Inactivation of Fructose-1,6-Bisphosphate Aldolase Prevents Optimal Co-catabolism of Glycolytic and Gluconeogenic Carbon Substrates in Mycobacterium tuberculosis

Metabolic pathways used by Mycobacterium tuberculosis (Mtb) to establish and maintain infections are important for our understanding of pathogenesis and the development of new chemotherapies. To investigate the role of fructose-1,6-bisphosphate aldolase (FBA), we engineered an Mtb strain in which FBA levels were regulated by anhydrotetracycline. Depletion of FBA resulted in clearance of Mtb in both the acute and chronic phases of infection in vivo, and loss of viability in vitro when cultured on single carbon sources. Consistent with prior reports of Mtb''s ability to co-catabolize multiple carbon sources, this in vitro essentiality could be overcome when cultured on mixtures of glycolytic and gluconeogenic carbon sources, enabling generation of an fba knockout (Δfba). In vitro studies of Δfba however revealed that lack of FBA could only be compensated for by a specific balance of glucose and butyrate in which growth and metabolism of butyrate were determined by Mtb''s ability to co-catabolize glucose. These data thus not only evaluate FBA as a potential drug target in both replicating and persistent Mtb, but also expand our understanding of the multiplicity of in vitro conditions that define the essentiality of Mtb''s FBA in vivo.     

Recommendations for the Empirical Treatment of Complicated Urinary Tract Infections Using Surveillance Data on Antimicrobial Resistance in the Netherlands

Background

Complicated urinary tract infections (c-UTIs) are among the most common nosocomial infections and a substantial part of the antimicrobial agents used in hospitals is for the treatment of c-UTIs. Data from surveillance can be used to guide the empirical treatment choices of clinicians when treating c-UTIs. We therefore used nation-wide surveillance data to evaluate antimicrobial coverage of agents for the treatment of c-UTI in the Netherlands.

Methods

We included the first isolate per patient of urine samples of hospitalised patients collected by the Infectious Disease Surveillance Information System for Antibiotic Resistance (ISIS-AR) in 2012, and determined the probability of inadequate coverage for antimicrobial agents based on species distribution and susceptibility. Analyses were repeated for various patient groups and hospital settings.

Results

The most prevalent bacteria in 27,922 isolates of 23,357 patients were Escherichia coli (47%), Enterococcus spp. (14%), Proteus mirabilis (8%), and Klebsiella pneumoniae (7%). For all species combined, the probability of inadequate coverage was <5% for amoxicillin or amoxicillin-clavulanic acid combined with gentamicin and the carbapenems. When including gram-negative bacteria only, the probability of inadequate coverage was 4.0%, 2.7%, 2.3% and 1.7%, respectively, for amoxicillin, amoxicillin-clavulanic acid, a second or a third generation cephalosporin in combination with gentamicin, and the carbapenems (0.4%). There were only small variations in results among different patient groups and hospital settings.

Conclusions

When excluding Enterococcus spp., considered as less virulent, and the carbapenems, considered as last-resort drugs, empirical treatment for c-UTI with the best chance of adequate coverage are one of the studied beta-lactam-gentamicin combinations. This study demonstrates the applicability of routine surveillance data for up-to-date clinical practice guidelines on empirical antimicrobial therapy, essential in patient care given the evolving bacterial susceptibility.     

Age Effects on Mediolateral Balance Control

BackgroundAge-related balance impairments, particularly in mediolateral direction (ML) may cause falls. Sufficiently sensitive and reliable ML balance tests are, however, lacking. This study is aimed to determine (1) the effect of age on and (2) the reliability of ML balance performance using Center of Mass (CoM) tracking.MethodsBalance performance of 19 young (26±3 years) and 19 older (72±5 years) adults on ML-CoM tracking tasks was compared. Subjects tracked predictable and unpredictable target displacements at increasing frequencies with their CoM by shifting their weight sideward. Phase-shift (response delay) and gain (amplitude difference) between the CoM and target in the frequency domain were used to quantify performance. Thirteen older and all young adults were reassessed to determine reliability of balance performance measures. In addition, all older adults performed a series of clinical balance tests and conventional posturography was done in a sub-sample.ResultsPhase-shift and gain dropped below pre-determined thresholds (−90 degrees and 0.5) at lower frequencies in the older adults and were even lower below these frequencies than in young adults. Performance measures showed good to excellent reliability in both groups. All clinical scores were close to the maximum and no age effect was found using posturography. ML balance performance measures exhibited small but systematic between-session differences indicative of learning.ConclusionsThe ability to accurately perform ML-CoM tracking deteriorates with age. ML-CoM tracking tasks form a reliable tool to assess ML balance in young and older adults and are more sensitive to age-related impairment than posturography and clinical tests.     

The Last Frontier: Catch Records of White Sharks (Carcharodon carcharias) in the Northwest Pacific Ocean

White sharks are highly migratory apex predators, globally distributed in temperate, sub-tropical, and tropical waters. Knowledge of white shark biology and ecology has increased recently based on research at known aggregation sites in the Indian, Atlantic, and Northeast Pacific Oceans; however, few data are available for the Northwest Pacific Ocean. This study provides a meta-analysis of 240 observations of white sharks from the Northwest Pacific Ocean between 1951 and 2012. Records comprise reports of bycatch in commercial fisheries, media accounts, personal communications, and documentation of shark-human interactions from Russia (n = 8), Republic of Korea (22), Japan (129), China (32), Taiwan (45), Philippines (1) and Vietnam (3). Observations occurred in all months, excluding October-January in the north (Russia and Republic of Korea) and July-August in the south (China, Taiwan, Philippines, and Vietnam). Population trend analysis indicated that the relative abundance of white sharks in the region has remained relatively stable, but parameterization of a 75% increase in observer effort found evidence of a minor decline since 2002. Reliably measured sharks ranged from 126–602 cm total length (TL) and 16–2530 kg total weight. The largest shark in this study (602 cm TL) represents the largest measured shark on record worldwide. For all countries combined the sex ratio was non-significantly biased towards females (1∶1.1; n = 113). Of 60 females examined, 11 were confirmed pregnant ranging from the beginning stages of pregnancy (egg cases) to near term (140 cm TL embryos). On average, 6.0±2.2 embryos were found per litter (maximum of 10) and gestation period was estimated to be 20 months. These observations confirm that white sharks are present in the Northwest Pacific Ocean year-round. While acknowledging the difficulties of studying little known populations of a naturally low abundance species, these results highlight the need for dedicated research to inform regional conservation and management planning.     

Tree Species Traits but Not Diversity Mitigate Stem Breakage in a Subtropical Forest following a Rare and Extreme Ice Storm

Future climates are likely to include extreme events, which in turn have great impacts on ecological systems. In this study, we investigated possible effects that could mitigate stem breakage caused by a rare and extreme ice storm in a Chinese subtropical forest across a gradient of forest diversity. We used Bayesian modeling to correct stem breakage for tree size and variance components analysis to quantify the influence of taxon, leaf and wood functional traits, and stand level properties on the probability of stem breakage. We show that the taxon explained four times more variance in individual stem breakage than did stand level properties; trees with higher specific leaf area (SLA) were less susceptible to breakage. However, a large part of the variation at the taxon scale remained unexplained, implying that unmeasured or undefined traits could be used to predict damage caused by ice storms. When aggregated at the plot level, functional diversity and wood density increased after the ice storm. We suggest that for the adaption of forest management to climate change, much can still be learned from looking at functional traits at the taxon level.     

Vulnerability of Mediterranean Ecosystems to Long-Term Changes along the Coast of Israel

Although human activity is considered to be a major driving force affecting the distribution and dynamics of Mediterranean ecosystems, the full consequences of projected climate variability and relative sea-level changes on fragile coastal ecosystems for the next century are still unknown. It is unclear how these waterfront ecosystems can be sustained, as well as the services they provide, when relative sea-level rise and global warming are expected to exert even greater pressures in the near future (drought, habitat degradation and accelerated shoreline retreat). Haifa Bay, northern Israel, has recorded a landward sea invasion, with a maximum sea penetration 4,000 years ago, during an important period of urban development and climate instability. Here, we examine the cumulative pressure of climate shifts and relative sea-level changes in order to investigate the patterns and mechanisms behind forest replacement by an open-steppe. We provide a first comprehensive and integrative study for the southern Levant that shows that (i) human impact, through urbanization, has been the main driver behind ecological erosion in the past 4,000 years; (ii) climate pressures have reinforced this impact; and (iii) local coastal changes have played a decisive role in eroding ecosystem resilience. These three parameters, which have closely interacted during the last 4,000 years in Haifa Bay, clearly indicate that for an efficient management of the coastal habitats, anthropogenic pressures linked to urban development must be reduced in order to mitigate the predicted effects of Global Change.     

Phonatory Dysfunction as a Preclinical Symptom of Huntington Disease

Purpose

Although dysphonia has been shown to be a common sign of Huntington disease (HD), the extent of phonatory dysfunction in gene positive premanifest HD individuals remains unknown. The aim of the current study was to explore the possible occurrence of phonatory abnormalities in prodromal HD.

Method

Sustained vowel phonations were acquired from 28 premanifest HD individuals and 28 healthy controls of comparable age. Data were analysed acoustically for measures of several phonatory dimensions including airflow insufficiency, aperiodicity, irregular vibration of vocal folds, signal perturbations, increased noise, vocal tremor and articulation deficiency. A predictive model was built to find the best combination of acoustic features and estimate sensitivity/specificity for differentiation between premanifest HD subjects and controls. The extent of voice deficits according to a specific phonatory dimension was determined using statistical decision making theory. The results were correlated to global motor function, cognitive score, disease burden score and estimated years to disease onset.

Results

Measures of aperiodicity and increased noise were able to significantly differentiate between premanifest HD individuals and controls (p<0.01). The combination of these aspects of dysphonia led to a sensitivity of 91.5% and specificity of 79.2% to correctly distinguish speakers with premanifest HD from healthy individuals. Some form of disrupted phonatory function was revealed in 68% of our premanifest HD subjects, where 18% had one affected phonatory dimension and 50% showed impairment of two or more dimensions. A relationship between pitch control and cognitive score was also observed (r = −0.50, p = 0.007).

Conclusions

Phonatory abnormalities are detectable even the in premotor stages of HD. Speech investigation may have the potential to provide functional biomarkers of HD and could be included in future clinical trials and therapeutic interventions.