Read, write, adapt:Challenges and opportunities during kinetoplastid genome replication

The genomes of all organisms are read throughout their growth and development, generating new copies during cell division and encoding the cellular activities dictated by the genome’s content. However, genomes are not invariant information stores but are purposefully altered in minor and major ways, adapting cellular behaviour and driving evolution. Kinetoplastids are eukaryotic microbes that display a wide range of such read–write genome activities, in many cases affecting critical aspects of their biology, such as host adaptation. Here we discuss the range of read–write genome changes found in two well-studied kinetoplastid parasites, Trypanosoma brucei and Leishmania, focusing on recent work that suggests such adaptive genome variation is linked to novel strategies the parasites use to replicate their unconventional genomes

Life in plastic, it’s fantastic! How Leishmania exploit genome instability to shape gene expression

Leishmania are kinetoplastid pathogens that cause leishmaniasis, a debilitating and potentially life-threatening infection if untreated. Unusually, Leishmania regulate their gene expression largely post-transcriptionally due to the arrangement of their coding genes into polycistronic transcription units that may contain 100s of functionally unrelated genes. Yet, Leishmania are capable of rapid and responsive changes in gene expression to challenging environments, often instead correlating with dynamic changes in their genome composition, ranging from chromosome and gene copy number variations to the generation of extrachromosomal DNA and the accumulation of point mutations. Typically, such events indicate genome instability in other eukaryotes, coinciding with genetic abnormalities, but for Leishmania, exploiting these products of genome instability can provide selectable substrates to catalyse necessary gene expression changes by modifying gene copy number. Unorthodox DNA replication, DNA repair, replication stress factors and DNA repeats are recognised in Leishmania as contributors to this intrinsic instability, but how Leishmania regulate genome plasticity to enhance fitness whilst limiting toxic under- or over-expression of co-amplified and co-transcribed genes is unclear. Herein, we focus on fresh, and detailed insights that improve our understanding of genome plasticity in Leishmania. Furthermore, we discuss emerging models and factors that potentially circumvent regulatory issues arising from polycistronic transcription. Lastly, we highlight key gaps in our understanding of Leishmania genome plasticity and discuss future studies to define, in higher resolution, these complex regulatory interactions

Using a validated instrument to assess pregnancy planning and preconception care at antenatal booking visits: a retrospective cohort study

Objective: To determine the completion rate for the London Measure of Unplanned Pregnancy (LMUP), a psychometrically validated measure of a woman's intention with regard to a current or recent pregnancy, during booking visits at two metropolitan antenatal care clinics; to identify socio-demographic characteristics associated with unplanned pregnancy. // Design, setting, participants: Retrospective cohort study; analysis of LMUP data for women attending antenatal care booking consultations as public patients in the Sydney Local Health District, 31 December 2019 – 30 November 2020. // Main outcome measures: Proportions of women with LMUP scores indicating unplanned (0–9) or planned pregnancies (10–12); associations between planned pregnancy and socio-demographic characteristics, crude and adjusted for age, parity, and socio-economic status (Index of Relative Socioeconomic Disadvantage). // Results: Of 4993 women with antenatal care bookings, the LMUP was completed by 2385 (47.8%; 1142 of 3564 women at the tertiary referral hospital [32.0%], 1118 of 1160 at the secondary hospital [96.3%]). Planned pregnancies were indicated by the total LMUP scores of 1684 women (70.6%); 1290 women (59.1%) reported no health actions in preparation for pregnancy. In multivariable analyses, planned pregnancies were more likely in all age groups than for women aged 24 years or younger (30–34 years: adjusted odds ratio [aOR], 2.54; 95% confidence interval [CI], 1.76–3.66; 35–39 years: aOR, 2.91; 95% CI, 1.95–4.33). The likelihood of planned pregnancy declined with increasing parity (v no previous births: three previous births: aOR, 0.25; 95% CI, 0.16–0.40; four or more previous births: aOR, 0.10; 95% CI, 0.05–0.19). // Conclusion: Seven in ten women who completed the LMUP had planned their pregnancies, but fewer than half had undertaken health-related actions prior to conceiving. Higher parity was associated with unplanned pregnancy, indicating the importance of postpartum contraception advice. Overcoming barriers to implementing the LMUP more widely would enhance preconception health monitoring

When the Love Hormone Leads to Violence: Oxytocin Increases Intimate Partner Violence Inclinations Among High Trait Aggressive People

This is the author's final draft. Copyright 2014 SAGE PublicationsDoes oxytocin influence intimate partner violence (IPV)? Clues from prior research suggest that oxytocin increases prosocial behavior, but this effect is reversed among people with aggressive tendencies or in situations involving defensive aggression. Animal research also indicates that oxytocin plays a central role in defensive maternal aggression (i.e., protecting pups from intruders). Among highly aggressive people, a boost of oxytocin may cause them to use aggression toward close others as a means of maintaining their relationship. Adopting an interactionist approach, we predicted that oxytocin would increase IPV inclinations, but this effect would be limited to people high in trait physical aggression. In a double-blind, placebo-controlled, between-subject experiment, participants varying in trait physical aggression received either 24 international unit of oxytocin or a placebo. Following two provocation tasks, participants rated the probability that they would engage in various aggressive behaviors (e.g., slapping, throwing an object that could hurt) toward a romantic partner. Oxytocin increased IPV inclinations, but this effect was limited to participants prone to physical aggression. These data offer the first evidence that IPV inclinations have a biological basis in a combination of oxytocin and trait physical aggressiveness

Large-scale discovery of enhancers from human heart tissue.

Development and function of the human heart depend on the dynamic control of tissue-specific gene expression by distant-acting transcriptional enhancers. To generate an accurate genome-wide map of human heart enhancers, we used an epigenomic enhancer discovery approach and identified ∼6,200 candidate enhancer sequences directly from fetal and adult human heart tissue. Consistent with their predicted function, these elements were markedly enriched near genes implicated in heart development, function and disease. To further validate their in vivo enhancer activity, we tested 65 of these human sequences in a transgenic mouse enhancer assay and observed that 43 (66%) drove reproducible reporter gene expression in the heart. These results support the discovery of a genome-wide set of noncoding sequences highly enriched in human heart enhancers that is likely to facilitate downstream studies of the role of enhancers in development and pathological conditions of the heart

Potent antitrypanosomal activities of 3-aminosteroids against African trypanosomes: investigation of cellular effects and of cross-resistance with existing drugs. Molecules

Treatment of animal African trypanosomiasis (AAT) requires urgent need for safe, potent and affordable drugs and this has necessitated this study. We investigated the trypanocidal activities and mode of action of selected 3-aminosteroids against Trypanosoma brucei brucei. The in vitro activity of selected compounds of this series against T. congolense (Savannah-type, IL3000), T. b. brucei (bloodstream trypomastigote, Lister strain 427 wild-type (427WT)) and various multi-drug resistant cell lines was assessed using a resazurin-based cell viability assay. Studies on mode of antitrypanosomal activity of some selected 3-aminosteroids against Tbb 427WT were also carried out. The tested compounds mostly showed moderate-to-low in vitro activities and low selectivity to mammalian cells. Interestingly, a certain aminosteroid, holarrhetine (10, IC50 = 0.045 ± 0.03 µM), was 2 times more potent against T. congolense than the standard veterinary drug, diminazene aceturate, and 10 times more potent than the control trypanocide, pentamidine, and displayed an excellent in vitro selectivity index of 2130 over L6 myoblasts. All multi-drug resistant strains of T. b. brucei tested were not significantly cross-resistant with the purified compounds. The growth pattern of Tbb 427WT on long and limited exposure time revealed gradual but irrecoverable growth arrest at ≥ IC50 concentrations of 3-aminosteroids. Trypanocidal action was not associated with membrane permeabilization of trypanosome cells but instead with mitochondrial membrane depolarization, reduced adenosine triphosphate (ATP) levels and G2/M cell cycle arrest which appear to be the result of mitochondrial accumulation of the aminosteroids. These findings provided insights for further development of this new and promising class of trypanocide against African trypanosomes

10,12-Dimethyl­pteridino[6,7-f][1,10]phenanthroline-11,13(10H,12H)-dione–chloro­form (1/1)

In the title co-crystal, C18H12N6O2·CHCl3, intra­molecular Cl3C—H⋯N hydrogen-bonding inter­actions occur between a single CHCl3 and both N atoms at the 1,10-positions on the phenanthroline portion of the mol­ecule. The inter­planar distance between inversion-related mol­ecules is 3.241 (2) Å

Sex and Socioeconomic Differentials in Child Health in Rural Bangladesh: Findings from a Baseline Survey for Evaluating Integrated Management of Childhood Illness

This paper reports on a population-based sample survey of 2,289 children aged less than five years (under-five children) conducted in 2000 as a baseline for the Bangladesh component of the Multi-country Evaluation (MCE) of the Integrated Management of Childhood Illness strategy. Of interest were rates and differentials by sex and socioeconomic status for three aspects of child health in rural Bangladesh: morbidity and hospitalizations, including severity of illness; care-seeking for childhood illness; and home-care for illness. The survey was carried out among a population of about 380,000 in Matlab upazila (subdistrict). Generic MCE Household Survey tools were adapted, translated, and pretested. Trained interviewers conducted the survey in the study areas. In total, 2,289 under-five children were included in the survey. Results showed a very high prevalence of illness among Bangladeshi children, with over two-thirds reported to have had at least one illness during the two weeks preceding the survey. Most sick children in this population had multiple symptoms, suggesting that the use of the IMCI clinical guidelines will lead to improved quality of care. Contrary to expectations, there were no significant differences in the prevalence of illness either by sex or by socioeconomic status. About one-third of the children with a reported illness did not receive any care outside the home. Of those for whom outside care was sought, 42% were taken to a village doctor. Only 8% were taken to an appropriate provider, i.e. a health facility, a hospital, a doctor, a paramedic, or a community-based health worker. Poorer children than less-poor children were less likely to be taken to an appropriate healthcare provider. The findings indicated that children with severe illness in the least poor households were three times more likely to seek care from a trained provider than children in the poorest households. Any evidence of gender inequities in child healthcare, either in terms of prevalence of illness or care-seeking patterns, was not found. Care-seeking patterns were associated with the perceived severity of illness, the presence of danger signs, and the duration and number of symptoms. The results highlight the challenges that will need to be addressed as IMCI is implemented in health facilities and extended to address key family and community practices, including extremely low rates of use of the formal health sector for the management of sick children. Child health planners and researchers must find ways to address the apparent population preference for untrained and traditional providers which is determined by various factors, including the actual and perceived quality of care, and the differentials in care-seeking practices that discriminate against the poorest households