Structural basis of Cfr-mediated antimicrobial resistance and mechanisms to evade it.

The bacterial ribosome is an essential drug target as many clinically important antibiotics bind and inhibit its functional centers. The catalytic peptidyl transferase center (PTC) is targeted by the broadest array of inhibitors belonging to several chemical classes. One of the most abundant and clinically prevalent resistance mechanisms to PTC-acting drugs in Gram-positive bacteria is C8-methylation of the universally conserved A2503 nucleobase by Cfr methylase in 23S ribosomal RNA. Despite its clinical importance, a sufficient understanding of the molecular mechanisms underlying Cfr-mediated resistance is currently lacking. Here, we report a set of high-resolution structures of the Cfr-modified 70S ribosome containing aminoacyl- and peptidyl-transfer RNAs. These structures reveal an allosteric rearrangement of nucleotide A2062 upon Cfr-mediated methylation of A2503 that likely contributes to the reduced potency of some PTC inhibitors. Additionally, we provide the structural bases behind two distinct mechanisms of engaging the Cfr-methylated ribosome by the antibiotics iboxamycin and tylosin.

Maternal prenatal paracetamol ingestion and scholastic attainments of the offspring.

Background: Fetal exposure to paracetamol (acetaminophen) has been shown to be associated with asthma and other atopic disorders, as well as behavioural problems including hyperactivity, in childhood. However, there is little information on scholastic abilities among children exposed to paracetamol in pregnancy. Objectives: To determine whether there are any differences in scholastic abilities among the offspring of women who ingested paracetamol during pregnancy compared with non-exposed children. Methods: Mothers enrolled in the Avon Longitudinal Study of Parents and Children (ALSPAC) had recorded the frequency with which they had taken the medication over two time periods during pregnancy: i) the first 18 weeks and ii) 18-32 weeks. The offspring have been followed up ever since. For this study we use as outcomes: a) 14 tests of ability at reading and 2 of spelling using the study's tests and the national education system test results; b) 6 of mathematical abilities including tests of arithmetic and mathematical reasoning, and c) 1 of scientific understanding. Multiple regression was used, adjusting for 15 different exposures including reasons for taking the medication as well as demographic features. Results: Almost all unadjusted and adjusted mean differences were negative (i.e., those exposed to maternal intake of paracetamol did less well), but negative associations for exposures between 18 and 32 weeks of gestation were much more evident than for exposures earlier in pregnancy. Of the later exposures, after adjustment, 12 of the 23 scholastic tests were associated with prenatal exposure to paracetamol at p < 0.05. These negative effects were found in the girls (12 tests at p < 0.05) but not boys (0 tests at p < 0.05). Conclusion: Evidence from this longitudinal study suggests that maternal exposure to paracetamol is associated with disadvantages to the offspring in scholastic abilities such as mathematics and reading at secondary school ages. This raises the question as to whether there are longer-lasting effects on educational attainment from age 15 years onwards, including at university level. Clearly these results should be tested in other settings, but meanwhile they add to a growing accumulation of known adverse effects of exposure to paracetamol in pregnancy.

Structural basis of Cfr-mediated antimicrobial resistance and mechanisms for its evasion.

The ribosome is an essential drug target as many classes of clinically important antibiotics bind and inhibit its functional centers. The catalytic peptidyl transferase center (PTC) is targeted by the broadest array of inhibitors belonging to several chemical classes. One of the most abundant and clinically prevalent mechanisms of resistance to PTC-acting drugs is C8-methylation of the universally conserved adenine residue 2503 (A2503) of the 23S rRNA by the methyltransferase Cfr. Despite its clinical significance, a sufficient understanding of the molecular mechanisms underlying Cfr-mediated resistance is currently lacking. In this work, we developed a method to express a functionally-active Cfr-methyltransferase in the thermophilic bacterium Thermus thermophilus and report a set of high-resolution structures of the Cfr-modified 70S ribosome containing aminoacyl- and peptidyl-tRNAs. Our structures reveal that an allosteric rearrangement of nucleotide A2062 upon Cfr-methylation of A2503 is likely responsible for the inability of some PTC inhibitors to bind to the ribosome, providing additional insights into the Cfr resistance mechanism. Lastly, by determining the structures of the Cfr-methylated ribosome in complex with the antibiotics iboxamycin and tylosin, we provide the structural bases behind two distinct mechanisms of evading Cfr-mediated resistance.

Ribosome heterogeneity results in leader sequence-mediated regulation of protein synthesis in Francisella tularensis.

Although ribosomes are generally examined in aggregate, ribosomes can be heterogenous in composition. Evidence is accumulating that changes in ribosome composition may result in altered function, such that ribosome heterogeneity may provide a mechanism to regulate protein synthesis. Ribosome heterogeneity in the human pathogen Francisella tularensis results from incorporation of one of three homologs of bS21, a small ribosomal subunit protein demonstrated to regulate protein synthesis in other bacteria. Loss of one homolog, bS21-2, results in genome-wide post-transcriptional changes in protein abundance. This suggests that bS21-2 can, either directly or indirectly, lead to preferential translation of particular mRNAs. Here, we examine the potential of bS21-2 to function in a leader sequence-dependent manner and to function indirectly, via Hfq. We found that the 5´ untranslated region (UTR) of some bS21-2-responsive genes, including key virulence genes, is sufficient to alter translation in cells lacking bS21-2. We further identify features of a 5´ UTR that allow responsiveness to bS21-2. These include an imperfect Shine-Dalgarno sequence and a particular six nucleotide sequence. Our results are consistent with a model in which a bS21 homolog increases the efficiency of translation initiation through interactions with specific leader sequences. With respect to bS21-2 indirectly regulating translation via the RNA-binding protein Hfq, we found that Hfq controls transcript abundance rather than protein synthesis, impacting virulence gene expression via a distinct mechanism. Together, we determined that ribosome composition in F. tularensis regulates translation in a leader sequence-dependent manner, a regulatory mechanism which may be used in other bacteria. IMPORTANCE Ribosome heterogeneity is common in bacteria, and there is mounting evidence that ribosome composition plays a regulatory role in protein synthesis. However, mechanisms of ribosome-driven gene regulation are not well understood. In the human pathogen Francisella tularensis, which encodes multiple homologs for the ribosomal protein bS21, loss of one homolog impacts protein synthesis and virulence. Here, we explore the mechanism behind bS21-mediated changes in protein synthesis, finding that they can be linked to altered translation initiation and are dependent on specific sequences in the leaders of transcripts. Our data support a model in which ribosome composition regulates gene expression through translation, a strategy that may be conserved in diverse organisms with various sources of ribosome heterogeneity.

Childhood life events of women enrolled in the Avon Longitudinal Study of Parents & Children (ALSPAC).

At the time of planning ALSPAC there was accumulating evidence that abuse and other childhood traumas were related to psychiatric problems later in life. In addition, the age at which such trauma occurred was likely to be important in influencing its long-term impact. Detailed data was therefore collected from enrolled women on traumatic events occurring during their own childhoods, along with their age at the time. The questionnaire entitled 'About Yourself' was sent out to expectant women who had enrolled in the study, which included a page in the form of a grid (an events diary) with one row per year of childhood and columns for recording where she was living at the time, who was looking after her, and any traumatic events that occurred. These free-text responses were then coded, and any events were assigned a score indicating the level of trauma the event was likely to have caused on a scale of 1 (highly traumatic) to 6 (least traumatic). This paper describes the variety of text data collected and how it was coded. The ALSPAC study has a great deal of follow-up data collected on the original respondents, as well as on their parents and grandparents, partners, offspring and their grandchildren, providing huge potential for analyses on the antecedents and outcomes of adverse childhood events across multiple generations.

Associations between autistic traits and early ear and upper respiratory signs: a prospective observational study of the Avon Longitudinal Study of Parents and Children (ALSPAC) geographically defined childhood population.

OBJECTIVE: To determine whether early ear and upper respiratory signs are associated with the development of high levels of autistic traits or diagnosed autism. DESIGN: Longitudinal birth cohort: Avon Longitudinal Study of Parents and Children (ALSPAC). SETTING: Area centred on the city of Bristol in Southwest England. Eligible pregnant women resident in the area with expected date of delivery between April 1991 and December 1992 inclusive. PARTICIPANTS: 10 000+ young children followed throughout their first 4 years. Their mothers completed three questionnaires between 18-42 months recording the frequency of nine different signs and symptoms relating to the upper respiratory system, as well as ear and hearing problems. OUTCOME MEASURES: Primary-high levels of autism traits (social communication, coherent speech, sociability, and repetitive behaviour); secondary-diagnosed autism. RESULTS: Early evidence of mouth breathing, snoring, pulling/poking ears, ears going red, hearing worse during a cold, and rarely listening were associated with high scores on each autism trait and with a diagnosis of autism. There was also evidence of associations of pus or sticky mucus discharge from ears, especially with autism and with poor coherent speech. Adjustment for 10 environmental characteristics made little difference to the results, and substantially more adjusted associations were at p<0.001 than expected by chance (41 observed; 0.01 expected). For example, for discharge of pus or sticky mucus from ears the adjusted odds ratio (aOR) for autism at 30 months was 3.29 (95% CI 1.85 to 5.86, p<0.001), and for impaired hearing during a cold the aOR was 2.18 (95% CI 1.43 to 3.31, p<0.001). CONCLUSIONS: Very young children exhibiting common ear and upper respiratory signs appear to have an increased risk of a subsequent diagnosis of autism or demonstrated high levels of autism traits. Results suggest the need for identification and management of ear, nose and throat conditions in autistic children and may provide possible indicators of causal mechanisms.

The beneficial role of personality in preserving well-being during the pandemic: A longitudinal population study.

BACKGROUND: The COVID-19 pandemic resulted in increased rates of mental health problems. We examined the possible role of the personality characteristic, Locus of Control (LOC), in moderating pandemic-induced stress. METHODS: The UK-based Avon Longitudinal Study of Parents & Children (ALSPAC), 7021 adults (mean ages: women 57.6 (SD = 4.48); partners 60.5 (SD = 5.36)) responded to a 2020 questionnaire which included a generalised measure of LOC. Between March 2020-January 2021, questionnaires focussed on the pandemic were administered, which included measures of mental health. Over 60 % of respondents completed questionnaires at three timepoints of interest. RESULTS: In those with an internal LOC higher rates of positive well-being and reduced likelihood of anxiety and depression were shown compared to those who were external, e.g. after adjustment for socioeconomic/demographic factors mean differences in well-being score for internal compared with external women was +2.01 (95%CI +1.02,+2.10) p = 0.0001; for their partners +2.52 (95%CI +1.22,+3.82) p = 0.0002. External women were more likely than internals to have depression (adjusted OR 3.41 [95%CI 1.77,6.57] p < 0.0005. LIMITATIONS: Attrition is a problem in this 30-year-old longitudinal cohort. Those still participating are more likely to have higher education and SES levels, be female and have an internal LOC. This population suffers from a lack of ethnic diversity. CONCLUSIONS: Having an internal LOC positively moderated the effects of pandemic-induced stress on the frequency of anxiety and depression in middle-age. Programmes geared to raise internality and coping strategies may have long-term benefits on well-being in stressful situations, especially for women and frontline health professionals.

Race and the infrapolitics of public space in the time of COVID-19: The case of Harlem, New York.

The COVID-19 pandemic has fundamentally altered our associational life and relationship to public space, revealing deadly inequities in access to health care and other resources, particularly in communities of color. In Harlem and other areas of New York City that are experiencing neoliberal redevelopment, the response to the pandemic has also rearticulated public spaces, introducing new and diverse spatial uses and users, and providing low-income and working-class African American and Latinx residents with increased opportunities to contest their exclusion from public and quasi-public spaces and the symbolic economy of gentrification. Based on ethnographic research conducted during the pandemic, I show how black and brown residents in West Harlem encountered, negotiated, and contested these race-cum-class-based, spatio-symbolic exclusions through infrapolitical practices and, in the process, demanded and exercised their "right to the city." [race, infrapolitics, public space, gentrification, redevelopment, right to the city, COVID-19, Harlem, New York City].

The benefits of fish intake: Results concerning prenatal mercury exposure and child outcomes from the ALSPAC prebirth cohort.

Health advice to pregnant women concerning consumption of mercury-containing foods has resulted in anxiety, with subsequent avoidance of fish consumption during pregnancy. However, seafood contains many nutrients crucial for children's growth and development. Longitudinal studies in the Seychelles, where fish is a major component of the diet, have not demonstrated harmful cognitive effects in children with increasing maternal mercury levels. Is the same true in a more developed country (the UK) where fish is eaten less frequently? We review publications using data collected by the Avon Longitudinal Study of Parents and Children (ALSPAC) to address this topic. Total mercury levels were measured in maternal whole blood and umbilical cord tissue. Offspring were followed throughout childhood, especially their cognitive development. No adverse associations were noted. Significantly beneficial associations with prenatal mercury levels were shown for total and performance IQ, mathematical/scientific reasoning, and birthweight in fish-consuming vs non-fish consuming mothers. These beneficial findings are similar to those observed in the Seychelles where fish consumption is high and prenatal Hg levels are x10 higher than US levels. Government recommendations should be reviewed to emphasise the beneficial value of fish consumption during pregnancy. DATA AVAILABILITY: ALSPAC data access is through a system of managed open access. The steps below highlight how to apply for access to the data included in this paper and all other ALSPAC data. If you have any questions about accessing data, please email: alspac-data@bristol.ac.uk.

Paternal grandmother's smoking in pregnancy is associated with extreme aversion to bitter taste in their grandchildren.

Although there are many examples in the experimental literature of an environmental exposure in one generation impacting the phenotypes of subsequent generations, there are few studies that can assess whether such associations occur in humans. The Avon Longitudinal Study of Parents and Children (ALSPAC) has, however, been able to determine whether there are associations between grandparental exposures and their grandchildren's development. Several of our studies, including sensitivity to loud noise, have shown associations between a grandmother smoking in pregnancy and the phenotype of the grandchild. These results were mostly specific to the sex of the grandchild and to whether the prenatal (i.e. during pregnancy) smoking occurred in the maternal or paternal grandmother. Here, we have used ancestral data on prenatal smoking among the grandmothers of the ALSPAC index children to examine possible effects on the grandchild's ability to detect the bitter taste of PROP (6 n-propylthiouracil), distinguishing between the 10% deemed 'extreme tasters', and the rest of the population (total N = 4656 children). We showed that grandchildren whose paternal (but not maternal) grandmothers had smoked in pregnancy were more likely than those of non-smoking grandmothers to be extreme tasters [odds ratio (OR) 1.28; 95% confidence interval (CI) 1.03, 1.59] and that this was more likely in granddaughters (OR 1.42; 95% CI 1.03, 1.95) than grandsons (OR 1.18; 95% CI 0.88, 1.60). This pattern of association between paternal foetal exposure and the granddaughter's development has been found with several other outcomes, suggesting that investigations should be undertaken to investigate possible mechanisms.

Regular smoking of male ancestors in adolescence and fat mass in young adult grandchildren and great-grandchildren.

Background: Previous studies using the Avon Longitudinal Study of Parents and Children (ALSPAC) have shown that if men commenced smoking prior to the onset of puberty their sons, their granddaughters and great-granddaughters were more likely to have excess fat (but not lean) mass during childhood, adolescence and early adulthood. In this study we assess associations between ancestral smoking during adolescence (ages 11-16 years) with fat and lean mass of subsequent generations at two ages. Methods: We analysed data on exposures of grandparents and great-grandparents collected by ALSPAC. The outcomes were the fat masses of their grandchildren and great-grandchildren measured at ages 17 and 24. Measures of lean mass were used as controls. Adjustment was made for 8-10 demographic factors using multiple regression. Results: We found associations between adolescent smoking of the paternal grandfathers and the adjusted fat mass of their grandchildren, but no associations with the grandchildren's lean mass. Grandchildren at age 17 had an average excess fat mass of +1.65 [95% CI +0.04, +3.26] Kg, and at age 24 an average excess of +1.55 [95% CI -0.27, +3.38] Kg. Adolescent smoking by the maternal grandfather showed similar, but weaker, associations: at 17 an average excess fat mass of +1.02 Kg [95% CI -0.20, +2.25] Kg, and at 24 an average excess of +1.28 [95% CI -0.11, +2.66] Kg. There were no pronounced differences between the sexes of the children. For the great-grandparents there were few convincing results, although numbers were small. Conclusions: We have shown associations between grandfathers' smoking in adolescence and increased fat (but not lean) mass in their children. Confirmation of these associations is required, either in a further data set or by demonstrating the presence of supportive biomarkers.

A Survey of Spontaneous Antibiotic-Resistant Mutants of the Halophilic, Thermophilic Bacterium Rhodothermus marinus.

Rhodothermus marinus is a halophilic extreme thermophile, with potential as a model organism for studies of the structural basis of antibiotic resistance. In order to facilitate genetic studies of this organism, we have surveyed the antibiotic sensitivity spectrum of R. marinus and identified spontaneous antibiotic-resistant mutants. R. marinus is naturally insensitive to aminoglycosides, aminocylitols and tuberactinomycins that target the 30S ribosomal subunit, but is sensitive to all 50S ribosomal subunit-targeting antibiotics examined, including macrolides, lincosamides, streptogramin B, chloramphenicol, and thiostrepton. It is also sensitive to kirromycin and fusidic acid, which target protein synthesis factors. It is sensitive to rifampicin (RNA polymerase inhibitor) and to the fluoroquinolones ofloxacin and ciprofloxacin (DNA gyrase inhibitors), but insensitive to nalidixic acid. Drug-resistant mutants were identified using rifampicin, thiostrepton, erythromycin, spiramycin, tylosin, lincomycin, and chloramphenicol. The majority of these were found to have mutations that are similar or identical to those previously found in other species, while several novel mutations were identified. This study provides potential selectable markers for genetic manipulations and demonstrates the feasibility of using R. marinus as a model system for studies of ribosome and RNA polymerase structure, function, and evolution.

Maternal prenatal vitamin B12 intake is associated with speech development and mathematical abilities in childhood.

Deficiencies of many nutrients in pregnancy have adverse effects on fetal brain development with consequent impaired cognitive function in childhood. However, it is unclear whether deficiencies of vitamin B12 prenatally are harmful to the developing fetus. We therefore used the Avon Longitudinal Study of Parents and Children to test the hypothesis that cognitive outcomes in childhood are reduced if their mothers consumed a diet low in vitamin B12 during pregnancy. A detailed exposome analysis was used to identify 9 factors independently associated with low vitamin B12 intake. These were taken into account in each of 26 outcome analyses. Results showed that the children of women with the lowest 10% intake of B12 were at increased risk of poor vocabulary at 24 months, reduced ability at combining words at 38 months, poor speech intelligibility at 6 years, poor mathematics comprehension at school years 4 and 6 (ages 8-9 and 10-11 years), and poor results on the national mathematics tests (age 13). There were no such significant adjusted associations for reading or spelling abilities, or for verbal or full-scale IQ (Intelligence Quotient) at 8 or at 15. Thus, we have confirmed that there are adverse effects on the child's development if the pregnant woman has a low intake of vitamin B12, and we have shown that these are specific to certain speech and mathematical abilities.

Structure of Erm-modified 70S ribosome reveals the mechanism of macrolide resistance.

Many antibiotics inhibit bacterial growth by binding to the ribosome and interfering with protein biosynthesis. Macrolides represent one of the most successful classes of ribosome-targeting antibiotics. The main clinically relevant mechanism of resistance to macrolides is dimethylation of the 23S rRNA nucleotide A2058, located in the drug-binding site, a reaction catalyzed by Erm-type rRNA methyltransferases. Here, we present the crystal structure of the Erm-dimethylated 70S ribosome at 2.4 Å resolution, together with the structures of unmethylated 70S ribosome functional complexes alone or in combination with macrolides. Altogether, our structural data do not support previous models and, instead, suggest a principally new explanation of how A2058 dimethylation confers resistance to macrolides. Moreover, high-resolution structures of two macrolide antibiotics bound to the unmodified ribosome reveal a previously unknown role of the desosamine moiety in drug binding, laying a foundation for the rational knowledge-based design of macrolides that can overcome Erm-mediated resistance.

Unexpected Associations between the Number of FRAXE Repeats in Boys and Evidence of Diabetes in Their Mothers and Maternal Grandmothers.

The FRAXE section of the FMR2 gene, located on the X chromosome, contains varying numbers of trinucleotide repeats; boys with over 200 repeats tend to have mild cognitive impairments, though this is rare. Little is known, however, concerning the phenotypes of individuals with smaller numbers of repeats. Here we answer the research question as to whether the health of ancestors of boys from whom the relevant X chromosome was inherited differed in any way according to the number of FRAXE repeats. Numbers of FRAXE repeats in 5057 boys from the Avon Longitudinal Study of Parents and Children (ALSPAC) were assessed. The distribution was bimodal, with the second smaller distribution starting at 22 repeats. We tested whether possession of 22+ repeats was associated with differences in the health of mothers (who share the X chromosome) and maternal grandmothers (half of whom share it). Female ancestors of boys with >21 repeats compared with <22 showed that maternal grandmothers (MGM) and mothers (M) had an increased risk of diabetes: MGM Type I odds ratio (OR) 2.40 [95%CI: 1.07,5.38]; MGM Type II OR 1.61 [0.96,2.70]; M OR 1.95 [0.96,3.94] using self-reported questionnaire measures. These results were confirmed from maternal medical records which revealed an increased level of diabetes [OR 2.40 (1.16,4.96)] and an increased risk of repeated glycosuria during pregnancy [OR 1.60 (1.08,2.36)]. We tested numbers of FRAXA repeats and showed no such associations, indicating that the findings were not associated with triploid repeats in general. If these findings are replicated elsewhere, there are at least three possible interpretations: (i) maternal diabetes/prediabetes results in an increased number of FRAXE repeats; (ii) women with high numbers of FRAXE repeats are at increased risk of diabetes; or (iii) some common factor, e.g. genomic instability, results in both diabetes and increased repeats.

Parental spiritual and religious beliefs and behaviour data collected from the Avon Longitudinal Study of Parents and Children, 2020.

There are few studies that chart the ways in which the religious beliefs and practices of parents and their offspring vary over time. Even fewer can relate this to aspects of their physical and mental health or distinguish the different facets of the environment that may have influenced the development or loss of religious/spiritual belief and behaviours over time. This paper describes the recent data collection in the Avon Longitudinal Study of Parents and Children (ALSPAC) on the beliefs and behaviours of the study parents some 27-28 years after the first measures were collected. Questions that were previously administered to the mother and her partner on religion, spirituality, behaviours, and beliefs (RSBB) were repeated for the fourth time, together with enhanced data on RSBB. The new data are described and compared with previous responses. The most notable difference between the 9 year and the 2020 sweep was the increase of professed non-believers in both the mothers (17.5% vs 29.8%) and partners (31.9% vs. 45.3%). As expected, on each occasion study partners were less likely to acknowledge RSBB compared to the study mothers. In the latest sweep, respondents were less likely to be unsure if they believed and more likely to not believe. Responses to "Do you believe in God or a divine power?" in mothers ranged from 49.9% stating 'yes' antenatally to 43.5% doing so in 2020; 14.9% vs 29.8% for 'no' and 35.2% to 26.6% for 'not sure'. For partners, the corresponding figures are: 'yes' 37.0% vs. 30.0%; 'no' 28.6% vs. 45.3% and 'not sure' 34.5% vs. 24.6%. We plan to undertake detailed analyses of the antecedents and consequences of RBSS. All data are available for use by interested researchers.

The mother during pregnancy and the puerperium: Detailed data abstracted from the clinical obstetric records of ALSPAC pregnancies.

Background: When the Avon Longitudinal Study of Parents and Children (ALSPAC) was planned, it was assumed that the clinical obstetric data would be easily accessible from the newly developed National Health Service computerised 'STORK' system. Pilot studies, however, showed that, although fairly accurate in regard to aspects of labour and delivery, it was, at the time (1990-2), inadequate for identifying the full antenatal and postnatal details of clinical complications and treatments of the women in the Study. Methods: A scheme was therefore developed to train research staff to find and abstract relevant details from clinical records onto proformas designed for the purpose. Extracting such data proved very time consuming (up to six hours for complicated pregnancies) and consequently expensive. Funding for the enterprise was obtained piecemeal using specific focussed grants to extract data for subsamples of the Study, including a random sample to serve as controls. Results: To date, detailed records have been completed for 8369 pregnancies, and a further 5336 (13,705 in total) have complete details on specific prenatal areas, including serial measures of maternal blood pressure, proteinuria and weight. In this Data Note we describe the information abstracted from the obstetric medical records concerning the mother during pregnancy, labour, delivery and the first two weeks of the puerperium. Information abstracted relating to the fetus (including fetal monitoring, presentation, method of delivery) and neonate (signs of asphyxia, resuscitation, treatment and well-being) have been described in a further Data Note. Conclusions: These data add depth to ALSPAC concerning ways in which the signs and symptoms, procedures and treatments of the mother prenatally, intrapartum and postnatally, may impact on the long-term health and development of both mother and child. They augment the data collected from the mothers' questionnaires (described elsewhere) and the 'STORK' digital hospital data.

Cryo-electron microscopy structure of the 70S ribosome from Enterococcus faecalis.

Enterococcus faecalis is a gram-positive organism responsible for serious infections in humans, but as with many bacterial pathogens, resistance has rendered a number of commonly used antibiotics ineffective. Here, we report the cryo-EM structure of the E. faecalis 70S ribosome to a global resolution of 2.8 Å. Structural differences are clustered in peripheral and solvent exposed regions when compared with Escherichia coli, whereas functional centres, including antibiotic binding sites, are similar to other bacterial ribosomes. Comparison of intersubunit conformations among five classes obtained after three-dimensional classification identifies several rotated states. Large ribosomal subunit protein bL31, which forms intersubunit bridges to the small ribosomal subunit, assumes different conformations in the five classes, revealing how contacts to the small subunit are maintained throughout intersubunit rotation. A tRNA observed in one of the five classes is positioned in a chimeric pe/E position in a rotated ribosomal state. The 70S ribosome structure of E. faecalis now extends our knowledge of bacterial ribosome structures and may serve as a basis for the development of novel antibiotic compounds effective against this pathogen.

Ancestral childhood environmental exposures occurring to the grandparents and great-grandparents of the ALSPAC study children.

Background: Cohort studies tend to be designed to look forward from the time of enrolment of the participants, but there is considerable evidence that the previous generations have a particular relevance not only in the genes that they have passed on, their cultural beliefs and attitudes, but also in the ways in which previous environmental exposures may have had non-genetic impacts, particularly for exposures during fetal life or in childhood. Methods: To investigate such non-genetic inheritance, we have collected information on the childhoods of the ancestors of the cohort of births comprising the original Avon Longitudinal Study of Parents and Children (ALSPAC). The data collected on the study child's grandparents and great grandparents comprise: (a) countries of birth; (b) years of birth; (c) age at onset of smoking; (d) whether the ancestral mothers smoked during pregnancy; (e) social class of the household; (f) information on 19 potentially traumatic situations in their childhoods such as death of a parent, being taken into care, not having enough to eat, or being in a war situation; (g) causes of death for those ancestors who had died. The ages at which the individual experienced the traumatic situations distinguished between ages <6; 6-11, and 12-16 years. The numbers of ancestors on which data were obtained varied from 1128 paternal great-grandfathers to 4122 maternal great grandmothers. These ancestral data will be available for analysis to bona fide researchers on application to the ALSPAC Executive Committee.

The correct genus for the Afrotropical woodpeckers Campethera caroli and Campethera nivosa (Aves: Piciformes, Picidae).

We argue that the correct generic name for the Afrotropical woodpeckers usually known as Campethera caroli and Campethera nivosa (Aves: Piciformes, Picidae) should be Pardipicus Bonaparte, 1854, and we choose and propose Chloropicus caroli Malherbe, 1852 as type species. Fuchs et al. (2018) had suggested Stictopicus Malherbe, 1861, following Wolters (1977), but that genus has as type species Picus nubicus Boddaert, 1783 (= Campethera nubica).