Proteomics of the heart.

Mass spectrometry-based proteomics is a sophisticated identification tool specializing in portraying protein dynamics at a molecular level. Proteomics provides biologists with a snapshot of context-dependent protein and proteoform expression, structural conformations, dynamic turnover, and protein-protein interactions. Cardiac proteomics can offer a broader and deeper understanding of the molecular mechanisms that underscore cardiovascular disease, and it is foundational to the development of future therapeutic interventions. This review encapsulates the evolution, current technologies, and future perspectives of proteomic-based mass spectrometry as it applies to the study of the heart. Key technological advancements have allowed researchers to study proteomes at a single-cell level and employ robot-assisted automation systems for enhanced sample preparation techniques, and the increase in fidelity of the mass spectrometers has allowed for the unambiguous identification of numerous dynamic posttranslational modifications. Animal models of cardiovascular disease, ranging from early animal experiments to current sophisticated models of heart failure with preserved ejection fraction, have provided the tools to study a challenging organ in the laboratory. Further technological development will pave the way for the implementation of proteomics even closer within the clinical setting, allowing not only scientists but also patients to benefit from an understanding of protein interplay as it relates to cardiac disease physiology.

Photonically active bowtie nanoassemblies with chirality continuum.

Chirality is a geometrical property described by continuous mathematical functions1-5. However, in chemical disciplines, chirality is often treated as a binary left or right characteristic of molecules rather than a continuity of chiral shapes. Although they are theoretically possible, a family of stable chemical structures with similar shapes and progressively tuneable chirality is yet unknown. Here we show that nanostructured microparticles with an anisotropic bowtie shape display chirality continuum and can be made with widely tuneable twist angle, pitch, width, thickness and length. The self-limited assembly of the bowties enables high synthetic reproducibility, size monodispersity and computational predictability of their geometries for different assembly conditions6. The bowtie nanoassemblies show several strong circular dichroism peaks originating from absorptive and scattering phenomena. Unlike classical chiral molecules, these particles show a continuum of chirality measures2 that correlate exponentially with the spectral positions of the circular dichroism peaks. Bowtie particles with variable polarization rotation were used to print photonically active metasurfaces with spectrally tuneable positive or negative polarization signatures for light detection and ranging (LIDAR) devices.

The AMBRA1 E3 ligase adaptor regulates the stability of cyclin D.

The initiation of cell division integrates a large number of intra- and extracellular inputs. D-type cyclins (hereafter, cyclin D) couple these inputs to the initiation of DNA replication1. Increased levels of cyclin D promote cell division by activating cyclin-dependent kinases 4 and 6 (hereafter, CDK4/6), which in turn phosphorylate and inactivate the retinoblastoma tumour suppressor. Accordingly, increased levels and activity of cyclin D-CDK4/6 complexes are strongly linked to unchecked cell proliferation and cancer2,3. However, the mechanisms that regulate levels of cyclin D are incompletely understood4,5. Here we show that autophagy and beclin 1 regulator 1 (AMBRA1) is the main regulator of the degradation of cyclin D. We identified AMBRA1 in a genome-wide screen to investigate the genetic basis of  the response to CDK4/6 inhibition. Loss of AMBRA1 results in high levels of cyclin D in cells and in mice, which promotes proliferation and decreases sensitivity to CDK4/6 inhibition. Mechanistically, AMBRA1 mediates ubiquitylation and proteasomal degradation of cyclin D as a substrate receptor for the cullin 4 E3 ligase complex. Loss of AMBRA1 enhances the growth of lung adenocarcinoma in a mouse model, and low levels of AMBRA1 correlate with worse survival in patients with lung adenocarcinoma. Thus, AMBRA1 regulates cellular levels of cyclin D, and contributes to cancer development and the response of cancer cells to CDK4/6 inhibitors.

Design Rules for Obtaining Narrow Luminescence from Semiconductors Made in Solution.

Solution-processed semiconductors are in demand for present and next-generation optoelectronic technologies ranging from displays to quantum light sources because of their scalability and ease of integration into devices with diverse form factors. One of the central requirements for semiconductors used in these applications is a narrow photoluminescence (PL) line width. Narrow emission line widths are needed to ensure both color and single-photon purity, raising the question of what design rules are needed to obtain narrow emission from semiconductors made in solution. In this review, we first examine the requirements for colloidal emitters for a variety of applications including light-emitting diodes, photodetectors, lasers, and quantum information science. Next, we will delve into the sources of spectral broadening, including "homogeneous" broadening from dynamical broadening mechanisms in single-particle spectra, heterogeneous broadening from static structural differences in ensemble spectra, and spectral diffusion. Then, we compare the current state of the art in terms of emission line width for a variety of colloidal materials including II-VI quantum dots (QDs) and nanoplatelets, III-V QDs, alloyed QDs, metal-halide perovskites including nanocrystals and 2D structures, doped nanocrystals, and, finally, as a point of comparison, organic molecules. We end with some conclusions and connections, including an outline of promising paths forward.

Mapping HIV prevalence in sub-Saharan Africa between 2000 and 2017.

HIV/AIDS is a leading cause of disease burden in sub-Saharan Africa. Existing evidence has demonstrated that there is substantial local variation in the prevalence of HIV; however, subnational variation has not been investigated at a high spatial resolution across the continent. Here we explore within-country variation at a 5 × 5-km resolution in sub-Saharan Africa by estimating the prevalence of HIV among adults (aged 15-49 years) and the corresponding number of people living with HIV from 2000 to 2017. Our analysis reveals substantial within-country variation in the prevalence of HIV throughout sub-Saharan Africa and local differences in both the direction and rate of change in HIV prevalence between 2000 and 2017, highlighting the degree to which important local differences are masked when examining trends at the country level. These fine-scale estimates of HIV prevalence across space and time provide an important tool for precisely targeting the interventions that are necessary to bringing HIV infections under control in sub-Saharan Africa.

Growth of Nanocrystal Superlattices from Liquid Crystals.

The growth of superlattices (SLs) made from self-assembled nanocrystals (NCs) is a powerful method for creating new materials and gaining insight into fundamental molecular dynamics. Previous explorations of NCSL syntheses have mostly compared them to crystallization. However, NCSL synthesis has not broadly shown cooling crystallization from saturated solutions as a reversible crystallization-dissolution process. We demonstrate the reversible growth of NCSLs by dispersing NCs in liquid crystal (LC) "smart solvents," and harnessing the transitions between the isotropic and nematic phases of the LCs. The growth mode and morphology can be tuned. This process is a model platform for studying crystallization and demonstrates great potential in manufacturing NCSLs as colloidal crystals through liquid-phase epitaxy or colloidal synthesis.

Dynamic Nanocrystal Superlattices with Thermally Triggerable Lubricating Ligands.

The size-dependent and collective physical properties of nanocrystals (NCs) and their self-assembled superlattices (SLs) enable the study of mesoscale phenomena and the design of metamaterials for a broad range of applications. However, the limited mobility of NC building blocks in dried NCSLs often hampers the potential for employing postdeposition methods to produce high-quality NCSLs. In this study, we present tailored promesogenic ligands that exhibit a lubricating property akin to thermotropic liquid crystals. The lubricating ability of ligands is thermally triggerable, allowing the dry solid NC aggregates deposited on the substrates with poor ordering to be transformed into NCSLs with high crystallinity and preferred orientations. The interplay between the dynamic behavior of NCSLs and the molecular structure of the ligands is elucidated through a comprehensive analysis of their lubricating efficacy using both experimental and simulation approaches. Coarse-grained molecular dynamic modeling suggests that a shielding layer from mesogens prevents the interdigitation of ligand tails, facilitating the sliding between outer shells and consequently enhancing the mobility of NC building blocks. The dynamic organization of NCSLs can also be triggered with high spatial resolution by laser illumination. The principles, kinetics, and utility of lubricating ligands could be generalized to unlock stimuli-responsive metamaterials from NCSLs and contribute to the fabrication of NCSLs.

Automated proteomic sample preparation: The key component for high throughput and quantitative mass spectrometry analysis.

Sample preparation for mass spectrometry-based proteomics has many tedious and time-consuming steps that can introduce analytical errors. In particular, the steps around the proteolytic digestion of protein samples are prone to inconsistency. One route for reliable sample processing is the development and optimization of a workflow utilizing an automated liquid handling workstation. Diligent assessment of the sample type, protocol design, reagents, and incubation conditions can significantly improve the speed and consistency of preparation. When combining robust liquid chromatography-mass spectrometry with either discovery or targeted methods, automated sample preparation facilitates increased throughput and reproducible quantitation of biomarker candidates. These improvements in analysis are also essential to process the large patient cohorts necessary to validate a candidate biomarker for potential clinical use. This article reviews the steps in the workflow, optimization strategies, and known applications in clinical, pharmaceutical, and research fields that demonstrate the broad utility for improved automation of sample preparation in the proteomic field.

Publisher Correction: Towards quantitative and multiplexed in vivo functional cancer genomics.

The originally published article failed to acknowledge the equal first authorship contribution of I. P. Winters and C. W. Murray. The article has now been corrected online. The editors apologize for this error.

Towards quantitative and multiplexed in vivo functional cancer genomics.

Large-scale sequencing of human tumours has uncovered a vast array of genomic alterations. Genetically engineered mouse models recapitulate many features of human cancer and have been instrumental in assigning biological meaning to specific cancer-associated alterations. However, their time, cost and labour-intensive nature limits their broad utility; thus, the functional importance of the majority of genomic aberrations in cancer remains unknown. Recent advances have accelerated the functional interrogation of cancer-associated alterations within in vivo models. Specifically, the past few years have seen the emergence of CRISPR-Cas9-based strategies to rapidly generate increasingly complex somatic alterations and the development of multiplexed and quantitative approaches to ascertain gene function in vivo.

Adolescence and the next generation.

Adolescent growth and social development shape the early development of offspring from preconception through to the post-partum period through distinct processes in males and females. At a time of great change in the forces shaping adolescence, including the timing of parenthood, investments in today's adolescents, the largest cohort in human history, will yield great dividends for future generations.

Publisher Correction: Adolescence and the next generation.

In Fig. 4a of this Analysis, owing to an error during the production process, the year in the header of the right column was '2016' rather than '2010'. In addition, in the HTML version of the Analysis, Table 1 was formatted incorrectly. These errors have been corrected online.

Mapping local variation in educational attainment across Africa.

Educational attainment for women of reproductive age is linked to reduced child and maternal mortality, lower fertility and improved reproductive health. Comparable analyses of attainment exist only at the national level, potentially obscuring patterns in subnational inequality. Evidence suggests that wide disparities between urban and rural populations exist, raising questions about where the majority of progress towards the education targets of the Sustainable Development Goals is occurring in African countries. Here we explore within-country inequalities by predicting years of schooling across five by five kilometre grids, generating estimates of average educational attainment by age and sex at subnational levels. Despite marked progress in attainment from 2000 to 2015 across Africa, substantial differences persist between locations and sexes. These differences have widened in many countries, particularly across the Sahel. These high-resolution, comparable estimates improve the ability of decision-makers to plan the precisely targeted interventions that will be necessary to deliver progress during the era of the Sustainable Development Goals.

Mapping child growth failure in Africa between 2000 and 2015.

Insufficient growth during childhood is associated with poor health outcomes and an increased risk of death. Between 2000 and 2015, nearly all African countries demonstrated improvements for children under 5 years old for stunting, wasting, and underweight, the core components of child growth failure. Here we show that striking subnational heterogeneity in levels and trends of child growth remains. If current rates of progress are sustained, many areas of Africa will meet the World Health Organization Global Targets 2025 to improve maternal, infant and young child nutrition, but high levels of growth failure will persist across the Sahel. At these rates, much, if not all of the continent will fail to meet the Sustainable Development Goal target-to end malnutrition by 2030. Geospatial estimates of child growth failure provide a baseline for measuring progress as well as a precision public health platform to target interventions to those populations with the greatest need, in order to reduce health disparities and accelerate progress.

Social support among English learners with disabilities and other adolescents.

INTRODUCTION: Social support is important for many youth but may be particularly important for English learners (ELs) with disabilities, a population that has historically faced barriers accessing resources to meet their educational needs. The current study investigates social support from parents, peers, teachers, and schools in a nationally representative sample of adolescents. METHOD: Data from the National Longitudinal Transition Study 2012 was used to evaluate potential group differences in social support among participants that included ELs with (n = 440) and without disabilities (n = 100) and non-ELs with (n = 4890) and without disabilities (n = 1090). A multivariate analysis of covariance was conducted to evaluate potential between-group variations in social support among these student groups after controlling for variations in background demographic characteristics. RESULTS AND CONCLUSIONS: Results showed between group differences in parental support and peer connectedness but not in teacher or school support. Parents of students with disabilities reported the highest levels of support, whereas parents of ELs without disabilities reported the lowest levels of support. Students with disabilities reported the lowest levels of peer connectedness among the four groups. Overall, levels of teacher and school supports were high across all four groups of students. These patterns contribute to our understanding of the social support network of ELs with disabilities in comparison to other students. Further investigation is needed to examine the mechanisms that contribute to these differences.

Frequency Stabilization and Optically Tunable Lasing in Colloidal Quantum Dot Superparticles.

Self-assembled superparticles composed of colloidal quantum dots establish microsphere cavities that support optically pumped lasing from whispering gallery modes. Here, we report on the time- and excitation fluence-dependent lasing properties of CdSe/CdS quantum dot superparticles. Spectra collected under constant photoexcitation reveal that the lasing modes are not temporally stable but instead blue-shift by more than 30 meV over 15 min. To counter this effect, we establish a high-fluence light-soaking protocol that reduces this blue-shift by more than an order of magnitude to 1.7 ± 0.5 meV, with champion superparticles displaying mode blue-shifts of <0.5 meV. Increasing the pump fluence allows for optically controlled, reversible, color-tunable red-to-green lasing. Combining these two paradigms suggests that quantum dot superparticles could serve in applications as low-cost, robust, solution-processable, tunable microlasers.

Temperature-Controlled Reversible Formation and Phase Transformation of 3D Nanocrystal Superlattices Through In Situ Small-Angle X-ray Scattering.

For decades, the spontaneous organization of nanocrystals into superlattices has captivated the scientific community. However, achieving direct control over the formation of the superlattice and its phase transformations has proven to be a grand challenge, often resulting in the generation of multiple symmetries under the same experimental conditions. Here, we achieve direct control over the formation of the superlattice and its phase transformations by modulating the thermal energy of a nanocrystal dispersion without relying on solvent evaporation. We follow the temperature-dependent dynamics of the self-assembly process using synchrotron-based small-angle X-ray scattering. When cooled below -24.5 °C, lead sulfide nanocrystals form micrometer-sized three-dimensional phase-pure body-centered cubic superlattices. When cooled below -35.1 °C, these superlattices undergo a collective diffusionless phase transformation that yields denser body-centered tetragonal phases. These structural changes can be reversed by increasing the temperature of the dispersion and may lead to the direct modulation of the optical properties of these artificial solids.

Self-Assembly of Atomically Aligned Nanoparticle Superlattices from Pt-Fe3O4 Heterodimer Nanoparticles.

Multicomponent nanoparticle superlattices (SLs) promise the integration of nanoparticles (NPs) with remarkable electronic, magnetic, and optical properties into a single structure. Here, we demonstrate that heterodimers consisting of two conjoined NPs can self-assemble into novel multicomponent SLs with a high degree of alignment between the atomic lattices of individual NPs, which has been theorized to lead to a wide variety of remarkable properties. Specifically, by using simulations and experiments, we show that heterodimers composed of larger Fe3O4 domains decorated with a Pt domain at one vertex can self-assemble into an SL with long-range atomic alignment between the Fe3O4 domains of different NPs across the SL. The SLs show an unanticipated decreased coercivity relative to nonassembled NPs. In situ scattering of the self-assembly reveals a two-stage mechanism of self-assembly: translational ordering between NPs develops before atomic alignment. Our experiments and simulation indicate that atomic alignment requires selective epitaxial growth of the smaller domain during heterodimer synthesis and specific size ratios of the heterodimer domains as opposed to specific chemical composition. This composition independence makes the self-assembly principles elucidated here applicable to the future preparation of multicomponent materials with fine structural control.

Synthesis and Characterization of Stable Cu-Pt Nanoparticles under Reductive and Oxidative Conditions.

We report a synthesis method for highly monodisperse Cu-Pt alloy nanoparticles. Small and large Cu-Pt particles with a Cu/Pt ratio of 1:1 can be obtained through colloidal synthesis at 300 °C. The fresh particles have a Pt-rich surface and a Cu-rich core and can be converted into an intermetallic phase after annealing at 800 °C under H2. First, we demonstrated the stability of fresh particles under redox conditions at 400 °C, as the Pt-rich surface prevents substantial oxidation of Cu. Then, a combination of in situ scanning transmission electron microscopy, in situ X-ray absorption spectroscopy, and CO oxidation measurements of the intermetallic CuPt phase before and after redox treatments at 800 °C showed promising activity and stability for CO oxidation. Full oxidation of Cu was prevented after exposure to O2 at 800 °C. The activity and structure of the particles were only slightly changed after exposure to O2 at 800 °C and were recovered after re-reduction at 800 °C. Additionally, the intermetallic CuPt phase showed enhanced catalytic properties compared to the fresh particles with a Pt-rich surface or pure Pt particles of the same size. Thus, the incorporation of Pt with Cu does not lead to a rapid deactivation and degradation of the material, as seen with other bimetallic systems. This work provides a synthesis route to control the design of Cu-Pt nanostructures and underlines the promising properties of these alloys (intermetallic and non-intermetallic) for heterogeneous catalysis.

Measuring contraceptive method mix, prevalence, and demand satisfied by age and marital status in 204 countries and territories, 1970-2019: a systematic analysis for the Global Burden of Disease Study 2019.

BACKGROUND: Meeting the contraceptive needs of women of reproductive age is beneficial for the health of women and children, and the economic and social empowerment of women. Higher rates of contraceptive coverage have been linked to the availability of a more diverse range of contraceptive methods. We present estimates of the contraceptive prevalence rate (CPR), modern contraceptive prevalence rate (mCPR), demand satisfied, and the method of contraception used for both partnered and unpartnered women for 5-year age groups in 204 countries and territories between 1970 and 2019. METHODS: We used 1162 population-based surveys capturing contraceptive use among women between 1970 and 2019, in which women of reproductive age (15-49 years) self-reported their, or their partner's, current use of contraception for family planning purposes. Spatiotemporal Gaussian process regression was used to generate estimates of the CPR, mCPR, demand satisfied, and method mix by age and marital status. We assessed how age-specific mCPR and demand satisfied changed with the Socio-demographic Index (SDI), a measure of social and economic development, using the meta-regression Bayesian, regularised, trimmed method from the Global Burden of Diseases, Injuries, and Risk Factors Study. FINDINGS: In 2019, 162·9 million (95% uncertainty interval [UI] 155·6-170·2) women had unmet need for contraception, of whom 29·3% (27·9-30·6) resided in sub-Saharan Africa and 27·2% (24·4-30·3) resided in south Asia. Women aged 15-19 years (64·8% [62·9-66·7]) and 20-24 years (71·9% [68·9-74·2]) had the lowest rates of demand satisfied, with 43·2 million (95% UI 39·3-48·0) women aged 15-24 years with unmet need in 2019. The mCPR and demand satisfied among women aged 15-19 years were substantially lower than among women aged 20-49 years at SDI values below 60 (on a 0-100 scale), but began to equalise as SDI increased above 60. Between 1970 and 2019, the global mCPR increased by 20·1 percentage points (95% UI 18·7-21·6). During this time, traditional methods declined as a proportion of all contraceptive methods, whereas the use of implants, injections, female sterilisation, and condoms increased. Method mix differs substantially depending on age and geography, with the share of female sterilisation increasing with age and comprising more than 50% of methods in use in south Asia. In 28 countries, one method was used by more than 50% of users in 2019. INTERPRETATION: The dominance of one contraceptive method in some locations raises the question of whether family planning policies should aim to expand method mix or invest in making existing methods more accessible. Lower rates of demand satisfied among women aged 15-24 years are also concerning because unintended pregnancies before age 25 years can forestall or eliminate education and employment opportunities that lead to social and economic empowerment. Policy makers should strive to tailor family planning programmes to the preferences of the groups with the most need, while maintaining the programmes used by existing users. FUNDING: Bill & Melinda Gates Foundation.