Fluctuations and the Effective Moduli of an Isotropic, Random Aggregate of Identical, Frictionless Spheres

We consider a random aggregate of identical frictionless elastic spheres that has first been subjected to an isotropic compression and then sheared. We assume that the average strain provides a good description of how stress is built up in the initial isotropic compression. However, when calculating the increment in the displacement between a typical pair of contaction particles due to the shearing, we employ force equilibrium for the particles of the pair, assuming that the average strain provides a good approximation for their interactions with their neighbors. The incorporation of these additional degrees of freedom in the displacement of a typical pair relaxes the system, leading to a decrease in the effective moduli of the aggregate. The introduction of simple models for the statistics of the ordinary and conditional averages contributes an additional decrease in moduli. The resulting value of the shear modulus is in far better agreement with that measured in numerical simulations

In Vitro Antibacterial Activity of Curcumin-Polymyxin B Combinations against Multidrug-Resistant Bacteria Associated with Traumatic Wound Infections

Bacterial infections resulting from nonsurgical traumatic wounds can be life threatening, especially those caused by multidrug-resistant (MDR) bacteria with limited therapeutic options. The antimicrobial activity of polymyxin B (1) and curcumin (2) alone and in combination was determined versus MDR bacterial isolates associated with traumatic wound infections. Cytotoxicity assays for 1 and 2 were undertaken in keratinocyte cell lines. Minimum inhibitory concentrations of 1 were significantly reduced in the presence of 2 (3- to 10-fold reduction), with synergy observed. Time− kill assays showed the combinations produced bactericidal activity. Cytotoxicity assays indicate the toxicity of 2 was reduced in the presence of 1

Expression of Cell-Cycle Regulatory Proteins pRb, Cyclin D1, and p53 Is Not Associated with Recurrence Rates of Equine Sarcoids

Sarcoids are among the most common tumors diagnosed in equids; their association with bovine papillomaviruses (BPV) infection has been widely reported, but the mechanism of carcinogenesis has not been fully elucidated. To verify whether BPV infection causes dysregulation of the pRb-Cyclin D1-p16CDKN2A-p53 pathway as reported for human papillomavirus (HPV), the study employed immunohistochemistry to test 55 equine sarcoid biopsies for the expression of pRb, Cyclin D1, and p53 cell cycle regulatory proteins and to evaluate the proliferative rate through Ki67. High Cyclin D1 and pRb expression were observed in 51% and 80% of cases, respectively, while low expression was observed in 49% and 20% of cases, respectively. Significantly higher Ki67 proliferation indexes were observed in fibroblastic, nodular, and mixed sarcoids compared to the occult and verrucous. High proliferation was significantly associated with high Cyclin D1 expression. In contrast with previous studies, p53 positivity was not observed in the cases examined in this study. Moreover, follow-up analysis revealed that fibroblastic, mixed sarcoids were associated with significantly higher local recurrence rates while the verrucous subtype was associated with higher rates of new sarcoid development at distant sites

The One Health European Joint Programme (OHEJP), 2018-2022: an exemplary One Health initiative

OverviewOne Health is an increasingly popular approach used to tackle complex health problems. The One Health concept recognizes that human health is tightly connected to the health of animals and the environment. Although the related fields are now more aware of the benefits of collaborative working, the full benefits have not yet been realized as research efforts are often focussed on just one of these health domains. To address regional and global issues such as foodborne zoonoses (FBZ), antimicrobial resistance (AMR) and emerging infectious threats (ET), there must be transdisciplinary collaboration between the health domains, in addition to active dialogue between scientists and international policy makers. This editorial introduces the One Health European Joint Programme (OHEJP) as an example of a One Health initiative.Zoonoses, AMR and their global burdenZoonoses are infectious diseases that can be transmitted directly or indirectly between humans and animals. Although the severity of zoonotic infections varies, their global impact is undisputable. The World Bank estimates that just six zoonotic disease outbreaks between 1997 and 2009 led to a global economic loss of US$80 billion [1]. This high cost is due to medical costs, loss of individual productivity and restrictions on trade and movement during outbreaks. Despite improvements in the management and treatment of zoonotic outbreaks, high disease burdens caused by zoonotic pathogens continue to be reported globally. These problems have been amply demonstrated recently by the SARS-CoV-2 pandemic. Although it is still too soon to fully assess the total economic and societal cost of this virus, recent publications, such as Nicola et al. [2] have begun to highlight just how widespread the impact of a truly global zoonotic disease can be.Alongside zoonoses, AMR is a growing international issue. The World Health Organization (WHO) has listed AMR as one of the ten greatest global health threats in 2019 [3]. AMR is defined as the ability of microorganisms to survive the effect of antimicrobial drugs, hindering not only our ability to treat infectious diseases, but also to perform medical procedures requiring prophylactic antibiotic administration. It has been predicted that by 2050, the number of deaths due to unresponsive infections will reach 10 million annually, with the associated costs being estimated at US$ 100 trillion [4]. Increased and inappropriate use of antimicrobials has contributed to the development and spread of AMR, which can be transmitted between humans, animals and the environment.The history of the ‘One Health’ conceptThe origins of One Health go as far back as 1855, when Rudolf Virchow founded comparative pathology, which could be seen as the origin of the One Health concept. Building upon this, Calvin W. Schwabe argued in the twentieth century against compartmentalization in medical research, using the term ‘One Medicine’. The term One Health was then popularized in 2004 by the Wildlife Conservation Society at a conference in New York [5], and its use has continued to evolve since then, fostering the revival of comparative medicine (Fig. 1, and reviewed in Gibbs [6]). One Health has now been adopted by the WHO [7], the Food and Agriculture Organization (FAO) [8] and the World Organization for Animal Health (OIE) [9]

Genome-wide association reveals host-specific genomic traits in Escherichia coli

Background Escherichia coli is an opportunistic pathogen which colonizes various host species. However, to what extent genetic lineages of E. coli are adapted or restricted to specific hosts and the genomic determinants of such adaptation or restriction is poorly understood. Results We randomly sampled E. coli isolates from four countries (Germany, UK, Spain, and Vietnam), obtained from five host species (human, pig, cattle, chicken, and wild boar) over 16 years, from both healthy and diseased hosts, to construct a collection of 1198 whole-genome sequenced E. coli isolates. We identified associations between specific E. coli lineages and the host from which they were isolated. A genome-wide association study (GWAS) identified several E. coli genes that were associated with human, cattle, or chicken hosts, whereas no genes associated with the pig host could be found. In silico characterization of nine contiguous genes (collectively designated as nan-9) associated with the human host indicated that these genes are involved in the metabolism of sialic acids (Sia). In contrast, the previously described sialic acid regulon known as sialoregulon (i.e. nanRATEK-yhcH, nanXY, and nanCMS) was not associated with any host species. In vitro growth experiments with a Δnan-9 E. coli mutant strain, using the sialic acids 5-N-acetylneuraminic acid (Neu5Ac) and N-glycolylneuraminic acid (Neu5Gc) as sole carbon source, showed impaired growth behaviour compared to the wild-type. Conclusions This study provides an extensive analysis of genetic determinants which may contribute to host specificity in E. coli. Our findings should inform risk analysis and epidemiological monitoring of (antimicrobial resistant) E. coli

Identification of a novel prophage regulator in Escherichia coli controlling the expression of type III secretion

This study has identified horizontally acquired genomic regions of enterohaemorrhagic Escherichia coli O157:H7 that regulate expression of the type III secretion (T3S) system encoded by the locus of enterocyte effacement (LEE). Deletion of O-island 51, a 14.93 kb cryptic prophage (CP-933C), resulted in a reduction in LEE expression and T3S. The deletion also had a reduced capacity to attach to epithelial cells and significantly reduced E. coli O157 excretion levels from sheep. Further characterization of O-island 51 identified a novel positive regulator of the LEE, encoded by ecs1581 in the E. coli O157:H7 strain Sakai genome and present but not annotated in the E. coli strain EDL933 sequence. Functionally important residues of ECs1581 were identified based on phenotypic variants present in sequenced E. coli strains and the regulator was termed RgdR based on a motif demonstrated to be important for stimulation of gene expression. While RgdR activated expression from the LEE1 promoter in the presence or absence of the LEE-encoded regulator (Ler), RgdR stimulation of T3S required ler and Ler autoregulation. RgdR also controlled the expression of other phenotypes, including motility, indicating that this new family of regulators may have a more global role in E. coli gene expression

Phenotypic microarrays suggest Escherichia coli ST131 is not a metabolically distinct lineage of extra-intestinal pathogenic E. coli

Extraintestinal pathogenic E. coli (ExPEC) are the major aetiological agent of urinary tract infections (UTIs) in humans. The emergence of the CTX-M producing clone E. coli ST131 represents a major challenge to public health worldwide. A recent study on the metabolic potential of E. coli isolates demonstrated an association between the E. coli ST131 clone and enhanced utilisation of a panel of metabolic substrates. The studies presented here investigated the metabolic potential of ST131 and other major ExPEC ST isolates using 120 API test reagents and found that ST131 isolates demonstrated a lower metabolic activity for 5 of 120 biochemical tests in comparison to non-ST131 ExPEC isolates. Furthermore, comparative phenotypic microarray analysis showed a lack of specific metabolic profile for ST131 isolates countering the suggestion that these bacteria are metabolically fitter and therefore more successful human pathogens

Disease control tools to secure animal and public health in a densely populated world

Animal health is a prerequisite for global health, economic development, food security, food quality, and poverty reduction, while mitigating against climate change and biodiversity loss. We did a qualitative review of 53 infectious diseases in terrestrial animals with data from DISCONTOOLS, a specialist database and prioritisation model focusing on research gaps for improving infectious disease control in animals. Many diseases do not have any appropriate control tools, but the prioritisation model suggests that we should focus international efforts on Nipah virus infection, African swine fever, contagious bovine pleuropneumonia, peste des petits ruminants, sheeppox and goatpox, avian influenza, Rift Valley fever, foot and mouth disease, and bovine tuberculosis, for the greatest impact on the UN's Sustainable Development Goals. Easy to use and accurate diagnostics are available for many animal diseases. However, there is an urgent need for the development of stable and durable diagnostics that can differentiate infected animals from vaccinated animals, to exploit rapid technological advances, and to make diagnostics widely available and affordable. Veterinary vaccines are important for dealing with endemic, new, and emerging diseases. However, fundamental research is needed to improve the convenience of use and duration of immunity, and to establish performant marker vaccines. The largest gap in animal pharmaceuticals is the threat of pathogens developing resistance to available drugs, in particular for bacterial and parasitic (protozoal, helminth, and arthropod) pathogens. We propose and discuss five research priorities for animal health that will help to deliver a sustainable and healthy planet: vaccinology, antimicrobial resistance, climate mitigation and adaptation, digital health, and epidemic preparedness