bluuebunny/crossref_metadata_2025 huggingface dataset:
Critical Exponent and Hausdorff Dimension in Pseudo-Riemannian Hyperbolic Geometry
Authors: Glorieux Olivier , Monclair Daniel
Published: April 2019

The aim of this article is to understand the geometry of limit sets in pseudo-Riemannian hyperbolic geometry. We focus on a class of subgroups of $\textrm{PO}(p,q+1)$ introduced by Danciger, Guéritaud, and Kassel, called ${\mathbb{H}}^{p,q}$-convex cocompact. We define a pseudo-Riemannian analogue of critical exponent and Hausdorff dimension of the limit set. We show that they are equal and bounded from above by the usual Hausdorff dimension of the limit set. We also prove a rigidity result in ${\mathbb{H}}^{2,1}={\mathbb{A}}\textrm{d}{\mathbb{S}}^3$, which can be understood as a Lorentzian version of a famous Theorem of R. Bowen in $3$D hyperbolic geometry.
Staphylococcus aureus Epicutaneous Infection Is Suppressed by Lactococcus lactis Strain Plasma via Interleukin 17A Elicitation
Authors: Tsuji Ryohei , Fujii Toshio , Nakamura Yuumi , Yazawa Kamiyu , Kanauchi Osamu
Published: April 2019

Background

Lactococcus lactis strain Plasma (LC-Plasma) was revealed to stimulate plasmacytoid dendritic cells and induce antiviral immunity in vitro and in vivo. In this study, we assessed the effects of LC-Plasma on skin immunity.

Methods

To evaluate the effect of LC-Plasma on skin immunity and Staphylococcus aureus epicutaneous infection, lymphocyte activities in skin-draining lymph nodes (SLNs) and gene expression in skin were analyzed after 2 weeks of oral administration of LC-Plasma. To evaluate the mechanisms of interleukin 17A production, SLN lymphocytes were cultured with or without LC-Plasma, and the interleukin 17A concentrations in supernatants were measured.

Results

Oral administration of LC-Plasma activated plasma dendritic cells in SLNs, augmented skin homeostasis, and elicited suppression of Staphylococcus aureus, Staphylococcus epidermidis, and Propionibacterium acnes proliferation. In addition, significant suppression of the S. aureus burden and reduced skin inflammation were observed following oral administration of LC-Plasma. Furthermore, a subsequent in vitro study revealed that LC-Plasma could elicit interleukin 17A production from CD8+ T cells and that its induction mechanism depended on the Toll-like receptor 9 signaling pathway, with type I interferon partially involved.

Conclusions

Our results suggest that LC-Plasma oral administration enhances skin homeostasis via plasma dendritic cell activation in SLNs, resulting in suppression of S. aureus epicutaneous infection and skin inflammation.
A Genome-Wide Functional Genomics Approach Identifies Susceptibility Pathways to Fungal Bloodstream Infection in Humans
Authors: Jaeger Martin , Matzaraki Vasiliki , Aguirre-Gamboa Raúl , Gresnigt Mark S , Chu Xiaojing , Johnson Melissa D , Oosting Marije , Smeekens Sanne P , Withoff Sebo , Jonkers Iris , Perfect John R , van de Veerdonk Frank L , Kullberg Bart-Jan , Joosten Leo A B , Li Yang , Wijmenga Cisca , Netea Mihai G , Kumar Vinod
Published: April 2019

Background

Candidemia, one of the most common causes of fungal bloodstream infection, leads to mortality rates up to 40% in affected patients. Understanding genetic mechanisms for differential susceptibility to candidemia may aid in designing host-directed therapies.

Methods

We performed the first genome-wide association study on candidemia, and we integrated these data with variants that affect cytokines in different cellular systems stimulated with Candida albicans.

Results

We observed strong association between candidemia and a variant, rs8028958, that significantly affects the expression levels of PLA2G4B in blood. We found that up to 35% of the susceptibility loci affect in vitro cytokine production in response to Candida. Furthermore, potential causal genes located within these loci are enriched for lipid and arachidonic acid metabolism. Using an independent cohort, we also showed that the numbers of risk alleles at these loci are negatively correlated with reactive oxygen species and interleukin-6 levels in response to Candida. Finally, there was a significant correlation between susceptibility and allelic scores based on 16 independent candidemia-associated single-nucleotide polymorphisms that affect monocyte-derived cytokines, but not with T cell-derived cytokines.

Conclusions

Our results prioritize the disturbed lipid homeostasis and oxidative stress as potential mechanisms that affect monocyte-derived cytokines to influence susceptibility to candidemia.
Epidemiology of Hepatitis E in England and Wales: A 10-Year Retrospective Surveillance Study, 2008–2017
Authors: Oeser Clarissa , Vaughan Aisling , Said Bengü , Ijaz Samreen , Tedder Richard , Haywood Becky , Warburton Fiona , Charlett Andre , Elson Richard , Morgan Dilys
Published: April 2019

Indigenous, foodborne transmission of hepatitis E virus genotype 3 (HEV G3) has become recognized as an emerging problem in industrialized countries. Although mostly asymptomatic, HEV G3 infection has a range of outcomes, including mild illness, severe acute hepatitis, and, of particular concern, chronic progressive hepatitis in immunocompromised patients. Public Health England has monitored cases of acute HEV infection in England and Wales since 2003. Between 2010 and 2017, enhanced surveillance using 2 linked laboratory databases and questionnaires on clinical features and risk factors was conducted. There was a year-on-year increase in the number of infections from 2008 (183) through 2016 (1243). Then, in 2017, the number of infections declined (to 912). As reported previously, HEV G3 group 2 (also known as “G3 abcdhij”) is the predominant cause of acute infections, and older men are most at risk. Consumption of pork and pork products was significantly higher among patients than in the general population, but other previously reported associations, such as consumption of shellfish, were not observed. Ongoing surveillance is required to monitor future trends and changes in the epidemiology of the virus. The changing methods of animal husbandry and processing and distribution of animal products needs to be further investigated.
Incidence of healthcare-associated Clostridioides difficile infections and association with ward-level antibiotic consumption in a German university hospital: an ecological study
Authors: Kipnis Marina , Schwab Frank , Kramer Tobias S , Stegemann Miriam S , Isner Caroline , Pilarski Georg , Märtin Nayana , Bui Minh Trang , Boldt Anne-C , Behnke Michael , Denkel Luisa A , Wiese-Posselt Miriam , Zweigner Janine , Gastmeier Petra , Rohde Anna M
Published: April 2019

Objectives

Clostridioides difficile infection (CDI) is one of the most important healthcare-associated infections. We aimed to describe the incidence density of healthcare-associated CDI (HA-CDI) in Germany’s largest hospital and to identify associations with ward-level antimicrobial consumption.

Methods

We used surveillance data on CDI and antimicrobial consumption from 2014 to 2017 and analysed a potential association by means of multivariable regression analysis.

Results

We included 77 wards with 404998 admitted patients and 1850862 patient-days. Six hundred and seventy-one HA-CDI cases were identified, resulting in a pooled mean incidence density of 0.36/1000 patient-days (IQR = 0.34–0.39). HA-CDI incidence density on ICU and haematological–oncological wards was about three times higher than on surgical wards [incidence rate ratio (IRR) = 3.00 (95% CI = 1.96–4.60) and IRR = 2.78 (95% CI = 1.88–4.11), respectively]. Ward-level consumption of third-generation cephalosporins was the sole antimicrobial risk factor for HA-CDI. With each DDD/100 patient-days administered, a ward’s HA-CDI incidence density increased by 2% [IRR = 1.02 (95% CI = 1.01–1.04)]. Other risk factors were contemporaneous community-associated CDI cases [IRR = 1.32 (95% CI = 1.07–1.63)] and CDI cases in the previous month [IRR = 1.27 (95% CI = 1.07–1.51)]. Furthermore, we found a significant decrease in HA-CDI in 2017 compared with 2014 [IRR = 0.68 (95% CI = 0.54–0.86)].

Conclusions

We confirmed that ward-level antimicrobial use influences HA-CDI and specifically identified third-generation cephalosporin consumption as a risk factor.
Effects of dietary soy isoflavones and soy protein source on response of weanling pigs to porcine reproductive and respiratory syndrome viral infection
Authors: Smith Brooke Nicole , Morris Antrison , Oelschlager Maci Lynn , Connor Jordan , Dilger Ryan Neil
Published: April 2019

Porcine reproductive and respiratory syndrome virus (PRRSV) is the most prevalent disease of swine globally. Infection of weanling pigs with PRRSV leads to a complex immune response resulting in significant disease and decreased growth performance. Previous experimental evidence suggests that increasing concentrations of soybean meal in the diet of young pigs confer benefits in terms of growth performance and immune parameters. The objective of this experiment was to identify potential modes of action for this benefit, specifically the ability for soy-derived isoflavones (ISF) to confer immunological benefits to young pigs infected with PRRSV. Four dietary treatments differing in soy protein source (soy protein concentrate vs. enzyme-treated soybean meal) and ISF supplementation (none vs. 1,500 mg total ISF/kg) were fed; the control diet (CON) contained soy protein concentrate and no supplemental ISF. Weanling pigs (60 barrows, 21 d of age, 5.71 ± 0.44 kg) from a naturally Mycoplasma hyopneumoniae (Mh)–infected source herd were individually housed in disease containment chambers and provided ad libitum access to experimental diets for 7 d before receiving either a sham inoculation or a 9.28 × 103 50% tissue culture infective dose of PRRSV at 28 d of age (0 d postinoculation). A total of 5 experimental treatments included an uninfected group receiving the CON diet, plus four infected groups each receiving a different dietary treatment. Growth performance and rectal temperatures were recorded throughout the study, and blood was collected for quantification of serum PRRSV load, presence of anti-PRRSV antibodies, differential complete blood counts, cytokine concentrations, and T-cell immunophenotyping. Data were analyzed as a 2-way or 3-way ANOVA for all treatments including PRRSV-infected pigs, in addition to a single degree of freedom contrast to compare uninfected and infected pigs receiving the CON diet. PRRSV-infection reduced growth rate and efficiency compared with noninfected controls with minimal influences by ISF. Supplemental ISF reduced PRRSV-induced band neutrophilia and improved cytotoxic-to-helper T-cell ratios. These results suggest that ISF contribute to activation of adaptive immune system pathways and could benefit recovery from and clearance of PRRSV infections.
Revenue-Capped Efficient Auctions
Authors: Muto Nozomu , Shirata Yasuhiro , Yamashita Takuro
Published: April 2019

We study an auction that maximizes the expected social surplus under an upper-bound constraint on the seller’s expected revenue, which we call a revenue cap. Such a constrained-efficient auction may arise, for example, when (i) the auction designer is “pro-buyer”, that is, he maximizes the weighted sum of the buyers’ and seller’s auction payoffs, where the weight for the buyers is greater than that for the seller; (ii) the auction designer maximizes the (unweighted) total surplus in a multiunit auction in which the number of units the seller owns is private information; or (iii) multiple sellers compete to attract buyers before the auction. We characterize the mechanisms for constrained-efficient auctions and identify their important properties. First, the seller sets no reserve price and sells the good for sure. Second, with a nontrivial revenue cap, “bunching” is necessary. Finally, with a sufficiently severe revenue cap, the constrained-efficient auction has a bid cap, so that bunching occurs at least “at the top,” that is, “no distortion at the top” fails.
Identifying the Perpetrators of Chemical Attacks in Syria
Authors: Sossai Mirko
Published: April 2019

In June 2018, the Conference of States Parties of the 1993 Convention on the Prohibition of the Development, Production, Stockpiling and Use of Chemical Weapons and on their Destruction (Chemical Weapons Convention) decided to create an Investigation and Identification Team. This is a new mechanism within the Organisation for the Prohibition of Chemical Weapons (OPCW) Technical Secretariat ‘to identify the perpetrators of the use of chemical weapons in the Syrian Arab Republic’. This article analyses the background and main features of this decision and draws some preliminary conclusions on the role of the Investigation and Identification Team and its potential impact for the investigation and prosecution of crimes linked to the use of chemical weapons in Syria. Thus, after describing the events surrounding various fact-finding missions in Syria under the auspices of the OPCW and the United Nations, it considers the legal basis to interpret the Chemical Weapons Convention as enabling the OPCW to put in place arrangements to identify the perpetrators of the use of chemical weapons in Syria and elsewhere.
A chromatin modulator sustains self-renewal and enables differentiation of postnatal neural stem and progenitor cells
Authors: Shah Kushani , King Gwendalyn D , Jiang Hao
Published: April 2019

It remains unknown whether H3K4 methylation, an epigenetic modification associated with gene activation, regulates fate determination of the postnatal neural stem and progenitor cells (NSPCs). By inactivating the Dpy30 subunit of the major H3K4 methyltransferase complexes in specific regions of mouse brain, we demonstrate a crucial role of efficient H3K4 methylation in maintaining both the self-renewal and differentiation capacity of postnatal NSPCs. Dpy30 deficiency disrupts development of hippocampus and especially the dentate gyrus and subventricular zone, the major regions for postnatal NSC activities. Dpy30 is indispensable for sustaining the self-renewal and proliferation of NSPCs in a cell-intrinsic manner and also enables the differentiation of mouse and human neural progenitor cells to neuronal and glial lineages. Dpy30 directly regulates H3K4 methylation and the induction of several genes critical in neurogenesis. These findings link a prominent epigenetic mechanism of gene expression to the fundamental properties of NSPCs and may have implications in neurodevelopmental disorders.
Do Forced-Choice (FC) Questions Trigger Deeper Cognition than Check-All-That-Apply (CATA) Questions?
Authors: Neuert Cornelia E
Published: April 2019

Existing research shows that response options are endorsed at a higher rate when presented in forced-choice format (FC, yes-no grids) than in check-all-that-apply format (CATA). Information Processing Theory explains this contrast with differential effects on the level of cognitive reflection. The study tests this hypothesis with eye movement data collected in a randomized laboratory experiment in which 131 respondents participated in a web survey with four treatment questions. In one condition (CATA) the questions were presented in check-all format, in the other (FC) in forced-choice structure. I find higher levels of affirmative responses and longer completion times in FC compared to CATA in three of the questions. With all four questions, respondents invested more cognitive effort—measured by fixation counts and times—in FC than in CATA when considering the question in total. I find no differences when considering only the list of response options, however. This indicates that the longer fixation times did not result from a more careful evaluation of the response options. Other possible causes and practical implications are discussed.
In vivo analysis of influenza A mRNA secondary structures identifies critical regulatory motifs
Authors: Simon Lisa Marie , Morandi Edoardo , Luganini Anna , Gribaudo Giorgio , Martinez-Sobrido Luis , Turner Douglas H , Oliviero Salvatore , Incarnato Danny
Published: April 2019

The influenza A virus (IAV) is a continuous health threat to humans as well as animals due to its recurring epidemics and pandemics. The IAV genome is segmented and the eight negative-sense viral RNAs (vRNAs) are transcribed into positive sense complementary RNAs (cRNAs) and viral messenger RNAs (mRNAs) inside infected host cells. A role for the secondary structure of IAV mRNAs has been hypothesized and debated for many years, but knowledge on the structure mRNAs adopt in vivo is currently missing. Here we solve, for the first time, the in vivo secondary structure of IAV mRNAs in living infected cells. We demonstrate that, compared to the in vitro refolded structure, in vivo IAV mRNAs are less structured but exhibit specific locally stable elements. Moreover, we show that the targeted disruption of these high-confidence structured domains results in an extraordinary attenuation of IAV replicative capacity. Collectively, our data provide the first comprehensive map of the in vivo structural landscape of IAV mRNAs, hence providing the means for the development of new RNA-targeted antivirals.
DIPG-03. TARGETING PI3K USING THE BLOOD BRAIN BARRIER PENETRABLE INHIBITOR, GDC-0084, FOR THE TREATMENT OF DIFFUSE INTRINSIC PONTINE GLIOMA (DIPG)
Authors: Duchatel Ryan , Jackson Evangeline , Patabendige Adjanie , Cain Jason , Tsoli Maria , Monje Michelle , Alvaro Frank , Ziegler David , Dun Matthew
Published: April 2019

BACKGROUND: Diffuse Intrinsic Pontine Glioma (DIPG) is a devastating, incurable childhood brain cancer. 80% of patients harbour a genetic lesion to Histone-H3 with a substitution of lysine 27 for a methionine (K27M) (H3F3A/H3.3 and HIST1H3B/H3.1) which results in the loss of methylation, interfering with chromatin function, activating oncogenic transcription. Unfortunately, H3 mutations are not directly targetable. RTK-RAS-PI3Kpathway alterations occur in more than half of these patients (69%), and may represent a more promising therapeutic target. However, PI3K inhibitors have been notoriously ineffective due to their inability to cross the blood-brain-barrier (BBB). Targeting downstream components of the PI3K-AKT-mTOR signalling axis is a promising paradigm for PI3K mutant patients. This project aims to overcome the limitations of targeting downstream effectors of the PI3K pathway by utilising a novel PIK3CA specific, BBB permeable inhibitor, GDC-0084, currently in clinical trials for Glioblastoma (GBM) and DIPG. METHODS: Utilising DIPG patient derived (PDX) cells harboringH3K27M mutations (n=6), and +/- PI3Kmutations, we examined the in-vitroefficacy of GDC-0084 on cell proliferation compared to Rapamycin. Phosphoproteomic profiling is currently underway investigating the role GDC-0084 has on inhibition of downstream oncogenic signalling pathways. Assessment of efficacy in a PDX in-vivo model is currently in progress. RESULTS: GDC-0084 significantly reduced the growth of all DIPG cell lines regardless of whether they harboredPI3K mutations (p=<0.001), and were significantly more cytotoxic than the mTORC1 inhibitor Rapamycin (p=<0.01). DIPG cell lines were also more sensitive to PI3K inhibition by GDC-0084 compared to GBM cell lines (n=4, p=<0.001) highlighting the therapeutic potential of GDC-0084 for the treatment of DIPG. Combining GDC-0084 and Vandetanib in DIPG revealed synergistic effects. CONCLUSIONS: While there are currently no therapeutics effective against the transcriptional programs elicited by H3 mutations, these studies re-ignite the potential for PI3K inhibition as a therapeutic target for DIPG.
The Relationship Between Migraine or Severe Headache and Chronic Health Conditions: A Cross-Sectional Study from the National Health Interview Survey 2013–2015
Authors: Minen Mia T , Weissman Judith , Tietjen Gretchen E
Published: April 2019

Objective

To estimate the prevalence of having at least one or two or more chronic health conditions among US adults with self-reported migraine or severe headaches.

Design

Cross-sectional study.

Methods

Using data collected from the 2013–2015 National Health Interview Survey, we examined adults with and without migraine or severe headache and associations with chronic obstructive pulmonary disease, cancer, heart disease, stroke, diabetes, and hypertension. We calculated point estimates, variances, and 95% confidence intervals and conducted bivariate and multivariable logistic regression modeling to examine the relationships between migraine or severe headache and each of the chronic health conditions, as well as multinomial modeling, to examine the relationship between migraine or severe headache and having one or more chronic health conditions.

Results

A total of 104,926 people were in the study. Adults aged 18 to 44 years (18.2%), women (20.1%), and those with some college education (17.6%) had the greatest proportion with migraine or severe headache (P < 0.0001). Using multinomial modeling with the number of chronic health conditions as the dependent variable, adults reporting migraine had an increased odds of reporting a single chronic health condition (adjusted odds ratio [aOR] = 1.7, 95% confidence interval [CI] = 1.6–1.8) and more than double the odds of reporting two or more chronic health conditions (aOR = 2.5, 95% CI = 2.3–2.8) compared with adults who did not have migraine or severe headache.

Conclusions

Our study confirms observed relationships between migraine or severe headache and chronic health conditions and supports the need for further research to uncover the shared biological pathways.
The Source and the Course of the Articular Branches to the T4-T8 Zygapophysial Joints
Authors: Joshi Anand , Amrhein Timothy J , Holmes Megan A , Talsma Joel , Shonyo Megan , Taylor Andrea B
Published: April 2019

Objective

To define the source and the course of the articular branches to the midthoracic zygapophysial (“z”) joints.

Design

Cadaveric dissection.

Setting

The Gross Anatomy Laboratory of the Duke University School of Medicine.

Subjects

Ten human cadaveric thoraces.

Methods

Gross and stereoscopic dissection of dorsal rami T4-T8 was performed bilaterally on 10 adult embalmed cadavers. The medial and lateral branches were traced to their origins from the dorsal rami, and the course of the articular nerves was documented through digital photography. Radio-opaque wire (20 gauge) was applied to the nerves. Fluoroscopic images were obtained to delineate their radiographic course with respect to osseous landmarks.

Results

Forty-eight inferior articular branches were identified. Three (6.3%) originated from the medial branch and 44 (91.7%) from the dorsal ramus. One was indeterminate. Fifty-one superior articular branches were identified. Eight (15.7%) originated from the medial branch and 43 (84.3%) from the dorsal ramus. In 12% of cases (6/50), there was side-to-side asymmetry in the origins of the articular branches. Nerves were commonly suspended in the intertransverse space. The articular branches contacted an osseous structure in only 39% of cases. As previously reported, a “descending branch” was not identified in any specimen.

Conclusions

Articular branches to the T4-T8 z-joints have substantial inter- and intraspecimen variability of origin. They typically arise from the dorsal ramus rather than the medial branch and frequently do not contact any osseous structure to allow percutaneous needle placement.
Dilemma of Addiction and Respiratory Depression in the Treatment of Pain: A Prototypical Endomorphin as a New Approach
Authors: Webster Lynn , Schmidt William K
Published: April 2019

Objective

Although mu-opioid receptor agonists have been the mainstay of analgesic regimens for moderate to severe pain, they are associated with serious side effects, risks, and limitations. We evaluate the most serious risks associated with conventional opioids and compare these with the pharmacology of CYT-1010, a prototypical endomorphin and mu-opioid receptor agonist.

Results

Addiction and respiratory depression are serious risks of traditional mu-opioid analgesics. Mitigation strategies have been inadequate at addressing the opioid crisis and may interfere with the effective treatment of pain. Improved understanding of mu-opioid receptor biology and the discovery in 1997 of an additional and unique family of endogenous opioid peptides (endomorphins) have provided a pathway for dissociating analgesia from opioid-related adverse events and developing new classes of mu-opioid receptor agonists that use biased signaling and/or target novel sites to produce analgesia with reduced side effect liability. Endomorphin-1 and -2 are endogenous opioid peptides highly selective for mu-opioid receptors that exhibit potent analgesia with reduced side effects. CYT-1010 is a cyclized, D-lysine-containing analog of endomorphin-1 with a novel mechanism of action targeting traditional mu- and exon 11/truncated mu-opioid receptor 6TM variants. CYT-1010 preclinical data have demonstrated reduced abuse potential and analgesic potency exceeding that of morphine. In an initial phase 1 clinical study, CYT-1010 demonstrated significant analgesia vs baseline and no respiratory depression at the dose levels tested.

Conclusions

CYT-1010 and other novel mu-opioid receptor agonists in clinical development are promising alternatives to conventional opioids that may offer the possibility of safer treatment of moderate to severe pain.
Silver nanoparticles enter the tree stem faster through leaves than through roots
Authors: Cocozza C , Perone A , Giordano C , Salvatici M C , Pignattelli S , Raio A , Schaub M , Sever K , Innes J L , Tognetti R , Cherubini P
Published: April 2019

A major environmental pollution problem is the release into the atmosphere of particulate matter, including nanoparticles (NPs), which causes serious hazards to human and ecosystem health, particularly in urban areas. However, knowledge about the uptake, translocation and accumulation of NPs in plant tissues is almost completely lacking. The uptake of silver nanoparticles (Ag-NPs) and their transport and accumulation in the leaves, stems and roots of three different tree species, downy oak (Quercus pubescens Willd.), Scots pine (Pinus sylvestris L.) and black poplar (Populus nigra L.), were assessed. In the experiment, Ag-NPs were supplied separately to the leaves (via spraying, the foliar treatment) and roots (via watering, the root treatment) of the three species. Uptake, transport and accumulation of Ag were investigated through spectroscopy. The concentration of Ag in the stem was higher in the foliar than in the root treatment, and in poplar more than in oak and pine. Foliar treatment with Ag-NPs reduced aboveground biomass and stem length in poplars, but not in oaks or pines. Species-specific signals of oxidative stress were observed; foliar treatment of oak caused the accumulation of H2O2 in leaves, and both foliar and root treatments of poplar led to increased O2− in leaves. Ag-NPs affected leaf and root bacteria and fungi; in the case of leaves, foliar treatment reduced bacterial populations in oak and poplar and fungi populations in pine, and in the case of roots, root treatment reduced bacteria and increased fungi in poplar. Species-specific mechanisms of interaction, transport, allocation and storage of NPs in trees were found. We demonstrated definitively that NPs enter into the tree stem through leaves faster than through roots in all of the investigated tree species.
Aluminum toxicity could be mitigated with boron by altering the metabolic patterns of amino acids and carbohydrates rather than organic acids in trifoliate orange
Authors: Yan Lei , Riaz Muhammad , Liu Yalin , Zeng Yu , Jiang Cuncang
Published: April 2019

Aluminum (Al) toxicity is the main constraint of root growth and productivity on arable acidic soil. Although boron (B) is used to ameliorate Al stress, the exact mechanisms underlying the effects of B on Al-induced alteration on root metabolites are poorly understood, especially in the trifoliate orange, which is an important rootstock in China. Therefore, a hydroponics experiment was conducted to explore the mechanisms of B mitigates Al toxicity in roots of citrus by metabolomics. A total of 60 metabolites were identified and analyzed in the present study. The 17 amino acids and 8 sugars were up-regulated in Al-treated roots, mainly histidine, cycloleucine, asparagine, citrulline, raffinose and trehalose, and increased by 38.5-, 8.7-, 6.0-, 6.0-, 7.5- and 6.6-fold, respectively. Meanwhile, significant down-regulation of aspartic acid, isoleucine, glutamic acid and six sugars were indicated under Al stress. Aluminum induced a decrease of nine organic acids, especially l-malic acid, citric acid and threonic acid, by 98.2, 93.6 and 95.1%, respectively. Interestingly, in the presence of Al, B application decreased the contents of asparagine, cycloleucine, citrulline and histidine as well as myo-inositol, raffinose, galactinol and 3,6-anhydro-d-galactose by 52.2, 57.4, 46.7, 63.0, 65.4, 74.3, 62.5 and 55.0%, respectively. However, there was no obvious difference in the organic acid contents in Al-stressed roots treated with B. Conclusively, our results show that B regulates the metabolic patterns of amino acids and carbohydrates and reduces Al toxicity. Nevertheless, B addition did not affect the Al-induced changes in the metabolic modes of organic acids.
First report of peritonitis caused by the vancomycin-resistant coccus Pediococcus pentosaceus in a patient on continuous ambulatory peritoneal dialysis
Authors: Gupta Shefali , Sahu Chinmoy , Nag Soumyabrata , Saha Uma Shankar , Prasad Narayan , Prasad Kashi Nath
Published: April 2019

Introduction. Worldwide, about one-tenth of end-stage renal disease (ESRD) patients are on peritoneal dialysis (PD). Peritonitis is a major cause of PD failure and change of therapy to haemodialysis. An update on peritoneal dialysis-related infections has recommended the use of a first generation cephalosporin or vancomycin as an empirical therapy for Gram-positive organisms.

Pediococcus

spp. is a Gram-positive environmental cocci that have been increasingly reported from various nosocomial infections but very rarely from peritoneal dialysis infections. It is intrinsically resistant to Vancomycin but sensitive to ampicillin. So, diagnosis of this bacteria is important if isolated from PD infections.

Case presentation. An elderly female patient of ESRD on continuous ambulatory peritoneal dialysis (CAPD) was admitted with complaints of high fever and cloudy PD effluent for 2 days. She was started with vancomycin and imipenem empirically but did not improve even after 4 days. Pus cells were seen when PD fluid was examined microscopically. BACTEC culture of PD fluid isolated growth of Gram-positive cocci, which was confirmed as

Pediococcus pentosaceus

. It was resistant to vancomycin. The antibiotic of the patient was changed to ciprofloxacin IV. The patient responded in 2 days and was discharged after 7 days.

Conclusion. This is the first case report of

Pediococcus pentosaceus

peritonitis in an ESRD patient on CAPD. Accurate diagnosis and antibiotic sensitivity test of the bacteria is important especially if isolated in critical patients as it is intrinsically resistant to vancomycin.
Dorsal and ventral hippocampus engage opposing networks in the nucleus accumbens
Authors: Sosa Marielena , Joo Hannah R. , Frank Loren M.
Published: April 2019

Memories of positive experiences require the brain to link places, events, and reward outcomes. Neural processing underlying the association of spatial experiences with reward is thought to depend on interactions between the hippocampus and the nucleus accumbens (NAc)1–9. Hippocampal projections to the NAc arise from both the ventral hippocampus (vH) and the dorsal hippocampus (dH)6–12, and studies using optogenetic interventions have demonstrated that either vH5, 6 or dH7 input to the NAc can support behaviors dependent on spatial-reward associations. It remains unclear, however, whether dH, vH, or both coordinate memory processing of spatial-reward information in the hippocampal-NAc circuit under normal conditions. Times of memory reactivation within and outside the hippocampus are marked by hippocampal sharp-wave ripples (SWRs)13–19, discrete events which facilitate investigation of inter-regional information processing. It is unknown whether dH and vH SWRs act in concert or separately to engage NAc neuronal networks, and whether either dH or vH SWRs are preferentially linked to spatial-reward representations. Here we show that dH and vH SWRs occur asynchronously in the awake state and that NAc spatial-reward representations are selectively activated during dH SWRs. We performed simultaneous extracellular recordings in the dH, vH, and NAc of rats learning and performing an appetitive spatial task and during sleep. We found that individual NAc neurons activated during SWRs from one subdivision of the hippocampus were typically suppressed or unmodulated during SWRs from the other. NAc neurons activated during dH versus vH SWRs showed markedly different task-related firing patterns. Only dH SWR-activated neurons were tuned to similarities across spatial paths and past reward, indicating a specialization for the dH-NAc, but not vH-NAc, network in linking reward to discrete spatial paths. These temporally and anatomically separable hippocampal-NAc interactions suggest that dH and vH coordinate opposing channels of mnemonic processing in the NAc.
Bioactivity-driven high throughput screening of microbiomes of medicinal plants for discovering new biological control agents
Authors: Iqrar Irum , Shinwari Zabta Khan , El-Sayed Ashraf , Ali Gul Shad
Published: April 2019

In a preliminary DNA-based microbiome studies, diverse culturable and unculturable bacterial taxa were identified in the roots and rhizospheres of different medicinal plants. In this report, culturable endophytic bacteria were isolated from four economically important medicinal plants Dodonaea viscosa, Fagonia indica, Caralluma tuberculata and Calendula arvensis. On the basis of initial antimicrobial screening, nine bacterial species in seven different genera, Streptomyces, Pseudomonas, Enterobacter, Bacillus, Pantoea, Pseudarthrobacter and Delftia, were selected for further analyses. These bacteria were identified using 16S rRNA gene sequencing. Antimicrobial assays of these selected bacteria revealed that Pseudomonas taiwanensis has strong anti-Phytophthora activity. Volatiles produced by P. taiwanensis inhibited growth of P. parasitica more than 80%. Ethyl acetate extracts of S. alboniger MOSEL-RD3, P. taiwanensis MOSEL-RD23, E. hormaechei MOSEL-FLS1 and B. tequilensis MOSEL-FLS3 and D. lacustris MB322 also displayed high potency against P. parasitica. All these bacterial extracts showed strong inhibition against P. parasitica at different concentrations (4 µg/mL – 400 µg/mL). Bacterial extracts showing higher bioactivity (>80% inhibition in vitro) were selected for detached-leaf assay against P. parasitica on tobacco. In detached-leaf assay, application of 1% ethyl acetate bacterial extract of MOSE L-RD3, MOSEL-RD23, MOSEL-FLS1, MOSEL-FLS3 and MB322 reduced lesion sizes and lesion frequencies caused by P. parasitica by 68 to 81%. Over all P. taiwenensis MOSEL-RD23 showed positive activities for all the assays. Analysing the potential of bacterial endophytes as biological control agents can potentially lead to the formulation of broad-spectrum biopesticides for sustainable production of crops.
Silencing cryptic specialized metabolism inStreptomycesby the nucleoid-associated protein Lsr2
Authors: Gehrke Emma J. , Zhang Xiafei , Pimentel-Elardo Sheila M. , Johnson Andrew R. , Rees Christiaan A. , Jones Stephanie E. , Hindra  , Gehrke Sebastian S. , Turvey Sonya , Boursalie Suzanne , Hill Jane E. , Carlson Erin E. , Nodwell Justin R. , Elliot Marie A.
Published: April 2019

Lsr2 is a nucleoid-associated protein conserved throughout the actinobacteria, including the antibiotic-producingStreptomyces.Streptomycesspecies encode paralogous Lsr2 proteins (Lsr2 and Lsr2-like, or LsrL), and we show here that of the two, Lsr2 has greater functional significance. We found that Lsr2 binds AT-rich sequences throughout the chromosome, and broadly represses gene expression. Strikingly, specialized metabolic clusters were over-represented amongst its targets, and the cryptic nature of many of these clusters appears to stem from Lsr2-mediated repression. Manipulating Lsr2 activity in model species and uncharacterized isolates resulted in the production of new metabolites not seen in wild type strains. Our results suggest that the transcriptional silencing of biosynthetic clusters by Lsr2 may protectStreptomycesfrom the inappropriate expression of specialized metabolites, and provide global control overStreptomyces’arsenal of signalling and antagonistic compounds.
The BvgS PAS domain: an independent sensory perception module in theBordetellaBvgAS phosphorelay
Authors: Sobran M. Ashley , Cotter Peggy A.
Published: April 2019

To detect and respond to the diverse environments they encounter, bacteria often use two-component regulatory systems (TCSs) to coordinate essential cellular processes required for survival. In pathogenicBordetellaspecies, the BvgAS TCS regulates expression of hundreds of genes, including those encoding all known protein virulence factors, and its kinase activity is essential for respiratory infection. Maintenance of BvgS kinase activity in the lower respiratory tract (LRT) depends on the function of another TCS, PlrSR. While the periplasmic venus fly-trap domains of BvgS have been implicated in responding to so-called modulating signalsin vitro(nicotinic acid and MgSO4), a role for the cytoplasmic Per-Arnt-Sim (PAS) domain in signal perception has not previously been demonstrated. By comparingB. bronchisepticastrains with mutations in the PAS domain-encoding region ofbvgSwith wild-type bacteriain vitroandin vivo, we found that although the PAS domain is not required to sense modulating signalsin vitro, it is required for the inactivation of BvgS that occurs in the absence of PlrS in the LRT of mice, suggesting that the BvgS PAS domain functions as an independent signal perception domain. Our data also indicate that the BvgS PAS domain is important for controlling absolute levels of BvgS kinase activity and the efficiency of the response to modulating signalsin vitro. Our results indicate that BvgS is capable of integrating sensory inputs from both the periplasm and the cytoplasm to control precise gene expression patterns in diverse environmental conditions.

Importance

Despite high rates of vaccination, Pertussis, a severe, highly contagious respiratory disease, caused by the bacteriumBordetella pertussis, has reemerged as a significant health threat. InBordetella pertussisand the closely related species,Bordetella bronchiseptica, activity of the BvgAS two-component regulatory system is critical for colonization of the human respiratory tract and other mammalian hosts, respectively. Here we show that the cytoplasmic PAS domain of BvgS can function as an independent signal perception domain that is capable of integrating environmental signals that influence overall BvgS activity. Our work is significant as it reveals a critical, yet previously unrecognized role, for the PAS domain in the BvgAS phosphorelay and provides a greater understanding of virulence regulation inBordetella.
Clustering by phenotype and genome-wide association study in autism
Authors: Narita Akira , Nagai Masato , Mizuno Satoshi , Ogishima Soichi , Tamiya Gen , Ueki Masao , Sakurai Rieko , Makino Satoshi , Obara Taku , Ishikuro Mami , Yamanaka Chizuru , Matsubara Hiroko , Kuniyoshi Yasutaka , Murakami Keiko , Ueno Fumihiko , Noda Aoi , Kobayashi Tomoko , Kobayashi Mika , Usuzaki Takuma , Ohseto Hisashi , Hozawa Atsushi , Kikuya Masahiro , Metoki Hirohito , Kure Shigeo , Kuriyama Shinichi
Published: April 2019

Background

Autism spectrum disorder (ASD) has phenotypically and genetically heterogeneous characteristics. A simulation study demonstrated that attempts to categorize patients with a complex disease into more homogeneous subgroups could have more power to elucidate hidden heritability.

Methods

We conducted cluster analyses using the k-means algorithm with a cluster number of 15 based on phenotypic variables from the Simons Simplex Collection (SSC). As a preliminary study, we conducted a conventional genome-wide association study (GWAS) with a dataset of 597 ASD cases and 370 controls. In the second step, we divided cases based on the clustering results and conducted GWAS in each of the subgroups vs controls (cluster-based GWAS). We also conducted cluster-based GWAS on another SSC dataset of 712 probands and 354 controls in the replication stage.

Results

In the preliminary study, we observed no significant associations. In the second step of cluster-based GWASs, we identified 65 chromosomal loci, which included 30 intragenic loci located in 21 genes and 35 intergenic loci that satisfied the threshold ofP<5.0×10−8. Some of these loci were located within or near previously reported candidate genes for ASD:CDH5, CNTN5, CNTNAP5, DNAH17, DPP10, DSCAM, FOXK1, GABBR2, GRIN2A5,ITPR1, NTM, SDK1, SNCAandSRRM4.Of these 65 significant chromosomal loci, rs11064685 located within theSRRM4gene had a significantly different distribution in the cases vs. controls in the replication cohort.

Conclusions

These findings suggest that clustering may successfully identify subgroups with relatively homogeneous disease etiologies. Further cluster validation and replication studies are warranted in larger cohorts.
Effects of bicycle geometry and riding position on the potential of residual limb muscles to pedaling with a transfemoral prosthesis: a computer simulation study
Authors: Okita Yusuke , Nakamura Takashi
Published: April 2019

We performed musculoskeletal simulations to provide information on the effects of riding position and bicycle geometry on pedaling with a transfemoral prosthesis. Sixty-four models and their corresponding kinematics in one pedaling cycle were generated from the baseline one-leg cycling model by varying one of the six variables (seat height, seat-tube angle, crank length, pelvic tilt, anteroposterior seating position, and thigh length relative to the leg). Induced acceleration analysis was performed to compute the potentials of the residual hip muscles for crank rotation in each model. The simulation results quantified the effects of each variable on the hip and knee kinematics and muscle potential during a pedaling cycle; seat height, crank length, and pelvic tilt were the primary candidates for bicycle fitting considering their accessibility and simple effects on the joint kinematics and muscle potential. The seat-tube angle (similar to pelvic tilt) and the anteroposterior seating position (similar to seat height and seat-tube angle) seemed to have an effect similar to the other variables and thus can be reserved for fine-tuning after gross fitting of the bicycle. Although not considered for adjustment, considering the effects of the thigh length could help as it affects hip kinematics and muscle potentials.
TonB dependent uptake of β-lactam antibiotics in the opportunistic human pathogen Stenotrophomonas maltophilia
Authors: Calvopiña Karina , Dulyayangkul Punyawee , Heesom Kate J. , Avison Matthew B.
Published: April 2019

The β-lactam antibiotic ceftazidime is one of only a handful of drugs with proven clinical efficacy against the opportunistic human pathogen Stenotrophomonas maltophilia, Here, we show that mutations in the energy transducer TonB, encoded by smlt0009 in S. maltophilia, confer ceftazidime resistance. This breaks the dogma that β-lactams enter Gram-negative bacteria only by passive diffusion through outer membrane porins. By confirming cross-resistance of Smlt0009 mutants with a siderophore-conjugated lactivicin antibiotic, we reveal that attempts to improve penetration of antimicrobials into Gram negative bacteria by conjugating them with TonB substrates is likely to select β-lactam resistance in S. maltophilia, increasing its clinical threat. Furthermore, we show that S. maltophilia clinical isolates that have an Smlt0009 mutation already exist. Remarkably, therefore, β-lactam use is already eroding the potential utility of currently experimental siderophore-conjugated antimicrobials against this species.
Revisiting Mitchell’s chemiosmotic theory in light of new stoichiometric reaction equations of ATPase II
Authors: Kushagra Arindam
Published: April 2019

Chemiosmotic theory has been reining the field of bioenergetics since its inception. As stoichiometric mechanisms of the underlying chemical reactions have now been elucidated, it calls for a revision in the relationships derived by Mitchell in his seminal review paper. Here in this work, new formulation of the relationship between the pH difference and transmembrane potential, as derived in light of modified ATPase II reaction stoichiometry, has been proposed for the first time. This formulation results in accurate estimation of dependence of transmembrane potential on the pH difference across the two sides of the mitochondrial membrane. Thus, this work is of potential interest and will enable researchers working in the field of bioenergetics involving chemiosmotic theory to come-up with more exact mechanistic explanations.
Spinal V2b neurons reveal a role for ipsilateral inhibition in speed control
Authors: Callahan Rebecca A. , Roberts Richard , Sengupta Mohini , Kimura Yukiko , Higashijima Shin-ichi , Bagnall Martha W.
Published: April 2019

The spinal cord contains a diverse array of interneurons that govern motor output. Traditionally, models of spinal circuits have emphasized the role of inhibition in enforcing reciprocal alternation between left and right sides or flexors and extensors. However, recent work has shown that inhibition also increases coincident with excitation during contraction. Here, using larval zebrafish, we investigate the V2b (Gata3+) class of neurons, which contribute to flexor-extensor alternation but are otherwise poorly understood. Using newly generated transgenic lines we define two stable subclasses with distinct neurotransmitter and morphological properties. These two V2b subclasses make direct synapses onto motor neurons with differential targeting to slower and faster circuits. In vivo, optogenetic suppression of V2b activity leads to increases in locomotor speed. We conclude that V2b neurons exert speed-specific influence over axial motor circuits throughout the rostrocaudal axis. Together, these results indicate a new role for ipsilateral inhibition in speed control.
Comparison of Multi-objective Evolutionary Algorithms to Solve the Modular Cell Design Problem for Novel Biocatalysis
Authors: Garcia Sergio , Trinh Cong
Published: April 2019

A large space of chemicals with broad industrial and consumer applications could be synthesized by engineered microbial biocatalysts. However, the current strain optimization process is prohibitively laborious and costly to produce one target chemical and often requires new engineering efforts to produce new molecules. To tackle this challenge, modular cell design based on a chassis strain that can be combined with different product synthesis pathway modules has been recently proposed. This approach seeks to minimize unexpected failure and avoid task repetition, leading to a more robust and faster strain engineering process. The modular cell design problem was mathematically formulated using a multi-objective optimization framework.[1] In this study, we evaluated a library of the state-of-the-art multi-objective evolutionary algorithms (MOEAs) to identify the most effective method to solve the modular cell design problem. Using the best MOEA, we found better solutions for modular cells compatible with many product synthesis modules. Furthermore, the best performing algorithm could provide better and more diverse design options that might help increase the likelihood of successful experimental implementation. We identified key parameter configurations to overcome the difficulty associated with multi-objective optimization problems with many competing design objectives. Interestingly, we found that MOEA performance with a real application problem, e.g., the modular strain design problem, does not always correlate with artificial benchmarks. Overall, MOEAs provide powerful tools to solve the modular cell design problem for novel biocatalysis.