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the task is to simplify the input abstract of a biomedical literature

***INPUT***
the input is the abstract of a biomedical literature

***OUTPUT***
the output is the simplified abstract for the input abstract of a biomedical literature
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Input: Functionally analogous enzymes are those that catalyze similar reactions on similar substrates but do not share common ancestry, providing a window on the different structural strategies nature has used to evolve required catalysts. Identification and use of this information to improve reaction classification and computational annotation of enzymes newly discovered in the genome projects would benefit from systematic determination of reaction similarities. Here, we quantified similarity in bond changes for overall reactions and catalytic mechanisms for 95 pairs of functionally analogous enzymes (non-homologous enzymes with identical first three numbers of their EC codes) from the MACiE database. Similarity of overall reactions was computed by comparing the sets of bond changes in the transformations from substrates to products. For similarity of mechanisms, sets of bond changes occurring in each mechanistic step were compared; these similarities were then used to guide global and local alignments of mechanistic steps. Using this metric, only 44% of pairs of functionally analogous enzymes in the dataset had significantly similar overall reactions. For these enzymes, convergence to the same mechanism occurred in 33% of cases, with most pairs having at least one identical mechanistic step. Using our metric, overall reaction similarity serves as an upper bound for mechanistic similarity in functional analogs. For example, the four carbon-oxygen lyases acting on phosphates (EC 4.2.3) show neither significant overall reaction similarity nor significant mechanistic similarity. By contrast, the three carboxylic-ester hydrolases (EC 3.1.1) catalyze overall reactions with identical bond changes and have converged to almost identical mechanisms. The large proportion of enzyme pairs that do not show significant overall reaction similarity (56%) suggests that at least for the functionally analogous enzymes studied here, more stringent criteria could be used to refine definitions of EC sub-subclasses for improved discrimination in their classification of enzyme reactions. The results also indicate that mechanistic convergence of reaction steps is widespread, suggesting that quantitative measurement of mechanistic similarity can inform approaches for functional annotation.
Output:  When species evolve, their genes duplicate and diverge to allow for adaptation of their functional repertoires to the changing environment. In this scenario, unrelated genes can convergently evolve to produce proteins with the same molecular function, termed “functionally analogous.” A quantitative determination of the reaction similarities among functionally analogous enzymes could provide insight about the different structural solutions nature has used to evolve similar catalysts. Bond changes between substrates and products, and between successive reaction intermediates, were used to compare the reactions catalyzed and the mechanisms of catalysis for 95 pairs of functionally analogous enzymes. Less than half of the reactions catalyzed by unrelated enzymes, but defined as similar by the Enzyme Commission (EC) classification, are similar in terms of bond changes, suggesting that this classification often fails to capture quantitative differences between many enzyme reactions. Furthermore, we addressed for the first time whether the chemical mechanisms by which similar overall reactions are achieved in functional analogs are also similar. We conclude that convergence of reaction is often accompanied by convergence of chemical mechanism. These results will be useful for classifying enzymes, guiding functional annotation of newly determined enzyme sequences and structures and for informing the engineering of enzymes with new functions.

Input:  Malaria transmission has declined substantially in the 21st century, but pregnant women in areas of sustained transmission still require protection to prevent the adverse pregnancy and birth outcomes associated with malaria in pregnancy (MiP). A recent call to action has been issued to address the continuing low coverage of intermittent preventive treatment of malaria in pregnancy (IPTp). This call has, however, been questioned by some, in part due to concerns about resistance to sulphadoxine-pyrimethamine (SP), the only drug currently recommended for IPTp.
Using an existing mathematical model of MiP, we combined estimates of the changing endemicity of malaria across Africa with maps of SP resistance mutations and current coverage of antenatal access and IPTp with SP (IPTp-SP) across Africa. Using estimates of the relationship between SP resistance mutations and the parasitological efficacy of SP during pregnancy, we estimated the varying impact of IPTp-SP across Africa and the incremental value of enhancing IPTp-SP uptake to match current antenatal care (ANC) coverage.
The risks of MiP and malaria-attributable low birthweight (mLBW) in unprotected pregnancies (i.e., those not using insecticide-treated nets [ITNs]) leading to live births fell by 37% (33%–41% 95% credible interval [crI]) and 31% (27%–34% 95% crI), respectively, from 2000 to 2015 across endemic areas in sub-Saharan Africa. However, these gains are fragile, and coverage is far from optimal. In 2015, 9.5 million (8.3 million–10.4 million 95% crI) of 30.6 million pregnancies in these areas would still have been infected with Plasmodium falciparum without intervention, leading to 750,000 (390,000–1.1 million 95% crI) mLBW deliveries. In all, 6.6 million (5.6 million–7.3 million 95% crI) of these 9.5 million (69.3%) pregnancies at risk of infection (and 53.4% [16.3 million/30.6 million] of all pregnancies) occurred in settings with near-perfect SP curative efficacy (>99%) based on the most recent estimates of resistance. Forty-four percent of these pregnancies (23% of all pregnancies) were not receiving any IPTp-SP despite making ≥3 ANC visits, representing 160,000 (94,000–236,000 95% crI) preventable low birthweight (LBW) deliveries. Only 4% (1.4 million) of pregnancies occurred in settings with >10% prevalence of the sextuple haplotype associated with compromised SP effectiveness. Forty-two percent of all pregnancies occurred in settings where the quintuple dhfr/dhps haplotype had become established but where in vivo efficacy data suggest SP maintains the majority of its effectiveness in clearing infections.
Not accounting for protection from the use of ITNs during pregnancy, expanding IPTp-SP to all women with ≥3 ANC visits in Africa could prevent an additional 215,000 (128,000–318,000 95% crI) LBW deliveries. In 26 countries with sufficient recent data to estimate ITN impact (population-based ITN usage data that can be stratified by gravidity), we estimate that, due primarily to low ITN use by primigravidae, only 16.5% of the potential LBW births prevented by scaling up IPTp-SP would in fact have already have been prevented through ITN use.
Our analysis also highlights the difficulties associated with estimating the relationship between the effectiveness of interventions against parasitological endpoints such as placental infection at delivery and health outcomes including birthweight, which is also determined by a wide range of unrelated factors. We also did not capture other aspects of malaria burden such as clinical malaria, maternal and neonatal anaemia, and miscarriage, all of which increase the overall importance of effective preventative strategies but have their own relationship with transmission intensity, parity, and SP resistance.
Despite recent declines in malaria transmission in Africa, the burden of MiP in the absence of adequate prevention remains substantial. Even accounting for SP resistance, extending IPTp-SP to all women attending ANC, as well as long-lasting insecticidal net distribution targeted towards first-time mothers, would have a sizeable impact upon maternal and infant health in almost all malaria-endemic settings in sub-Saharan Africa.


Output:

Universal access to intermittent preventive treatment of malaria in pregnancy with the drug sulphadoxine-pyrimethamine (IPTp-SP) has been a cornerstone of prevention of malaria in pregnancy, and a Global Call to Action has been launched by the Roll Back Malaria Partnership based upon its high safety, acceptability, effectiveness, and cost-effectiveness.
The development of resistance by the parasite in some regions—particularly a sequential chain of six mutations that may severely compromise the efficacy of the drug—and recent falls in malaria transmission have led some to question the wisdom of this call to action.
Using a mathematical model, we combined maps of the current risk of malaria in pregnancy with maps of the level of drug resistance across Africa to estimate the likely impact of scaling up IPTp-SP, taking into account the effects of resistance.
We found that in the large majority of pregnancies in areas of sustained malaria transmission in Africa, IPTp-SP is likely to retain substantial effectiveness against malaria in pregnancy, with areas affected by the sextuple mutation representing a small proportion of these pregnancies.
We found that, even accounting for recent declines in malaria transmission, the benefits of providing IPTp-SP in lots of areas of Africa remain substantial, but uptake of the intervention remains low despite large increases in antenatal clinic attendance in many countries.
In general, these findings support the suggestion that, if successful, the drive to increase IPTp-SP use will have a substantial and, given that the majority of women already access antenatal care, highly cost-effective impact upon maternal and neonatal health.
Although the sextuple mutation was confined to only a small proportion of areas in Africa as of 2010, there are large areas of Africa (one in five women of childbearing age at risk reside in such areas) where the quintuple mutation (the immediate precursor to having the sextuple mutation) has reached saturation, which highlights the need for careful monitoring of the spread of resistance and also highlights the benefits of research into alternative strategies if the sextuple mutation spreads.
