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On a population basis multiple nutrient deficiencies are common in developing countries, whereas in developed countries obesity and vitamin D deficiency are important health issues. While nutrient deficiencies can lead to disease, the results of clinical trials investigating the influence of supplementing various nutrients such as essential fatty acids, iron, and vitamin A on upper respiratory disease have been mixed. Probiotics may have a role in the treatment of upper respiratory disease, but appropriate probiotic strain/strains, supplement timing, as well as the dosage and method of administration continue to be debated. In clinical practice, many patients report that a milk exclusion diet is beneficial in reducing respiratory mucus production; however, the scientific basis for this remains controversial. Increasing evidence indicates that zinc supplementation is beneficial in the management of upper respiratory infections. A number of clinical trials also indicate that vitamin D supplementation has a potential role in the prevention of upper respiratory disease. Optimal vitamin D levels and dosages remain to be determined.

La Trobe University Faculty of Science, Technology and Engineering Murray Darling Freshwater Research CentreMDFRC item.Despite the critical role of water movement in the nutrient dynamics of wetlands, few wetland studies of nutrient imports, exports and cycling have been based on comprehensive water balance studies. In particular, many investigations have underestimated the importance and role of groundwater movement. Nutrient loads entering and leaving a 2 ha reed swamp in the Kiewa Valley, North-east Victoria showed the swamp to be a nutrient source within the landscape under both base flow and storm flow conditions. During a dry period between February 1994 and January 1995 the wetland itself exported 230 kg of Total Nitrogen (115 kg ha−1 yr−1) and 24 kg of Total Phosphorus (12 kg−1 ha−1 yr−1). Investigations confirmed that the wetland was a significant discharge area, and that groundwater accounted for 97% of the surface water and 50% of the Total Nitrogen and Total Phosphorus load leaving the system. A further 30% of Total Nitrogen and 26% of Total Phosphorus leaving the wetland was not attributable to rain/dust, surface water inputs or groundwater, and most likely resulted from the flushing of previously stored nitrogen and phosphorus. A fire which burnt most of the wetland area in September 1994 had little immediate impact on nutrient loads leaving the system. The study illustrates the complexity of assessing the nutrient dynamics and hydrology of natural wetlands, and raises questions with respect to the use of such systems for the interception of diffuse source nutrient loads within rural catchments.

Objective Leukocytes play an important role in the body's immune system. The aim of this study was to assess alterations in neutrophil phenotype and function in pump-assisted circulation in-vitro. Methods Human blood was circulated for four hours in three circulatory flow loops with a CentriMag blood pump operated at a flow of 4.5 L/min at three rotational speeds (2100, 2800, and 4000 rpm), against three pressure heads (75 mmHg, 150 mmHg, and 350 mmHg), respectively. Blood samples were collected hourly for analyses of neutrophil activation state (Mac-1, CD62L, CD162), neutrophil reactive oxygen species (ROS) production, apoptosis, and neutrophil phagocytosis. Results Activated neutrophils indicated by both Mac-1 expression and decreased surface expression of CD62L and CD162 receptors increased with time in three loops. The highest level of neutrophil activation was observed in the loop with the highest rotational speed. Platelet-neutrophil aggregates (PNAs) progressively increased in two loops with lower rotational speeds. PNAs peaked at one hour after circulation and decreased subsequently in the loop with the highest rotational speed. Neutrophil ROS production dramatically increased at one hour after circulation and decreased subsequently in all three loops with similar levels and trends. Apoptotic neutrophils increased with time in all three loops. Neutrophil phagocytosis capacity in three loops initially elevated at one hour after circulation and decreased subsequently. Apoptosis and altered phagocytosis were dependent on rotational speed. Conclusions Our study revealed that the pump-assisted circulation induced neutrophil activation, apoptosis, and functional impairment. The alterations were strongly associated with pump operating condition and duration.

Traumatic injuries afflict more than 5 million people globally every year. Current and past animal research has demonstrated association among alcohol, trauma, and impaired immune function, whereas human registries have shown association between alcohol and morbidity as well as mortality. The purpose of this study is to elucidate the immune interactions with alcohol in traumatically injured patients. We prospectively enrolled 379 patients after trauma at three medical centers in the Surgical Critical Care Initiative. Plasma was analyzed using Luminex for up to 35 different cytokines. Collected samples were grouped by patients with detectable plasma alcohol levels versus those without. Univariate testing determined differences in analytes between groups. We built Bayesian belief networks with multiple minimum descriptive lengths to compare the two groups. All 379 patient samples were analyzed. Two hundred eighty‐two (74.4%) patients were men, and 143 (37.7%) were White. Patients had a median intensive care unit length of stay (LOS) of 5.8 days and hospital LOS of 12 days. Using single variate analyses, eight different cytokines were differentially associated with alcohol. Cytokines IL‐12 and IL‐6 were important nodes in both models and IL‐10 was a prominent node in the nonalcohol model. This study found select immune function differed between traumatically injured patients with measurable serum alcohol levels as compared with those without. Traumatically injured patients with positive blood alcohol content appear less able to inhibit inflammatory stress. Alcohol appears to suppress pro‐inflammatory IL‐12 and IL‐6, whereas patients without alcohol have greater levels of anti‐inflammatory IL‐10 expressed at injury and may better regulate anti‐inflammatory pathways. Future studies should determine the relationship with these markers with clinically oriented outcomes.

Three protein emulsifiers encapsulating β-carotene (BC) with accompanying lipids into nanoemulsions (NEs) or without lipids into nanoparticles (NPs) were fabricated to study the effect of the type of interfacial protein on carrier design and the structure remodeling during digestion on the overall uptake and metabolism of BC in Caco-2 cells. BC-loaded micelles and micellar-like aggregates were collected after in vitro digestion and applied to Caco-2 cell monolayers. The digestion process significantly enhanced the cellular uptake of BC by 1.2-2.2 times and 4.1-8.2 times loaded in NEs and NPs, respectively. Whey protein isolate-based carriers improved the absorption but decreased the metabolism of BC to retinyl palmitate. The presence of lipids was found to improve metabolism and aid the transport of retinoids to the basolateral side of Caco-2 monolayers. Understanding the transportation behavior of the protein-based nanocarries after digestion may contribute to the design of biosafe carriers with higher bioavailability to deliver lipophilic nutrients.

Introduction Advances in transjugular intrahepatic portosystemic shunt (TIPS) technology have led to expanded use. We sought to characterize contemporary outcomes of TIPS by common indications. Methods This was a multicenter, retrospective cohort study using data from the Advancing Liver Therapeutic Approaches study group among adults with cirrhosis who underwent TIPS for ascites/hepatic hydrothorax (ascites/HH) or variceal bleeding (2010-2015). Adjusted competing risk analysis was used to assess post-TIPS mortality or liver transplantation (LT). Results Among 1,129 TIPS recipients, 58% received TIPS for ascites/HH and 42% for variceal bleeding. In patients who underwent TIPS for ascites/HH, the subdistribution hazard ratio (sHR) for death was similar across all Model for End-Stage Liver Disease Sodium (MELD-Na) categories with an increasing sHR with rising MELD-Na. In patients with TIPS for variceal bleeding, MELD-Na ≥20 was associated with increased hazard for death, whereas MELD-Na ≥22 was associated with LT. In a multivariate analysis, serum creatinine was most significantly associated with death (sHR 1.2 per mg/dL, 95% confidence interval [CI] 1.04-1.4 and 1.37, 95% CI 1.08-1.73 in ascites/HH and variceal bleeding, respectively). Bilirubin and international normalized ratio were most associated with LT in ascites/HH (sHR 1.23, 95% CI 1.15-1.3; sHR 2.99, 95% CI 1.76-5.1, respectively) compared with only bilirubin in variceal bleeding (sHR 1.06, 95% CI 1.00-1.13). Discussion MELD-Na has differing relationships with patient outcomes dependent on TIPS indication. These data provide new insights into contemporary predictors of outcomes after TIPS.

Cu/ZnO catalyst precursors for industrial methanol synthesis catalysts are traditionally synthesised by coprecipitation. In this study, a new precipitation route has been investigated based on anti-solvent precipitation using a switchable solvent system of triethylamine and water. This system forms a biphasic system under a nitrogen atmosphere and can be switched to an ionic liquid single phase under a carbon dioxide atmosphere. When metal nitrate solutions were precipitated from water using triethylamine–water as the anti-solvent a hydroxynitrate phase, gerhardite, was formed, rather than the hydroxycarbonate, malachite, formed by coprecipitation. When calcined and reduced, the gerhardite precursors formed Cu/ZnO catalysts which showed better productivity for methanol synthesis from CO2 hydrogenation than a traditional malachite precursor, despite their larger CuO crystallite size determined by X-ray diffraction. The solvents could be recovered by switching to the biphasic system after precipitation, to allow solvent recycling in the process, reducing waste associated with the catalyst synthesis.

Time-distinctive features within carbonate rocks, specifically the presence, abundance and distribution of stromatolites, molar-tooth fabric and specific morphologies of marine cement, have been identified as potential indicators of global-scale changes in the chemistry of marine environments. Recently, Cantineet al.(2019) introduced a database approach seeking to quantify spatial and temporal patterns in these carbonate features through the Precambrian. Despite the coarse temporal scale, results support earlier inferences of temporal change in carbonate sedimentation. Here, we use original field notes to dissect late Mesoproterozoic (˜1.3 to 1.0 Ga) carbonate strata at a high resolution, analyse time-distinctive carbonate fabrics within a database context and compare sedimentological patterns within this narrow time range to observations of the Proterozoic as a whole. Late Mesoproterozoic strata contain a variety of features (e.g. stromatolites, seafloor precipitates, herringbone carbonate, molar-tooth carbonate), often in close spatial and temporal proximity, that are commonly considered to be temporally restricted during the Precambrian. The spatial distribution of such features within Mesoproterozoic basins demonstrates the importance of recognizing even rare occurrences of time-distinctive facies and permits inference of environmental drivers that may have interacted to affect carbonate precipitation. Such spatial variability reflects a subtle division of Mesoproterozoic carbonate platform environments driven by globally high sea level, elevated carbonate saturation and a low-oxygen water column. The heterogeneous, mosaic nature of environments appears to be a hallmark of Mesoproterozoic carbonate sedimentation and emphasizes the importance of these basins in understanding longer-term trends in carbonate deposition.

Identifying the mechanisms through which genetic risk causes dementia is an imperative for new therapeutic development. Here, we apply a multistage, systems biology approach to elucidate the disease mechanisms in frontotemporal dementia. We identify two gene coexpression modules that are preserved in mice harboring mutations in MAPT, GRN and other dementia mutations on diverse genetic backgrounds. We bridge the species divide via integration with proteomic and transcriptomic data from the human brain to identify evolutionarily conserved, disease-relevant networks. We find that overexpression of miR-203, a hub of a putative regulatory microRNA (miRNA) module, recapitulates mRNA coexpression patterns associated with disease state and induces neuronal cell death, establishing this miRNA as a regulator of neurodegeneration. Using a database of drug-mediated gene expression changes, we identify small molecules that can normalize the disease-associated modules and validate this experimentally. Our results highlight the utility of an integrative, cross-species network approach to drug discovery.

There is an ongoing need for noninvasive tools to manipulate brain activity with molecular, spatial and temporal specificity. Here we have investigated the use of MRI-visible, albumin-based nanoclusters for noninvasive, localized and temporally specific drug delivery to the rat brain. We demonstrated that IV injected nanoclusters could be deposited into target brain regions via focused ultrasound facilitated blood brain barrier opening. We showed that nanocluster location could be confirmed in vivo with MRI. Additionally, following confirmation of nanocluster delivery, release of the nanocluster payload into brain tissue can be triggered by a second focused ultrasound treatment performed without circulating microbubbles. Release of glutamate from nanoclusters in vivo caused enhanced c-Fos expression, indicating that the loading capacity of the nanoclusters is sufficient to induce neuronal activation. This novel technique for noninvasive stereotactic drug delivery to the brain with temporal specificity could provide a new way to study brain circuits in vivo preclinically with high relevance for clinical translation.

Background. Individuals with cystic fibrosis (CF) have persistent lung infections, necessitating the frequent use of antibiotics for pulmonary exacerbations. Some respiratory pathogens have intrinsic resistance to the currently available antibiotics, and any pathogen may acquire resistance over time, posing a challenge to CF care. Gaseous nitric oxide has been shown to have antimicrobial activity against a wide variety of microorganisms, including common CF pathogens, and offers a potential inhaled antimicrobial therapy. Case Presentation. Here, we present the case of a 16-year-old female with CF who experienced a precipitous decline in lung function over the prior year in conjunction with worsening antibiotic resistance of her primary pathogen, Burkholderia multivorans. She received 46 intermittent inhalations of 160 parts-per-million nitric oxide over a 28-day period. The gas was administered via a mechanical ventilator fitted with nitrogen dioxide scavenging chambers. Conclusions. High-dose inhaled nitric oxide was safe, well tolerated, and showed clinical benefit in an adolescent with cystic fibrosis and pulmonary colonization with Burkholderia multivorans.

The transcriptional coactivator peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) is a critical regulator of genes involved in neuronal metabolism, neurotransmission, and morphology. Reduced PGC-1α expression has been implicated in several neurological and psychiatric disorders. An understanding of PGC-1α’s roles in different cell types will help determine the functional consequences of PGC-1α dysfunction and/or deficiency in disease. Reports from our laboratory and others suggest a critical role for PGC-1α in inhibitory neurons with high metabolic demand such as fast-spiking interneurons. Here, we document a previously unrecognized role for PGC-1α in maintenance of gene expression programs for synchronous neurotransmitter release, structure, and metabolism in neocortical and hippocampal excitatory neurons. Deletion of PGC-1α from these neurons caused ambulatory hyperactivity in response to a novel environment and enhanced glutamatergic transmission in neocortex and hippocampus, along with reductions in mRNA levels from several PGC-1α neuron-specific target genes. Given the potential role for a reduction in PGC-1α expression or activity in Huntington Disease (HD), we compared reductions in transcripts found in the neocortex and hippocampus of these mice to that of an HD knock-in model; few of these transcripts were reduced in this HD model. These data provide novel insight into the function of PGC-1α in glutamatergic neurons and suggest that it is required for the regulation of structural, neurosecretory, and metabolic genes in both glutamatergic neuron and fast-spiking interneuron populations in a region-specific manner. These findings should be considered when inferring the functional relevance of changes in PGC-1α gene expression in the context of disease.

In order to explore the role of a disintegrin and metalloproteinase (ADAM) proteolysis and direct mechanical damage in non-physiologic shear stress (NPSS)-caused platelet receptor shedding, the healthy donor blood treated with/without ADAM inhibitor was exposed to NPSS (150 Pa). The expression of the platelet surface receptors glycoprotein (GP) Ibα and glycoprotein (GP) VI (GPVI) in NPSS-damaged blood was quantified with flow cytometry. The impact of ADAM inhibition on adhesion of NPSS-damaged platelets on von Willibrand factor (VWF) and collagen was explored with fluorescence microscopy. The impact of ADAM inhibition on ristocetin- and collagen-caused aggregation of NPSS-damaged platelets was examined by aggregometry. The results showed that ADAM inhibition could lessen the NPSS-induced loss of platelet surface receptor GPIbα (12%) and GPVI (9%), moderately preserve adhesion of platelets on VWF (7.4%) and collagen (8.4%), and partially restore the aggregation of NPSS-sheared platelets induced by ristocetin (18.6 AU*min) and collagen (48.2 AU*min). These results indicated that ADAM proteolysis played a role in NPSS-induced receptor shedding. However, the ADAM inhibition couldn't completely suppress the NPSS-caused loss of the platelet surface receptors (GPIbα and GPVI), only partially prevented the NPSS-induced reduction of platelet adhesion to VWF and collagen, and the agonist (ristocetin and collagen)-caused platelet aggregation. These results suggested that the direct mechanical damage is partially responsible for NPSS-induced receptor shedding in addition to the ADAM proteolysis. In conclusion, NPSS relevant to blood contacting medical devices can induce ADAM proteolysis and direct mechanical damage on the platelet receptor GPIbα and GPVI, leading to comprised hemostasis.

OBJECTIVE: The roles of the large membrane surface of the oxygenator and the high mechanical shear stress (HMSS) of the pump in the ECMO circuit were examined under a pediatric support setting. METHODS: A clinical centrifugal pump and a pediatric oxygenator were used to construct the ECMO circuit. An identical circuit without the oxygenator was constructed for comparison. Fresh human blood was circulated in the two circuits for 4 hours under the identical pump speed and flow. Blood samples were collected hourly for blood damage assessment, including platelet activation, generation of platelet-derived microparticles (PDMP), losses of key platelet hemostasis receptors (glycoprotein (GP) Ibα (GPIbα) and GPVI) and high molecular weight multimers (HMWM) of von Willebrand factor (VWF) and plasma free hemoglobin (PFH). Platelet adhesion on fibrinogen, VWF and collagen was further examined. RESULTS: The levels of platelet activation and generation of PDMP and PFH exhibited an increasing trend with circulation time while the expression levels of GPIbα and GPVI receptors on the platelet surface decreased. Correspondingly, the platelets in the blood samples exhibited increased adhesion capacity to fibrinogen and decreased adhesion capacities on VWF and collagen with circulation time. Loss of HMWM of VWF occurred in both circuits. No statistically significant differences were found in all the measured parameters for blood damage and platelet adhesion function between the two circuits. CONCLUSIONS: The results indicate that HMSS from the pump played a dominant role in blood damage associated with ECMO and the impact of the large surface of the oxygenator on blood damage was insignificant.

The AP-2γ transcription factor, encoded by the TFAP2C gene, regulates the expression of estrogen receptor-alpha (ERα) and other genes associated with hormone response in luminal breast cancer. Little is known about the role of AP-2γ in other breast cancer subtypes. A subset of HER2+ breast cancers with amplification of the TFAP2C gene locus becomes addicted to AP-2γ. Herein, we sought to define AP-2γ gene targets in HER2+ breast cancer and identify genes accounting for physiologic effects of growth and invasiveness regulated by AP-2γ. Comparing HER2+ cell lines that demonstrated differential response to growth and invasiveness with knockdown of TFAP2C, we identified a set of 68 differentially expressed target genes. CDH5 and CDKN1A were among the genes differentially regulated by AP-2γ and that contributed to growth and invasiveness. Pathway analysis implicated the MAPK13/p38δ and retinoic acid regulatory nodes, which were confirmed to display divergent responses in different HER2+ cancer lines. To confirm the clinical relevance of the genes identified, the AP-2γ gene signature was found to be highly predictive of outcome in patients with HER2+ breast cancer. We conclude that AP-2γ regulates a set of genes in HER2+ breast cancer that drive cancer growth and invasiveness. The AP-2γ gene signature predicts outcome of patients with HER2+ breast cancer and pathway analysis predicts that subsets of patients will respond to drugs that target the MAPK or retinoic acid pathways. Implications: A set of genes regulated by AP-2γ in HER2+ breast cancer that drive proliferation and invasion were identified and provided a gene signature that is predictive of outcome in HER2+ breast cancer.

Despite rigorous sterilization protocols placed in surgical procedures, there is demonstrated evidence that show patients contract infections while hospitalized. This study aims to investigate the presence of biological materials in osteotome surgical tools after sterilization processes, determine the relationship between lack of sharpness and cross-contamination, and evaluate the influence of materials surface coating as a potential contamination preventive. Three commercially available osteotomes with different surface coatings were studied and submitted to a procedure of bone-cutting cycles. After use, each was sterilized and examined under SEM and EDS. Bone contaminants were detected in each osteotome although the PVD coated osteotome demonstrated significantly less contamination than either the as-supplied or electroless nickel coated one. According to the results, there is an association between blade sharpness and post-sterilization bone contamination. These findings suggest either disposable osteotomes should be used in surgical procedures, or an effective sharpen process should both be established and monitored to minimise post-operative infections.

Among individuals with hypertension, controlling high blood pressure (BP) reduces the risk for cardiovascular events and death. Reducing dietary sodium can help achieve BP control. The study aim was to use a population-based sample utilizing the gold-standard for urinary sodium to quantify the degree with which sodium was independently associated with BP control among individuals with hypertension. Participants included 1 568 adults from the Heart Follow-Up Study, a New York City population-based representative study conducted in 2010. Participants collected urine for 24 hours and had BP and other anthropometrics measured. Hypertension was defined as systolic BP ≥ 140 mmHg, diastolic BP ≥ 90 mmHg, or being on BP lowering medication. Sodium intake (mg/day) was measured from a single 24-hour urine collection. Hypertension prevalence was 30.8%. Among those with hypertension, 64.6% were aware, 56.3% were treated, and 40.3% were controlled. Among those treated for hypertension, 73.0% were controlled. Mean sodium intake among those with hypertension was 3 564 mg/day. From multivariable adjusted logistic regression models, each 500mg decrease in 24-hour urinary sodium excretion was associated with a 18% higher odds of hypertension control among those with hypertension (1.18, 95% CI: 1.07, 1.30). In New York City, approximately one in three people has hypertension with a majority uncontrolled. Sodium intake among those with hypertension was 55% greater than recommended upper limit of 2 300 mg per day. Among individuals with hypertension, lower sodium intake was associated with hypertension control.

Many clinical studies utilizing MSCs (mesenchymal stem cells, mesenchymal stromal cells, or multipotential stromal cells) are underway in multiple clinical settings; however, the ideal approach to prepare these cells in vitro and to deliver them to injury sites in vivo with maximal effectiveness remains a challenge. Here, pretreating MSCs with agents that block the apoptotic pathways were compared with untreated MSCs. The treatment effects were evaluated in the myocardial infarct setting following direct injection, and physiological parameters were examined at 4 weeks post-infarct in a rat permanent ligation model. The prosurvival treated MSCs were detected in the hearts in greater abundance at 1 week and 4 weeks than the untreated MSCs. The untreated MSCs improved ejection fraction in infarcted hearts from 61% to 77% and the prosurvival treated MSCs further improved ejection fraction to 83% of normal. The untreated MSCs improved fractional shortening in the infarcted heart from 52% to 68%, and the prosurvival treated MSCs further improved fractional shortening to 77% of normal. Further improvements in survival of the MSC dose seems possible. Thus, pretreating MSCs for improved in vivo survival has implications for MSC-based cardiac therapies and in other indications where improved cell survival may improve effectiveness.

Extra- and trans-cellular barriers are essential for root function under even mild stress. New research shows that establishing both the lignin and suberin barriers in the Arabidopsis endodermis requires phenylpropanoid biosynthesis by endodermal cells themselves.

Helminth infections are ubiquitous in grazing ruminant production systems, and are responsible for significant costs and production losses. Anthelmintic Resistance (AR) in parasites is now widespread throughout Europe, although there are still gaps in our knowledge in some regions and countries. AR is a major threat to the sustainability of modern ruminant livestock production, resulting in reduced productivity, compromised animal health and welfare, and increased greenhouse gas emissions through increased parasitism and farm inputs. A better understanding of the extent of AR in Europe is needed to develop and advocate more sustainable parasite control approaches. A database of European published and unpublished AR research on gastrointestinal nematodes (GIN) and liver fluke (Fasciola hepatica) was collated by members of the European COST Action "COMBAR" (Combatting Anthelmintic Resistance in Ruminants), and combined with data from a previous systematic review of AR in GIN. A total of 197 publications on AR in GIN were available for analysis, representing 535 studies in 22 countries and spanning the period 1980-2020. Reports of AR were present throughout the European continent and some reports indicated high within-country prevalence. Heuristic sample size-weighted estimates of European AR prevalence over the whole study period, stratified by anthelmintic class, varied between 0 and 48%. Estimated regional (country) prevalence was highly heterogeneous, ranging between 0% and 100% depending on livestock sector and anthelmintic class, and generally increased with increasing research effort in a country. In the few countries with adequate longitudinal data, there was a tendency towards increasing AR over time for all anthelmintic classes in GIN: aggregated results in sheep and goats since 2010 reveal an average prevalence of resistance to benzimidazoles (BZ) of 86%, macrocyclic lactones except moxidectin (ML) 52%, levamisole (LEV) 48%, and moxidectin (MOX) 21%. All major GIN genera survived treatment in various studies. In cattle, prevalence of AR varied between anthelmintic classes from 0-100% (BZ and ML), 0-17% (LEV) and 0-73% (MOX), and both Cooperia and Ostertagia survived treatment. Suspected AR in F. hepatica was reported in 21 studies spanning 6 countries. For GIN and particularly F. hepatica, there was a bias towards preferential sampling of individual farms with suspected AR, and research effort was biased towards Western Europe and particularly the United Kingdom. Ongoing capture of future results in the live database, efforts to avoid bias in farm recruitment, more accurate tests for AR, and stronger appreciation of the importance of AR among the agricultural industry and policy makers, will support more sophisticated analyses of factors contributing to AR and effective strategies to slow its spread.Importance croissante de la résistance aux anthelminthiques chez les ruminants européens : création et méta-analyse d’une base de données ouverte.Les helminthes sont omniprésents dans les systèmes de production de ruminants au pâturage et sont responsables de coûts et de pertes de production importants. La résistance aux anthelminthiques (RA) des parasites est maintenant répandue dans toute l’Europe, bien qu’il existe encore des lacunes dans nos connaissances dans certaines régions et certains pays. La RA est une menace majeure pour la pérennité de la production moderne de ruminants, en diminuant la productivité, en compromettant la santé et le bien-être des animaux, et en augmentant les émissions de gaz à effet de serre au travers d’une augmentation du parasitisme et des intrants agricoles. Une meilleure compréhension de l’étendue de la RA en Europe est nécessaire pour développer et préconiser des approches de lutte antiparasitaire plus durables. Une base de données intégrant des informations publiées et non publiées en Europe concernant la RA des nématodes gastro-intestinaux (NGI) et de la douve du foie (Fasciola hepatica) a été compilée par les membres de l’action européenne COST « COMBAR » (« Combattre la résistance aux anthelminthiques chez les ruminants ») et combinée avec les données d’une précédente étude systématique concernant la RA des NGI. Au total, 197 publications sur la RA des NGI étaient disponibles pour analyse, représentant 535 études dans 22 pays et couvrant la période 1980–2020. Des signalements de RA étaient présents sur tout le continent européen et certains rapports indiquaient une forte prévalence nationale. Les estimations heuristiques pondérées par la taille de l’échantillon de la prévalence de la RA en Europe sur toute la période d’étude, stratifiées par classe d’anthelminthiques, variaient de 0 à 48 %. La prévalence régionale (nationale) estimée était très hétérogène, variant entre 0 % et 100 % selon le secteur de l’élevage et la classe d’anthelminthique, et augmentait généralement avec les efforts de recherche dans le pays. Dans les quelques pays disposant de données longitudinales adéquates, il y avait une tendance à l’augmentation de la RA au fil du temps pour toutes les classes d’anthelminthiques des NGI : les résultats agrégés chez les ovins et caprins depuis 2010 révèlent une prévalence moyenne de résistance aux benzimidazoles (BZ) de 86 %, aux lactones macrocycliques sauf moxidectine (ML) de 52 %, au lévamisole (LEV) de 48 % et à la moxidectine (MOX) de 21 %. Tous les genres principaux de NGI ont survécu au traitement dans diverses études. Chez les bovins, la prévalence de la RA variait selon les classes d’anthelminthiques de 0 à 100 % (BZ et ML), 0 à 17 % (LEV) et 0 à 73 % (MOX), et Cooperia et Ostertagia ont survécu aux traitements. Une RA suspectée chez F. hepatica a été signalée dans 21 études portant sur 6 pays. Pour les NGI, et encore plus pour F. hepatica, il y avait un biais d’échantillonnage en faveur des exploitations individuelles suspectées de RA, et l’effort de recherche était biaisé vers l’Europe occidentale et en particulier le Royaume-Uni. La capture continue des résultats futurs dans la base de données, en direct, les efforts pour éviter les biais dans le recrutement des exploitations, des tests plus précis pour la RA et une meilleure appréciation de l’importance de la RA parmi l’industrie agricole et les décideurs politiques, soutiendront des analyses plus sophistiquées des facteurs contribuant à la RA, et des stratégies efficaces pour ralentir sa propagation.

Integrated quantum photonic devices require the combination of quantum light sources, elements for guiding and manipulating the photonic states and detectors [1] . In a fully-integrated platform, the operating conditions for each component must be mutually compatible. Whilst parametric down-conversion (PDC) as a source for photonic states is well-established under ambient conditions [2] , other quantum photonic technologies require cryogenic operation temperatures, in particular superconducting single-photon detectors [3] .

The realisation of light modulation based on single photon detection events is an important step towards feed-forward-modulation, which is required for many quantum optics protocols. This requires combining detection events with modulation in a device with a small physical footprint, for which integrated optics is ideal. Several platforms for integrated quantum optics have been developed to generate, modulate, and detect quantum features in the light over the last years. Titanium in-diffused waveguides in lithium niobate is a promising candidate for quantum communication applications [1] , [2] , however, single photon detection with superconducting photon detectors (SNSPDs) require cryogenic temperatures. Therefore, optimising the nonlinear optical properties of these waveguides under cryogenic operating conditions is an important task. Previously, we have demonstrated frequency conversion [3] , electro-optical modulation [4] and integrated single photon detection [5] at cryogenic temperatures.

Progestogens are frequently administered during early pregnancy to patients undergoing assisted reproductive techniques (ART) to overcome progesterone deficits following ART procedures. Orally administered dydrogesterone (DG) shows equal efficacy to other progestogens with a higher level of patient compliance. However, potential harmful effects of DG on critical pregnancy processes and on the health of the progeny are not yet completely ruled out. We treated pregnant mice with DG in the mode, duration, and doses comparable to ART patients. Subsequently, we studied DG effects on embryo implantation, placental and fetal growth, fetal-maternal circulation, fetal survival, and the uterine immune status. After birth of in utero DG-exposed progeny, we assessed their sex ratios, weight gain, and reproductive performance. Early-pregnancy DG administration did not interfere with placental and fetal development, fetal-maternal circulation, or fetal survival, and provoked only minor changes in the uterine immune compartment. DG-exposed offspring grew normally, were fertile, and showed no reproductive abnormalities with the exception of an altered spermiogram in male progeny. Notably, DG shifted the sex ratio in favor of female progeny. Even though our data may be reassuring for the use of DG in ART patients, the detrimental effects on spermatogenesis in mice warrants further investigations and may be a reason for caution for routine DG supplementation in early pregnancy.

Stable carbon isotope geochemistry is a well-established and reliable tool for studying metabolisms of microbial communities in the Precambrian record; however, the isotopic effects of high-temperature alteration from igneous intrusions (i.e., contact metamorphism) have not been thoroughly explored. The Mesoproterozoic (∼1.4 Ga) Middlebrun Bay Member of the Rossport Formation, Sibley Group, in Ontario, Canada, is composed of carbonaceous stromatolites and microbial laminites preserved in an evaporitic, lacustrine chert–carbonate deposit and is cross-cut by an intrusive mafic sill at the studied locality. Sedimentary organic matter (kerogen) was investigated along two vertical stratigraphic transects to determine the spatial variability of its geochemical preservation. Thermal alteration of the preserved kerogen (as measured by Raman spectroscopy) increased toward the mafic sill, but the alteration was greater for kerogen preserved in carbonate mineralogies compared to that preserved in quartz (chert). Bulk δ13Corg values fluctuate throughout each vertical section, with a total average of −28.2‰ ± 0.8‰; however, values are unexpectedly lower for samples near the mafic sill, approaching −30‰, inconsistent with previously reported patterns. These measurements indicate that thermal alteration of sedimentary rocks does not universally result in 13C enrichment and increased δ13Corg values and suggests that ancient kerogen may be preferentially shielded from postdepositional heating effects due to micrometre-scale differences in mineralogy.

Background The objective of this study was to determine the demographic and clinical features of youth supported by member associations of the Federación Mexicana de Diabetes and the Life for a Child Program (LFAC). Methods An analysis of 2017 Annual Clinical Data Sheets of 306 subjects from five Mexican centers was performed. Results Type 1 diabetes (T1D) was diagnosed in 292 subjects; 54.6% were female, with six diagnosed aged 1c (HbA1c) levels for those with duration ≥6 months were 8.7/8.4% (72/68 mmol/mol) and were higher in adolescents vs. children. Elevated body mass index SD, triglycerides (≥150 mg/dL) and non-high-density lipoprotein (HDL)-cholesterol (≥130 mg/dL) were common: 7.6%, 11.0% and 12.7% (n = 288, 218 and 180, respectively). Serum creatinine levels were normal in all tested subjects (n = 194). Conclusions Youth with diabetes in less-resourced families in Mexico are achieving reasonable glycemia. Most T1D patients use a basal bolus insulin regimen and test blood glucose several times daily. Some subjects have adverse vascular risk factor profiles. Further attention is needed to prevent chronic complications. Monogenic diabetes is very likely in some youth, and genetic testing is indicated.

Low-temperature depolymerization of biomass sugars is a less capital-intensive way to produce secondary fuel precursors. Solvolysis of bagasse using polyol cosolvents reduces sugar dehydration and limits unwanted side reactions. Ethylene glycol (EG) as cosolvent (50 v/v%) was found to increase formic acid, levulinates, and furfural yields from 71 to 100 mol %, 59 to 70 mol %, and 44 to 59 mol %, respectively, based on the theoretical yield of the cellulose component of bagasse. The exceptionally high formic acid yield is attributed to it being produced not only from cellulose but also via hemicellulose and EG conversion pathways. Increasing concentrations of EG proportionally reduced furfural yield. Delignification of bagasse prior to solvolysis with 50 v/v% EG decreased the yields of both formic acid (84 mol %) and furfural (52%) but increased the levulinates yield to 80 mol %.

Reconstructing Earth's oxygenation history is key to deciphering environmental controls on early biospheric evolution. During the mid-Proterozoic Eon, low (but potentially variable) atmospheric pO2 led to highly heterogeneous marine redox conditions, with most studies indicating a relatively shallow depth of oxygen penetration. The relative proportion of oxic, anoxic and iron-rich (ferruginous), and anoxic and sulfide-rich (euxinic) conditions on the global seafloor is difficult to quantify, however, due to a general reliance on local redox proxies applied to the temporally discontinuous black shale record. It is particularly important to constrain the global prevalence of euxinic bottom waters because sulfide toxicity has been implicated as a primary constraint on evolution in mid-Proterozoic oceans and limits the solubility of bioessential trace metals such as copper, zinc, and molybdenum. Here, we present a suite of new uranium (U) isotope data from marine carbonate rocks that span the entire mid-Proterozoic interval (∼1.8 to 0.8 Ga). U-isotopes in well-preserved carbonate rocks represent a powerful new proxy that can be used to quantitatively constrain the global extent of marine euxinia. The median δ 238 U value for mid-Proterozoic carbonate samples is −0.43‰, which is lower than the median value for modern post-depositional carbonate sediments from the Bahamas, yet significantly higher than carbonate δ 238 U values recorded during other times of expanded anoxia in Earth history, such as during the end-Permian mass extinction. When paired with a three-sink isotope mass balance model, our data indicate that no more than 7% of the global seafloor was euxinic during the mid-Proterozoic Eon, although transient pulses of expanded euxinia are recorded. Although these results challenge early expectations of a sulfide-rich mid-Proterozoic ocean, they are consistent with more recent inferences from the black shale trace metal record. Evidence therefore indicates that euxinic bottom waters were relatively limited in their spatial extent in the mid-Proterozoic oceans.

We have investigated the production of benzyl alcohols and bioaromatics via the reductive lignin depolymerization process over Fe/H-style ultrastable Y (HUSY), Ni/HUSY, and Ni-Fe/HUSY catalysts using HCOOK/ETOH in air. Synergy effect between HCOOK and the catalysts improved the depolymerization process, resulting in a higher bio-oil recovery. HCOOK does not act solely as an in situ hydrogen source; it also interacts with lignin to enable its initial depolymerization via a base-catalyzed mechanism to low-molecular-weight fragments, and in tandem with the catalyst, the hydrogenolysis rate of the depolymerized lignin monomers was enhanced. Fe/HUSY displayed an excellent activity for the catalytic reductive step in contrast to Ni/HUSY and Ni-Fe/HUSY by facilitating methoxy group removal via hydrogenolysis, thereby contributing to the yield and stabilization of the low-molecular-weight aromatics [diethyl ether (DEE)-soluble products]. Fe/HUSY gave the highest DEE product yield of >99 wt % and a total benzyl alcohol yield of 16 wt % with a total selectivity of 47 wt % (60 wt % for aromatic alcohols). Fe/HUSY was reused for the lignin depolymerization reaction without much loss of its initial activity, giving 13 wt % yield of benzyl alcohols with a selectivity of 58 wt % (77 wt % for aromatic alcohols).

We have undertaken a detailed analysis of the biotransformation of five of the most therapeutically important benzimidazole anthelmintics - albendazole (ABZ), mebendazole (MBZ), thiabendazole (TBZ), oxfendazole (OxBZ) and fenbendazole (FBZ) - in Caenorhabditis elegans and the ruminant parasite Haemonchus contortus. Drug metabolites were detected by LC-MS/MS analysis in supernatants of C. elegans cultures with a hexose conjugate, most likely glucose, dominating for all five drugs. This work adds to a growing body of evidence that glucose conjugation is a major pathway of xenobiotic metabolism in nematodes and may be a target for enhancement of anthelmintic potency. Consistent with this, we found that biotransformation of albendazole by C. elegans reduced drug potency. Glucose metabolite production by C. elegans was reduced in the presence of the pharmacological inhibitor chrysin suggesting that UDP-glucuronosyl/glucosyl transferase (UGT) enzymes may catalyze benzimidazole glucosidation. Similar glucoside metabolites were detected following ex vivo culture of adult Haemonchus contortus. As a step towards identifying nematode enzymes potentially responsible for benzimidazole biotransformation, we characterised the transcriptomic response to each of the benzimidazole drugs using the C. elegans resistant strain CB3474 ben-1(e1880)III. In the case of albendazole, mebendazole, thiabendazole, and oxfendazole the shared transcriptomic response was dominated by the up-regulation of classical xenobiotic response genes including a shared group of UGT enzymes (ugt-14/25/33/34/37/41/8/9). In the case of fenbendazole, a much greater number of genes were up-regulated, as well as developmental and brood size effects suggesting the presence of secondary drug targets in addition to BEN-1. The transcriptional xenobiotic response of a multiply resistant H. contortus strain UGA/2004 was essentially undetectable in the adult stage but present in the L3 infective stage, albeit more muted than C. elegans. This suggests that xenobiotic responses may be less efficient in stages of parasitic nematodes that reside in the host compared with the free-living stages., Graphical abstract Image 1, Highlights • C. e. & H. c. display hexose conjugation (likely glucose) and excretion of 5 BZs. • C. elegans (C.e.) biotransformation of ABZ reduces drug potency. • UGT inhibitor chrysin reduces ABZ biotransformation by C. elegans. • Transcriptomic response of C. e. (ben-1) to 5 BZs dominated by xenobiotic response and additional targets for FBZ. • Minimal transcriptomic response of H. contortus to ABZ exposure.

Fructose is widely used as a sweetener in processed food and is also associated with metabolic disorders, such as obesity. However, the underlying cellular mechanisms remain unclear, in particular, regarding the pancreatic β-cell. Here, we investigated the effects of chronic exposure to fructose on the function of insulinoma cells and isolated mouse and human pancreatic islets. Although fructose per se did not acutely stimulate insulin exocytosis, our data show that chronic fructose rendered rodent and human β-cells hyper-responsive to intermediate physiological glucose concentrations. Fructose exposure reduced intracellular ATP levels without affecting mitochondrial function, induced AMP-activated protein kinase activation, and favored ATP release from the β-cells upon acute glucose stimulation. The resulting increase in extracellular ATP, mediated by pannexin1 (Panx1) channels, activated the calcium-mobilizer P2Y purinergic receptors. Immunodetection revealed the presence of both Panx1 channels and P2Y1 receptors in β-cells. Addition of an ectonucleotidase inhibitor or P2Y1 agonists to naïve β-cells potentiated insulin secretion stimulated by intermediate glucose, mimicking the fructose treatment. Conversely, the P2Y1 antagonist and Panx1 inhibitor reversed the effects of fructose, as confirmed using Panx1-null islets and by the clearance of extracellular ATP by apyrase. These results reveal an important function of ATP signaling in pancreatic β-cells mediating fructose-induced hyper-responsiveness.

Autophagy is critical for maintaining cellular function via clearance of excess nutrients and damaged organelles. In pancreatic β-cells, it helps counter the endoplasmic reticulum (ER) stress that impairs insulin secretory capacity during Type 2 diabetes. Chronic exposure of β-cells to saturated fatty acids (FAs) such as palmitate stimulates ER stress and modulates autophagy, but the effects of unsaturated FAs such as oleate, which are also elevated during obesity, are less well understood. We therefore treated MIN6 cells and mouse islets for 8–48 h with either palmitate or oleate, and then monitored autophagic flux, signaling pathways, lysosomal biology, and phospholipid profiles. Compared with palmitate, oleate more effectively stimulated both autophagic flux and clearance of autophagosomes. The flux stimulation occurred independently of ER stress, nutrient-sensing (mTOR) and signaling pathways (protein kinases A, C, and D). Instead the mechanism involved the exchange factor directly activated by cAMP 2 (EPAC2). Oleate reduced cellular cAMP, and its effects on autophagic flux were reproduced or inhibited, respectively, by Epac2 knockdown or activation. Oleate also increased lysosomal acidity and increased phospholipid saturation, consistent with improved autophagosomal fusion with lysosomes. We conclude that a potent stimulation of autophagy might help explain the known benefits of unsaturated FAs in countering the toxicity of saturated FAs in β-cells during obesity and lipid loading.

The development of viable biorefinery routes for the valorization of lignocellulosics into usable products remains a challenge. Despite the significant progress in lignin valorization using the lignin-first approach or lignin-stabilization strategy, a number of issues still remain including poor monomer yield with grasses and the use of toxic chemicals and H2 with high pressure. Herein, we report a highly effective oxidation–hydrogenation catalytic process for the complete depolymerization of sugarcane bagasse using Pd/C in the presence of atmospheric pressure O2 and alcohol as a solvent. Under the optimum reaction conditions, 31.7 wt% of ferulic acid (FA) and p-coumaric acid (pCA) derived aromatic esters and 25.8 wt% of other four aromatic monomers were obtained based on the lignin content. In this one step approach, molecular O2 adsorbed on the catalyst surface enhanced the formation of atomic hydrogen by alcohol oxidation, and hence improved the efficiency of the overall reductive depolymerization process. A linear correlation between the pCA content and its corresponding ester was obtained irrespective of the biomass source or whether the lignin is in the native or technical form. Another feature of this process is the separation of methylated mono-sugar derivatives and a cellulose-rich solid fraction that is readily fermentable. A plausible reaction mechanism was hypothesized which indicates that the carbon defect on the surface and the enhanced oxygen content are strongly correlated with the high activity of the Pd/C catalyst.

The current effort demonstrates that lutetium oxyorthosilicate doped with 1–10% cerium (Lu2SiO5:Ce, LSO:Ce) radioluminescent particles can be coated with a single dye or multiple dyes and generate an effective energy transfer between the core and dye(s) when excited via X-rays. LSO:Ce particles were surface modified with an alkyne modified naphthalimide (6-piperidin-1-yl-2-prop-2-yn-1-yl-1H-benzo[de]isoquinoline-1,3-(2H)-dione, AlNap) and alkyne modified rhodamine B (N-(6-diethylamino)-9-{2-[(prop-2-yn-1-yloxy)carbonyl]phenyl}-3H-xanthen-3-ylidene)-N-ethylethanaminium, AlRhod) derivatives to tune the X-ray excited optical luminescence from blue to green to red using Forster Resonance Energy Transfer (FRET). As X-rays penetrate tissue much more effectively than UV/visible light, the fluorophore modified phosphors may have applications as bioimaging agents. To that end, the phosphors were incubated with rat cortical neurons and imaged after 24 h. The LSO:Ce surface modified with AlNap was able to be success...

Current stratification systems for patients presenting with acute type A aortic dissection rely on signs of malperfusion to predict mortality. The authors sought to develop an algorithm to readily risk stratify these patients using admission characteristics.Two hundred sixty-nine consecutive patients who underwent type A repair between 2002 and 2015 were reviewed for easily obtainable preoperative demographics and laboratory values deemed a priori as potential predictors of operative mortality. Multiple logistic regression analysis was performed to determine independent significance, and linear regression was performed to generate the concomitant regression expression of the variables significant on bivariate analysis.Operative mortality was 16% (43/269) and was 29% (34/119) among patients who presented with malperfusion. Upon multivariate analysis, creatinine (p = 0.008), liver malperfusion (p = 0.006), and lactic acid level (p = 0.0007) remained independent significant predictors. Regression coefficients allowed the generation of a risk score as 5.5 × (lactic acid [mmol/L]) + 8 × (creatinine [mg/dL]) ± 8 (+ if liver malperfusion presents, - if no liver malperfusion). Upon receiver-operating characteristic curve analysis this model generated a c-statistic of 0.75. Operative mortality among patients within the lowest tertile (risk score7) was 4%, whereas patients in the middle (7 to 20) and highest (≥20) tertiles had mortality rates of 14% 37%, respectively.Although still requiring external validation, the innovative risk score presented necessitates knowledge of lactic acid, serum creatinine, and liver function tests. The algorithm predicts operative mortality with high accuracy and offers clinicians a novel tool to improve preoperative guidance and prognosis.

The structural integrity of platelet receptors is essential for platelets to play the normal hemostatic function. The high non-physiological shear stress (NPSS) commonly exists in blood contacting medical devices and has been shown to cause platelet receptor shedding. The loss of platelet receptors may impair the normal hemostatic function of platelets. The aim of this study was to quantify NPSS-induced shedding of three key receptors on the platelet surface. Human blood was subjected to the matrix of well-defined shear stresses and exposure times, generated by using a custom-designed blood shearing device. The expression of three key platelet receptors, glycoprotein (GP) Ibα, GPVI and GPIIb/IIIa in sheared blood was quantified using flow cytometry. The quantitative relationship between the loss of each of the three receptors on the platelet surface and shear condition (shear stress level and exposure time) was explored. It was found that these relationships followed well the power law functional form. The coefficients of the power law models for the shear-induced shedding of these platelet receptors were derived with coefficients of determination (R(2)) of 0.77, 0.73, and 0.78, respectively. The power law models with these coefficients may be potentially used to predict the shear-induced platelet receptor shedding of human blood.

Titanium in-diffused waveguides in lithium niobate is a promising integration platform for building devices for quantum communication, due to its low-loss propagation, high-efficiency coupling to telecom fiber, high second order nonlinearity and electro-optic coefficient. Over recent years we have been investigating the integration of superconducting nanowire single photon detectors (SNSPDs) in this platform, together with the Integrated Quantum Optics group at Paderborn University and colleagues at NIST Boulder. I will report on the proof-of-principle demonstrations of functional devices, as well as discuss our progress to improve the efficiency and yield of on-chip detectors.

We demonstrate the integration of amorphous tungsten silicide superconducting nanowire single-photon detectors on titanium in-diffused lithium niobate waveguides. We show proof-of-principle detection of evanescently-coupled photons of 1550nm wavelength using bidirectional waveguide coupling for two orthogonal polarization directions. We investigate the internal detection efficiency as well as detector absorption using coupling-independent characterization measurements. Furthermore, we describe strategies to improve the yield and efficiency of these devices., Comment: 7 pages, 6 figures