Mind the Gap: Understanding Differences Between Sexual and Reproductive Health-Related Legal Frameworks on Paper and in Practice.

Introduction: UNFPA recently developed a composite indicator to assess sexual and reproductive health (SRH)-related laws as part of the Sustainable Development Goals monitoring framework (Indicator 5.6.2). However, there is still little understanding of how best to ensure a supportive SRH-related legal framework can improve SRH outcomes. This research draws on country case studies (Colombia, Malawi, Uruguay, Zambia) to provide more generalizable lessons on the processes by which these laws are translated into practice and their impact on lived realities. Methods: Peer-reviewed and gray literature on laws and policies related to maternity care, contraception, sexuality education, HIV and HPV was reviewed. Key informant interviews were carried out with 8-16 people in each country, including representatives of government, civil society and academia to understand factors affecting implementation of relevant laws and policies. Findings were thematically analyzed by country and contextualized within each country's score on Indicator 5.6.2 and relevant SRH outcome data. Findings: Across these countries, some common organizational steps help move from laws on paper to impacting people's lives including budget allocation, development of technical guidance, health worker training, population awareness creation and demand generation. It is also important to address sociocultural challenges such as entrenched inequalities, conservative cultural and religious beliefs and the potential existence of customary law. Challenges can be encountered across all these steps and can vary based on the area of SRH: implementation of laws to reduce maternal mortality is generally less controversial than laws around abortion, often making the latter harder to implement. Local specificities in structures, systems and cultures bring opportunities and challenges, highlighting the need for tailored actions. Discussion: A legal framework supportive to SRH is critical, particularly in the face of backlash against sexual and reproductive rights, but alone it is insufficient. Understanding that a generic pathway exists for moving laws into practice is a critical starting point for exploring the specificities of each national context as a way of identifying entry points for action. These findings can be used to inform advocacy and monitoring to help ensure that the potential benefits of supportive SRH-related laws can be realized in these four countries and around the world.

Mechanistic evidence for tracking the seasonality of photosynthesis with solar-induced fluorescence.

Northern hemisphere evergreen forests assimilate a significant fraction of global atmospheric CO2 but monitoring large-scale changes in gross primary production (GPP) in these systems is challenging. Recent advances in remote sensing allow the detection of solar-induced chlorophyll fluorescence (SIF) emission from vegetation, which has been empirically linked to GPP at large spatial scales. This is particularly important in evergreen forests, where traditional remote-sensing techniques and terrestrial biosphere models fail to reproduce the seasonality of GPP. Here, we examined the mechanistic relationship between SIF retrieved from a canopy spectrometer system and GPP at a winter-dormant conifer forest, which has little seasonal variation in canopy structure, needle chlorophyll content, and absorbed light. Both SIF and GPP track each other in a consistent, dynamic fashion in response to environmental conditions. SIF and GPP are well correlated (R2 = 0.62-0.92) with an invariant slope over hourly to weekly timescales. Large seasonal variations in SIF yield capture changes in photoprotective pigments and photosystem II operating efficiency associated with winter acclimation, highlighting its unique ability to precisely track the seasonality of photosynthesis. Our results underscore the potential of new satellite-based SIF products (TROPOMI, OCO-2) as proxies for the timing and magnitude of GPP in evergreen forests at an unprecedented spatiotemporal resolution.

Synthesis and structure-activity relationship of furoquinolinediones as inhibitors of Tyrosyl-DNA phosphodiesterase 2 (TDP2).

Tyrosyl-DNA phosphodiesterase 2 (TDP2) is a recently discovered enzyme specifically repairing topoisomerase II (TOP2)-mediated DNA damage. It has been shown that inhibition of TDP2 synergize with TOP2 inhibitors. Herein, we report the discovery of the furoquinolinedione chemotype as a suitable skeleton for the development of selective TDP2 inhibitors. Compound 1 was identified as a TDP2 inhibitor as a result of screening our in-house compound library for compounds selective for TDP2 vs. TDP1. Further SAR studies provide several selective TDP2 inhibitors at low-micromolar range. The most potent compound 74 shows inhibitory activity with IC50 of 1.9 and 2.1 µM against recombinant TDP2 and TDP2 in whole cell extracts (WCE), respectively.

Discovery of selective inhibitors of tyrosyl-DNA phosphodiesterase 2 by targeting the enzyme DNA-binding cleft.

Tyrosyl-DNA phosphodiesterase 2 (TDP2) processes protein/DNA adducts resulting from abortive DNA topoisomerase II (Top2) activity. TDP2 inhibition could provide synergism with the Top2 poison class of chemotherapeutics. By virtual screening of the NCI diversity small molecule database, we identified selective TDP2 inhibitors and experimentally verified their selective inhibitory activity. Three inhibitors exhibited low-micromolar IC50 values. Molecular dynamics simulations revealed a common binding mode for these inhibitors, involving association to the TDP2 DNA-binding cleft. MM-PBSA per-residue energy decomposition identified important interactions of the compounds with specific TDP2 residues. These interactions could provide new avenues for synthetic optimization of these scaffolds.

Investigation of the Structure-Activity Relationships of Aza-A-Ring Indenoisoquinoline Topoisomerase I Poisons.

Several indenoisoquinolines have shown promise as anticancer agents in clinical trials. Incorporation of a nitrogen atom into the indenoisoquinoline scaffold offers the possibility of favorably modulating ligand-binding site interactions, physicochemical properties, and biological activities. Four series of aza-A-ring indenoisoquinolines were synthesized in which the nitrogen atom was systematically rotated through positions 1, 2, 3, and 4. The resulting compounds were tested to establish the optimal nitrogen position for topoisomerase IB (Top1) enzyme poisoning activity and cytotoxicity to human cancer cells. The 4-aza compounds were the most likely to yield derivatives with high Top1 inhibitory activity. However, the relationship between structure and cytotoxicity was more complicated since the potency was influenced strongly by the side chains on the lactam nitrogen. The most cytotoxic azaindenoisoquinolines 45 and 46 had nitrogen in the 2- or 3-positions and a 3'-dimethylaminopropyl side chain, and they had MGM GI50 values that were slightly better than the corresponding indenoisoquinoline 64.