Differences in the regulatory strategies of marine oligotrophs and copiotrophs reflect differences in motility.

Aquatic bacteria frequently are divided into lifestyle categories oligotroph or copiotroph. Oligotrophs have proportionately fewer transcriptional regulatory genes than copiotrophs and are generally non-motile/chemotactic. We hypothesized that the absence of chemotaxis/motility in oligotrophs prevents them from occupying nutrient patches long enough to benefit from transcriptional regulation. We first confirmed that marine oligotrophs are generally reduced in genes for transcriptional regulation and motility/chemotaxis. Next, using a non-motile oligotroph (Ca. Pelagibacter st. HTCC7211), a motile copiotroph (Alteromonas macleodii st. HOT1A3), and [14 C]l-alanine, we confirmed that l-alanine catabolism is not transcriptionally regulated in HTCC7211 but is in HOT1A3. We then found that HOT1A3 took 2.5-4 min to initiate l-alanine oxidation at patch l-alanine concentrations, compared to <30 s for HTCC7211. By modelling cell trajectories, we predicted that, in most scenarios, non-motile cells spend <2 min in patches, compared to >4 min for chemotactic/motile cells. Thus, the time necessary for transcriptional regulation to initiate prevents transcriptional regulation from being beneficial for non-motile oligotrophs. This is supported by a mechanistic model we developed, which predicted that HTCC7211 cells with transcriptional regulation of l-alanine metabolism would produce 12% of their standing ATP stock upon encountering an l-alanine patch, compared to 880% in HTCC7211 cells without transcriptional regulation.

Status of HIV Epidemic Control Among Adolescent Girls and Young Women Aged 15-24 Years - Seven African Countries, 2015-2017.

In 2016, an estimated 1.5 million females aged 15-24 years were living with human immunodeficiency virus (HIV) infection in Eastern and Southern Africa, where the prevalence of HIV infection among adolescent girls and young women (3.4%) is more than double that for males in the same age range (1.6%) (1). Progress was assessed toward the Joint United Nations Programme on HIV/AIDS (UNAIDS) 2020 targets for adolescent girls and young women in sub-Saharan Africa (90% of those with HIV infection aware of their status, 90% of HIV-infected persons aware of their status on antiretroviral treatment [ART], and 90% of those on treatment virally suppressed [HIV viral load <1,000 HIV RNA copies/mL]) (2) using data from recent Population-based HIV Impact Assessment (PHIA) surveys in seven countries. The national prevalence of HIV infection in adolescent girls and young women aged 15-24 years, the percentage who were aware of their status, and among those persons who were aware, the percentage who had achieved viral suppression were calculated. The target for viral suppression among all persons with HIV infection is 73% (the product of 90% x 90% x 90%). Among all seven countries, the prevalence of HIV infection among adolescent girls and young women was 3.6%; among those in this group, 46.3% reported being aware of their HIV-positive status, and 45.0% were virally suppressed. Sustained efforts by national HIV and public health programs to diagnose HIV infection in adolescent girls and young women as early as possible to ensure rapid initiation of ART should help achieve epidemic control among adolescent girls and young women.

Whole cell affinity for 4-amino-5-hydroxymethyl-2-methylpyrimidine (HMP) in the marine bacterium Candidatus Pelagibacter st. HTCC7211 explains marine dissolved HMP concentrations.

Vitamin B1 is a universally required coenzyme in carbon metabolism. However, most marine microorganisms lack the complete biosynthetic pathway for this compound and must acquire thiamin, or precursor molecules, from the dissolved pool. The most common version of Vitamin B1 auxotrophy is for thiamin's pyrimidine precursor moiety, 4-amino-5-hydroxymethyl-2-methylpyrimidine (HMP). Frequent HMP auxotrophy in plankton and vanishingly low dissolved concentrations (approximately 0.1-50 pM) suggest that high-affinity HMP uptake systems are responsible for maintaining low ambient HMP concentrations. We used tritium-labelled HMP to investigate HMP uptake mechanisms and kinetics in cell cultures of Candidatus Pelagibacter st. HTCC7211, a representative of the globally distributed and highly abundant SAR11 clade. A single protein, the sodium solute symporter ThiV, which is conserved across SAR11 genomes, is the likely candidate for HMP transport. Experimental evidence indicated transport specificity for HMP and mechanistically complex, high-affinity HMP uptake kinetics. Km values ranged from 9.5 pM to 1.2 nM and were dramatically lower when cells were supplied with a carbon source. These results suggest that HMP uptake in HTCC7211 is subject to complex regulation and point to a strategy for high-affinity uptake of this essential growth factor that can explain natural HMP levels in seawater.

Leveraging multisectoral approach to understand the determinants of childhood stunting in Rwanda: a systematic review and meta-analysis.

BACKGROUND: Addressing childhood stunting is a priority and an important step in the attainment of Global Nutrition Targets for 2025 and Sustainable Development Goals (SDGs). In Rwanda, the prevalence of child stunting remains high despite concerted efforts to reduce it. METHODS: Utilizing the United Nations International Children's Emergency Fund (UNICEF) framework on maternal and child nutrition, this study systematically evaluated the determinants of child stunting in Rwanda and identified available gaps. Twenty-five peer-reviewed papers and five Demographic and Health Surveys (DHS) reports were included in the final selection of our review, which allowed us to identify determinants such as governance and norms including wealth index, marital status, and maternal education, while underlying determinants were maternal health and nutrition factors, early initiation of breastfeeding, water treatment and sanitation, and immediate factors included infections. RESULTS: A total of 75% of the overall inequality in stunting was due to the difference in the social determinants of stunting between poor and nonpoor households. Maternal education (17%) and intergenerational transfer (31%) accounted for most of the inequalities in stunting, and an increase in gross domestic product per capita contributed to a reduction in its prevalence. There is a paucity of information on the impact of sociocultural norms, early life exposures, maternal health and nutrition, and Rwandan topography. CONCLUSION: The findings of this study suggest that improving women's status, particularly maternal education and health; access to improved water, sanitation, and hygiene-related factors; and the socioeconomic status of communities, especially those in rural areas, will lay a sound foundation for reducing stunting among under-5 children.

United Kingdom medical student expansion - Can new medical schools seize the initiative?

In June 2023, National Health Service (NHS) England published a Long-Term Workforce Plan 'to put staffing on a sustainable footing and improve patient care.' The plan falls in to three main areas: train, retain and reform. Currently there are around 7,500 medical school places available annually in England, but it is proposed to increase this to 10,000 by 2028 and to 15,000 by 2031. Five new medical schools were approved in the 2018 expansion and others are preparing applications in anticipation of future expansion. In this article, we discuss what factors might shape a new medical school, ensuring it meets the standards required by the UK regulator (General Medical Council) set out in Promoting Excellence and in Outcomes for Graduates.

Crosstalk between the Rho and Rab family of small GTPases in neurodegenerative disorders.

Neurodegeneration is associated with defects in cytoskeletal dynamics and dysfunctions of the vesicular trafficking and sorting systems. In the last few decades, studies have demonstrated that the key regulators of cytoskeletal dynamics are proteins from the Rho family GTPases, meanwhile, the central hub for vesicle sorting and transport between target membranes is the Rab family of GTPases. In this regard, the role of Rho and Rab GTPases in the induction and maintenance of distinct functional and morphological neuronal domains (such as dendrites and axons) has been extensively studied. Several members belonging to these two families of proteins have been associated with many neurodegenerative disorders ranging from dementia to motor neuron degeneration. In this analysis, we attempt to present a brief review of the potential crosstalk between the Rab and Rho family members in neurodegenerative pathologies such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington disease, and amyotrophic lateral sclerosis (ALS).

A Computational Text Mining-Guided Meta-Analysis Approach to Identify Potential Xerostomia Drug Targets.

Xerostomia (subjective complaint of dry mouth) is commonly associated with salivary gland hypofunction. Molecular mechanisms associated with xerostomia pathobiology are poorly understood, thus hampering drug development. Our objectives were to (i) use text-mining tools to investigate xerostomia and dry mouth concepts, (ii) identify associated molecular interactions involving genes as candidate drug targets, and (iii) determine how drugs currently used in clinical trials may impact these genes and associated pathways. PubMed and PubMed Central were used to identify search terms associated with xerostomia and/or dry mouth. Search terms were queried in pubmed2ensembl. Protein-protein interaction (PPI) networks were determined using the gene/protein network visualization program search tool for recurring instances of neighboring genes (STRING). A similar program, Cytoscape, was used to determine PPIs of overlapping gene sets. The drug-gene interaction database (DGIdb) and the clinicaltrials.gov database were used to identify potential drug targets from the xerostomia/dry mouth PPI gene set. We identified 64 search terms in common between xerostomia and dry mouth. STRING confirmed PPIs between identified genes (CL = 0.90). Cytoscape analysis determined 58 shared genes, with cytokine-cytokine receptor interaction representing the most significant pathway (p = 1.29 × 10-23) found in the Kyoto encyclopedia of genes and genomes (KEGG). Fifty-four genes in common had drug interactions, per DGIdb analysis. Eighteen drugs, targeting the xerostomia/dry mouth PPI network, have been evaluated for xerostomia, head and neck cancer oral complications, and Sjögren's Syndrome. The PPI network genes IL6R, EGFR, NFKB1, MPO, and TNFSF13B constitute a possible biomarker signature of xerostomia. Validation of the candidate biomarkers is necessary to better stratify patients at the genetic and molecular levels to facilitate drug development or to monitor response to treatment.

Erroneous attribution of relevant transcription factor binding sites despite successful prediction of cis-regulatory modules.

BACKGROUND: Cis-regulatory modules are bound by transcription factors to regulate gene expression. Characterizing these DNA sequences is central to understanding gene regulatory networks and gaining insight into mechanisms of transcriptional regulation, but genome-scale regulatory module discovery remains a challenge. One popular approach is to scan the genome for clusters of transcription factor binding sites, especially those conserved in related species. When such approaches are successful, it is typically assumed that the activity of the modules is mediated by the identified binding sites and their cognate transcription factors. However, the validity of this assumption is often not assessed. RESULTS: We successfully predicted five new cis-regulatory modules by combining binding site identification with sequence conservation and compared these to unsuccessful predictions from a related approach not utilizing sequence conservation. Despite greatly improved predictive success, the positive set had similar degrees of sequence and binding site conservation as the negative set. We explored the reasons for this by mutagenizing putative binding sites in three cis-regulatory modules. A large proportion of the tested sites had little or no demonstrable role in mediating regulatory element activity. Examination of loss-of-function mutants also showed that some transcription factors supposedly binding to the modules are not required for their function. CONCLUSIONS: Our results raise important questions about interpreting regulatory module predictions obtained by finding clusters of conserved binding sites. Attribution of function to these sites and their cognate transcription factors may be incorrect even when modules are successfully identified. Our study underscores the importance of empirical validation of computational results even when these results are in line with expectation.

Comparative Analysis of Swept-Source Optical Coherence Tomography and Partial Coherence Interferometry Biometers in the Prediction of Cataract Surgery Refractive Outcomes.

PURPOSE: To compare the accuracy of pre-operative corneal measurements obtained with four devices, and the refractive outcomes of two optical biometers. SETTING: Private practice. DESIGN: Retrospective. METHODS: Data taken from biometric measurements on 299 consecutive eyes prior to cataract surgery were retrospectively analyzed using the Argos SS-Optical Biometer and the Lenstar LS900 PCI optical biometer. As part of the standard cataract surgery pre-operative exam, patients also underwent placido disk topography and Scheimpflug tomography. Keratometry, anterior chamber depth, corneal diameter, pupil diameter, central corneal thickness and axial length were all measured. The comparable measurements were compared. Finally, for those eyes where cataract surgery was performed, the post-operative refractive results were compared to the predictive results of the two biometers. RESULTS: The SS-OCT Argos was able to measure all eyes, while five eyes could not be measured with the Lenstar LS900 PCI. Axial length measurements were performed only with the Argos and Lenstar devices. The eyes that could not be measured by the Lenstar LS900 PCI included dense grade IV nuclear sclerosis and large posterior subcapsular cataracts. In the primary endpoints, there was strong correlation between the Argos and the Lenstar devices in eyes with an axial length between 20 and 30 mm. CONCLUSION: The predictive accuracies of the Argos Optical Biometer and Lenstar LS900 PCI are similar, except in medium and long eyes, in which the predictive accuracy of Argos SS-OCT biometry was higher. The Argos system was found easier to use by technicians when compared to the other biometry devices.

Optimizing Corneal Cross-Linking in the Treatment of Keratoconus: A Comparison of Outcomes After Standard- and High-Intensity Protocols.

PURPOSE: To evaluate and compare the safety and efficacy of accelerated (AXL) and standard corneal cross-linking (CXL) protocols in patients with progressive keratoconus. METHODS: Progressive keratoconus patients (14-40 years) received either standard-intensity CXL or high-intensity CXL (AXL). Corneas were exposed to ultraviolet-A 365 nm light for 30 minutes at an irradiance of 3.0 mW/cm in the standard CXL group and to ultraviolet-A 365 nm light for 10 minutes at 9.0 mW/cm in the AXL group. Changes in uncorrected visual acuity, best spectacle-corrected visual acuity, refractive astigmatism, Kmax, and Kmean were used to determine treatment efficacy. Safety was determined by the incidence of adverse events and occurrence of loss of 2 or more lines of best spectacle-corrected visual acuity. Outcomes for CXL versus AXL were compared to determine differences in safety and efficacy between treatment groups. RESULTS: Thirty-six eyes of 34 patients (mean age, 27.9 ± 7.6 years) underwent AXL; 66 eyes of 53 patients (mean age, 30.0 ± 8.0 years) underwent standard-intensity CXL. There was no significant difference in any outcome measures between the groups. For AXL, there seemed to be more corneal flattening, with a statistically significant reduction in Kmean at 6 and 12 months postoperatively, when compared preoperatively (P < 0.01). There were no adverse events or complications in any patients. CONCLUSIONS: There was more corneal flattening in AXL patients 6 to 12 months postoperatively, suggesting that AXL may be a promising alternative to CXL in stabilizing corneal ectasia.

Prevalence and predictors of return visits to pediatric emergency departments.

OBJECTIVE: To determine the rate of return visits to pediatric emergency departments (EDs) and identify patient- and visit-level factors associated with return visits and hospitalization upon return. DESIGN AND SETTING: Retrospective cohort study of visits to 23 pediatric EDs in 2012 using data from the Pediatric Health Information System. PARTICIPANTS: Patients <18 years old discharged following an ED visit. MEASURES: The primary outcomes were the rate of return visits within 72 hours of discharge from the ED and of return visits within 72 hours resulting in hospitalization. RESULTS: 1,415,721 of the 1,610,201 ED visits to study hospitals resulted in discharge. Of the discharges, 47,294 patients (3.3%) had a return visit. Of these revisits, 9295 (19.7%) resulted in hospitalization. In multivariate analyses, the odds of having a revisit were higher for patients with a chronic condition (odds ratio [OR]: 1.91, 95% confidence interval [CI]: 1.86-1.96), higher severity scores (OR: 1.42, 95% CI: 1.40-1.45), and age <1 year (OR: 1.32, 95% CI: 1.22-1.42). The odds of hospitalization on return were higher for patients with higher severity (OR: 3.42, 95% CI: 3.23-3.62), chronic conditions (OR: 2.92, 95% CI: 2.75-3.10), age <1 year (1.7-2.5 times the odds of other age groups), overnight arrival (OR: 1.84, 95% CI: 1.71-1.97), and private insurance (OR: 1.47, 95% CI: 1.39-1.56). Sickle cell disease and cancer patients had the highest rates of return at 10.7% and 7.3%, respectively. CONCLUSIONS: Multiple patient- and visit-level factors are associated with revisits. These factors may provide insight in how to optimize care and decrease avoidable ED utilization.