Metagenomic Insights into Transferable Antibiotic Resistance in Oral Bacteria

Antibiotic resistance is considered one of the greatest threats to global public health. Resistance is often conferred by the presence of antibiotic resistance genes (ARGs), which are readily found in the oral microbiome. In-depth genetic analyses of the oral microbiome through metagenomic techniques reveal a broad distribution of ARGs (including novel ARGs) in individuals not recently exposed to antibiotics, including humans in isolated indigenous populations. This has resulted in a paradigm shift from focusing on the carriage of antibiotic resistance in pathogenic bacteria to a broader concept of an oral resistome, which includes all resistance genes in the microbiome. Metagenomics is beginning to demonstrate the role of the oral resistome and horizontal gene transfer within and between commensals in the absence of selective pressure, such as an antibiotic. At the chairside, metagenomic data reinforce our need to adhere to current antibiotic guidelines to minimize the spread of resistance, as such data reveal the extent of ARGs without exposure to antimicrobials and the ecologic changes created in the oral microbiome by even a single dose of antibiotics. The aim of this review is to discuss the role of metagenomics in the investigation of the oral resistome, including the transmission of antibiotic resistance in the oral microbiome. Future perspectives, including clinical implications of the findings from metagenomic investigations of oral ARGs, are also considered

Body Segment Differences in Surface Area, Skin Temperature and 3D Displacement and the Estimation of Heat Balance during Locomotion in Hominins

The conventional method of estimating heat balance during locomotion in humans and other hominins treats the body as an undifferentiated mass. This is problematic because the segments of the body differ with respect to several variables that can affect thermoregulation. Here, we report a study that investigated the impact on heat balance during locomotion of inter-segment differences in three of these variables: surface area, skin temperature and rate of movement. The approach adopted in the study was to generate heat balance estimates with the conventional method and then compare them with heat balance estimates generated with a method that takes into account inter-segment differences in surface area, skin temperature and rate of movement. We reasoned that, if the hypothesis that inter-segment differences in surface area, skin temperature and rate of movement affect heat balance during locomotion is correct, the estimates yielded by the two methods should be statistically significantly different. Anthropometric data were collected on seven adult male volunteers. The volunteers then walked on a treadmill at 1.2 m/s while 3D motion capture cameras recorded their movements. Next, the conventional and segmented methods were used to estimate the volunteers' heat balance while walking in four ambient temperatures. Lastly, the estimates produced with the two methods were compared with the paired t-test. The estimates of heat balance during locomotion yielded by the two methods are significantly different. Those yielded by the segmented method are significantly lower than those produced by the conventional method. Accordingly, the study supports the hypothesis that inter-segment differences in surface area, skin temperature and rate of movement impact heat balance during locomotion. This has important implications not only for current understanding of heat balance during locomotion in hominins but also for how future research on this topic should be approached

The spatial and temporal patterns of falciparum and vivax malaria in Perú: 1994–2006

<p>Abstract</p> <p>Background</p> <p>Malaria is the direct cause of approximately one million deaths worldwide each year, though it is both preventable and curable. Increasing the understanding of the transmission dynamics of falciparum and vivax malaria and their relationship could suggest improvements for malaria control efforts. Here the weekly number of malaria cases due to <it>Plasmodium falciparum </it>(1994–2006) and <it>Plasmodium vivax </it>(1999–2006) in Perú at different spatial scales in conjunction with associated demographic, geographic and climatological data are analysed.</p> <p>Methods</p> <p>Malaria periodicity patterns were analysed through wavelet spectral analysis, studied patterns of persistence as a function of community size and assessed spatial heterogeneity via the Lorenz curve and the summary Gini index.</p> <p>Results</p> <p>Wavelet time series analyses identified annual cycles in the incidence of both malaria species as the dominant pattern. However, significant spatial heterogeneity was observed across jungle, mountain and coastal regions with slightly higher levels of spatial heterogeneity for <it>P. vivax </it>than <it>P. falciparum</it>. While the incidence of <it>P. falciparum </it>has been declining in recent years across geographic regions, <it>P. vivax </it>incidence has remained relatively steady in jungle and mountain regions with a slight decline in coastal regions. Factors that may be contributing to this decline are discussed. The time series of both malaria species were significantly synchronized in coastal (ρ = 0.9, P < 0.0001) and jungle regions (ρ = 0.76, P < 0.0001) but not in mountain regions. Community size was significantly associated with malaria persistence due to both species in jungle regions, but not in coastal and mountain regions.</p> <p>Conclusion</p> <p>Overall, findings highlight the importance of highly refined spatial and temporal data on malaria incidence together with demographic and geographic information in improving the understanding of malaria persistence patterns associated with multiple malaria species in human populations, impact of interventions, detection of heterogeneity and generation of hypotheses.</p

Measurement of the Negative Muon Anomalous Magnetic Moment to 0.7 ppm

The anomalous magnetic moment of the negative muon has been measured to a precision of 0.7 parts per million (ppm) at the Brookhaven Alternating Gradient Synchrotron. This result is based on data collected in 2001, and is over an order of magnitude more precise than the previous measurement of the negative muon. The result a_mu= 11 659 214(8)(3) \times 10^{-10} (0.7 ppm), where the first uncertainty is statistical and the second is sytematic, is consistend with previous measurements of the anomaly for the positive and negative muon. The average for the muon anomaly a_{mu}(exp) = 11 659 208(6) \times 10^{-10} (0.5ppm).Comment: 4 pages, 4 figures, submitted to Physical Review Letters, revised to reflect referee comments. Text further revised to reflect additional referee comments and a corrected Fig. 3 replaces the older versio

Potent Tetrahydroquinolone Eliminates Apicomplexan Parasites

Apicomplexan infections cause substantial morbidity and mortality, worldwide. New, improved therapies are needed. Herein, we create a next generation anti-apicomplexan lead compound, JAG21, a tetrahydroquinolone, with increased sp3-character to improve parasite selectivity. Relative to other cytochrome b inhibitors, JAG21 has improved solubility and ADMET properties, without need for pro-drug. JAG21 significantly reduces Toxoplasma gondii tachyzoites and encysted bradyzoites in vitro, and in primary and established chronic murine infections. Moreover, JAG21 treatment leads to 100% survival. Further, JAG21 is efficacious against drug-resistant Plasmodium falciparum in vitro. Causal prophylaxis and radical cure are achieved after P. berghei sporozoite infection with oral administration of a single dose (2.5 mg/kg) or 3 days treatment at reduced dose (0.625 mg/kg/day), eliminating parasitemia, and leading to 100% survival. Enzymatic, binding, and co-crystallography/pharmacophore studies demonstrate selectivity for apicomplexan relative to mammalian enzymes. JAG21 has significant promise as a pre-clinical candidate for prevention, treatment, and cure of toxoplasmosis and malaria

The long-term fate of the hip arthrodesis: does it remain a valid procedure for selected cases in the 21st century?

Even in current orthopaedic practice, some cases are still not suitable candidates for hip replacement and hip fusion remains the only option in these highly selected patients. In this retrospective study we describe the long-term clinical outcome, quality of life and radiological evaluation of all adjacent joints in a cohort of 47 hip fusions. The main objective of our study was to show the long-term effects of a fusion. Thirty patients were analysed after an average of 18.2 years (range 6.2–30.5 years) with a mean SMFA of 31.2 (range 9–70). The VAS for pain for the fused hip was an average 1.9 (range 0–8), for the contralateral hip 2.0 (0–8), for the ipsilateral knee 2.0 (0–8), for the contralateral knee 1.8 (0–8) and for the lower back 3.6 (0–8). Average walking distance was 115 minutes (range 10–unlimited). Although the hip arthrodesis has lost popularity, it still is an option for the young patient with severe hip disorders, while leaving the possibility to perform a THA at a later stage. If the arthrodesis is performed with an optimal alignment of the leg, complaints from the adjacent joints are minimal, even in the long-term, and an acceptable quality of life can be obtained. We believe that in highly selected cases a hip fusion, even in current practice, is still a valid option

Two novel human cytomegalovirus NK cell evasion functions target MICA for lysosomal degradation

NKG2D plays a major role in controlling immune responses through the regulation of natural killer (NK) cells, αβ and γδ T-cell function. This activating receptor recognizes eight distinct ligands (the MHC Class I polypeptide-related sequences (MIC) A andB, and UL16-binding proteins (ULBP)1–6) induced by cellular stress to promote recognition cells perturbed by malignant transformation or microbial infection. Studies into human cytomegalovirus (HCMV) have aided both the identification and characterization of NKG2D ligands (NKG2DLs). HCMV immediate early (IE) gene up regulates NKGDLs, and we now describe the differential activation of ULBP2 and MICA/B by IE1 and IE2 respectively. Despite activation by IE functions, HCMV effectively suppressed cell surface expression of NKGDLs through both the early and late phases of infection. The immune evasion functions UL16, UL142, and microRNA(miR)-UL112 are known to target NKG2DLs. While infection with a UL16 deletion mutant caused the expected increase in MICB and ULBP2 cell surface expression, deletion of UL142 did not have a similar impact on its target, MICA. We therefore performed a systematic screen of the viral genome to search of addition functions that targeted MICA. US18 and US20 were identified as novel NK cell evasion functions capable of acting independently to promote MICA degradation by lysosomal degradation. The most dramatic effect on MICA expression was achieved when US18 and US20 acted in concert. US18 and US20 are the first members of the US12 gene family to have been assigned a function. The US12 family has 10 members encoded sequentially through US12–US21; a genetic arrangement, which is suggestive of an ‘accordion’ expansion of an ancestral gene in response to a selective pressure. This expansion must have be an ancient event as the whole family is conserved across simian cytomegaloviruses from old world monkeys. The evolutionary benefit bestowed by the combinatorial effect of US18 and US20 on MICA may have contributed to sustaining the US12 gene family

Human Leg Model Predicts Ankle Muscle-Tendon Morphology, State, Roles and Energetics in Walking

A common feature in biological neuromuscular systems is the redundancy in joint actuation. Understanding how these redundancies are resolved in typical joint movements has been a long-standing problem in biomechanics, neuroscience and prosthetics. Many empirical studies have uncovered neural, mechanical and energetic aspects of how humans resolve these degrees of freedom to actuate leg joints for common tasks like walking. However, a unifying theoretical framework that explains the many independent empirical observations and predicts individual muscle and tendon contributions to joint actuation is yet to be established. Here we develop a computational framework to address how the ankle joint actuation problem is resolved by the neuromuscular system in walking. Our framework is founded upon the proposal that a consideration of both neural control and leg muscle-tendon morphology is critical to obtain predictive, mechanistic insight into individual muscle and tendon contributions to joint actuation. We examine kinetic, kinematic and electromyographic data from healthy walking subjects to find that human leg muscle-tendon morphology and neural activations enable a metabolically optimal realization of biological ankle mechanics in walking. This optimal realization (a) corresponds to independent empirical observations of operation and performance of the soleus and gastrocnemius muscles, (b) gives rise to an efficient load-sharing amongst ankle muscle-tendon units and (c) causes soleus and gastrocnemius muscle fibers to take on distinct mechanical roles of force generation and power production at the end of stance phase in walking. The framework outlined here suggests that the dynamical interplay between leg structure and neural control may be key to the high walking economy of humans, and has implications as a means to obtain insight into empirically inaccessible features of individual muscle and tendons in biomechanical tasks.National Institutes of Health (U.S.) (NIH Pioneer Award DP1 OD003646)Massachusetts Institute of Technology. Media Laboratory (Consortia Account 2736448)Massachusetts Institute of Technology. Media Laboratory (Consortia Account 6895867