Molecular and Functional Characterization of Lymphoid Progenitor Subsets Reveals a Bipartite Architecture of Human Lymphopoiesis.

The classical model of hematopoiesis established in the mouse postulates that lymphoid cells originate from a founder population of common lymphoid progenitors. Here, using a modeling approach in humanized mice, we showed that human lymphoid development stemmed from distinct populations of CD127- and CD127+ early lymphoid progenitors (ELPs). Combining molecular analyses with in vitro and in vivo functional assays, we demonstrated that CD127- and CD127+ ELPs emerged independently from lympho-mono-dendritic progenitors, responded differently to Notch1 signals, underwent divergent modes of lineage restriction, and displayed both common and specific differentiation potentials. Whereas CD127- ELPs comprised precursors of T cells, marginal zone B cells, and natural killer (NK) and innate lymphoid cells (ILCs), CD127+ ELPs supported production of all NK cell, ILC, and B cell populations but lacked T potential. On the basis of these results, we propose a "two-family" model of human lymphoid development that differs from the prevailing model of hematopoiesis.

Environmentally Benign Fast-Degrading Conductive Composites.

An environmentally benign conductive composite that rapidly degrades in the presence of warm water via enzyme-mediated hydrolysis is described. This represents the first time that hydrolytic enzymes have been immobilized onto eco-friendly conductive carbon sources with the express purpose of degrading the encapsulating biodegradable plastic. Amano Lipase (AL)-functionalized carbon nanofibers (CNF) were compounded with polycaprolactone (PCL) to produce the composite film CNFAL-PCL (thickness ∼ 600 µm; CNFAL = 20.0 wt %). To serve as controls, films of the same thickness were also produced, including CNF-AL5-PCL (CNF mixed with AL and PCL; CNF = 19.2 wt % and AL = 5.00 wt %), CNF-PCL (CNF = 19.2 wt %), ALx-PCL (AL = x = 1.00 or 5.00 wt %), and PCL. The electrical performance of the CNF-containing composites was measured, and conductivities of 14.0 ± 2, 22.0 ± 5, and 31.0 ± 6 S/m were observed for CNFAL-PCL, CNF-AL5-PCL, and CNF-PCL, respectively. CNFAL-PCL and control films were degraded in phosphate buffer (2.00 mg/mL film/buffer) at 50 °C, and their average percent weight loss (Wtavg%) was recorded over time. After 3 h CNFAL-PCL degraded to a Wtavg% of 90.0% and had completely degraded after 8 h. This was considerably faster than CNF-AL5-PCL, which achieved a total Wtavg% of 34.0% after 16 days, and CNF-PCL, which was with a Wtavg% of 7.00% after 16 days. Scanning electron microscopy experiments (SEM) found that CNFAL-PCL has more open pores on its surface and that it fractures faster during degradation experiments which exposes the interior enzyme to water. An electrode made from CNFAL-PCL was fabricated and attached to an AL5-PCL support to form a fast-degrading thermal sensor. The resistance was measured over five cycles where the temperature was varied between 15.0-50.0 °C. The sensor was then degraded fully in buffer at 50 °C over a 48 h period.

A spatio-temporal analysis of marine diatom communities associated with pristine and aged plastics.

Complex microbial communities colonize plastic substrates over time, strongly influencing their fate and potential impacts on marine ecosystems. Among the first colonizers, diatoms play an important role in the development of this 'plastiphere'. We investigated 936 biofouling samples and the factors influencing diatom communities associated with plastic colonization. These factors included geographic location (up to 800 km apart), duration of substrate submersion (1 to 52 weeks), plastics (5 polymer types) and impact of artificial ageing with UV light. Diatom communities colonizing plastic debris were primarily determined by their geographic location and submersion time, with the strongest changes occurring within two weeks of submersion. Several taxa were identified as early colonizers (e.g. Cylindrotheca, Navicula and Nitzschia spp.) with known strong adhesion capabilities. To a lesser extent, plastic-type and UV-ageing significantly affected community composition, with 14 taxa showing substrate-specificity. This study highlights the role of plastics types-state for colonization in the ocean.

An investigation into the stability and degradation of plastics in aquatic environments using a large-scale field-deployment study.

The fragmentation of plastic debris is a key pathway to the formation of microplastic pollution. These disintegration processes depend on the materials' physical and chemical characteristics, but insight into these interrelationships is still limited, especially under natural conditions. Five plastics of known polymer/additive compositions and processing histories were deployed in aquatic environments and recovered after six and twelve months. The polymer types used were linear low density polyethylene (LLDPE), oxo-degradable LLDPE (oxoLLDPE), poly(ethylene terephthalate) (PET), polyamide-6 (PA6), and poly(lactic acid) (PLA). Four geographically distinct locations across Aotearoa/New Zealand were chosen: three marine sites and a wastewater treatment plant (WWTP). Accelerated UV-weathering under controlled laboratory conditions was also carried out to evaluate artificial ageing as a model for plastic degradation in the natural environment. The samples' physical characteristics and surface microstructures were studied for each deployment location and exposure time. The strongest effects were found for oxoLLDPE upon artificial ageing, with increased crystallinity, intense surface cracking, and substantial deterioration of its mechanical properties. However, no changes to the same extent were found after recovery of the deployed material. In the deployment environments, the chemical nature of the plastics was the most relevant factor determining their behaviours. Few significant differences between the four aquatic locations were identified, except for PA6, where indications for biological surface degradation were found only in seawater, not the WWTP. In some cases, artificial ageing reasonably mimicked the changes which some plastic properties underwent in aquatic environments, but generally, it was no reliable model for natural degradation processes. The findings from this study have implications for the understanding of the initial phases of plastic degradation in aquatic environments, eventually leading to microplastics formation. They can also guide the interpretation of accelerated laboratory ageing for the fate of aquatic plastic pollution, and for the testing of aged plastic samples.

Magnetic phase diagram of (Mo2/3RE1/3)2AlC, RE=Tb and Dy, studied by magnetization, specific heat, and neutron diffraction analysis.

We report the results of magnetization, heat capacity, and neutron diffraction measurements on (Mo2/3RE1/3)2AlC with RE = Dy and Tb. Temperature and field-dependent magnetization as well as heat capacity were measured on a powder sample and on a single crystal allowing the construction of the magnetic field-temperature phase diagram. To study the magnetic structure of each magnetic phase, we applied neutron diffraction in a magnetic field up to 6 T. For (Mo2/3Dy1/3)2AlC in zero field, a spin density wave is stabilized at 16 K, with antiferromagnetic ordering at 13 K. Furthermore, we identify the coexistence of ferromagnetic and antiferromagnetic phases induced by magnetic fields for both RE = Tb and Dy. The origin of the field induced phases is resulting from the competing ferromagnetic and antiferromagnetic interactions.

Transcontinental spread and evolution of Mycobacterium tuberculosis W148 European/Russian clade toward extensively drug resistant tuberculosis.

Transmission-driven multi-/extensively drug resistant (M/XDR) tuberculosis (TB) is the largest single contributor to human mortality due to antimicrobial resistance. A few major clades of the Mycobacterium tuberculosis complex belonging to lineage 2, responsible for high prevalence of MDR-TB in Eurasia, show outstanding transnational distributions. Here, we determined factors underlying the emergence and epidemic spread of the W148 clade by genome sequencing and Bayesian demogenetic analyses of 720 isolates from 23 countries. We dated a common ancestor around 1963 and identified two successive epidemic expansions in the late 1980s and late 1990s, coinciding with major socio-economic changes in the post-Soviet Era. These population expansions favored accumulation of resistance mutations to up to 11 anti-TB drugs, with MDR evolving toward additional resistances to fluoroquinolones and second-line injectable drugs within 20 years on average. Timescaled haplotypic density analysis revealed that widespread acquisition of compensatory mutations was associated with transmission success of XDR strains. Virtually all W148 strains harbored a hypervirulence-associated ppe38 gene locus, and incipient recurrent emergence of prpR mutation-mediated drug tolerance was detected. The outstanding genetic arsenal of this geographically widespread M/XDR strain clade represents a "perfect storm" that jeopardizes the successful introduction of new anti-M/XDR-TB antibiotic regimens.

Quantifying the Shape Memory Performance of a Three-Dimensional-Printed Biobased Polyester/Cellulose Composite Material.

A biobased composite material with heat-triggered shape memory ability was successfully formulated for three-dimensional (3D) printing. It was produced from cellulose nanocrystals and cellulose micro-powder particles within a bioderived thermally cured polyester matrix based on glycerol, citric acid, and sebacic acid. The effect of curing duration on the material's shape memory behavior was quantified by using two thermo-mechanical approaches to measure recovery: (1) displacement in three-point bending and (2) angular recovery from a beam bent at 90° in a single cantilever setup. Extending curing duration increased the material's glass-transition temperature from -26°C after 6 h to 13°C after 72 h of curing. Fourier-transform infrared spectroscopy confirmed the associated progressive conversion of functional groups consistent with polyester formation. Slow recovery rates and low levels of shape recovery (22-70%) were found for samples cured less than 24 h. Those results also indicated a high dependence on the measurement approach. In contrast, samples cured for 48 and 72 h exhibited faster recovery rates, a significantly higher recovery percentage (90-100%) and were less sensitive to the measurement approach. Results demonstrated that once a sufficient curing threshold was achieved, additional curing time could be used to tune the material glass-transition temperature and create heat-triggered 3D-printed products.

Niche specialization and spread of Staphylococcus capitis involved in neonatal sepsis.

The multidrug-resistant Staphylococcus capitis NRCS-A clone is responsible for sepsis in preterm infants in neonatal intensive care units (NICUs) worldwide. Here, to retrace the spread of this clone and to identify drivers of its specific success, we investigated a representative collection of 250 S. capitis isolates from adults and newborns. Bayesian analyses confirmed the spread of the NRCS-A clone and enabled us to date its emergence in the late 1960s and its expansion during the 1980s, coinciding with the establishment of NICUs and the increasing use of vancomycin in these units, respectively. This dynamic was accompanied by the acquisition of mutations in antimicrobial resistance- and bacteriocin-encoding genes. Furthermore, combined statistical tools and a genome-wide association study convergently point to vancomycin resistance as a major driver of NRCS-A success. We also identified another S. capitis subclade (alpha clade) that emerged independently, showing parallel evolution towards NICU specialization and non-susceptibility to vancomycin, indicating convergent evolution in NICU-associated pathogens. These findings illustrate how the broad use of antibiotics can repeatedly lead initially commensal drug-susceptible bacteria to evolve into multidrug-resistant clones that are able to successfully spread worldwide and become pathogenic for highly vulnerable patients.

Compensatory evolution drives multidrug-resistant tuberculosis in Central Asia.

Bacterial factors favoring the unprecedented multidrug-resistant tuberculosis (MDR-TB) epidemic in the former Soviet Union remain unclear. We utilized whole genome sequencing and Bayesian statistics to analyze the evolutionary history, temporal emergence of resistance and transmission networks of MDR Mycobacterium tuberculosis complex isolates from Karakalpakstan, Uzbekistan (2001-2006). One clade (termed Central Asian outbreak, CAO) dating back to 1974 (95% HPD 1969-1982) subsequently acquired resistance mediating mutations to eight anti-TB drugs. Introduction of standardized WHO-endorsed directly observed treatment, short-course in Karakalpakstan in 1998 likely selected for CAO-strains, comprising 75% of sampled MDR-TB isolates in 2005/2006. CAO-isolates were also identified in a published cohort from Russia (2008-2010). Similarly, the presence of mutations supposed to compensate bacterial fitness deficits was associated with transmission success and higher drug resistance rates. The genetic make-up of these MDR-strains threatens the success of both empirical and standardized MDR-TB therapies, including the newly WHO-endorsed short MDR-TB regimen in Uzbekistan.

Changing patterns of human migrations shaped the global population structure of Mycobacterium tuberculosis in France.

Mycobacterium tuberculosis (Mtb) exhibits a structured phylogeographic distribution worldwide linked with human migrations. We sought to infer how the interactions between distinct human populations shape the global population structure of Mtb on a regional scale. We applied the recently described timescaled haplotypic density (THD) technique on 638 minisatellite-based Mtb genotypes from French tuberculosis patients. THD with a long-term (200 y) timescale indicated that Mtb population in France had been mostly influenced by interactions with Eastern and Southern Europe and, to a lesser extent, Northern and Middle Africa, consistent with historical migrations favored by geographic proximity or commercial exchanges with former French colonies. Restricting the timescale to 20 y, THD identified a sustained influence of Northern Africa, but not Europe where tuberculosis incidence decreased sharply. Evolving interactions between human populations, thus, measurably influence the local population structure of Mtb. Relevant information on such interactions can be inferred using THD from Mtb genotypes.

Economic Synergy between Dry Cow Diet Improvement and Monensin Bolus Use to Prevent Subclinical Ketosis: An Experimental Demonstration Based on Available Literature.

The prevention of subclinical ketosis (SCK) is based on maintaining adequate nutrition in dairy cows during the dry period and close to calving. Recently, an oral-route monensin bolus to prevent SCK was approved in Europe. The present study aims to define the allocation of resources for SCK management at the herd level and evaluate the profitability of administering monensin boluses in cows at risk for SCK. A stochastic model was used to calculate the total cost of SCK for a population with a given prevalence of cows at risk for SCK. This model included the ability of the farmer to correctly target and preventatively treat these cows at risk for SCK. The results clearly demonstrated economic synergy between two management practices. First, reducing the prevalence of cows at risk for SCK dramatically reduces the total cost of SCK and seems profitable in most situations. Second, monensin bolus use to reduce the occurrence of SCK in cows already at risk for SCK is cost-effective. The results also highlighted three economic strategies to manage SCK in the dairy industry in Europe. First, monensin bolus use throughout an entire herd when the prevalence of cows at risk for SCK is high is only profitable in the short-term as a tool to correct acute deterioration at the herd level. Second, decreasing the prevalence of cows at risk for SCK through adequate feeding in the dry period is of financial interest as a baseline strategy when prevalence is high, assuming moderate additional cost linked to the new diet. Third, monensin bolus use when the prevalence of cows at risk for SCK is low is also profitable as a long-term strategy when only cows at high risk for SCK (such as cows that are over-conditioned, old, or have a previous history of SCK-related disorders) are targeted for preventative treatment. Authors suggest to use the present results considering that farmers have a correct, but not perfect, ability to target animals to be preventively targeted with the monensin bolus. Further work is required to facilitate the early identification of cows at risk for SCK.

Strain-specific estimation of epidemic success provides insights into the transmission dynamics of tuberculosis.

The transmission dynamics of tuberculosis involves complex interactions of socio-economic and, possibly, microbiological factors. We describe an analytical framework to infer factors of epidemic success based on the joint analysis of epidemiological, clinical and pathogen genetic data. We derive isolate-specific, genetic distance-based estimates of epidemic success, and we represent success-related time-dependent concepts, namely epidemicity and endemicity, by restricting analysis to specific time scales. The method is applied to analyze a surveillance-based cohort of 1,641 tuberculosis patients with minisatellite-based isolate genotypes. Known predictors of isolate endemicity (older age, native status) and epidemicity (younger age, sputum smear positivity) were identified with high confidence (P < 0.001). Long-term epidemic success also correlated with the ability of Euro-American and Beijing MTBC lineages to cause active pulmonary infection, independent of patient age and country of origin. Our results demonstrate how important insights into the transmission dynamics of tuberculosis can be gained from active surveillance data.

The Evolutionary History, Demography, and Spread of the Mycobacterium tuberculosis Complex.

With the advent of next-generation sequencing technology, the genotyping of clinical Mycobacterium tuberculosis strains went through a major breakup that dramatically improved the field of molecular epidemiology but also revolutionized our deep understanding of the M. tuberculosis complex evolutionary history. The intricate paths of the pathogen and its human host are reflected by a common geographical origin in Africa and strong biogeographical associations that largely reflect the past migration waves out of Africa. This long coevolutionary history is cardinal for our understanding of the host-pathogen dynamic, including past and ongoing demographic components, strains' genetic background, as well as the immune system genetic architecture of the host. Coalescent- and Bayesian-based analyses allowed us to reconstruct population size changes of M. tuberculosis through time, to date the most recent common ancestor and the several phylogenetic lineages. This information will ultimately help us to understand the spread of the Beijing lineage, the rise of multidrug-resistant sublineages, or the fall of others in the light of socioeconomic events, antibiotic programs, or host population densities. If we leave the present and go through the looking glass, thanks to our ability to handle small degraded molecules combined with targeted capture, paleomicrobiology covering the Pleistocene era will possibly unravel lineage replacements, dig out extinct ones, and eventually ask for major revisions of the current model.

How Metabolic Diseases Impact the Use of Antimicrobials: A Formal Demonstration in the Field of Veterinary Medicine.

Decreasing the use of antimicrobials has become a primary objective for both human and veterinary medicine in many countries. Medical prevention and good nutrition are seen as key parameters for reducing antimicrobial use. However, little consideration has been given to how metabolic diseases may influence the use of antimicrobials in humans and animals through limiting the prevalence and severity of infectious diseases. To quantify this relationship using the example of a common metabolic disease in dairy cows (subclinical ketosis, SCK), we constructed a stochastic model reporting the total quantity of curative antimicrobials for a given population with the prevalence of cows at risk for SCK. We considered the prevalence of SCK, the relative risk of the disease in cases of SCK compared to no SCK and the use of antimicrobials to treat SCK-induced infectious diseases. Reducing the percentage of cows at risk for SCK from 80% to 10% was associated with an average decrease in the use of antimicrobials of 11% (prevalence of SCK from 34% to 17%, respectively) or 25% (prevalence of SCK from 68% to 22%, respectively), depending on the relative risk to contract SCK if risk was present. For a large percentage of the cows at risk for SCK, using a preventive bolus of monensin reduced the use of curative antimicrobials to the same level that was observed when the percentage of cows at risk for SCK was low. The present work suggests similar approaches for obesity and diabetes.

Demography and Intercontinental Spread of the USA300 Community-Acquired Methicillin-Resistant Staphylococcus aureus Lineage.

UNLABELLED: Community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA) was recognized worldwide during the 1990s; in less than a decade, several genetically distinct CA-MRSA lineages carrying Panton-Valentine leukocidin genes have emerged on every continent. Most notably, in the United States, the sequence type 18-IV (ST8-IV) clone known as USA300 has become highly prevalent, outcompeting methicillin-susceptible S. aureus (MSSA) and other MRSA strains in both community and hospital settings. CA-MRSA bacteria are much less prevalent in Europe, where the European ST80-IV European CA-MRSA clone, USA300 CA-MRSA strains, and other lineages, such as ST22-IV, coexist. The question that arises is whether the USA300 CA-MRSA present in Europe (i) was imported once or on very few occasions, followed by a broad geographic spread, anticipating an increased prevalence in the future, or (ii) derived from multiple importations with limited spreading success. In the present study, we applied whole-genome sequencing to a collection of French USA300 CA-MRSA strains responsible for sporadic cases and micro-outbreaks over the past decade and United States ST8 MSSA and MRSA isolates. Genome-wide phylogenetic analysis demonstrated that the population structure of the French isolates is the product of multiple introductions dating back to the onset of the USA300 CA-MRSA clone in North America. Coalescent-based demography of the USA300 lineage shows that a strong expansion occurred during the 1990s concomitant with the acquisition of the arginine catabolic mobile element and antibiotic resistance, followed by a sharp decline initiated around 2008, reminiscent of the rise-and-fall pattern previously observed in the ST80 lineage. A future expansion of the USA300 lineage in Europe is therefore very unlikely. IMPORTANCE: To trace the origin, evolution, and dissemination pattern of the USA300 CA-MRSA clone in France, we sequenced a collection of strains of this lineage from cases reported in France in the last decade and compared them with 431 ST8 strains from the United States. We determined that the French CA-MRSA USA300 sporadic and micro-outbreak isolates resulted from multiple independent introductions of the USA300 North American lineage. At a global level, in the transition from an MSSA lineage to a successful CA-MRSA clone, it first became resistant to multiple antibiotics and acquired the arginine catabolic mobile element and subsequently acquired resistance to fluoroquinolones, and these two steps were associated with a dramatic demographic expansion. This expansion was followed by the current stabilization and expected decline of this lineage. These findings highlight the significance of horizontal gene acquisitions and point mutations in the success of such disseminated clones and illustrate their cyclic and sporadic life cycle.