An analysis of the gender gap among African scien4sts

Sophie Dabo-Niang i , Maria J. Esteban ii , Cole9e Guillopé iii , Marie-Françoise Roy iv Introduc4on.

The demand for equal representa3on of women and men in academic posi3ons as well as in poli3cs, in corporate management posi3ons in firms and in local ins3tu3ons has become very strong nowadays. A wide range of interna3onal ins3tu3ons have taken ini3a3ves to promote inclusion of women to achieve gender equality, which also happens to be one of the United Na3ons' seventeen sustainable development goals 1 , thus turning the issue of gender equality into a topic of global debate. Some studies on the global gender gap in science can be found in [START_REF] Zahidi | The Global Gender Gap Report 2006[END_REF][START_REF]Global Gender Gap Report 2022[END_REF][START_REF]Harcèlement sexuel et sexisme au sein du monde scientifique[END_REF][START_REF]Gender, Power and Higher Education in a Globalised World, Palgrave Studies in Gender and Education[END_REF][START_REF] Wang | Gender gap in science, technology, engineering, and mathematics (STEM): Current knowledge, implications for practice, policy, and future directions[END_REF][START_REF]Addressing Obstacles for Women in Science Will Accelerate Humanity's Progress. Fondation L'Oréal[END_REF].

This paper provides a detailed analysis of the answers from Africa to the Global Survey of Scien3sts [START_REF] Ivie | Measuring and analyzing the gender gap in science through the global survey of scientists[END_REF]. The ques3ons we address are the following: are the answers from Africa and the answers from the World similar? In which cases is the situa3on in Africa different from the situa3on in the World? BePer or worse? These ques3ons are par3cularly relevant given the specific situa3on of the African con3nent in terms of science, which is quite dis3nct from the situa3on of science in the World. Indeed, there are very few scien3sts in Africa, fewer than 100 per 1 million inhabitants, whereas the World average in 2020 is over 1,000 per 1 million inhabitants [START_REF][END_REF], and the level of funding of scien3fic R&D in Africa is low, the share being 0.4 % of the GDP compared with a World average of 1.7% [3]. Given this specific situa3on, what are the characteris3cs of the gender gap among scien3sts? The percentage of women among scien3sts in Africa is about 31.8%, which is slightly higher than the propor3on of women worldwide [START_REF]SAGA Science, Technology and Innovation Gender Objectives List. Working Paper 2: The SAGA Toolkit[END_REF]. How do these women scien3sts in Africa experience their studies, their careers, the balance between professional and family life or specific problems such as sexual harassment, compared to women scien3sts worldwide?

In 2017, as part of the ac3vi3es organized within the "Gender Gap in Science" project (2017-2019) [START_REF]Gender Gap in Science[END_REF][START_REF]A Global Approach to the Gender Gap in Mathematical, Computing and Natural Sciences: How to Measure It, How to Reduce It?[END_REF], a global survey among scien3sts of all con3nents was launched to evaluate and understand the gender gap in science. A total of 30,037 persons responded globally, half of them women and half men.

The results of this survey were analysed in the book "A Global Approach to the Gender Gap in Mathema3cal, Compu3ng, and Natural Sciences: How to measure it, How to Reduce it?" [START_REF]A Global Approach to the Gender Gap in Mathematical, Computing and Natural Sciences: How to Measure It, How to Reduce It?[END_REF], where the analysis made was global and did not go into too much detail about specific topics or World regions. In this ar3cle we aim to further understand the results of the survey for the African con3nent, to analyse in detail the gender gap in Science among scien3sts working in Africa, but also to compare these results with the rest of the World, to see how economic and cultural differences may affect the gender gap among scien3sts. To do this, a specific sta3s3cal analysis of the data has been carried out. (See the Appendix and [START_REF] Rivera Martinez | Gender Gap in Science: Mathematics, Applied Mathematics, and Africa[END_REF].)

In that survey, the ques3ons were broadly organized around 9 themes: (1) Secondary degree;

(2) First university degree; (3) Master and Doctoral degree; (4) Employment; (5) Grants, publica3ons, and related topics; [START_REF]A Global Approach to the Gender Gap in Mathematical, Computing and Natural Sciences: How to Measure It, How to Reduce It?[END_REF] Interrup3ons in studies and career; (7) Marriage, partnership, and parenthood; (8) Discouragement and discrimina3on; and (9) Sexual harassment. It should be noted that this survey addresses several aspects that are ojen not measured in bibliographic metadata, such as work-life balance, family support, access to resources and sexual harassment.

It is also important to note that although the number of answers was high, both in Africa and worldwide, these figures are low compared to the overall popula3on of scien3sts. In addi3on, the ques3ons also ask what people feel about a specific topic. All this to say that the image given by this survey, and what we will state out below, is only an image that probably reflects aspects of reality, but that should be taken with a grain of salt.

Next, let us explain the methodology we used to collect the data. As there is no single network or resource available for contac3ng all students and professional scien3sts worldwide, we used a snowball sampling method to tap into as many personal networks as possible. We used the contact databases of the project's partner organiza3ons to reach students and professional scien3sts around the World and asked them to complete the survey and invite their contacts to complete it. Snowball sampling is a non-probability data collec3on method that does not provide a sta3s3cally representa3ve sample. As a result, our findings only indicate trends observed among those who responded to the survey, not the overall popula3on of scien3sts. However, the consistency of most of our findings across disciplines, geographical zones and level of development is reassuring. For more details about the methodology, see the Appendix and [START_REF] Rivera Martinez | Gender Gap in Science: Mathematics, Applied Mathematics, and Africa[END_REF].

The results of our sta3s3cal analysis of data concerning Africa and the World are presented in the website below 2 . This ar3cle presents some of the main results which can be consulted in this website, where more visual informa3on is gathered.

Collected data.

Considering the filtering process described above, the survey received a total of 1,265 answers in Africa where the gender was indicated, 774 from women (61%) and 491 from men. On average, the age of African women (43) who answered the survey was higher than that of the men (40). The answers came from the 28 African countries that took part in the survey. They are, in alphabe3cal order, Algeria, Benin, Botswana, Burundi, Burkina Faso, Cameroon, Democra3c Republic of the Congo, Egypt, Ethiopia, Ghana, Kenya, Madagascar, Malawi, Mali, Mauri3us, Morocco, Mozambique, Namibia, Nigeria, Rwanda, Senegal, Sudan, South Africa, Tanzania, Tunisia, Uganda, Zambia, Zimbabwe (Fig. 1).

Studies.

A large majority of the respondents had a university degree: 98% of women compared with 96% of men, a master's degree (82% of women, 74% of men) and a doctoral degree (58% of women, 56% of men).

The level of women's most recent degree was higher in Africa than at the global level, while it was lower for men (Fig. 2). When it comes to the subjects of their first university degree, men in Africa study more than women in Physics and Engineering, but less than women in Biology, Chemistry, Educa3on, and Environmental Science, and slightly less in Computer Science, while their propor3ons are comparable in Mathema3cs (Fig. 3). The same trends can be observed about the main subjects chosen for their master's degrees, for both women and men.

A large majority of those who obtained their secondary degree in an African country also obtained their first university degree in Africa, for both women and men, and among those who lej Africa to go to university, there were more women than men (Fig. 4).

But ajer undergraduate studies, when doctoral studies were due to begin, more Africans lej their countries for other con3nents: 28% of women compared with 32% of men, so the propor3ons have changed in this case. Of these, more men went to Western Europe 3 , Northern America 4 , and Eastern and Southeastern Asia 5 , in that order, while more women went to Western Europe, Northern Europe6 and Northern America (Fig. 5). Only in Northern Europe did they go in greater percentage than men. As a result, women lej Africa less than men when they want to go to university for graduate studies, or to work ajer their studies.

3 Austria, Belgium, Switzerland, Germany, France, Liechtenstein, Luxembourg, Monaco, Netherlands (the).

4

Canada, United States.

5

Brunei Darussalam, China, Indonesia, Japan, Cambodia, Korea (The Republic of), Laos, Myanmar, Mongolia, Malaysia, Philippines (The), Korea (The Democra7c People's Republic of), Singapore, Thailand, Timor-Leste, Taiwan, Viet Nam. In terms of the environment in which African scien3sts grow and work, we observe that in Africa, during their studies, women feel much less supported than men by their teachers and mentors, whereas away from Africa, both women and men are very much supported by teachers, professors, and mentors (Fig. 6). Another major difference is observed in spousal or partner support, which is favorable to women everywhere, but shows a much greater gap in Africa than worldwide between women and men (Fig. 7). Other interes3ng comparisons appear concerning the support felt by women or men from their community or friends and from other students (Fig. 8). Let us now look at what the survey tells us about the doctorate level in Africa. S3ll at this level, we find that among scien3sts who answered the survey, there are more men than women who obtained a doctoral degree in Physics, Mathema3cs and a liPle more in Computer Science, but fewer in other fields, including Biology, Chemistry, Social Sciences, etc. The percentages are more or less the same in other con3nents. We note an interes3ng fact: while in Africa the same percentages of men and women studied Mathema3cs at undergraduate and master's level, contrary to what happens worldwide, at doctoral level we find in Africa, as worldwide, a greater percentage of men than women (Fig. 9). Women and men are more sa3sfied in Africa than worldwide with their doctoral program, the rela3on with their supervisors, the quality of the program and the number of professional contacts, but less sa3sfied with respect to other students, par3cularly women. African women are less sa3sfied than men concerning their rela3onship with their PhD supervisor (Fig. 10,11). The posi3ve impressions of African scien3sts about their doctoral program described above seem to be at odds with the fact that they feel less sa3sfied with the level of funding, office and laboratory space, travel money, clerical support, compu3ng facili3es, access to scien3fic literature, access to data and technical support they have obtained, compared to what people in other con3nents think about these maPers. And in all these respects, African men tend to be even less sa3sfied than women (Fig. 1213141516). Regarding how scien3sts finance their doctoral studies, we find that in Africa the money for PhDs comes more from personal and family sources or loans than worldwide, whereas in other con3nents the opposite is true (Fig. 17,18). The above comparison between women and men in Africa shows that women receive more scholarships and funding from jobs other than teaching and research than men, and significantly more from their spouses or partners, but less from all other sources.

If we consider the interrup3ons that occurred during doctoral studies, both men and women had more of them in Africa than worldwide, especially women who had more than men everywhere. When we look at this subject in Africa alone, we see that men had many more interrup3ons than women due to military service, of course, and also due to unemployment, financial difficul3es, poli3cal turmoil and conflict, but far less than women due to family obliga3ons of all kinds, even if we note that in this respect, both women and men have more interrup3ons in Africa than worldwide (Fig. 19, 20).

Work.

Let us now look at the employment and working condi3ons of African scien3sts. In Africa, as worldwide, most of the people who answered the survey work in universi3es, but some also have jobs in government or in companies, and others are students. Not surprisingly, among those employed in Africa, and indeed worldwide, there are more men than women in Physics-related jobs (13% compared with 5% in Africa, and 23% compared with 13% worldwide), almost as many in Mathema3cs (18% compared with 17% in Africa, and 19% compared with 15% worldwide), fewer in other fields, including Biology, Chemistry, the Social Sciences, and less in Computer Science, a difference with other con3nents (see Fig. 21). From what we have said above, we already know that of those employed in Africa, most of them obtained their secondary diploma in Africa, but only a quarter obtained their doctorate there, for both women and men.

In terms of how scien3sts in Africa feel treated by their bosses and employers, both women and men feel bePer treated than in other con3nents, especially women (Fig. 22). When it comes to working condi3ons, African scien3sts are less sa3sfied than scien3sts worldwide, in terms of funding levels, travel money, access to data, office and laboratory space, equipment and so on. African women are only more sa3sfied than men when it comes to the support they receive as working parents and access to data and the scien3fic literature; in all other areas, they feel less happy than men (Fig. 23, 24). In Africa, scien3sts have more difficul3es than worldwide in finding a job or a posi3on, and women even more so than men. This is a general trend, not only in Africa, but in all regions of the World, namely the difficulty for women to find employment.

When it comes to salary, African women feel less sa3sfied than men, which is unfortunately a universal reality. When it comes to career progression in rela3on to those with whom they studied in the past, men in Africa are more sa3sfied than men in other con3nents and more sa3sfied than women in Africa.

Regarding the distribu3on of grants (research trips, etc.), scien3sts in Africa obtained more grants than those worldwide among those having answered the survey. This simply means that, for some reason, those who have answered in Africa are more those who have got grants. But in all cases, women received fewer grants than men, even if the difference is not significant.

In Africa, as worldwide, women give fewer lectures than men at conferences, but they aPend them more ojen. Women conduct less research abroad and, as worldwide, women in Africa are less likely than men to hold posi3ons of responsibility. One posi3ve point in Africa is that women are as likely as men to be in boards of directors and gran3ng agencies, but on the other hand they are more rarely members of editorial boards.

In Africa scien3sts who answered the survey are much more likely to be in the leadership of learned associa3ons than worldwide, and women even more so than men (Fig. 25). If we talk about publica3on paPerns and look at publica3ons in top journals, we can see that everywhere women submit more ar3cles when it comes to people who submit few ar3cles, but if we talk about who publish a lot, men submit more ar3cles than women, both in Africa and worldwide, without the differences being huge. Another important issue in certain scien3fic fields is the way in which the ranking of authors is decided in publica3ons. The order is determined by professional ranking more ojen for men than for women in Africa, but not worldwide (Fig. 26).

Fig. 26. Ranking criteria to determine who will be the first, middle, or last author: professional ranking.

Another subject that is important to study and analyse in rela3on to the gender gap is the number and dura3on of interrup3ons that occur during scien3sts' careers (22% versus 31% in Africa for men and women, and 16% versus 34% worldwide). As we saw above, African scien3sts seemed to have experienced more interrup3ons during their studies, in some cases for family reasons (women) and in other for poli3cal or social ones (men). But if we look at interrup3ons once the scien3sts have a job or posi3on, we find that women have fewer interrup3ons in Africa than worldwide, but the opposite is true for men (Fig. 27). In Africa, women and men take leaves more ojen (six 3mes more) than worldwide to take care of children, and they both take leaves much more ojen to look ajer other family members than children, par3cularly men. African men seem to interrupt their career rela3vely ojen to take care of their family members, much more than men in other con3nents (Fig. 28). It is interes3ng to note that career breaks seem to affect the careers of both women and men in Africa less than worldwide. And men's careers seem to be globally less affected overall than those of women worldwide (Fig. 29). This can certainly be explained by the fact that in Africa, obliga3ons to the extended family weigh heavily on the shoulders of those with a profession, both because of the rules of society and the lack of social security.

Balance work-family life.

How do the family life and the existence of partners, spouses and children affect African scien3sts? First, it should be noted that more African scien3sts who answered the ques3onnaire are married or living with a partner than in other con3nents, and it is a clear paPern that both women and men in Africa married or started living with a partner earlier than in other con3nents, ojen during their university studies or doctorate, especially for women (Fig. 30). The same applies to the age at which a woman has her first child. African women feel less supported than men when it comes to their careers, and less supported than in other con3nents. The reverse is true for men, who feel more supported than worldwide. Another interes3ng fact revealed by the survey is that the academic level (degree level) of spouses is generally lower in Africa than worldwide, for both women and men, and especially for women. In Africa, men are more ojen married to unemployed spouses (Fig. 31). As far as salaries are concerned, it is not surprising that everywhere they are lower for the spouses of male scien3sts than for the spouses of female scien3sts. Also, men everywhere are more likely be married to someone in their own field than women, and this phenomenon is more marked in Africa than worldwide.

As far as the guardianship of children is concerned, both women as well as men in Africa are much more ojen in this posi3on than in other con3nents (Fig. 32). Regarding maternity and paternity leave, we do not find a big difference for women in Africa compared to other con3nents, but we do find that men take fewer paternity leaves in Africa, which is consistent with other results of the survey that we have already discussed. At the same 3me, bringing up children seems to affect parents in Africa less than worldwide: they ask for flexible working hours less ojen than worldwide, for instance, both women and men, although women do so more ojen everywhere, of course; they also change their employment less ojen; they do not reduce working hours to the same extent. And it has not affected their produc3vity, or they have not felt that their parenthood has slowed down their careers as much as in other con3nents (Fig. 33). But if we look at the percentage of scien3sts who have become parents staying at home at some point, we see that more women have done so in Africa than worldwide, and that many more men have done so too (Fig. 34). Overall, scien3sts in Africa feel that having children has affected their careers less than in other con3nents, par3cularly men. One interes3ng point concerns the effect that taking care of family members (not children) has on their careers, and we find that in Africa this happens much more ojen than worldwide to everyone, men, and women alike, which has to be interpreted in sociological terms, of course.

As far as the support received from employers or bosses is concerned, men in Africa say that they have received liPle support compared to what happens worldwide, while women receive the same support everywhere, but not that much (Fig. 35). But if we look at who does the household chores, we see that unfortunately, in African households, it is women who seem to do most of the work, much more so than in other con3nents. Equal sharing is much less frequent in Africa than in the rest of the World. On the other hand, help of domes3c workers is more common in Africa than elsewhere (Fig. 36). When it comes to discouragement among scien3sts during their careers, women are always more discouraged than men, everywhere and on every subject. But overall, scien3sts in Africa feel more discouraged by the lack of funding, the work environment and family commitments, but less so by research, interac3on with colleagues and personal life.

Difficul4es.

In Africa, scien3sts find it more difficult to raise concerns about their career with their boss or supervisor than in other con3nents, and the percentage is the same for women and men.

As far as discussions with colleagues and co-workers are concerned, women in Africa discuss funding less ojen than men, but this is not the case worldwide. When it comes to personal life and family commitments, the same is true, but a greater difference between Africa and other con3nents is observed. On the other hand, the opposite seems to be true when it comes to salary. One posi3ve difference is that scien3sts in Africa feel less that they have not lived up to expecta3ons at certain periods of their careers. This is the case for both women and men; but, of course, the overall situa3on here remains worse for women than for men.

Women everywhere find it more difficult than men to deliver what they are supposed to do because of pregnancy and childcare, but the percentage is unfortunately much higher in Africa (44%) than worldwide (33%).

Interes3ngly, men and women in Africa experience the same propor3on of difficul3es in caring for family members. We also find fewer mental health problems in Africa (6% compared to 12% for women and men in Africa; 21% compared to 28% worldwide) and it is interes3ng to note that the percentage of divorce-related difficul3es are about 50/50 worldwide, but very low for women compared to men in Africa (Fig. 37). We now come to the ques3on of discrimina3on and find that although women everywhere feel much more discriminated against than men in their work (43% compared to 5%), the propor3on is lower in Africa than worldwide (8.7% compared to 10.1%). Women feel more discriminated against than men in Africa about age (18% compared to 10%) and much more about gender, religion, and marital status, but less about social status and race. Overall, men feel less discriminated against in Africa than worldwide, but women feel slightly more discriminated against (Fig. 38). The final ques3on in this survey concerned sexual harassment, another important subject when it comes to the gender gap. Here too, we found some interes3ng answers: in Africa as elsewhere, women experience and witness more sexual harassment situa3ons than men, but far less than in other con3nents (Fig. 39). With regard to sexual harassment in science, interes3ng data and analyses can be found in [START_REF]Sexual harassment and sexism in science, Fonda3on L'Oréal and IPSOS[END_REF].

Conclusion.

While African girls are discriminated against in primary educa3on7 African women scien3sts do not seem to be discriminated against in rela3on to men in cases where the opposite occurs overall in the World. This is the case when it comes to the encouragement received from spouses, partners, family, friends, and other students during their university studies.

During the doctorate, African women do not seem to be discriminated against in terms of general support as men3oned above, and here again in terms of support from their thesis supervisor during the doctorate. They do not seem to be discriminated against either in terms of access to data or scien3fic literature, office and laboratory space, equipment, money for travel and support as a working mother.

In terms of research ac3vi3es once employed, women in Africa do not seem to be discriminated against with respect to access to equipment and compu3ng facili3es nor in terms of support for working parents. The same applies to par3cipa3on in conferences abroad or membership of gran3ng body commiPees and learned associa3ons.

In all the cases men3oned above, we do not see any unfavorable gender gap for women among scien3sts in Africa, whereas we clearly see it worldwide. There are therefore important aspects of study and the working condi3ons that seem to be bePer balanced within the scien3fic community in Africa than elsewhere.

But there are of course many areas in which women are discriminated against compared to men in Africa. For instance, when they study, women receive much less support than men from their teachers and mentors, which is not the case worldwide. When it comes to their working condi3ons, women in Africa are more sa3sfied than men only in terms of the support they receive as working parents and access to data and scien3fic literature; in all other areas, women in Africa are less sa3sfied than men. Similarly, unlike worldwide, once they have their first child, women feel less supported than men in terms of their career and less supported than in other con3nents. Even though women find it harder than men to do what they are supposed to do because of pregnancy and childcare, the percentage is unfortunately much higher in Africa (44%) than worldwide (33%).

As far as discrimina3on based on who you are or what you do is concerned, women in Science in Africa feel very much discriminated against because of their gender and marital status, and to a large extent because of their religion, but not because of their social status. The percentages of women and men in science outside of Africa who say that they never experienced discrimina3on is significantly lower than in Africa.

Finally, where the gap between female and male scien3sts in Africa is most marked, and far greater than worldwide, is in the career breaks they experience in their studies or careers due to family problems, childcare, and housework. In these areas, African women fare less well than their non-African colleagues, but, surprisingly, they do not seem to complain about it, and do not seem to think that it affects their careers too nega3vely. In any case, these feelings seem to be much less acute than outside of Africa.

The results of this survey show that the gender gap among scien3sts is less harsh in Africa than in other parts of the World and that, in some cases, it is even non-existent in situa3ons where it is clearly observed outside of Africa. Having said that, we also observe that scien3sts in Africa, both women and men, enjoy more difficult study and work condi3ons than worldwide. For instance, as noted above, scien3sts in Africa are less sa3sfied than scien3sts worldwide, about funding levels, travel money, access to data, office and laboratory space and equipment. These results are consistent with the limited funds available for research in Africa.

Finally, it should be noted that by seeking to compare the gender gap in Africa and the World among scien3sts, we were able to draw some interes3ng conclusions about the African scien3fic community as a whole, compared with the World scien3fic community.

Appendix: Methods of data analysis.

Data.

We use aggregated data collected as part of the Gender Gap project. The data was accessed and extracted via a platform (Aircloak) based at the American Institute of Physics, which protects and anonymizes individual data. Aircloak ensures anonymity by applying some filters and distortion to the extracted information, which had the effect of limiting the access of the data.

The databases at our disposal are anonymized, aggregated and available in the form of frequency tables.

It is important to mention that all the data we are working with is categorical, which means that is has a structure of possible answers. Most questions have two possible answers like 'yes' or 'no', but we also have questions with three or more possible answers. For instance, for the question "Have you encountered sexual harassment at school or work?" The possible answer choices are "selected" or "not selected". Gender is identified as "female" or "male", and the Human Development Index (HDI) has four categories: "Very high", "high", "medium", and "low".

Considering the aggregated structure of our data, in a first statistical analysis we looked at the gender distribution for each question, then we applied comparison of proportions tests to assess whether the distributions of the question studied for the two populations of interest (men and women) were statistically equal. This gives an indication of the distribution of individuals and makes it possible to distinguish the existence of groups sharing similar characteristics in our data.

In addition to these analyses, we performed multivariate analysis using Logistic and Multinomial aggregated regression models [START_REF] Gareth | An introduction to statistical learning: with applications in R[END_REF] since most questions have two possible answers (e.g., 'yes', 'no'), and a small number of questions have three or more possible answers. The logistic (resp. multinomial) regression model uses a distribution function to model a binary dependent variable (resp. one with multiple nominal values) in relation to other exogenous variables. Using these models, in particular the odds-ratio, we can estimate a potential effect of the gender gap that we want to measure given a certain number of confounding variables. It is important to note that these multivariate models are adapted to take into account the aggregated structure of our data.

In all the results we presented in the article to illustrate the gender gap, the multivariate analysis confirmed that the difference we observe between women and men is not due to confounding variables such as age, sector of employment, geographical region, or the country's HDI (human development index).

Filtered Data.

Filtering was performed on the original individual data using a zero-mean Gaussian noise and low count filtering to avoid accessing individual and infrequent answers. The zero-mean noise filter adds a zero-mean Gaussian noise to the query output tables containing the number, sum, mean, standard deviation, and variance. The noise is proportional to the users most influential on the output, and it means that the extracted tables will contain a variation from one to six observations from the raw tables. Noise is proportional to query complexity, meaning that the more complex the query, the more noise is introduced in the output table. For example, a simple query requesting frequency tables for two variables has a base noise layer equal to 2.

It modifies values of outlying data, particularly those associated with minimum and maximum values.

Low count filtering eliminates values that do not appear frequently enough, or outlying observations. It removes a line when the individual contributing to a single output is too small. More precisely, when the output line contains several observations less than or equal to four, the line is automatically hidden.

In some cases, the data may pass the low-count filtering, but there is not enough information to provide the aggregate value requested, such as the average, variance, etc. In this case, the output table will indicate a null value for the lines concerned.

The reported table may contain some lines in italics, which means that the aggregate for that specific line is calculated with several observations less or equal to 15. This is also as a reminder that the results contain a high relative noise.

In addition, we observe that the more disaggregated the information we want to extract from a single table, the more that table will be penalized. In line with the recommendations of the Aircloak user guide, we construct a query by placing categorical variables with few possible answers first and adding categorical variables with greater number of possible answers at the end. So instead of having individual data with specific characteristics, we have a group of individuals who share those specific characteristics.

Fig. 1 .

 1 Fig. 1. Sample countries are shown in blue.

Fig. 2 .

 2 Fig. 2. Answers to the ques7on: "Do you have a university or equivalent degree?".

Fig 3 .

 3 Fig 3. Distribu7on of women and men in various scien7fic areas or in various parts of the World (above) and in Africa (below).

Fig. 4 .Fig. 5 .

 45 Fig. 4. Where did the students who graduated from secondary school in Africa obtained their first university degree?

Fig. 6 .

 6 Fig. 6. Percentage of women and men who feel encouraged in their studies by their teachers.

Fig. 7 .

 7 Fig. 7. Percentage of women and men who feel encouraged in their studies by their spouse or partner.

Fig 8 .

 8 Fig 8. Percentage of women/men who feel encouraged in their studies by other students.

Fig. 9 .

 9 Fig. 9. Percentage of women and men who pursue doctoral degrees in Physics, Mathema7cs, Computer Science, and other fields, including Biology, Chemistry, and the Social Sciences, worldwide and in Africa.

Fig. 10 .

 10 Fig. 10. Percentage of women and men who think that their doctoral program treated everyone fairly (leg); and that other students were respeciul of everyone (right).

Fig. 11 .

 11 Fig. 11. Percentage of women and men who think that they had support from their advisor or supervisor.

Fig 12 .

 12 Fig 12. Percentage of women and men who, during the doctoral studies, have enough access to equipment (leg) and clerical support (right) to conduct or present their research.

Fig 13 .

 13 Fig 13. Percentage of women and men who, during the doctoral studies, have enough funding (leg) and access to scien7fic literature (right) to conduct or present their research.

Fig. 14 .Fig. 15 .

 1415 Fig. 14. Percentage of women and men who, during their doctoral studies, have enough of compu7ng capability (leg) and access to data (right) to conduct or present their research.

Fig 17 .

 17 Fig 17. Primary sources of financial support during the doctoral studies: loans or debit (leg); parents or family (right).

Fig. 18 .

 18 Fig. 18. Primary sources of financial support during the doctoral studies: personal savings (leg); spouse or partner (right).

Fig. 19 .

 19 Fig. 19. Interrup7ons during the doctoral studies (leg); for poli7cal turmoil, conflict, or war (right).

Fig 20 .

 20 Fig 20. Interrup7ons during the doctoral studies for family obliga7ons or change in family situa7on (leg); for financial constraints (right).

Fig. 21 .

 21 Fig. 21. Percentage of women and men employed in various scien7fic fields worldwide and in Africa.

Fig 22 .

 22 Fig 22. Answers to the ques7on: "Does your employer treat everybody fairly?".

Fig. 23 .

 23 Fig. 23. Percentage of women and men acknowledging support as working parents (leg), and in terms of travel money (right).

Fig. 24 .

 24 Fig. 24. Percentage of women and men acknowledging support in terms of funding (leg), and of equipment (right).

Fig. 25 .

 25 Fig. 25. Percentage of women and men who lead learned associa7ons.

Fig. 27 .

 27 Fig. 27. Percentage of career breaks ager receiving the highest degree.

Fig. 28 .

 28 Fig. 28. Interrup7ons to care for family members.

Fig. 29 .

 29 Fig. 29. Answers to the ques7on: "Did interrup7ons break or slow down professional credibility or reputa7on?".

Fig. 30 .

 30 Fig. 30. Answers to: "Have you been married or in a similar long-term partnership?" (leg); "Since when are you in your current or most recent marriage or long-term partnership?"(right).

Fig. 31 .

 31 Fig. 31. Percentage of ages at which the first child was born.

Fig. 32 .

 32 Fig. 32. Answers to the ques7on: "Are you the guardian of at least one child?".

Fig. 33 .

 33 Fig. 33. Percentage of respondents who said that they spent less 7me at work because they are parents (leg)and that bringing up children has slowed down their careers (right).

Fig. 34 .

 34 Fig. 34. Percentage of women and men becoming a stay-at-home parent.

Fig. 35 .

 35 Fig. 35. Percentage for support from employers as working parents.

Fig 36 .

 36 Fig 36. Who is responsible for most of the housekeeping in your household?

Fig. 37 .

 37 Fig. 37. Percentage of women and men who were unable to do what was expected of them at work because of childcare or pregnancy (leg); because of mental health problems (right).

Fig 38 .

 38 Fig 38. Percentages of women and men who have felt discriminated against at work because of gender (leg), and never felt discriminated against at work (right).

Fig 39 .

 39 Fig 39. Percentages of women and men who responded to the ques7on of sexual harassment: "yes, it has happened to me" (leg); "no, I have not encountered it" (right).

h#ps://gender-gap-in-science.org/africavisualisa7on/

Denmark, Estonia, Finland, United Kingdom, Ireland, Lithuania, Latvia, Norway, Sweden.

h#p://uis.unesco.org/sites/default/files/documents/new-methodology-shows-258-million-childrenadolescents-and-youth-are-out-school.pdf

Acknowledgement. The authors wish to thank Marie Françoise Ouedraogo for many interesting discussions related to this work, and Cecilia Rivera Mar3nez for her sta3s3cal analysis of the data from the Aircloak plaworm.


Miao Feng

Jean-Philippe Rosa

Regis Bobe
email: regis.bobe@inserm.fr

Les pompes à calcium SERCA3 : à la découverte d'une nouvelle voie de signalisation calcique potentialisant l'activation plaquettaire SERCA3 calcium pump: discovery of a new calcium signalling pathway that triggers platelet activation

Keywords: SERCA, sécrétion plaquettaire, signalisation calcique SERCA, platelet secretion, calcium signalling

La signalisation calcique, correspondant à la variation de concentration cellulaire en ions calcium (Ca 2+ ), est l'un des plus importants mécanismes ubiquitaires de communication interet intracellulaire. Celle-ci est finement régulée conduisant à des messages précis dans le temps et dans l'espace subcellulaire. Les mécanismes impliqués et les messages créés représentent aujourd'hui un défi technique et scientifique pour être décodés et corrigés en cas de nécessité. L'activation plaquettaire via le collagène ou la thrombine conduit à la mobilisation du Ca 2+ depuis des réserves intracellulaires. Cette augmentation de Ca 2+ est nécessaire à la sécrétion des activateurs secondaires tels que le thromboxane ou l'ADP des granules denses. Notre équipe s'intéresse en particulier aux pompes à Ca 2+ appelées Sarco/Endoplasmic Reticulum Ca 2+ ATPase (SERCA) permettant la création de ces réserves intracellulaires de calcium. Nos travaux ont montré que, dans les plaquettes, les 2 isoformes (SERCA2b et SERCA3) sont impliquées dans des voies de signalisation distinctes, et ont mis en évidence une nouvelle voie engageant la mobilisation des réserves spécifiquement contrôlées par SERCA3 par le Nicotinic Acid Adenine Dinucleotide Phosphate (NAADP). Cette mobilisation de Ca 2+ permet l'activation plaquettaire en réponse à de faibles doses d'activateur en induisant une sécrétion rapide d'ADP qui vient renforcer la voie de signalisation classique nécessitant la mobilisation des réserves de Ca 2+ dépendantes de SERCA2b par l'inositol trisphosphate (IP3).

La concentration en Ca 2+ cytosolique ([Ca 2+ ] i ) joue un rôle central dans la signalisation cellulaire. De fait, il existe de nombreux mécanismes de régulation de la [Ca 2+ ] i qui mènent à la création, dans l'espace subcellulaire et le temps, de messages précis nécessaires aux fonctionnements cellulaires. Parmi les acteurs impliqués dans l'homéostasie calcique, nous distinguons les Ca 2+ ATPases du réticulum sarco-endoplasmique (SERCA). Ces protéines sont des pompes transmembranaires qui stockent le Ca 2+ dans les réserves intracellulaires réduisant ainsi directement la [Ca 2+ ] i , et permettant le maintien d'un gradient de concentration de Ca 2+ entre le cytosol (100 nmol/L) et le réticulum endoplasmique (RE) (1 mmol/L). L'autre rôle, fondamental, est la participation à la phase ascendante du signal calcique : cette phase est la composante complexe résultant de la mobilisation instantanée de Ca 2+ des réserves et de sa recapture plus ou moins rapide par les SERCAs, selon leurs caractéristiques intrinsèques (affinité, activité catalytique, seuil de déclenchement, qui diffèrent entre SERCA2b et SERCA3), mais aussi leur topographie qui semble différente dans l'espace subcellulaire. L'activité des SERCAs est donc au coeur du signal calcique.

Les SERCAs sont codées par 3 gènes, ATP2A1, ATP2A2 et ATP2A3, qui produisent plusieurs transcrits alternatifs et isoformes de protéines : SERCA1a/b, SERCA2a-c et SERCA3a-f. Ces protéines sont retrouvées dans plusieurs tissus. Les plaquettes sont depuis longtemps utilisées comme un modèle non musculaire pour étudier la régulation du Ca 2+ . Ces cellules anucléées expriment en particulier une quantité importante de SERCAs, y compris les isoformes SERCA2b et SERCA3 [START_REF] Bobe | How many Ca 2+ ATPase isoforms are expressed in a cell type? A growing family of membrane proteins illustrated by studies in platelets[END_REF]. De plus, la mobilisation du Ca 2+ depuis des réserves internes des plaquettes est décrite comme un événement précoce en amont de toutes les autres voies de signalisation. Cette mobilisation du Ca 2+ est très importante car elle permet l'activation des plaquettes, la sécrétion des granules denses et alpha, et l'engagement de l'intégrine IIb3 dans l'agrégation.

Depuis plusieurs années, nous nous intéressons au système multi-SERCA plaquettaire et nous nous interrogeons sur la possibilité de rôles distincts entre SERCA2b et SERCA3, notamment pour expliquer pourquoi coexistent 2 activités SERCAs, avec des caractéristiques différentes, et ce de façon relativement conservée dans l'évolution puisque retrouvées dans des espèces éloignées comme l'Homme et la souris.

Bien sûr des études biochimiques ont montré que si les SERCAs partagent des structures similaires, elles présentent des activités intrinsèques distinctes : l'affinité pour le Ca 2+ est plus élevée pour SERCA2b que pour SERCA3 (K D ~ 0,27 µmol/L contre 1 µmol/L), mais la capacité de transport du Ca 2+ est plus faible pour SERCA2b que pour SERCA3 (respectivement 7 nmol/min/mg de protéine contre 21 nmol/min/mg). Ces caractères semblent requis pour que les deux SERCAs maintiennent de concert le Ca 2+ à de faibles niveaux dans les cellules au repos [START_REF] Lytton | Functional comparisons between isoforms of the sarcoplasmic or endoplasmic reticulum family of calcium pumps[END_REF][START_REF] Poch | Functional characterization of alternatively spliced human SERCA3 transcripts[END_REF]. Mais ces données ne permettaient pas de répondre à toutes nos interrogations.

Dans les plaquettes, les études d'immuno-localisation par microscopie électronique ont suggéré des topologies distinctes pour les SERCAs : périphériques pour les SERCA3, et plus centrales pour les SERCA2b (4). Une colocalisation de SERCA3 avec STIM1 a aussi été décrite : STIM1 est une protéine sensible à la teneur en Ca 2+ des réserves intracellulaires, et, quand celle-ci diminue, STIM1 peut s'associer aux canaux SOCE (Store Operated Calcium Entry) de la membrane plasmique et activer leur ouverture. Ce mécanisme permettrait, en augmentant [Ca 2+ ] i dans l'environnement de ces réserves, de les réapprovisionner en Ca 2+ par les pompes SERCA3 [START_REF] Lopez | STIM1 regulates acidic Ca2+ store refilling by interaction with SERCA3 in human platelets[END_REF]. Par ailleurs, une différenciation fonctionnelle entre SERCA3 et SERCA2b a été proposée à la suite d'études pharmacologiques (basée sur l'inhibition préférentielle de SERCA3 par le 2,5-di(ter-butyl)-1,4-hydroquinone (tBHQ)) suggérant une association de SERCA3 avec les réserves acides de Ca 2+ [START_REF] Lopez | Two distinct Ca(2+) compartments show differential sensitivity to thrombin, ADP and vasopressin in human platelets[END_REF].

C'est l'utilisation du modèle murin knock-out pour SERCA3 (Serca3 -/-) qui a permis la mise en évidence de rôles distincts pour les deux types de pompes SERCA2b et SERCA3, dévoilant une signalisation plaquettaire plus complexe qu'initialement décrite. Les souris Serca3 -/-existent depuis 1997 [START_REF] Liu | Defective endotheliumdependent relaxation of vascular smooth muscle and endothelial cell Ca 2+ signaling in mice lacking sarco(endo)plasmic reticulum Ca 2+ ATPase isoform 3[END_REF], et aucune altération phénotypique majeure n'avait été décrite, à l'exception d'une réponse altérée du nerf gustatif. In vitro, une relaxation altérée des anneaux de l'aorte associée à une relaxation défectueuse des cellules musculaires lisses vasculaires a été objectivée, avec une signalisation Ca 2+ altérée, et une faible production de NO (7) [START_REF] Kao | Ablation of the SERCA3 gene alters epitheliumdependent relaxation in mouse tracheal smooth muscle[END_REF]. En comparant les plaquettes issues d'animaux sauvages et Serca3 -/-, nos travaux ont récemment montré que les pompes SERCA3 et SERCA2b contrôlaient des réserves de calcium distinctes, avec une mobilisation de celles-ci impliquant des voies de signalisation différentes en réponse en particulier à la thrombine que nous avons privilégiée dans nos études.

SERCA3 ET SERCA2b

CONTRÔLENT 1).

IMPORTANCE EN PHYSIO-PATHOLOGIE HUMAINE

Si une grande partie des travaux a été réalisée avec nos modèles murins, l'utilisation du tBHQ, pour inhiber préférentiellement SERCA3, et du Ned-19, pour inhiber le NAADP, nous a permis de confirmer l'existence d'une voie de signalisation similaire dans les plaquettes humaines, dont l'inhibition se traduit par une réduction de l'activation plaquettaire en réponse à de faibles stimulations. De plus, nous avons récemment observé, dans les plaquettes de patients souffrant d'obésité sévère, une diminution acquise de l'expression de SERCA3 associée à une diminution des capacités des plaquettes à être activées. Les plaquettes de patients ont été réanalysées après amaigrissement, un an après un by-pass gastrique, et la perte de poids a été associée à une normalisation de l'activation plaquettaire et une restauration du niveau d'expression de SERCA3 plaquettaire [START_REF] Elaib | Platelet Functions are Decreased in Obesity and Restored after Weight Loss: Evidence for a Role of the SERCA3-Dependent ADP Secretion Pathway[END_REF]. Nous avons alors proposé que l'obésité sévère est un état pathologique pro-thrombotique, et que la réduction de l'activité plaquettaire est une réponse adaptative qui permet d'atténuer le risque de thromboses. Cette observation suggère que le ciblage de la voie de signalisation NAADP/SERCA3 pourrait être un moyen de limiter l'activation plaquettaire spontanée, sans complètement inhiber l'activité plaquettaire hémostatique.

Il est donc important de connaître l'ensemble des protéines impliquées dans cette voie pour déterminer quelle pourrait être la meilleure cible thérapeutique.

LA VOIE NAADP/SERCA3

La voie de signalisation impliquant la mobilisation de réserves SERCA3 par le NAADP reste entièrement à découvrir. Plusieurs pistes sont actuellement explorées.

La source du NAADP

La rapide mobilisation des réserves SERCA3 suggère une génération rapide de NAADP ou l'existence de réserves de NAADP. Le rôle de CD38, une enzyme membranaire qui catalyse l'échange du groupe nicotinamide du NADP+ avec l'acide nicotinique pour synthétiser le NAADP, a été proposé dans les fonctions plaquettaires, mais l'implication de cette enzyme devra être confirmée car elle est plutôt décrite comme impliquée dans des processus plus longs de l'ordre de 30 secondes [START_REF] Cosker | The ecto-enzyme CD38 is a nicotinic acid adenine dinucleotide phosphate (NAADP) synthase that couples receptor activation to Ca2+ mobilization from lysosomes in pancreatic acinar cells[END_REF][START_REF] Mushtaq | Critical role for CD38-mediated Ca2+ signaling in thrombininduced procoagulant activity of mouse platelets and hemostasis[END_REF].

La cible du NAADP

La cible du NAADP a fait l'objet de nombreuses publications, et aujourd'hui il semble qu'un consensus se fasse autour de l'hypothèse selon laquelle les canaux TPC (Two Pore Channel) sont ouverts par le NAADP, même si aucune interaction directe entre ces deux molécules n'a pu être démontrée et que l'action d'une protéine intermédiaire est possible [START_REF] Capel | Two-pore Channels (TPC2s) and Nicotinic Acid Adenine Dinucleotide Phosphate (NAADP) at Lysosomal-Sarcoplasmic Reticular Junctions Contribute to Acute and Chronic beta-Adrenoceptor Signaling in the Heart[END_REF]

Figure 1 :

 1 Figure 1 : Schéma de l'activation plaquettaire. Les plaquettes au repos possèdent au moins deux réserves de Ca 2+ distinctes contrôlées respectivement par SERCA2b et SERCA3. La stimulation à une faible concentration de thrombine conduit à une synthèse ou une libération de NAADP, qui mobilise rapidement (de 0 à 5 secondes) du Ca 2+ à partir des réserves SERCA3, conduisant à la sécrétion primaire d'ADP. Cette sécrétion primaire d'ADP agit dans un deuxième temps (5 à 10 secondes) de façon autocrine (probablement via les récepteurs P2Y), et renforce très probablement par une synthèse accrue d'IP3 la mobilisation du Ca 2+ à partir des réserves SERCA2b menant à la sécrétion secondaire d'ADP qui devient prédominante à partir de 10 secondes.

Figure 1 :

 1 Figure 1: Diagram showing platelet activation.At rest, platelets display at least two different Ca 2+ stores controlled by SERCA2b and SERCA3 respectively. Stimulation with low concentration of thrombin leads to synthesis or liberation of NAADP which rapidly mobilises (0 -5 sec) Ca 2+ from SERCA3 stores resulting in primary ADP secretion. This primary ADP secretion acts then (5 to 10 seconds) in an autocrine way (probably via P2Y receptors) to trigger Ca 2+ mobilisation from SERCA2b store, most probably by an increased

DES RÉSERVES DE Ca 2+ PHYSIOLOGIQUEMENT DISTINCTES En

  , ou inversement par des expériences analysant les réponses plaquettaires induites par le NAADP exogène (NAADP-AM). De plus, nous avons montré que la mobilisation des réserves SERCA3 était insensible à l'inhibition de la La mesure de la cinétique de sécrétion a, par la suite, démontré que la mobilisation du Ca 2+ des réserves SERCA3 entraînait surtout une sécrétion en phase précoce, bien que celle-ci soit également impliquée tout au long de la sécrétion. En effet, en comparant les cinétiques de

	Il semble que ce défaut de sécrétion ne soit pas dû à un défaut global de l'augmentation
	cytosolique du Ca 2+ , car une concentration élevée de thrombine (0,1 mU/mL), rétablissant des
	niveaux normaux de mobilisation du Ca 2+ (mesurée sur l'ensemble du volume plaquettaire)
	phospholipase C (principale productrice d'inositol 1,4,5 trisphosphate (IP3)) (9). En revanche, dans les plaquettes Serca3 -/-, ne permet pas de rétablir une sécrétion comparable à celle
	les réserves contrôlées par SERCA2b (réserves SERCA2b) sont mobilisées par l'IP3, et cette observée dans les plaquettes de souris sauvages. Ces résultats suggèrent donc un rôle de la
	mobilisation semble être potentialisée par la voie NAADP/SERCA3. Nos systèmes mobilisation des réserves SERCA3 dans une sécrétion spécifique qui ne peut pas être
	d'enregistrement ne pouvant pas faire la distinction entre les cinétiques de mobilisation du compensée en l'absence de SERCA3 ou en présence d'un inhibiteur de cette mobilisation
	Ca 2+ dépendantes des voies SERCA3/NAADP et SERCA2b/IP3, il est possible que toutes les comme avec l'antagoniste du NAADP.
	deux sont initiées dans le même laps de temps. Par contre, nos résultats montrent que la voie Par ailleurs, il est notable qu'en présence d'une faible concentration de thrombine, l'ajout PLC/IP3 est amplifiée par la mobilisation du Ca 2+ des réserves SERCA3, et que cette d'ADP exogène permet de compenser en grande partie (mais pas totalement) le défaut de amplification est liée à la sécrétion précoce de l'ADP. En effet, la seule mobilisation du Ca 2+ à sécrétion observé en l'absence de SERCA3 ou en présence de Ned-19, antagoniste du
	NAADP. Ceci suggère fortement que la sécrétion précoce d'ADP par la voie
	NAADP/SERCA3 permet de potentialiser l'autre sécrétion (que nous appelons secondaire car
	nous la détectons après 10 secondes) en renforçant la mobilisation de Ca 2+ de la voie
	SERCA2b/IP3.
	sécrétion des plaquettes sauvages et Serca3 -/-après stimulation par la thrombine à faible
	concentration (0,04 mU/mL), nous avons observé que la sécrétion précoce (à 5 secondes) est
	abolie en l'absence de SERCA3. À partir de 10 secondes, une sécrétion secondaire est visible
	dans les plaquettes Serca3 -/-, mais elle reste moins importante que dans les plaquettes

utilisant deux sondes fluorescentes dédiées à la mesure de la [Ca 2+ ] i (le fura2 et le fura2-NM), nous avons pu confirmer que les activités des deux pompes concernent des réserves ayant des localisations subcellulaires distinctes. Alors que le fura2 évalue la [Ca 2+ ] i globale, le fura2-NM, qui reste accroché au feuillet interne de la membrane, mesure uniquement la concentration de calcium dans l'environnement sous membranaire. La comparaison des données obtenues avec ces deux sondes a montré que le fura2-NM ne détecte que le Ca 2+ libéré des réserves contrôlées par SERCA3 (réserves SERCA3), confirmant une localisation sous membranaire de ces réserves et une mobilisation calcique se produisant de préférence près de la membrane plasmique. La possibilité de visualiser la mobilisation de réserves SERCA3 a permis de montrer qu'elles sont spécifiquement mobilisées par le NAADP (Nicotinic acid adenine dinucleotide phosphate). Ceci a pu être démontré par des expériences analysant le signal calcique et la sécrétion en réponse à la thrombine en présence d'un antagoniste spécifique du NAADP (partir des réserves SERCA3, directement induite par le NAADP-AM ou par la thrombine en présence d'apyrase, ne déclenche ou n'amplifie pas une mobilisation secondaire du Ca 2+ . Ceci indique que dans les plaquettes nous n'observons pas un mécanisme du type CICR (Calcium Induced Calcium Release) où l'augmentation de [Ca 2+ ] i favoriserait d'elle-même l'ouverture des récepteurs de l'IP3. LA VOIE NAADP/SERCA3 PERMET UNE SÉCRÉTION D'ADP PRÉCOCE QUI AMPLIFIE L'ACTIVATION PLAQUETTAIRE Nous avons récemment montré que la mobilisation du Ca 2+ des réserves SERCA3 permettait une sécrétion spécifique d'ATP et d'ADP nécessaire à l'activation complète des plaquettes en réponse à de faibles concentrations d'agonistes (10). sauvages, et, après 3 minutes, elle reste défectueuse. Les mêmes résultats ont été obtenus avec l'inhibiteur pharmacologique de SERCA3 (tBHQ), mais pas de SERCA2b (thapsigargine). Cependant, la mobilisation directe du Ca 2+ par NAADP-AM ne permet pas, seule, d'induire de sécrétion primaire ni d'agrégation plaquettaire, ces deux phénomènes nécessitant un stimulus supplémentaire. Ce n'est que lorsque le NAADP-AM est associé au PMA ou à l'OAG-AM, tous deux activateurs de PKC, qu'une sécrétion d'ADP du même niveau que celle observée à 5 secondes de stimulation par la thrombine a été observée. Ce résultat suggère que le Ca 2+ mobilisé à partir des réserves SERCA3 et le diacyl-glycérol (DAG, provenant de la dégradation des phospholipides par les phospholipases) sont tous deux nécessaires pour induire la sécrétion primaire d'ADP (Figure

  ADP, agissant de façon autocrine, est une cible clé, et il existe déjà des inhibiteurs contre ses récepteurs spécifiques, à savoir P2Y1 et P2Y12. Dans le cas de P2Y12, son inhibition est déjà au coeur de traitements antithrombotiques, et l'inhibition de ce récepteur se traduit par une forte inhibition de l'agrégation plaquettaire soutient que son implication dans l'activation des plaquettes va bien au-delà d'un effet sur la voie NAADP/SERCA3.

	. La présence L'une de nos conclusions les plus importantes est que la sécrétion précoce d'ADP, détectable et l'implication des TPC devront être étudiées dans les plaquettes. La cible de l'ADP de la sécrétion primaire dans les secondes suivant la stimulation par un agoniste des plaquettes, est totalement dépendante de la voie SERCA3-NAADP, tandis qu'une voie de sécrétion secondaire d'ADP, dépendante de SERCA2b et IP3, apparaît entre 5 et 10 secondes. Le décalage entre ces deux sécrétions peut être dû à la localisation de deux voies de signalisation et/ou à la machinerie sécrétoire : par exemple, les réserves SERCA3 qui sont périphériques permettent la sécrétion de granules périphériques nécessitant une très faible réorganisation du cytosquelette et des membranes, tandis que les réserves SERCA2b, plus centrales, mobilisent des granules plus éloignés de la membrane dont l'exocytose prend plus de temps. La conséquence majeure est Une des questions concerne la sécrétion initiale d'ADP (et d'ATP) ; Dépend-elle de 2 populations distinctes de granules denses, chacune étant associée à un type de voie de signalisation des réserves de Ca 2+ du SERCA : dans ce cas, un sous-type de granules denses serait physiquement et/ou fonctionnellement associé aux réserves SERCA3, et serait le seul capable de libérer son contenu lors de la mobilisation du Ca 2+ des réserves SERCA3. Les granules restants libèreraient ensuite leur contenu lors de la mobilisation du Ca 2+ à partir des réserves SERCA2b. Alternativement, la population de granules denses serait homogène, mais les granules proches des réserves de SERCA3 (et près de la membrane plasmique) sécréteraient leur contenu lors de la mobilisation du Ca 2+ à partir de ces réserves. Il est aussi L'CONCLUSION possible que SERCA3 soit directement insérée dans la membrane d'un granule qui serait

que les deux voies initient la sécrétion de manière séquentielle. Cette organisation temporelle, avec une mobilisation du Ca 2+ dépendant du NAADP avant les autres voies de mobilisation, a déjà été observée dans un certain nombre d'autres types de cellules, mais ces études n'ont pas cherché à corréler cette signalisation calcique avec des mécanismes de sécrétion. Il est possible qu'une voie de mobilisation du Ca 2+ NAADP-SERCA3 régulant une sécrétion précoce soit un mécanisme plus général retrouvé dans d'autres systèmes cellulaires. sécrété suite à la mobilisation de son propre Ca 2+ . L'identification de ces différents mécanismes nécessitera des études plus approfondies.