Global diversity and antimicrobial resistance of typhoid fever pathogens: Insights from a meta-analysis of 13,000 Salmonella Typhi genomes

Background: The Global Typhoid Genomics Consortium was established to bring together the typhoid research community to aggregate and analyse Salmonella enterica serovar Typhi (Typhi) genomic data to inform public health action. This analysis, which marks 22 years since the publication of the first Typhi genome, represents the largest Typhi genome sequence collection to date (n=13,000). Methods: This is a meta-analysis of global genotype and antimicrobial resistance (AMR) determinants extracted from previously sequenced genome data and analysed using consistent methods implemented in open analysis platforms GenoTyphi and Pathogenwatch. Results: Compared with previous global snapshots, the data highlight that genotype 4.3.1 (H58) has not spread beyond Asia and Eastern/Southern Africa; in other regions, distinct genotypes dominate and have independently evolved AMR. Data gaps remain in many parts of the world, and we show the potential of travel-associated sequences to provide informal ‘sentinel’ surveillance for such locations. The data indicate that ciprofloxacin non-susceptibility (>1 resistance determinant) is widespread across geographies and genotypes, with high-level ciprofloxacin resistance (=3 determinants) reaching 20% prevalence in South Asia. Extensively drug-resistant (XDR) typhoid has becomedominant in Pakistan (70% in 2020) but has not yet become established elsewhere. Ceftriaxone resistance has emerged in eight non-XDR genotypes, including a ciprofloxacin-resistant lineage (4.3.1.2.1) in India. Azithromycin resistance mutations were detected at low prevalence in South Asia, including in two common ciprofloxacin-resistant genotypes. Conclusions: The consortium’s aim is to encourage continued data sharing and collaboration to monitor the emergence and global spread of AMR Typhi, and to inform decision-making around the introduction of typhoid conjugate vaccines (TCVs) and other prevention and control strategies

Linking early-life NMDAR hypofunction and oxidative stress in schizophrenia pathogenesis.

Molecular, genetic and pathological evidence suggests that deficits in GABAergic parvalbumin-positive interneurons contribute to schizophrenia pathophysiology through alterations in the brain's excitation-inhibition balance that result in impaired behaviour and cognition. Although the factors that trigger these deficits are diverse, there is increasing evidence that they converge on a common pathological hub that involves NMDA receptor hypofunction and oxidative stress. These factors have been separately linked to schizophrenia pathogenesis, but evidence now suggests that they are mechanistically interdependent and contribute to a common schizophrenia-associated pathology

Assessing human diet and movement in the Tongan maritime chiefdom using isotopic analyses.

The rise of stratified societies fundamentally influences the interactions between status, movement, and food. Using isotopic analyses, we assess differences in diet and mobility of individuals excavated from two burial mounds located at the `Atele burial site on Tongatapu, the main island of the Kingdom of Tonga (c. 500 - 150 BP). The first burial mound (To-At-1) was classified by some archaeologists as a commoner's mound while the second burial mound (To-At-2) was possibly used for interment of the chiefly class. In this study, stable isotope analyses of diet (δ13C, δ15N, and δ34S; n = 41) are used to asses paleodiet and 87Sr/86Sr ratios (n = 30) are analyzed to investigate individual mobility to test whether sex and social status affected these aspects of life. Our results show significant differences in diet between burial mounds and sexes. Those interred in To-At-2 displayed lower δ13C values, indicating they ate relatively more terrestrial plants (likely starchy vegetable staples) compared with To-At-1 individuals. Females displayed significantly lower δ15N values compared with males within the entire assemblage. No differences in δ34S values were observed between sexes or burial mound but it is possible that sea spray or volcanism may have affected these values. One individual displayed the strontium isotopic composition representative of a nonlocal immigrant (outside 2SD of the mean). This suggests the hegemonic control over interisland travel, may have prevented long-term access to the island by non-Tongans exemplifying the political and spiritual importance of the island of Tongatapu in the maritime chiefdom

Molecular mechanisms governing aquaporin relocalisation

The aquaporins (AQPs) form a family of integral membrane proteins that facilitate the movement of water across biological membrane by osmosis, as well as facilitating the diffusion of small polar solutes. AQPs have been recognised as drug targets for a variety of disorders associated with disrupted water or solute transport, including brain oedema following stroke or trauma, epilepsy, cancer cell migration and tumour angiogenesis, metabolic disorders, and inflammation. Despite this, drug discovery for AQPs has made little progress due to a lack of reproducible high-throughput assays and difficulties with the druggability of AQP proteins. However, recent studies have suggested that targetting the trafficking of AQP proteins to the plasma membrane is a viable alternative drug target to direct inhibition of the water-conducting pore. Here we review the literature on the trafficking of mammalian AQPs with a view to highlighting potential new drug targets for a variety of conditions associated with disrupted water and solute homeostasis

PolyMetformin combines carrier and anticancer activities for in vivo siRNA delivery

Metformin, a widely implemented anti-diabetic drug, exhibits potent anticancer efficacies. Herein a polymeric construction of Metformin, PolyMetformin (PolyMet) is successfully synthesized through conjugation of linear polyethylenimine (PEI) with dicyandiamide. The delocalization of cationic charges in the biguanide groups of PolyMet reduces the toxicity of PEI both in vitro and in vivo. Furthermore, the polycationic properties of PolyMet permits capture of siRNA into a core-membrane structured lipid-polycation-hyaluronic acid (LPH) nanoparticle for systemic gene delivery. Advances herein permit LPH-PolyMet nanoparticles to facilitate VEGF siRNA delivery for VEGF knockdown in a human lung cancer xenograft, leading to enhanced tumour suppressive efficacy. Even in the absence of RNAi, LPH-PolyMet nanoparticles act similarly to Metformin and induce antitumour efficacy through activation of the AMPK and inhibition of the mTOR. In essence, PolyMet successfully combines the intrinsic anticancer efficacy of Metformin with the capacity to carry siRNA to enhance the therapeutic activity of an anticancer gene therapy