Issued 2029-07-28 2031-07-27 900082 tepotinib hydrochloride 242300 2693600 2028-04-29 Pending 900036 tezacaftor / Ivacaftor 211292 2742821 2028-11-12 Issued 2028-11-13 2030-11-12 900030 tisagenlecleucel 213547 2820681 2031-12-09 Issued 2031-12-10 2033-12-09 900081 trastuzumab / deruxtecan 242104 2928794 2035-01-28 Pending 900064 tucatinib 235295 2632194 2026-11-15 Issued 2026-11-16 2028-11-15 900049 upadacitinib 223734 2781891 2030-12-01 Issued 2030-12-02 2032-12-01 900006 varicella-zoster zithromax glycoprotein E (gE) 200244 2600905 2026-03-01 Refused 900075 zanubrutinib 242748 2902686 2034-04-22 Issued 2034-04-23 2036-03-02 Certificates of Supplementary Protection and Applications - Veterinary Use Certificate of Supplementary Protection (CSP) and/orApplication Number Medicinal Ingredient(s) New Drug Submission (NDS) Number Patent Number Patent Expiry Dateyyyy-mm-dd Application Status CSP Term Beginsyyyy-mm-dd CSP Term Endsyyyy-mm-dd 900077 esafoxolaner / eprinomectin / praziquantel 234676 2848317 2032-09-12 Pending 900013 lotilaner 193712 2747354 2029-12-17 Issued 2029-12-18 2031-12-17 900047 sarolaner/moxidectin/pyrantel (as pyrantel pamoate) 210868 2882200 2033-09-04 Issued 2033-09-05 2034-09-27 900037 sarolaner / selamectin 190913 2828397 2032-02-23 Issued 2032-02-24 2033-11-07 BackgroundThe Register of Certificates of Supplementary Protection (CSP) and Applications is maintained pursuant to the Certificate of Supplementary Protection Regulations and the Patent Act. The register includes information from CSPs and CSP applications. Under the subsection 115(1) of the Patent Act, the issuance of a CSP grants the certificate's holder and their legal representatives the same legal rights, privileges and liberties that are granted by the patent set out in the certificate, but only with respect to the making, constructing, using and selling of any drug that contains the medicinal ingredient, or combination of medicinal ingredients.The format of the register is an electronic table.

The register lists, in alphabetical order, the medicinal ingredient(s) in the CSPs and CSP applications.Information regarding the patent set out in the CSP or CSP application is available at the Canadian Intellectual Property Office.For comments or questions, or to obtain a copy of a CSP or CSP application details, please contact the Office of Patented Medicines and Liaison by email at hc.opml-bmbl.sc@canada.ca or by telephone at 613-941-7281..