Coevolutionary Information Captures Catalytic Functions and Reveals Divergent Roles of Terpene Synthase Interdomain Connections.

Inferring the historical and biophysical causes of diversity within protein families is a complex puzzle. A key to unraveling this problem is characterizing the rugged topography of sequence-function adaptive landscapes. Using biochemical data from a 2 = 512 combinatorial library of tobacco 5--aristolochene synthase (TEAS) mutants engineered to make the native major product of Egyptian henbane premnaspirodiene synthase (HPS) and a complementary 512 mutant HPS library, we address the question of how product specificity is controlled.

Overcoming resolution attenuation during tilted cryo-EM data collection.

Structural biology efforts using cryogenic electron microscopy are frequently stifled by specimens adopting "preferred orientations" on grids, leading to anisotropic map resolution and impeding structure determination. Tilting the specimen stage during data collection is a generalizable solution but has historically led to substantial resolution attenuation. Here, we develop updated data collection and image processing workflows and demonstrate, using multiple specimens, that resolution attenuation is negligible or significantly reduced across tilt angles.

Visualizing the Interface of Biotin and Fatty Acid Biosynthesis through SuFEx Probes.

Site-specific covalent conjugation offers a powerful tool to identify and understand protein-protein interactions. In this study, we discover that sulfur fluoride exchange (SuFEx) warheads effectively crosslink the acyl carrier protein (AcpP) with its partner BioF, a key pyridoxal 5'-phosphate (PLP)-dependent enzyme in the early steps of biotin biosynthesis by targeting a tyrosine residue proximal to the active site. We identify the site of crosslink by MS/MS analysis of the peptide originating from both partners.

Prevalence, correlates and explanatory models of cognitive deficits in patients with schizophrenia-A cross sectional study.

Background: Schizophrenia may cause significant impairment in social and economic aspects of a patient's life. Current evidence suggests that cognitive deficits may affect the functioning of a person with schizophrenia more than positive or negative symptoms. There is a lack of literature on explanatory models of cognitive deficits in schizophrenia that can influence help-seeking behavior.

Cardiac Autonomic Activity, Personality Traits, and Academic Performance in First-Year Medical Students: A Gender-Specific Relation.

Background It is not always the sincere or hardworking or intelligent student that gets the highest grades. Exploring unknown dimensions that may distinguish academic performance in adolescents/youth migrating from a high school study environment to that of a professional school and in a learning environment without parental supervision for the first time remains important. We hypothesized that cardiac autonomic activity influenced by cognitive domain factors and emotions would predict academic success in them.

Masked cerulenin enables a dual-site selective protein crosslink.

Protein-reactive natural products such as the fungal metabolite cerulenin are recognized for their value as therapeutic candidates, due to their ability to selectively react with catalytic residues within a protein active site or a complex of protein domains. Here, we explore the development of fatty-acid and polyketide-synthase probes by synthetically modulating cerulenin's functional moieties. Using a mechanism-based approach, we reveal unique reactivity within cerulenin and adapt it for fluorescent labeling and crosslinking of fatty-acid and iterative type-I polyketide synthases.

Overcoming Resolution Attenuation During Tilted Cryo-EM Data Collection.

Structural biology efforts using cryogenic electron microscopy are frequently stifled by specimens adopting "preferred orientations" on grids, leading to anisotropic map resolution and impeding structure determination. Tilting the specimen stage during data collection is a generalizable solution but has historically led to substantial resolution attenuation. Here, we develop updated data collection and image processing workflows and demonstrate, using multiple specimens, that resolution attenuation is negligible or significantly reduced across tilt angles.

Progress towards achieving child survival goals in Kenya after devolution: Geospatial analysis with scenario-based projections, 2015-2025.

Subnational projections of under-5 mortality (U5M) have increasingly become an essential planning tool to support Sustainable Development Goals (SDGs) agenda and strategies for improving child survival. To support child health policy, planning, and tracking child development goals in Kenya, we projected U5M at units of health decision making. County-specific annual U5M were estimated using a multivariable Bayesian space-time hierarchical model based on intervention coverage from four alternate intervention scale-up scenarios assuming 1) the highest subnational intervention coverage in 2014, 2) projected coverage based on the fastest county-specific rate of change observed in the period between 2003-2014 for each intervention, 3) the projected national coverage based on 2003-2014 trends and 4) the country-specific targets of intervention coverage relative to business as usual (BAU) scenario.

Role of anchoring groups on the light harvesting and optoelectronic properties of triphenylamine derivatives: insights from theory.

Background: In the present work, DFT and time-dependent DFT calculations were performed to investigate the role of anchoring groups on the photophysical properties and reveal structure-property correlations of triphenylamine (TPA) derivatives. The selected anchoring groups are tetrazole, acrylamide, hydantoin, and rhodanine.

Results: Our results show that the different anchoring groups employed alter the planarity, intramolecular charge transfer properties, and HOMO-LUMO gap and hence influence the optoelectronic properties of the dyes.

Spatial variation and inequities in antenatal care coverage in Kenya, Uganda and mainland Tanzania using model-based geostatistics: a socioeconomic and geographical accessibility lens.

Background: Pregnant women in sub-Saharan Africa (SSA) experience the highest levels of maternal mortality and stillbirths due to predominantly avoidable causes. Antenatal care (ANC) can prevent, detect, alleviate, or manage these causes. While eight ANC contacts are now recommended, coverage of the previous minimum of four visits (ANC4+) remains low and inequitable in SSA.

Cangrelor Dosing and Monitoring for Prevention of Acute Systemic-to-Pulmonary Artery Shunt Thrombosis in Neonates.

Objective: Systemic-to-pulmonary artery shunts are amongst the most common palliative procedures performed in neonates with congenital heart defects. These procedures require immediate postoperative thromboprophylaxis to prevent life-threatening shunt thrombosis. The novel use of intravenous P2Y platelet receptor antagonists has led to a need for dosing recommendations and monitoring.

Mechanism-based cross-linking probes capture the Escherichia coli ketosynthase FabB in conformationally distinct catalytic states.

Ketosynthases (KSs) catalyse essential carbon-carbon bond-forming reactions in fatty-acid biosynthesis using a two-step, ping-pong reaction mechanism. In Escherichia coli, there are two homodimeric elongating KSs, FabB and FabF, which possess overlapping substrate selectivity. However, FabB is essential for the biosynthesis of the unsaturated fatty acids (UFAs) required for cell survival in the absence of exogenous UFAs.

Structural Basis of Stereospecific Vanadium-Dependent Haloperoxidase Family Enzymes in Napyradiomycin Biosynthesis.

Vanadium-dependent haloperoxidases (VHPOs) from bacteria differ from their counterparts in fungi, macroalgae, and other bacteria by catalyzing organohalogenating reactions with strict regiochemical and stereochemical control. While this group of enzymes collectively uses hydrogen peroxide to oxidize halides for incorporation into electron-rich organic molecules, the mechanism for the controlled transfer of highly reactive chloronium ions in the biosynthesis of napyradiomycin and merochlorin antibiotics sets the vanadium-dependent chloroperoxidases apart. Here we report high-resolution crystal structures of two homologous VHPO family members associated with napyradiomycin biosynthesis, NapH1 and NapH3, that catalyze distinctive chemical reactions in the construction of meroterpenoid natural products.

Single-Particle Cryo-EM Data Collection with Stage Tilt using Leginon.

Single-particle analysis (SPA) by cryo-electron microscopy (cryo-EM) is now a mainstream technique for high-resolution structural biology. Structure determination by SPA relies upon obtaining multiple distinct views of a macromolecular object vitrified within a thin layer of ice. Ideally, a collection of uniformly distributed random projection orientations would amount to all possible views of the object, giving rise to reconstructions characterized by isotropic directional resolution.

Plant-based CO drawdown and storage as SiC.

Since the 1950's the Earth's natural carbon cycle has not sufficiently sequestrated excess atmospheric CO contributed by human activities. CO levels rose above 400 ppm in 2013 and are forecasted to exceed 500 ppm by 2070, a level last experienced during the Paleogene period 25-65 MYA. While humanity benefits from the extraction and combustion of carbon from Earth's crust, we have overlooked the impact on global climate change.

Implementation of clinical audit to improve adherence to guideline-recommended therapy in acute coronary syndrome.

Background: Despite global consensus on the management of acute coronary syndrome (ACS), implementation of strategies to improve adherence of guideline-directed medical therapy (GDMT) remains sub-optimal, especially in developing countries. Thus, we aimed to assess the effect of clinical pharmacist-led clinical audit to improve the compliance of discharge prescriptions in patients admitted with ACS. It is a prospective clinical audit of ACS patients which was carried out for 12 months.

Nature and Correlates of Executive Dysfunction in Schizophrenia: An Exploratory Study.

Background: Executive function (EF) impairment has been demonstrated in patients with schizophrenia. This study attempted to examine the clinical and demographic correlates associated with the different components of EF in these patients using a comprehensive battery of neuropsychological tests.

Materials And Methods: Consecutive inpatients with schizophrenia in remission were recruited.

Structure and mechanistic analyses of the gating mechanism of elongating ketosynthases.

Ketosynthases (KSs) catalyze carbon-carbon bond forming reactions in fatty acid synthases (FASs) and polyketide synthases (PKSs). KSs utilize a two-step ping pong kinetic mechanism to carry out an overall decarboxylative thio-Claisen condensation that can be separated into the transacylation and condensation reactions. In both steps, an acyl carrier protein (ACP) delivers thioester tethered substrates to the active sites of KSs.

A quality improvement initiative to reduce hypothermia in a Baby-Friendly nursery - our story of algorithms, K-cards, and Key cards.

Background: Baby-Friendly hospitals encourage rooming-in newborns with mothers. In our institution, we noticed increased incidence of hypothermia following Baby-Friendly designation. We aimed to reduce the incidence of hypothermia in the mother-baby-unit to <15% and to decrease the rate of isolated hypothermia admissions to the neonatal intensive care unit (NICU) by 20% over two years.

The impact of child health interventions and risk factors on child survival in Kenya, 1993-2014: a Bayesian spatio-temporal analysis with counterfactual scenarios.

Background: During the millennium development goals period, reduction in under-five mortality (U5M) and increases in child health intervention coverage were characterised by sub-national disparities and inequities across Kenya. The contribution of changing risk factors and intervention coverage on the sub-national changes in U5M remains poorly defined.

Methods: Sub-national county-level data on U5M and 43 factors known to be associated with U5M spanning 1993 and 2014 were assembled.

Subnational estimates of factors associated with under-five mortality in Kenya: a spatio-temporal analysis, 1993-2014.

Background: To improve child survival, it is necessary to describe and understand the spatial and temporal variation of factors associated with child survival beyond national aggregates, anchored at decentralised health planning units. Therefore, we aimed to provide subnational estimates of factors associated with child survival while elucidating areas of progress, stagnation and decline in Kenya.

Methods: Twenty household surveys and three population censuses conducted since 1989 were assembled and spatially aligned to 47 subnational Kenyan county boundaries.

Spatial access inequities and childhood immunisation uptake in Kenya.

Background: Poor access to immunisation services remains a major barrier to achieving equity and expanding vaccination coverage in many sub-Saharan African countries. In Kenya, the extent to which spatial access affects immunisation coverage is not well understood. The aim of this study was to quantify spatial accessibility to immunising health facilities and determine its influence on immunisation uptake in Kenya while controlling for potential confounders.

Interfacial plasticity facilitates high reaction rate of FAS malonyl-CoA:ACP transacylase, FabD.

Fatty acid synthases (FASs) and polyketide synthases (PKSs) iteratively elongate and often reduce two-carbon ketide units in de novo fatty acid and polyketide biosynthesis. Cycles of chain extensions in FAS and PKS are initiated by an acyltransferase (AT), which loads monomer units onto acyl carrier proteins (ACPs), small, flexible proteins that shuttle covalently linked intermediates between catalytic partners. Formation of productive ACP-AT interactions is required for catalysis and specificity within primary and secondary FAS and PKS pathways.