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.

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.

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.

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.

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.

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'.

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'.

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'.

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.

Identification of risk factors associated with carriage of resistant Escherichia coli in three culturally diverse ethnic groups in Tanzania: a biological and socioeconomic analysis.

BACKGOUND: Improved antimicrobial stewardship, sanitation, and hygiene are WHO-inspired priorities for restriction of the spread of antimicrobial resistance. Prioritisation among these objectives is essential, particularly in low-income and middle-income countries, but the factors contributing most to antimicrobial resistance are typically unknown and could vary substantially between and within countries. We aimed to identify the biological and socioeconomic risk factors associated with carriage of resistant Escherichia coli in three culturally diverse ethnic groups in northern Tanzania. METHODS: We developed a survey containing more than 200 items and administered it in randomly selected households in 13 Chagga, Arusha, or Maasai villages chosen on the basis of ethnic composition and distance to urban centres. Human stool samples were collected from a subset of households, as were liquid milk samples and swabs of milk containers. Samples were processed and plated onto MacConkey agar plates, then presumptive E coli isolates were identified on the basis of colony morphology. Susceptibility of isolates was then tested against a panel of nine antimicrobials (ampicillin, ceftazidime, chloramphenicol, ciprofloxacin, kanamycin, streptomycin, sulfamethoxazole, tetracycline, and trimethoprim) via a breakpoint assay. Susceptibility findings were matched with data across a wide range of household characteristics, including education, hygiene practices, wealth, livestock husbandry, and antibiotic use. FINDINGS: Between March 23, 2012, and July 30, 2015, we interviewed 391 households (118 Arusha, 100 Chagga, and 173 Maasai). Human stool samples were collected at 226 (58%) households across the 13 villages. 181 milk samples and 191 milk-container swabs were collected from 117 households across seven villages. 11 470 putative E coli samples were isolated from stool samples. Antimicrobial use in people and livestock was not associated with prevalence of resistance at the household level. Instead, the factors with the greatest predictive value involved exposure to bacteria, and were intimately connected with fundamental cultural differences across study groups. These factors included how different subsistence types (pastoralists vs farmers) access water sources and consumption of unboiled milk, reflecting increased exposure to resistant bacteria in milk. INTERPRETATION: When cultural and ecological conditions favour bacterial transmission, there is a high likelihood that people will harbour antimicrobial-resistant bacteria irrespective of antimicrobial use practices. Public health interventions to limit antimicrobial resistance need to be tailored to local practices that affect bacterial transmission. FUNDING: US National Science Foundation; Biotechnology and Biological Sciences Research Council, UK Medical Research Council; and the Allen School.

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.

Greater wealth inequality, less polygyny: rethinking the polygyny threshold model.

Monogamy appears to have become the predominant human mating system with the emergence of highly unequal agricultural populations that replaced relatively egalitarian horticultural populations, challenging the conventional idea-based on the polygyny threshold model-that polygyny should be positively associated with wealth inequality. To address this polygyny paradox, we generalize the standard polygyny threshold model to a mutual mate choice model predicting the fraction of women married polygynously. We then demonstrate two conditions that are jointly sufficient to make monogamy the predominant marriage form, even in highly unequal societies. We assess if these conditions are satisfied using individual-level data from 29 human populations. Our analysis shows that with the shift to stratified agricultural economies: (i) the population frequency of relatively poor individuals increased, increasing wealth inequality, but decreasing the frequency of individuals with sufficient wealth to secure polygynous marriage, and (ii) diminishing marginal fitness returns to additional wives prevent extremely wealthy men from obtaining as many wives as their relative wealth would otherwise predict. These conditions jointly lead to a high population-level frequency of monogamy.

Medicinal foods and beverages among Maasai agro-pastoralists in northern Tanzania.

ETHNOPHARMACOLOGICAL RELEVANCE: Pastoralist Maasai populations of east Africa use several different wild plants as dietary and medicinal additives in beverages (soups and teas), yet little is known about how the plants used and the rationales for use compare and contrast across different Maasai beverages, including how gender specific dietary and health concerns structure patterns of intake. AIM OF THE STUDY: We investigated three Maasai beverages: almajani (tea or herbal infusion); motorí (traditional soup); and okiti (psychoactive herbal tea). In order to build knowledge about the cultural functions of these Maasai food-medicines and their incidence of use we also investigated use rationales and self-reported frequencies of use. We conclude by examining gender differences and the possible pharmacological antimicrobial activity of the most frequently used plants. MATERIALS AND METHODS: Research was conducted in 2015, with a population of semi-nomadic agropastoralist Maasai residing in northern Tanzania. Data were collected using key informant interviews, plant collections, n = 32 structured surveys, and n = 40 freelist interviews followed by a literature review to determine the known antimicrobial activity of the most used plants. RESULTS: We identified 20 plants that Maasai add to soup, 11 in tea, and 11 in the psychoactive tea, for a total of 24 herbal additives. Seven plant species were used in all three Maasai beverages, and these clustered with 10 common ailments. Based on self-reports, women use the beverages less frequently and in smaller amounts than men. There were also several gender differences in the plants that Maasai add to motorí and their associated use rationales. CONCLUSIONS: There are several intersections concerning the plant species used and their associated rationales for use in almajani, motori, and okiti. Moving outward, Maasai beverages and their additives increasingly involve gender specific concerns. Female use of food-medicines, relative to men, is structured by concerns over pregnancy, birth, and lactation. The frequent consumption of herbal additives, many of which contain antimicrobial compounds, potentially helps modulate infections, but could have other unintentional effects as well.

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.

Bem viver para a próxima geração: entre subjetividade e bem comum a partir da perspectiva da ecossocioeconomia / Good living for the next generation: between subjectivity and common good from the perspective of eco-socio-economy

Resumo Bem Viver (BV) é tema intrigante quando se distancia da chamada sociedade de consumo. Diante do fenômeno das mudanças climáticas, não faz sentido discutir BV subjetivamente, sem correlacioná-lo ao significado de bem comum. O objetivo é dialogar sobre o tema do BV, relevando o interesse das gerações futuras, a partir da relação dialética entre subjetividade e bem comum e da complementaridade entre a dinâmica entre ser humano e natureza. Trata-se de um ensaio. A discussão remete à visão ecocêntrica, em que sugere que o sistema social está interconectado ao ecológico, sobretudo na ocasião em que se considera a produção do BV para gerações futuras. O BV, mais do que condição material, socioeducacional e de saúde, é estado particular de felicidade, no qual vigoram padrões culturais distintos. Não se nega abstrair a lógica econômica - na qual o sujeito calcula consequências individuais, mas releva territorialmente o bem comum -, e não é ela hegemônica ou mesmo determinante nos processos de produção e reprodução humana, dos quais resulta o sujeito esvaziado. Por fim, o BV não pode ficar relegado a conquistas de outras gerações ou ainda a um modo de vida "cool", desresponsabilizado e descontextualizado em relação a gerações futuras. Subjetividade e bem comum podem se reconciliar no plano de uma esfera societária que não seja reduzida a mero cálculo e em que o ser humano não deponha, nem ao outro (política) nem a si (psique), na produção de caminho ecossocioeconômico, o que constitui uma vida humana associada que não relegue sistemicamente o seu próprio processo de socialização.

Abstract Good Living (GL) is an intriguing theme when apart from the consumer society. It is purposeless to discuss GL subjectively in the face of climate change, without associating it with the meaning of common good. The aim is to discuss GL, taking the interest of future generations into account, from the dialectic relationship between subjectivity and common good and the complementarity between human beings and nature. This is an essay. The discussion refers to the ecocentric perspective, which suggests that the social system is interconnected with the ecological system, especially when one considers the creation of GL for future generations. GL, more than just material, health and socio-educational conditions, is a particular state of happiness, in which different cultural patterns prevail. One does not deny abstracting economic logic - in which the subject calculates individual consequences, but territorially ignores the common good - and it does not prevail over or even determine production processes and human reproduction, from which arises the emptied subject. Finally, GL cannot be relegated to achievements of other generations, or else to a "cool" way of life, without responsibilities and decontextualized from future generations. Subjectivity and common good can be reconciled in a societal dimension that is not reduced to mere calculation and where human beings do not put aside, nor to others (politics) nor to themselves (psyche), in the production of the eco-socio-economical path, what makes an associated human life that does not systemically relegate its own process of socialization.

Medical pluralism and livestock health: ethnomedical and biomedical veterinary knowledge among East African agropastoralists.

BACKGROUND: Human and animal health are deeply intertwined in livestock dependent areas. Livestock health contributes to food security and can influence human health through the transmission of zoonotic diseases. In low-income countries diagnosis and treatment of livestock diseases is often carried out by household members who draw upon both ethnoveterinary medicine (EVM) and contemporary veterinary biomedicine (VB). Expertise in these knowledge bases, along with their coexistence, informs treatment and thus ultimately impacts animal and human health. The aim of the current study was to determine how socio-cultural and ecological differences within and between two livestock-keeping populations, the Maasai of northern Tanzania and Koore of southwest Ethiopia, impact expertise in EVM and VB and coexistence of the two knowledge bases. METHODS: An ethnoveterinary research project was conducted to examine dimensions of EVM and VB knowledge among the Maasai (N = 142 households) and the Koore (N = 100). Cultural consensus methods were used to quantify expertise and the level of agreement on EVM and VB knowledge. Ordinary least squares regression was used to model patterns of expertise and consensus across groups and to examine associations between knowledge and demographic/sociocultural attributes. RESULTS: Maasai and Koore informants displayed high consensus on EVM but only the Koore displayed consensus on VB knowledge. EVM expertise in the Koore varied across gender, herd size, and level of VB expertise. EVM expertise was highest in the Maasai but was only associated with age. The only factor associated with VB expertise was EVM expertise in the Koore. CONCLUSIONS: Variation in consensus and the correlates of expertise across the Maassi and the Koore are likely related to differences in the cultural transmission of EVM and VB knowledge. Transmission dynamics are established by the integration of livestock within the socioecological systems of the Maasai and Koore and culture historical experiences with livestock disease. Consideration of the nature and coexistence of EVM and VB provides insight into the capacity of groups to cope with disease outbreaks, pharmaceutical use patterns, and the development of community health interventions.

Antimicrobial Use and Veterinary Care among Agro-Pastoralists in Northern Tanzania.

Frequent and unregulated use of antimicrobials (AM) in livestock requires public health attention as a likely selection pressure for resistant bacteria. Studies among small-holders, who own a large percentage of the world's livestock, are vital for understanding how practices involving AM use might influence resistance. We present a cultural-ecological mixed-methods analysis to explore sectors of veterinary care, loosely regulated AM use, and human exposure to AMs through meat and milk consumption across three rural to peri-urban Tanzanian ethnic groups (N = 415 households). Reported use of self-administered AMs varied by ethnic group (Maasai: 74%, Arusha: 21%, Chagga: 1%) as did consultation with professional veterinarians (Maasai: 36%, Arusha: 45%, Chagga: 96%) and observation of withdrawal of meat and milk from consumption during and following AM treatment (Maasai: 7%, Arusha: 72%, Chagga: 96%). The antibiotic oxytetracycline was by far the most common AM in this sample. Within ethnic groups, herd composition differences, particularly size of small-stock and cattle herds, were most strongly associated with differences in lay AM use. Among the Arusha, proxies for urbanization, including owning transportation and reliance on "zero-grazing" herds had the strongest positive associations with veterinarian consultation, while distance to urban centers was negatively associated. For Maasai, consultation was negatively associated with use of traditional healers or veterinary drug-shops. Observation of withdrawal was most strongly associated with owning technology among Maasai while Arusha observance displayed seasonal differences. This "One-Health" analysis suggests that livelihood and cultural niche factors, through their association with practices in smallholder populations, provide insight into the selection pressures that may contribute to the evolution and dissemination of antimicrobial resistance.

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.