Inhibition of the SUV4-20 H1 histone methyltransferase increases frataxin expression in Friedreich's ataxia patient cells.

The molecular mechanisms of reduced frataxin (FXN) expression in Friedreich's ataxia (FRDA) are linked to epigenetic modification of the FXN locus caused by the disease-associated GAA expansion. Here, we identify that SUV4-20 histone methyltransferases, specifically SUV4-20 H1, play an important role in the regulation of FXN expression and represent a novel therapeutic target. Using a human FXN-GAA-Luciferase repeat expansion genomic DNA reporter model of FRDA, we screened the Structural Genomics Consortium epigenetic probe collection. We found that pharmacological inhibition of the SUV4-20 methyltransferases by the tool compound A-196 increased the expression of FXN by ∼1.5-fold in the reporter cell line. In several FRDA cell lines and patient-derived primary peripheral blood mononuclear cells, A-196 increased FXN expression by up to 2-fold, an effect not seen in WT cells. SUV4-20 inhibition was accompanied by a reduction in H4K20me2 and H4K20me3 and an increase in H4K20me1, but only modest (1.4-7.8%) perturbation in genome-wide expression was observed. Finally, based on the structural activity relationship and crystal structure of A-196, novel small molecule A-196 analogs were synthesized and shown to give a 20-fold increase in potency for increasing FXN expression. Overall, our results suggest that histone methylation is important in the regulation of FXN expression and highlight SUV4-20 H1 as a potential novel therapeutic target for FRDA.

Famine-related mortality in early life and accelerated life histories in nineteenth-century Belgium.

Density-dependent and extrinsic mortality are predicted to accelerate reproductive maturation. The first 5 years of life is a proposed sensitive period for life-history regulation. This study examines the ways in which local mortality during this sensitive period was related to subsequent marriage timing in nineteenth-century Belgium (n women = 11 892; n men = 14 140). Local mortality during the sensitive period was inversely associated with age at first marriage for men and women controlling for literacy, occupational status, population growth and migration. Cox regression indicated decreased time to marriage for women (HR = 1.661, 95% CI: 1.542-1.789) and men (HR = 1.327, 95% CI: 1.238-1.422) from high mortality municipalities. Rising population growth rates were associated with earlier marriage for men and women. Migration in general was associated with later marriage for men and women. Consistent with life-history predictions, harsh ecological conditions during early life such as famine coincided with earlier marriage.

Post-translational site-selective protein backbone α-deuteration.

Isotopic replacement has long-proven applications in small molecules. However, applications in proteins are largely limited to biosynthetic strategies or exchangeable (for example, N-H/D) labile sites only. The development of postbiosynthetic, C-1H → C-2H/D replacement in proteins could enable probing of mechanisms, among other uses. Here we describe a chemical method for selective protein α-carbon deuteration (proceeding from Cys to dehydroalanine (Dha) to deutero-Cys) allowing overall 1H→2H/D exchange at a nonexchangeable backbone site. It is used here to probe mechanisms of reactions used in protein bioconjugation. This analysis suggests, together with quantum mechanical calculations, stepwise deprotonations via on-protein carbanions and unexpected sulfonium ylides in the conversion of Cys to Dha, consistent with a 'carba-Swern' mechanism. The ready application on existing, intact protein constructs (without specialized culture or genetic methods) suggests this C-D labeling strategy as a possible tool in protein mechanism, structure, biotechnology and medicine.

The Medial Pillar Island Flap for Oncoplastic Breast Reconstruction of Upper Pole Defects.

BACKGROUND: Breast deformity is common following lumpectomy. Use of ptotic lower pole tissue for restoration of volume in the upper pole is quite appealing since it allows for a concomitant lift. This study presents the medial pillar island flap technique of oncoplastic breast reconstruction of upper pole defects. METHODS: Vascular anatomy of the lower pole of the breast was investigated with cadaver study. The medial pillar island flap was designed utilizing the territory of the inferior pole of the breast as an island flap pedicled medially by the internal mammary artery perforators surrounded by the soft tissue of the medial pillar. It was transposed to the upper pole lumpectomy defect as an independent flap from superomedial pedicle which was utilized for nipple transposition. RESULTS: The dominant internal mammary artery perforator supplying the medial pillar island flap was consistently found in the fourth interspace at a mean distance of 8.5 cm (range, 8 to 10) from the sternal midline. Thirty patients underwent the procedure, with a mean age of 61 years and mean body mass index of 28.9. The average size of the defect was 170 cm(3) (range, 48 to 295 cm(3)). The majority of the patients (n = 28) underwent opposite breast symmetry surgery as well. The average follow up was 12 months. Complication rate was 23.3%. Reoperation rate was 16.7%. There was no evidence of flap compromise or nipple areola complex necrosis. Patient satisfaction was high, with a mean score of 4.1 (range, 2 to 5) out of 5. CONCLUSIONS: The medial pillar island flap has reliable vascularity based on the internal mammary artery system. The flap carries lower pole breast tissue as confined by the medial and lateral pillars of a vertical mastopexy design, offering unrestricted arc of rotation for effective reconstruction of upper pole lumpectomy defects as it is completely dissected from the chest wall and the inframammary fold. The two flap design, along with superomedial pedicle, accomplishes versatility for flap inset. The technique was proven to result in safe outcomes without major complications.

Intramolecular Inverse Electron-Demand [4 + 2] Cycloadditions of Ynamides with Pyrimidines: Scope and Density Functional Theory Insights.

4-Aminopyridines are valuable scaffolds for the chemical industry in general, from life sciences to catalysis. We report herein a collection of structurally diverse polycyclic fused and spiro-4-aminopyridines that are prepared in only three steps from commercially available pyrimidines. The key step of this short sequence is a [4 + 2]/retro-[4 + 2] cycloaddition between a pyrimidine and an ynamide, which constitutes the first examples of ynamides behaving as electron-rich dienophiles in [4 + 2] cycloaddition reactions. In addition, running the ihDA/rDA reaction in continuous mode in superheated toluene, to overcome the limited scalability of MW reactions, results in a notable production increase compared to batch mode. Finally, density functional theory investigations shed light on the energetic and geometric requirements of the different steps of the ihDA/rDA sequence.

A two-month follow-up evaluation testing interventions to limit the emergence and spread of antimicrobial resistant bacteria among Maasai of northern Tanzania.

BACKGROUND: In sub-Saharan Africa, efforts to control antimicrobial resistance (AMR) are aggravated by unregulated drug sales and use, and high connectivity between human, livestock, and wildlife populations. Our previous research indicates that Maasai agropastoralists-who have high exposure to livestock and livestock products and self-administer veterinary antibiotics-harbor antibiotic resistant Escherichia coli (E. coli). Here, we report the results of a public health intervention project among Maasai aimed at reducing selection and transmission of E. coli bacteria. METHODS: Research was conducted in two Maasai communities in Northern Tanzania. Participants were provided with health knowledge and technological innovations to facilitate: 1) the prudent use of veterinary antibiotics (tape measures and dosage charts to calculate livestock weight for more accurate dosage), and, 2) the pasteurization of milk (thermometers), the latter of which was motivated by findings of high levels of resistant E. coli in Maasai milk. To determine knowledge retention and intervention adoption, we conducted a two-month follow-up evaluation in the largest of the two communities. RESULTS: Retention of antimicrobial knowledge was positively associated with retention of bacterial knowledge and, among men, retention of bacterial knowledge was associated with greater wealth. Bacterial and AMR knowledge were not, however, associated with self-reported use of the innovations. Among women, self-reported use of the thermometers was associated with having more children and greater retention of knowledge about the health benefits of the innovations. Whereas 70% of women used their innovations correctly, men performed only 18% of the weight-estimation steps correctly. Men's correct use was associated with schooling, such that high illiteracy rates remain an important obstacle to the dissemination and diffusion of weight-estimation materials. CONCLUSION: Our results indicate that dietary preferences for unboiled milk, concerns over child health, and a desire to improve the health of livestock are important cultural values that need to be incorporated in future AMR-prevention interventions that target Maasai populations. More generally, these findings inform future community-health interventions to limit AMR.

Cultural consonance, deprivation, and psychological responses for niche construction.

Cultural consonance is a measure of culturally encoded goals relevant to psychological, behavioral, and health responses to deprivation. Similar to extrinsic mortality, low cultural consonance and an associated inability to predict adaptive outcomes may activate impulsivity, delay discounting, and reward seeking. Low cultural consonance could promote "fast life history" in low-quality environments and motivate cultural niche construction for local adaptation.

Cooperative breeding and Aka children's nutritional status: is flexibility key?

Research suggests that nonmaternal caregivers (allomothers) offer essential assistance through caregiving and provisioning, helping to support lengthy child development. Here, we examine the role of allomothers and the broader social and sharing network on Aka forager children's anthropometrics. We hypothesize that nonmaternal investors strategically target their assistance when it is most needed and when it will have the greatest effect. We evaluate children's nutritional status using WHO standards [weight-for-age (WAZ), height-for-age (HAZ), and weight-for-height (WHZ)] during four periods of child development [early infancy (birth to <9 months), mobility to weaning (9 to <36 months), early childhood (36 to <72 months), and middle childhood (72 to <120 months); N = 127]. We explore the effects of allomothers and the social network across these different risk periods and examine whether the broader social network buffers the loss of a primary allomother. ANOVA results suggest that girls may be experiencing some growth faltering, while boys start smaller and remain small across these stages. We used OLS multiple regression models to evaluate the effects of sex, camp composition, risk periods, and allomothers' presence on WAZ, HAZ, and WHZ. Grandmothers are the most influential allomother, with their effect most evident during the 9 to <36 month period. Camp size was also associated with greater WAZ, suggesting that children residing in small camps may be disadvantaged. Our findings also indicate that, under specific residence patterns, cooperative child rearing networks buffer the loss of a grandmother. Overall, our results suggest the importance of social networks to children's nutritional status and that individuals target investment to critical phases.

Cooperative behaviour and prosocial reputation dynamics in a Dominican village.

Prosocial reputations play an important role, from the evolution of language to Internet transactions; however, questions remain about their behavioural correlates and dynamics. Formal models assume prosocial reputations correlate with the number of cooperative acts one performs; however, if reputations flow through information networks, then the number of individuals one assists may be a better proxy. Formal models demonstrate indirect experience must track behaviour with the same fidelity as direct experience for reputations to become viable; however, research on corporate reputations suggests performance change does not always affect reputation change. Debate exists over the cognitive mechanisms employed for assessing reputation dynamics. Image scoring suggests reputations fluctuate relative to the number of times one fails to assist others in need, while standing strategy claims reputations fluctuate relative to the number of times one fails to assist others in good standing. This study examines the behavioural correlates of prosocial reputations and their dynamics over a 20-month period in an Afro-Caribbean village. Analyses suggest prosocial reputations: (i) are correlated with the number of individuals one assists in economic production, not the number of cooperative acts; (ii) track cooperative behaviour, but are anchored across time; and (iii) are captured neither by image scoring nor standing strategy-type mechanisms.

Cooperative breeding and maternal energy expenditure among Aka foragers.

OBJECTIVES: Previous research among foragers and theory suggests that nonmaternal caregivers offer essential assistance, which supports female reproduction and the costs associated with lengthy child development. Mothers' face trade-offs in energy allocation between work and childcare, particularly when mothers have an infant. These trade-offs likely have crucial impacts on the pace of reproduction and child health. Caregivers can help mothers with childcare or they can reduce a mother's nonchildcare workload. If caregivers assist mothers by substituting childcare, then maternal energy expenditure (EE) in other work activities should increase. If caregivers assist mothers by substituting labor, then maternal EE in work activities should decrease when caregivers are present. METHODS: Utilizing detailed, quantitative behavioral observations and EE data, we test these propositions with data from 28 Aka forager mothers with children <35 months old. We isolate paternal, grandmaternal, and other caregiver effects on maternal EE and childcare in multivariate analyses. RESULTS: Our results show that caregivers (largely grandmothers) significantly reduce mothers' work EE by as much 216 kcal across a 9-hour observation period, while fathers and juveniles appear to increase maternal EE. Direct childcare from grandmothers decreases maternal direct care by about one-to-one indicating a labor substitution. Direct childcare from fathers decreases maternal care by almost 4 to 1, resulting in a net reduction of total direct care from all caregivers. CONCLUSIONS: Our results indicate that there are multiple pathways by which helpers offset maternal work/childcare trade-offs.

Adolescent fertility and risky environments: a population-level perspective across the lifespan.

Timing of first reproduction is a key life-history variable with important implications for global economic development and health. Life-history theory predicts that human reproductive strategies are shaped by mortality regimes. This study provides the first test of the relationship between population-level adolescent fertility (AF) and extrinsic risk at two time points. Data are from United Nations database and were analysed using mediation and moderation techniques. The goals were to determine whether (i) early risk has a stronger impact on fertility than current risk; (ii) current risk mediates the relationship between early risk and fertility outcomes; and (iii) different levels of early risk influence the relationship between current risk and fertility. Results indicated that current risk partially mediated the relationship between early risk and fertility, with early risk having the strongest impact on reproduction. Measures for early and current mortality did not show significant interaction effects. However, a series of separate regression analyses using a quantile split of early risk indicated that high levels of early risk strengthened the relationship between current risk and AF. Overall, these findings demonstrate that reproductive strategies are significantly influenced by fluctuations of early mortality as well as current environmental cues of harshness.

Resource availability, mortality, and fertility: a path analytic approach to global life-history variation.

Humans exhibit considerable diversity in timing and rate of reproduction. Life-history theory (LHT) suggests that ecological cues of resource richness and survival probabilities shape human phenotypes across populations. Populations experiencing high extrinsic mortality due to uncertainty in resources should exhibit faster life histories. Here we use a path analytic (PA) approach informed by LHT to model the multiple pathways between resources, mortality rates, and reproductive behavior in 191 countries. Resources that account for the most variance in population mortality rates are predicted to explain the most variance in total fertility rates. Results indicate that resources (e.g., calories, sanitation, education, and health-care expenditures) influence fertility rates in paths through communicable and noncommnunicable diseases. Paths acting through communicable disease are more strongly associated with fertility than are paths through noncommunicable diseases. These results suggest that a PA approach may help disaggregate extrinsic and intrinsic mortality factors in cross-cultural analyses. Such knowledge may be useful in developing targeted policies to decrease teenage pregnancy, total fertility rates, and thus issues associated with overpopulation.

Chemogenomics for drug discovery: clinical molecules from open access chemical probes.

In recent years chemical probes have proved valuable tools for the validation of disease-modifying targets, facilitating investigation of target function, safety, and translation. Whilst probes and drugs often differ in their properties, there is a belief that chemical probes are useful for translational studies and can accelerate the drug discovery process by providing a starting point for small molecule drugs. This review seeks to describe clinical candidates that have been inspired by, or derived from, chemical probes, and the process behind their development. By focusing primarily on examples of probes developed by the Structural Genomics Consortium, we examine a variety of epigenetic modulators along with other classes of probe.

A ride through the epigenetic landscape: aging reversal by reprogramming.

Aging has become one of the fastest-growing research topics in biology. However, exactly how the aging process occurs remains unknown. Epigenetics plays a significant role, and several epigenetic interventions can modulate lifespan. This review will explore the interplay between epigenetics and aging, and how epigenetic reprogramming can be harnessed for age reversal. In vivo partial reprogramming holds great promise as a possible therapy, but several limitations remain. Rejuvenation by reprogramming is a young but rapidly expanding subfield in the biology of aging.

Two-stage prosthetic breast reconstruction with latissimus flap: Prepectoral versus subpectoral approach.

BACKGROUND: Use of latissimus flap in prosthetic breast reconstruction after mastectomy is an established approach, particularly in patients who have failed breast-conserving therapy. This study presents a comparison of the prepectoral and the subpectoral approach for two-stage prosthetic breast reconstruction with a latissimus flap. METHODS: A retrospective review of outcomes and complications was completed between the prepectoral group (n = 33 patients, 50 reconstructed breasts) and the subpectoral group (n = 22 patients, 36 reconstructed breasts). RESULTS: The demographics were similar between the prepectoral and subpectoral groups in terms of mean age (52.4 vs. 52.5 years, p = 0.97), smoking history (15.1% vs. 13.6%; p = 1.00), radiation history (75.8% vs. 91.0%; p = 0.28), and mean length of follow-up (479 vs. 680 days; p = 0.07). The body mass index was significantly higher in the prepectoral group (27.6 vs. 25.2 kg/m2; p = 0.03). Complications were similar between the groups in terms of hematoma (9.1% vs. 0.0%, p = 0.26), infection resulting in implant failure (9.1% vs. 4.5%, p = 0.64), thromboembolic events (3.0% vs. 4.5%, p = 1.0), donor site seroma (66.7% vs. 40.9%, p = 0.09), breast seroma (18.2% vs. 27.3%, p = 0.51), capsular contracture (9.1% vs. 4.5%, p = 0.64), animation deformity (39.4% vs. 50.0%, p = 0.58), and reoperation (24.2% vs. 22.8%, p = 1.00). Patient satisfaction scores were also similar between the groups (4.33 ±â€¯1.08 vs. 4.14 ±â€¯1.13, p = 0.52). CONCLUSIONS: The prepectoral approach for two-stage immediate prosthetic reconstruction with a latissimus flap has similar outcomes and complications to those of the subpectoral approach, yet obviating the need for any pectoralis major muscle dissection.

Antimicrobial resistant enteric bacteria are widely distributed amongst people, animals and the environment in Tanzania.

Antibiotic use and bacterial transmission are responsible for the emergence, spread and persistence of antimicrobial-resistant (AR) bacteria, but their relative contribution likely differs across varying socio-economic, cultural, and ecological contexts. To better understand this interaction in a multi-cultural and resource-limited context, we examine the distribution of antimicrobial-resistant enteric bacteria from three ethnic groups in Tanzania. Household-level data (n = 425) was collected and bacteria isolated from people, livestock, dogs, wildlife and water sources (n = 62,376 isolates). The relative prevalence of different resistance phenotypes is similar across all sources. Multi-locus tandem repeat analysis (n = 719) and whole-genome sequencing (n = 816) of Escherichia coli demonstrate no evidence for host-population subdivision. Multivariate models show no evidence that veterinary antibiotic use increased the odds of detecting AR bacteria, whereas there is a strong association with livelihood factors related to bacterial transmission, demonstrating that to be effective, interventions need to accommodate different cultural practices and resource limitations.

Emergent matriliny in a matrifocal, patrilineal population: a male coalitionary perspective.

Daughter-biased parental investment and limited paternal care promote matrifocality and matrilineal descent, both of which are forms of matricentric social organization. However, matrifocality can occur under patrilineal descent. We hypothesize that matrilineal descent could emergently organize social relationships if a society were normatively patrilineal but matrifocal. Furthermore, in matrifocal environments, male and female social lives are envisioned as sex-specific adaptive strategies. Males purportedly form large, flexible social support networks that conflict with conjugal partnership investment owing to a tradeoff in the allocation of effort associated with either investing in male social support or provisioning the conjugal household. However, no quantitative analyses exist about the effect of conjugal partnership formation on male social relations in matrifocal communities. Here we examine whether matrilineal kinship organizes male same-sex social relationships and the effect of conjugal partnerships on male social support in a normatively patrilineal, but matrifocal village. We find that matrilineal kinship influences male social support networks, but not labour cooperation. Consistent with a tradeoff associated with investing in male social support or a conjugal union, we find that labouring with a conjugal partner, but not conjugal partnership itself, reduces male labour and social support outcomes. Our results suggest new insights into men's roles in matricentric social organization: (1) matriliny can emerge in patrilineal systems when household economics shift toward matrifocality in which matrilineal descent is used to organize male social support, and (2) the degree to which this shift occurs depends on the proportion of men who invest in same-sex social networks as opposed to a conjugal partner and offspring. This article is part of the theme issue 'The evolution of female-biased kinship in humans and other mammals'.

The expendable male hypothesis.

Matriliny is a system of kinship in which descent and inheritance are conferred along the female line. The theoretically influential concept of the matrilineal puzzle posits that matriliny poses special problems for understanding men's roles in matrilineal societies. Ethnographic work describes the puzzle as the tension experienced by men between the desire to exert control over their natal kin (i.e. the lineage to which they belong) and over their affinal kin (i.e. their spouses and their biological children). Evolutionary work frames the paradox as one resulting from a man investing in his nieces and nephews at the expense of his own biological offspring. In both cases, the rationale for the puzzle rests on two fundamental assumptions: (i) that men are in positions of authority over women and over resources; and (ii) that men are interested in the outcomes of parenting. In this paper, we posit a novel hypothesis that suggests that certain ecological conditions render men expendable within local kinship configurations, nullifying the above assumptions. This arises when (i) women, without significant assistance from men, are capable of meeting the subsistence needs of their families; and (ii) men have little to gain from parental investment in children. We conclude that the expendable male hypothesis may explain the evolution of matriliny in numerous cases, and by noting that female-centred approaches that call into doubt assumptions inherent to male-centred models of kinship are justified in evolutionary perspective. This article is part of the theme issue 'The evolution of female-biased kinship in humans and other mammals'.

Kinship ties across the lifespan in human communities.

A hypothesis for the evolution of long post-reproductive lifespans in the human lineage involves asymmetries in relatedness between young immigrant females and the older females in their new groups. In these circumstances, inter-generational reproductive conflicts between younger and older females are predicted to resolve in favour of the younger females, who realize fewer inclusive fitness benefits from ceding reproduction to others. This conceptual model anticipates that immigrants to a community initially have few kin ties to others in the group, gradually showing greater relatedness to group members as they have descendants who remain with them in the group. We examine this prediction in a cross-cultural sample of communities, which vary in their sex-biased dispersal patterns and other aspects of social organization. Drawing on genealogical and demographic data, the analysis provides general but not comprehensive support for the prediction that average relatedness of immigrants to other group members increases as they age. In rare cases, natal members of the community also exhibit age-related increases in relatedness. We also find large variation in the proportion of female group members who are immigrants, beyond simple traditional considerations of patrilocality or matrilocality, which raises questions about the circumstances under which this hypothesis of female competition are met. We consider possible explanations for these heterogenous results, and we address methodological considerations that merit increased attention for research on kinship and reproductive conflict in human societies. This article is part of the theme issue 'The evolution of female-biased kinship in humans and other mammals'.