Explore the vast range of titles available.

A mobile colistin resistance gene mcr was first reported in 2016 in China and has since been found with increasing prevalence across South-East Asia. Here we survey the presence of mcr genes in 4907 rectal swabs from mothers and neonates from three hospital sites across Nigeria; a country with limited availability or history of colistin use clinically. Forty mother and seven neonatal swabs carried mcr genes in a range of bacterial species: 46 Enterobacter spp. and single isolates of; Shigella , E. coli and Klebsiella quasipneumoniae . Ninety percent of the genes were mcr-10 ( n  = 45) we also found mcr-1 ( n  = 3) and mcr - 9 ( n  = 1). While the prevalence during this collection (2015-2016) was low, the widespread diversity of mcr -gene type and range of bacterial species in this sentinel population sampling is concerning. It suggests that agricultural colistin use was likely encouraging sustainment of mcr -positive isolates in the community and implementation of medical colistin use will rapidly select and expand resistant isolates. Here, the authors report the results of a BARNARDS sub-study identifying a 1% mobile colistin resistance gene (mcr) carriage rate in around 5000 rectal swabs from mothers and neonates across Nigeria, of which 90% were mcr-10 (mostly Enterobacter spp.) and 10% were mcr-1 and mcr9.

Early development of the microbiome has been shown to affect general health and physical development of the infant and, although some studies have been undertaken in high-income countries, there are few studies from low- and middle-income countries. As part of the BARNARDS study, we examined the rectal microbiota of 2,931 neonates (term used up to 60 d) with clinical signs of sepsis and of 15,217 mothers screening for bla CTX-M-15 , bla NDM , bla KPC and bla OXA-48 -like genes, which were detected in 56.1%, 18.5%, 0% and 4.1% of neonates’ rectal swabs and 47.1%, 4.6%, 0% and 1.6% of mothers’ rectal swabs, respectively. Carbapenemase-positive bacteria were identified by MALDI-TOF MS and showed a high diversity of bacterial species (57 distinct species/genera) which exhibited resistance to most of the antibiotics tested. Escherichia coli , Klebsiella pneumoniae and Enterobacter cloacae / E. cloacae complex, the most commonly found isolates, were subjected to whole-genome sequencing analysis and revealed close relationships between isolates from different samples, suggesting transmission of bacteria between neonates, and between neonates and mothers. Associations between the carriage of antimicrobial resistance genes (ARGs) and healthcare/environmental factors were identified, and the presence of ARGs was a predictor of neonatal sepsis and adverse birth outcomes. Analysis of gut microbiota of mothers and its neonates—as part of the BARNARDS study—reveals associations between β-lactamase gene carriage and neonatal sepsis risk in low-income settings.

We report here an unliganded receptor structure in the common gamma-chain (γc) family of receptors and cytokines. The crystal structure of the unliganded form of the interleukin-7 alpha receptor (IL-7Rα) extracellular domain (ECD) at 2.15 Å resolution reveals a homodimer forming an \"X\" geometry looking down onto the cell surface with the C termini of the two chains separated by 110 Å and the dimer interface comprising residues critical for IL-7 binding. Further biophysical studies indicate a weak association of the IL-7Rα ECDs but a stronger association between the γc/IL-7Rα ECDs, similar to previous studies of the full-length receptors on CD4+ T cells. Based on these and previous results, we propose a molecular mechanism detailing the progression from the inactive IL-7Rα homodimer and IL-7Rα–γc heterodimer to the active IL-7–IL-7Rα–γc ternary complex whereby the two receptors undergo at least a 90° rotation away from the cell surface, moving the C termini of IL-7Rα and γc from a distance of 110 Å to less than 30 Å at the cell surface. This molecular mechanism can be used to explain recently discovered IL-7– and γc-independent gain-of-function mutations in IL-7Rα from B- and T-cell acute lymphoblastic leukemia patients. The mechanism may also be applicable to other γc receptors that form inactive homodimers and heterodimers independent of their cytokines.

Background Almost two million stillbirths occur annually, most occurring in low- and middle-income countries. Nigeria is reported to have one of the highest stillbirth rates on the African continent. The aim was to identify sociodemographic, living environment, and health status factors associated with stillbirth and determine the associations between pregnancy and birth factors and stillbirth in the Murtala Mohammed Specialist Hospital, Kano, Nigeria. Methods A three-month single-site prospective observational feasibility study. Demographic and clinical data were collected. We fitted bivariable and multivariable models for stillbirth (yes/no) and three-category livebirth/macerated stillbirth/non-macerated stillbirth outcomes to explore their association with demographic and clinical factors. Findings 1,998 neonates and 1,926 mothers were enrolled. Higher odds of stillbirth were associated with low-levels of maternal education, a further distance to travel to the hospital, living in a shack, maternal hypertension, previous stillbirth, birthing complications, increased duration of labour, antepartum haemorrhage, prolonged or obstructed labour, vaginal breech delivery, emergency caesarean-section, and signs of trauma to the neonate following birth. Interpretation This work has obtained data on some factors influencing stillbirth. This in turn will facilitate the development of improved public health interventions to reduce preventable deaths and to progress maternal health within this site.

Inflammation is implicated in placental dysfunction leading to stillbirth, yet evidence of a systemic immune response during parturition remains unclear. Here, we present the first transcriptomic analysis of maternal systemic responses associated with stillbirth, using a minimally invasive finger-prick method for whole blood collection in labouring women in northern Nigeria. This approach facilitated participant recruitment with minimal disruption to care and provided high-quality RNA for transcriptomic profiling. Contrary to expectations, no major differences were observed in systemic immune states between propensity-matched live births and stillbirths. These findings suggest several possibilities, including the dominance of a parturition response masking an underlying immune state, physical protective barriers, or placental tolerance mechanisms. This study offers novel insights into maternal systemic immune health during stillbirth and highlights the need for further research. It also contributes to the broader “Stillbirths in Kano” initiative, aimed at reducing stillbirth rates through enhanced prenatal care.

The incidence of infections caused by antimicrobial-resistant Enterobacteriaceae in Thailand is increasing and human intestinal flora is an important reservoir for these organisms. This study was carried out to determine the intestinal carriage of blaCTX-M extended spectrum ß-lactamase-positive Enterobacteriaceae (ESBL + E) and AmpC-positive Enterobacteriaceae in a community setting in Northern Thailand, and to identify potential risk factors for carriage. A total of 307 fecal samples were collected from healthy volunteers in Phitsanulok province, and cefotaxime-resistant Enterobacteriaceae (CtxRE) were isolated using selective media. Polymerase chain reaction (PCR) was used to detect ESBL and AmpC genes. Risk factors were analyzed using multiple logistic regression. Genotyping was performed by multilocus sequence typing (MLST) analysis. Two hundred ninety-one CtxRE isolates were obtained and Escherichia coli was the predominant organism (66.3%). The intestinal carriage rates of blaCTX-M ESBL + E and AmpC-positive Enterobacteriaceae were 52.1% and 6.2%, respectively. Comparative levels of blaCTX-M group 1 and blaCTX-M group 9 were found while blaCMY-2 was the predominant genotype among AmpC genes. Co-existence of two ß-lactamase genes in a single isolate was found in 6.5% of isolates. Consumption of undercooked meat was strongly associated with intestinal carriage of blaCTX-M ESBL + E (p = 0.003, OR = 2.133, 95% CI = 1.289–3.530). Phylogenetic grouping and MLST analysis of E. coli isolates revealed the presence of E. coli B2-ST131 (n = 8). Of these, seven carried blaCTX-M-group 9 and 1 carried blaCMY-2. Our results suggest that residents in Thailand are at high risk for developing endogenous infections caused by antibiotic-resistant Enterobacteriaceae.

Tumours growing in a sheet-like manner on the surface of organs and tissues with complex topologies represent a difficult-to-treat clinical scenario. Their complete surgical resection is difficult due to the complicated anatomy of the diseased tissue. Residual cancer often responds poorly to systemic therapy and locoregional treatment is hindered by the limited accessibility to microscopic tumour foci. Here we engineered a peptide-based surface-fill hydrogel (SFH) that can be syringe- or spray-delivered to surface cancers during surgery or used as a primary therapy. Once applied, SFH can shape change in response to alterations in tissue morphology that may occur during surgery. Implanted SFH releases nanoparticles composed of microRNA and intrinsically disordered peptides that enter cancer cells attenuating their oncogenic signature. With a single application, SFH shows efficacy in four preclinical models of mesothelioma, demonstrating the therapeutic impact of the local application of tumour-specific microRNA, which might change the treatment paradigm for mesothelioma and possibly other surface cancers. Tumours that grow on organ surfaces are difficult to eradicate as the complex topology of underlying tissues might hamper accessibility to tumour foci even after surgery. In this paper the authors engineer a peptide-based hydrogel that can be applied on surface tumours before or after resection, conform to the tissue underneath and release therapeutics.

Growth hormone regulates its biological properties via a sequential hormone-induced receptor homodimerization mechanism. Using a mutagenesis-scanning analysis of 81 single and 32 pairwise double mutations, we show that the hormone's two spatially distal receptor binding sites (Site1 and Site2) are allosterically coupled. These allosteric effects are focused among a relatively few residues centered around the interaction between Asp-116 of the hormone and Trp-169 of the receptor in Site2. A rearrangement of this interaction triggered by mutations in Site1 produces both a major conformation and energetic reorganization of Site2, surprisingly without a reduction in overall binding affinity. Additionally, the data suggest a change in the conformational dynamics of several groups in Site2 that appear to be important in defining the Site2 interaction. Changes in binding energy of the affected Site2 residues usually range in magnitude from 3- to 60-fold, but in one case are as large as 104.

Although de novo protein design is an important endeavor with implications for understanding protein folding, until now, structures have been determined for only a few 25- to 30-residue designed miniproteins. Here, the NMR solution structure of a complex 73-residue three-helix bundle protein, α 3D, is reported. The structure of α 3D was not based on any natural protein, and yet it shows thermodynamic and spectroscopic properties typical of native proteins. A variety of features contribute to its unique structure, including electrostatics, the packing of a diverse set of hydrophobic side chains, and a loop that incorporates common capping motifs. Thus, it is now possible to design a complex protein with a well defined and predictable three-dimensional structure.

To investigate the antibiotic and biocide susceptibilities of clinical isolates of rarely encountered Gram-negative, non-fermenting bacteria. Thirty Gram-negative non-fermenting bacterial strains were isolated from blood cultures of oncology patients. These were studied for their resistance to 11 antibiotics. Their susceptibilities to seven biocides used in hospitals were also examined. Isolates of Stenotrophomonas maltophilia and Ochrohadrum anthropi were generally resistant to at least five of the antibiotics, whereas isolates ofComamonas acidivorans, Flavohaderium oryzihabitans, Aeromonas hydrophila, Sphingobacterium spiritivorum, Acinetobacter junii and Acinetobacter lwoffi were generally sensitive to at least nine of the antibiotics. Trovafloxacin and trimethoprim—sulfamethoxazole were the most effective antibacterial agents tested, with 0% and 7%, respectively, of isolates being resistant, whereas 63% of isolates were resistant to aztreonam. Some isolates, sensitive to meropenem and/or ceftazidime in vitro, possessed very high MBC/MIC ratios for these β-lactams. Two out of three biocides used in hospital pharmacies showed lethal activity towards all strains tested when used at less than one-third of their recommended in-use concentration. Proceine 40 failed to give a 5 log reduction in bacterial cell number for the isolates tested when used at its ‘in-use’ concentration. A concentration of >500 mg/L chlorhexidine was required to achieve a 5 log reduction for the same isolates. We have examined the antibiotic susceptibilities of non-fermenting Gram-negative bacterial strains isolated from immunocompromised patients. Despite being sensitive to certain antibiotics in vitro, some isolates were still able to cause serious bacteremia. We have also reported for the first time the susceptibilities of non-fermenting Gram-negative bacteria to common biocides used in hospital infection control, and have shown that some strains are able to persist at the ‘in-use’ concentration of particular biocides. It is therefore important to study further this particular group of organisms, and, in particular, to examine whether there exists a link between resistance to antibiotics and resistance to biocides.