bluuebunny/crossref_metadata_2025 huggingface dataset:
Water Sector Reforms, Commercialization and Financial Sustainability of Public Water Utilities in Kenya: The Case of Homa Bay Water and Sewerage Company Limited
Authors: Maryline Akinyi Agwa , Odundo Paul A.
Published: June 2018

Reforms in the Kenyan water sector entrenched the aspect of commercialization, which subjected water services to market forces and necessitated establishment of autonomous public utilities, such as Homa Bay Water and Sewerage Company Limited, to improve cost recovery, efficiency and sustainability. This study focused on how commercialization, as an aspect of the reforms, influenced the utility’s financial sustainability. A cross-sectional design, with mixed methods approach, guided the study. Primary data were sourced in mid 2017, from water officers, water users and water committee members. Quantitative techniques included cross-tabulation with Chi square statistic, Relative Importance Index and Kendall’s Coefficient of Concordance. The results show that compliance of procurement activities to relevant legislations was the most important aspect influencing the utility’s financial sustainability (relative weight = 0.838); followed by effectiveness of internal audit in enforcing expenditure policies (relative weight = 0.825); and relevance of activities on which water revenues were spent (relative weight = 0.812). The analysis obtained a strong and significant concordance of respondents’ views regarding relationship between financial management practices and the utility’s financial sustainability (Kendall’s W= 0.862, x2= 64.491, df = 4 & p-value = 0.000). Consequently, ensuring that procurement activities are strictly guided by procurement laws is important for preventing irregularities and minimizing loss of financial resources; while strengthening capacity of the internal audit department and enhancing its independence, are crucial antecedents for the utility’s financial sustainability.
The Influence of Integrated Reporting on Management Control Systems: A Case Study
Authors: Chiucchi Maria Serena , Montemari Marco , Gatti Marco
Published: June 2018

The purpose of this paper is to investigate how Integrated Reporting can influence Management Control Systems (MCSs). To this aim, the paper presents a case study of a company which designed and implemented an Integrated Report (IR) that was used as a tool for communicating the company performance to the entrepreneur and as a tool for enriching the company MCS to visualize and measure the overall company performance. The case analysis shows that Integrated Reporting improves the measurement focus of the MCS thanks to the role played by the company’s Business Model (BM) throughout the IR development and to the process adopted to map the BM itself. The BM mapping process was highly iterative and allowed for a better understanding of the items affecting the value creation process and of their interconnections, thus directing the MCS to what really deserved to be measured. Strategic discussion around the BM also entailed an evolution of the control system, which became a strategic control system, able to support the discussion and the creation of new strategies. Moreover, the BM ensured a high level of integration and consistency between departmental reports and the company IR, on the one hand, and among the departmental reports themselves, on the other hand. In addition, the case analysis shows that financial indicators risk becoming “phagocytized” by non-financial ones and that the implementation process of the IR can lead to a heavier workload for the Management Control Department to provide for the non-financial aspects of performance. Finally, the case analysis shows that the Integrated Reporting visual representation and its underlying logic may not work if the tool is used for managerial decision making. While the guiding principles of Integrated Reporting were accepted by the company’s actors, the Integrated Reporting representation model based on the logic inputs-BM-outputs-outcomes was criticized as it was considered too complex and not able to represent the company’s integrated performance, reflecting instead a series of disconnected and disjointed individual performances. The critiques of this model were so sharp that they resulted in a change to its logic and the adoption of a different model, namely that of cause-and-effect relationships.
Green Real Estate: Does It Create Value? Financial and Sustainability Analysis on European Green REITs
Authors: Mariani Massimo , Amoruso Paola , Caragnano Alessandra , Zito Marianna
Published: June 2018

Sustainability represents an innovative component of profitability for real estate finance, and among other instruments, real estate funds include a “green” component represented by certified buildings.In particular, the adopted selection criteria refer to the two European most widespread certifications: LEED and BREEAM.The objective is to demonstrate the degree of correlation between the adoption of implemented sustainable policies and financial performance. For this purpose Fama-French Five Factor Model has been applied.This work is oriented in validating the hypothesis, which states that sustainable and environmentally friendly components positively affect the performances of investment portfolios, focusing on the European property management industry. Therefore, this paper has the ambitious aim of filling  the gap in current literature on REITs mainly focused on the US market.
Genome sequencing uncovers phenocopies in primary progressive multiple sclerosis
Authors: Jia Xiaoming , Madireddy Lohith , Caillier Stacy , Santaniello Adam , Esposito Federica , Comi Giancarlo , Stuve Olaf , Zhou Yuan , Taylor Bruce , Kilpatrick Trevor , Martinelli‐Boneschi Filippo , Cree Bruce A.C. , Oksenberg Jorge R. , Hauser Stephen L. , Baranzini Sergio E
Published: June 2018

Objective

Primary progressive multiple sclerosis (PPMS) causes accumulation of neurological disability from disease onset without clinical attacks typical of relapsing multiple sclerosis (RMS). However, whether genetic variation influences the disease course remains unclear. We aimed to determine whether mutations causative of neurological disorders that share features with multiple sclerosis (MS) contribute to risk for developing PPMS.

Methods

We examined whole‐genome sequencing (WGS) data from 38 PPMS and 81 healthy subjects of European ancestry. We selected pathogenic variants exclusively found in PPMS patients that cause monogenic neurological disorders and performed two rounds of replication genotyping in 746 PPMS, 3,049 RMS, and 1,000 healthy subjects. To refine our findings, we examined the burden of rare, potentially pathogenic mutations in 41 genes that cause hereditary spastic paraplegias (HSPs) in PPMS (n = 314), secondary progressive multiple sclerosis (SPMS; n = 587), RMS (n = 2,248), and healthy subjects (n = 987) genotyped using the MS replication chip.

Results

WGS and replication studies identified three pathogenic variants in PPMS patients that cause neurological disorders sharing features with MS: KIF5A p.Ala361Val in spastic paraplegia 10; MLC1 p.Pro92Ser in megalencephalic leukodystrophy with subcortical cysts, and REEP1 c.606 + 43G>T in Spastic Paraplegia 31. Moreover, we detected a significant enrichment of HSP‐related mutations in PPMS patients compared to controls (risk ratio [RR] = 1.95; 95% confidence interval [CI], 1.27–2.98; p = 0.002), as well as in SPMS patients compared to controls (RR = 1.57; 95% CI, 1.18–2.10; p = 0.002). Importantly, this enrichment was not detected in RMS.

Interpretation

This study provides evidence to support the hypothesis that rare Mendelian genetic variants contribute to the risk for developing progressive forms of MS. Ann Neurol 2018;83:51–63
Designed Macrocyclic Peptides as Nanomolar Amyloid Inhibitors Based on Minimal Recognition Elements
Authors: Spanopoulou Anna , Heidrich Luzia , Chen Hong‐Ru , Frost Christina , Hrle Dean , Malideli Eleni , Hille Kathleen , Grammatikopoulos Alexandros , Bernhagen Jürgen , Zacharias Martin , Rammes Gerhard , Kapurniotu Aphrodite
Published: June 2018

Amyloid self‐assembly is linked to the pathogenesis of Alzheimer's disease (AD) and type 2 diabetes (T2D), but so far, no anti‐amyloid compound has reached the clinic. Macrocyclic peptides belong to the most attractive drug candidates. Herein we present macrocyclic peptides (MCIPs) designed using minimal IAPP‐derived recognition elements as a novel class of nanomolar amyloid inhibitors of both Aβ40(42) and IAPP or Aβ40(42) alone and show that chirality controls inhibitor selectivity. Sequence optimization led to the discovery of an Aβ40(42)‐selective MCIP exhibiting high proteolytic stability in human plasma and human blood–brain barrier (BBB) crossing ability in a cell model, two highly desirable properties for anti‐amyloid AD drugs. Owing to their favorable properties, MCIPs should serve as leads for macrocyclic peptide‐based anti‐amyloid drugs and scaffolds for the design of small‐molecule peptidomimetics for targeting amyloidogenesis in AD or in both AD and T2D.
Serpin A1 and the modulation of type I collagen turnover: Effect of the C‐terminal peptide 409–418 (SA1‐III) in human dermal fibroblasts
Authors: Cipriani Caterina , Pascarella Simona , Errante Fosca , Menicacci Beatrice , Magnelli Lucia , Mocali Alessandra , Rovero Paolo , Giovannelli Lisa
Published: June 2018

The pharmacological modulation of collagen turnover is a strategy potentially useful in different skin conditions. The serine protease inhibitor Serpin A1 and portions of its C‐terminal region have been investigated as collagen modulators. To clarify the mechanisms by which the C‐terminal 409–418 peptide SA1‐III increases extracellular type I collagen levels, to compare its activities range with that of the originator molecule Serpin A1, and to evaluate its efficacy in primary cultures from adult and aged human subjects. The different forms of type I collagen were analyzed by means of western blot in cell lysates and cell‐conditioned media of primary human dermal fibroblasts obtained from subjects of different ages. Gelatin zymography was used to investigate the degrading enzymes. Cell viability and in vitro wound healing tests were used to evaluate cell proliferation. The SA1‐III peptide increased extracellular collagen levels by reducing degradation, with no effect on cellular biosynthesis or cell proliferation mechanisms. A reduced level of MMP‐2 and MMP‐9 was also found in cell media upon peptide treatment. No peptide effect was detected on inflammatory mediators gene expression in resting and LPS‐stimulated fibroblasts, or in the wound healing test. The SA1‐III peptide is a good collagen modulator candidate, protecting collagen against degradation without detectable actions on biosynthesis, acting at reasonably low concentrations, and non‐interfering with cell proliferation. It is effective in primary fibroblasts from young and aged subjects. These effects can prove useful in pathological and physiological skin conditions in which collagen degradation is excessive compared to the synthetic capacity.
Rational Design of Alkali‐Resistant NO Reduction Catalysts using a Stable Hexagonal V‐Doped MoO3 Support for Alkali Trapping
Authors: Liu Xiaona , Gao Jiayi , Chen Yaxin , Li Chao , Chen Junxiao , Qu Weiye , Chen Xin , Ma Zhen , Tang Xingfu
Published: June 2018

To avoid alkali poisoning in the selective catalytic reduction (SCR) of NOx with NH3, it is desirable to design SCR catalysts with abundant alkali‐trapping sites spatially separated from catalytically active sites. Here we develop such a catalyst with strong resistance against alkali poisoning by using hexagonal vanadium‐doped MoO3 (V‐HMoO) with alkali‐trapping tunnels as a catalyst support. Although pure HMoO also possesses strong alkali resistance due to size‐suitable tunnels, active Mo5+ ions on the framework make HMoO thermally unstable, and hence pure HMoO is not able to be used as a suitable support for SCR in a normal operating temperature window of 280–420 °C. We substitute the active Mo5+ by stable V5+ due to its fully unoccupied electron configuration to achieve a thermally stable V‐HMoO support, as confirmed by various characterization results. After loading active V2O5 onto the V‐HMoO support, the catalyst shows high SCR activity with excellent alkali resistance due to the alkali trapping function of V‐HMoO. This work may give a strategy to design stable alkali‐trapping SCR catalysts in general.
The mechanosensory‐motor apparatus of antennae in the Oleander hawk moth (Daphnis nerii, Lepidoptera)
Authors: Sant Harshada H. , Sane Sanjay P.
Published: June 2018

Insect antennae are sensory organs of great importance because they can sense diverse environmental stimuli. In addition to serving as primary olfactory organs of insects, antennae also sense a wide variety of mechanosensory stimuli, ranging from low‐frequency airflow or gravity cues to high‐frequency antennal vibrations due to sound, flight or touch. The basal segments of the antennae house multiple types of mechanosensory structures that prominently include the sensory hair plates, or Böhm's bristles, which measure the gross extent of antennal movement, and a ring of highly sensitive scolopidial neurons, collectively called the Johnston's organs, which record subtle flagellar vibrations. To fulfill their multifunctional mechanosensory role, the antennae of insects must actively move thereby enhancing their ability to sense various cues in the surrounding environment. This tight coupling between antennal mechanosensory function and antennal movements means that the underlying mechanosensory‐motor apparatus constitutes a highly tuned feedback‐controlled system. Our study aims to explore how the sensory and motor components of this system are configured to enable such functional versatility. We describe antennal mechanosensory neurons, their central projections in the brain relative to antennal motor neurons and the internal morphology of various antennal muscles that actuate the basal segments of the antenna. We studied these in the Oleander hawk moth (Daphnis nerii) using a combination of techniques such as neural dye fills, confocal microscopy, scanning electron microscopy and X‐ray tomography. Our study thus provides a detailed anatomical picture of the antennal mechanosensory‐motor apparatus, which in turn provides key insights into its multifunctional role.
From Euclidean sources to Lorentzian spacetimes in holographic conformal field theories
Authors: Marolf Donald , Parrikar Onkar , Rabideau Charles , Rad Ali Izadi , Van Raamsdonk Mark
Published: June 2018

Abstract

We consider states of holographic conformal field theories constructed by adding sources for local operators in the Euclidean path integral, with the aim of investigating the extent to which arbitrary bulk coherent states can be represented by such Euclidean path-integrals in the CFT. We construct the associated dual Lorentzian spacetimes perturbatively in the sources. Extending earlier work, we provide explicit formulae for the Lorentzian fields to first order in the sources for general scalar field and metric perturbations in arbitrary dimensions. We check the results by holographically computing the Lorentzian one-point functions for the sourced operators and comparing with a direct CFT calculation. We present evidence that at the linearized level, arbitrary bulk initial data profiles can be generated by an appropriate choice of Euclidean sources. However, in order to produce initial data that is very localized, the amplitude must be taken small at the same time otherwise the required sources diverge, invalidating the perturbative approach.
Probing the top-Higgs Yukawa CP structure in dileptonic $$ t\overline{t}h $$ with M2-assisted reconstruction
Authors: Gonçalves Dorival , Han Kim Jeong , Kong Kyoungchul
Published: June 2018

Abstract

Constraining the Higgs boson properties is a cornerstone of the LHC program. We study the potential to directly probe the Higgs-top CP-structure via the

$$ t\overline{t}h $$

t

t
¯

h

channel at the LHC with the Higgs boson decaying to a bottom pair and top-quarks in the dileptonic mode. We show that a combination of laboratory and

$$ t\overline{t} $$

t

t
¯

rest frame observables display large CP-sensitivity, exploring the spin correlations in the top decays. To efficiently reconstruct our final state, we present a method based on simple mass minimization and prove its robustness to shower, hadronization and detector effects. In addition, the mass reconstruction works as an extra relevant handle for background suppression. Based on our results, we demonstrate that the Higgs-top CP-phase (α) can be probed up to cos α < 0.7 at the high luminosity LHC.
A facile synthesis for BeCl2, BeBr2and BeI2
Authors: Müller Matthias , Pielnhofer Florian , Buchner Magnus R.
Published: June 2018

A facile synthesis for anhydrous berylliumhalides is presented and their vibrational spectra have been measured for the first time.
Structural characterization and immunomodulatory activity of a novel polysaccharide fromFicus carica
Authors: Du Juan , Li Jingjing , Zhu Jianhua , Huang Chunhua , Bi Sixue , Song Liyan , Hu Xianjing , Yu Rongmin
Published: June 2018

A novel polysaccharide (FCPW80-2) with a molecular weight of 1.21 × 105Da was first isolated fromFicus caricathrough hot water extraction and several chromatographic methods.
: a new information theoretic measure of sparsity
Authors: Meena V. , Abhilash G.
Published: June 2018

Sparse representation of signals has gained significant importance in the recent times due to its wide range of applications in diverse fields. is introduced, a new measure of sparsity, and that satisfies all the attributes and properties which any sparsity measure should satisfy are mathematically proved.
Magnetically aligned straight depolarization canals and the rolling Hough transform
Authors: Jelić Vibor , Prelogović David , Haverkorn Marijke , Remeijn Jur , Klindžić Dora
Published: June 2018

Aims. We aim to characterize the properties of the straight depolarization canals detected in the Low Frequency Array (LOFAR) polarimetric observations of a field centered on the extragalactic source 3C 196. We also compare the canal orientations with magnetically aligned HI filaments and the magnetic field probed by polarized dust emission.

Methods. We used the rolling Hough transform (RHT) to identify and characterize the orientation of the straight depolarization canals in radio polarimetric data and the filaments in HI data.

Results. The majority of the straight depolarization canals and the Hi filaments are inclined by ~10° with respect to the Galactic plane and are aligned with the plane-of-sky magnetic field orientation probed by the Planck dust polarization data. The other distinct orientation, of −65° with respect to the Galactic plane, is associated with the orientation of a bar-like structure observed in the 3C 196 field at 350 MHz.

Conclusions. An alignment between three distinct tracers of the (local) interstellar medium (ISM) suggests that an ordered magnetic field plays a crucial role in confining different ISM phases. The majority of the straight depolarization canals are a result of a projection of the complicated 3D distribution of the ISM. The RHT analysis is a robust method for identifying and characterizing the straight depolarization canals observed in radio-polarimetric data.
Distal-to-Snuffbox Arteriovenous Fistula
Authors: Maharaj Dale , Baksh Rayaad , Oladiran Adedapo , Budhoo Emerson , Ramdass Michael
Published: June 2018

The dogma for optimal arteriovenous fistula (AVF) creation is based on starting as distally as possible on the upper limb and progressing proximally. We herein present our findings of an AVF that is as distal as possible on the hand. To document primary patency rates of the distal-to-snuffbox AVF. A 10-year prospective study (2006–2016) involving 31 patients whose distal cephalic vein diameter was ≥3 mm with a normal Allen's test was conducted. Patients were excluded if the radial artery in the wrist was highly calcified, the cephalic vein did not dilate more than 3 mm with proximal compression, and there was previously failed AVF of the limb or previous trauma to the limb. The procedure was performed under local anesthetic, and the anastomosis performed with a 6.0 polypropylene suture in an end-to-side fashion. Thirty-one patients with end-stage renal disease underwent distal vascular access using the distal-to-snuffbox (Hitchhiker's) AVF (HAVF). During follow-up, eight patients died with an adequately functioning HAVF. The primary patency rates at 12, 24, 48, and 60 months were 90, 87, 85, and 82%, respectively. Failure occurred in six (19%) cases over the follow-up period, two in the first 2 weeks and four over a span of 60 months.

Conclusion The creation of radiocephalic AVFs in the first web space, distal to the tendon of the extensor pollicis longus, serves as a viable option with acceptable success rates. This allows the surgeon more options with proper patient selection for this procedure.
Heart specific PGC-1α deletion identifies metabolome of cardiac restricted metabolic heart failure
Authors: Kärkkäinen Olli , Tuomainen Tomi , Mutikainen Maija , Lehtonen Marko , Ruas Jorge L , Hanhineva Kati , Tavi Pasi
Published: June 2018

Aims

Heart failure (HF) is associated with drastic changes in metabolism leading to a cardiac energy deficiency well as maladaptive changes in multiple other tissues. It is still unclear which of these changes originates from cardiomyocyte metabolic remodelling or whether they are induced secondarily by systemic factors. Our aim here was to induce cardiac restricted metabolic changes mimicking those seen in HF and to characterize the associated metabolite changes in the heart, circulation, and peripheral tissues.

Methods and results

We generated a cardiac specific PGC-1α knockout mice (KO) to specifically induce metabolic dysregulation typically accompanied by HF and performed a non-targeted LC-MS metabolite profiling analysis of heart, plasma, liver, and skeletal muscle to identify metabolites associated with cardiac specific metabolic remodelling. The KO animals developed a progressive cardiomyopathy with cardiac dilatation leading to fatal HF. At 17 weeks of age, when significant remodelling had occurred but before the onset of HF, isolated PGC-1α deficient cardiomyocytes had suppressed glucose and fatty acid oxidation as well as blunted anaerobic metabolism. KO hearts displayed a distinctive metabolite profile with 92 significantly altered molecular features including metabolite changes in energy metabolism, phospholipid metabolism, amino acids, and oxidative stress signalling. Some of the metabolite changes correlated with the specific parameters of cardiac function. We did not observe any significant alterations in the metabolomes of the other measured tissues or in plasma.

Conclusions

Heart specific PGC-1α KO induces metabolic, functional, and structural abnormalities leading to dilating cardiomyopathy and HF. The metabolic changes were limited to the cardiac tissue indicating that cardiomyocyte metabolic remodelling is not sufficient to evoke the body wide metabolic alterations usually associated with HF.
Combinatorics of Generalized Exponents
Authors: Lecouvey Cédric , Lenart Cristian
Published: June 2018

We give a purely combinatorial proof of the positivity of the stabilized forms of the generalized exponents associated to each classical root system. In finite type $A_{n-1}$, we rederive the description of the generalized exponents in terms of crystal graphs without using the combinatorics of semistandard tableaux or the charge statistic. In finite type $C_{n}$, we obtain a combinatorial description of the generalized exponents based on the so-called distinguished vertices in crystals of type $A_{2n-1}$, which we also connect to symplectic King tableaux. This gives a combinatorial proof of the positivity of Lusztig $t$-analogs associated to zero-weight spaces in the irreducible representations of symplectic Lie algebras. We also present three applications of our combinatorial formula and discuss some implications to relating two type $C$ branching rules. Our methods are expected to extend to the orthogonal types.
Connectome preprocessing by Consensus Clustering increases separability in group neuroimaging studies
Authors: Rasero Javier , Cortes Jesus M , Marinazzo Daniele , Stramaglia Sebastiano
Published: June 2018

One of the biggest challenges in preprocessing pipelines for neuroimaging data is to increase the signal-to-noise ratio of the data which will be used for subsequent analyses. In the same line, we suggest in the present work that the application of consensus clustering for brain connectivity matrices to find subgroups of subjects can be a valid additional”connectome processing” step helpful to reduce intra-group variability and therefore increase the separability of distinct classes. In addition, by partitioning the data before any group comparison, we demonstrate that unique regions within each cluster arise and bring new information that could be relevant from a clinical point of view.
Unaltered prion disease in mice lacking developmental endothelial locus-1 (Del-1)
Authors: Zhu Caihong , Li Zhihao , Li Bei , Pfammatter Manuela , Aguzzi Adriano
Published: June 2018

Progression of prion diseases is driven by the accumulation of prions in the brain. Ablation of microglia or deletion of the eat-me-signal milk-fat globule EGF factor VIII (Mfge8) accelerate prion pathogenesis, suggesting that microglia defends the brain by phagocytosing prions. Like Mfge8, Developmental endothelial locus-1 (Del-1) is a secreted protein that acts as an opsonin bridging phagocytes and apoptotic cells to facilitate phagocytosis. We therefore asked whether Del-1 might play a role in controlling prion pathogenesis. We first determined the expression pattern of Del-1 in mice, and found that the brain expresses the highest level of Del-1. In mouse brains, Del-1 was mainly expressed by neurons. We then assessed the anti-inflammatory and phagocytosis-promoting functions of Del-1 in prion disease, and determined whether Del-1 complements Mfge8 in prion clearance in mice with a C57BL/6J genetic background. We found that Del-1 deficiency did not change prion disease progression and lesion patterns. Also, prion clearance and PrPSc deposition were unaltered in Del-1 deficient mice. Additionally, prioninduced neuroinflammation was not affected by Del-1 deficiency. We conclude that Del-1 is not a major determinant of prion pathogenesis in this context.
Cortical state fluctuations during sensory decision making
Authors: Jacobs Elina A. K. , Steinmetz Nicholas A. , Carandini Matteo , Harris Kenneth D.
Published: June 2018

Neocortical activity varies between states of “synchronization” and “desynchronization”, with desynchronized states believed to occur specifically in regions engaged by the task. To disambiguate whether desynchronization is linked to task performance or engagement, we trained mice on tasks in which incorrect responses due to disengagement (neglect) differed from inaccurate task performance (incorrect choices). Using widefield calcium imaging to measure cortical state across many areas simultaneously, we found that desynchronization was correlated with engagement rather than accuracy. Consistent with this link between desynchronization and engagement, we found that rewards had a long-lasting desynchronizing effect. To determine whether engagement-related changes in cortical state depended on the sensory modality, we trained mice on visual and auditory task versions and found that desynchronization was similar in both and more pronounced in somatomotor than either sensory cortex. We conclude that variations in cortical state are predominately global and closely relate to variations in task engagement.
Proviral sequencing suggests the majority of the HIV reservoir is expressed over time but significant decay is obscured by clonal expansion
Authors: Rita Pinzone Marilia , VanBelzen D. Jake , Weissman Sam , Bertuccio Maria Paola , Cannon LaMont , Hwang Wei-Ting , Sherman Brad , O’Doherty Una
Published: June 2018

After initiating antiretroviral therapy (ART), a rapid decline in plasma viremia is followed by reservoir stabilization. Viral outgrowth assay suggests the reservoir continues to decline slowly, but variation over time and among individuals complicates our understanding of selective pressures during ART. We used full-length sequencing to study more than 800 HIV proviruses of two subjects on ART at four time points over nine years to investigate the selection pressures influencing the dynamics of the reservoir. We found that intact as well as defective proviruses capable of significant protein expression decrease over time. Moreover, proviruses lacking genetic elements to promote viral protein expression, yet containing strong splice donor sequences increase relative to other defectives over time, especially among clones. Our work suggests that HIV expression occurs to a significant extent during ART and results in HIV clearance, but this is obscured by clones generated by donor splice site-enhanced clonal expansion.
Maternal group 2 innate lymphoid cells contribute to fetal growth and protection from endotoxin-induced abortion in mice
Authors: Balmas Elisa , Rana Batika MJ , Hamilton Russell S , Shreeve Norman , Kieckbusch Jens , Aye Irving , Hawkes Delia A , Trotter Sophie , López-Tello Jorge , Yong Hannah EJ , Valenti Salvatore , Sferruzi-Perri Amanda N , Gaccioli Francesca , McKenzie Andrew NJ , Colucci Francesco
Published: June 2018

Group 2 innate lymphoid cells (ILC2s) adapt to tissue physiology and contribute to immunity, inflammatory pathology and metabolism. We show that mouse uterine ILC2s have a heightened type-2 gene signature and expand during pregnancy. Indeed, maternal ILC2s promote fetal growth and protect against fetal mortality upon systemic endotoxin challenge. Absence of ILC2s leads to utero-placental abnormalities, including poor vascular remodelling, increasedIl1band decreasedIl4, Il5, andIl13gene expression, and reduced alternative activation of dendritic cells (DCs) and macrophages. Placentas exhibit signs of adaptation to stress, including larger maternal blood spaces and increased expression of nutrient transporter genes. Endotoxin induces the expansion of IL-1β-producing uterine DCs and, in response, more uterine ILC2s produce IL-4, IL-5 and IL-13. In a protective feedback mechanism, these cytokines suppress IL-1β-producing DCs, in line with a protective role of uILC2s against endotoxin-induced abortion. Uterine ILC2s emerge as pivotal for both normal and complicated pregnancies.
Towards a universal structural and energetic model for prokaryotic promoters
Authors: Mishra A. , Siwach P. , Misra P. , Jayaram B. , Bansal M. , Olson W.K. , Thayer K.M. , Beveridge D.L.
Published: June 2018

With almost no consensus promoter sequence in prokaryotes, recruitment of RNA polymerase (RNAP) to precise transcriptional start sites (TSSs) has remained an unsolved puzzle. Uncovering the underlying mechanism is critical for understanding the principle of gene regulation. We attempted to search the hidden code in ~16500 promoters, of twelve prokaryotes representing two kingdoms, in their structure and energetics. Twenty eight fundamental parameters of DNA structure including backbone angles, base pair axis, inter base pair and intra base pair parameters were used and information was extracted from X-ray crystallography (XRC) data. Three parameters (solvation energy, hydrogen bond energy and stacking energy) were selected for creating energetics profiles using in-house programs. DNA was found to be inherently designed to undergo a change in every parameter undertaken, from some distance upstream of TSSs to adopt a signature state at these locations in all prokaryotes. These signature states might be the universal hidden codes recognised by RNAP. This observation was reiterated when randomly selected promoter sequences (with little sequence conservation) were subjected to structure generation; all developed into very similar three dimensional structures, quite distinct from those of conventional B-DNA and coding sequences. Fine structural details at important motifs (viz. −11, −35, −75 positions relative to TSS) of promoters reveal novel and pointed insights for RNAP interaction at these locations; it could be correlated that how some particular structural changes at −11 region may allow insertion of RNAP amino acids in inter-base pair space as well as facilitate the flipping out of bases from DNA duplex.
Mito-nuclear effects uncovered in admixed populations
Authors: Zaidi Arslan A. , Makova Kateryna D.
Published: June 2018

To function properly, mitochondria utilize products of 37 and >1,000 genes encoded by the mitochondrial and nuclear genomes, respectively, which should be compatible with each other. Discordance between mitochondrial and nuclear genetic ancestry could contribute to phenotypic variation in admixed populations. Here we explored potential mito-nuclear incompatibility in six admixed human populations from the Americas: African Americans, African Caribbeans, Colombians, Mexicans, Peruvians, and Puerto Ricans. For individuals in these populations, we determined nuclear genome proportions derived from Africans, Europeans, and Native Americans, the geographic origins of the mitochondrial DNA (mtDNA), as well as mtDNA copy number in lymphoblastoid cell lines. By comparing nuclear vs. mitochondrial ancestry in admixed populations, we show that, first, mtDNA copy number decreases with increasing discordance between nuclear and mitochondrial DNA ancestry, in agreement with mito-nuclear incompatibility. The direction of this effect is consistent across mtDNA haplogroups of different geographic origins. This observation suggests suboptimal regulation of mtDNA replication when its components are encoded by nuclear and mtDNA genes with different ancestry. Second, while most populations analyzed exhibit no such trend, in Puerto Ricans and African Americans we find a significant enrichment of ancestry at nuclear-encoded mitochondrial genes towards the source populations contributing the most prevalent mtDNA haplogroups (Native American and African, respectively). This likely reflects compensatory effects of selection in recovering mito-nuclear interactions optimized in the source populations. Our results provide the first evidence of mito-nuclear effects in human admixed populations and we discuss its implications for human health and disease.
Laminin α1 orchestrates VEGFA functions in the ecosystem of colorectal carcinoma
Authors: Mammadova‐Bach Elmina , Rupp Tristan , Spenlé Caroline , Jivkov Ivo , Shankaranarayanan Pattabhiraman , Klein Annick , Pisarsky Laura , Méchine‐Neuville Agnès , Cremel Gérard , Kedinger Michèle , De Wever Olivier , Ambartsumian Noona , Robine Sylvie , Pencreach Erwan , Guenot Dominique , Simon‐Assmann Patricia , Goetz Jacky G. , Orend Gertraud , Lefebvre Olivier
Published: June 2018

Background Information

Tumor stroma remodeling is a key feature of malignant tumors and can promote cancer progression. Laminins are major constituents of basement membranes that physically separate the epithelium from the underlying stroma.

Results

By employing mouse models expressing high and low levels of the laminin α1 chain (LMα1), we highlighted its implication in a tumor‐stroma crosstalk, thus leading to increased colon tumor incidence, angiogenesis and tumor growth. The underlying mechanism involves attraction of carcinoma‐associated fibroblasts by LMα1, VEGFA expression triggered by the complex integrin α2β1‐CXCR4 and binding of VEGFA to LM‐111, which in turn promotes angiogenesis, tumor cell survival and proliferation. A gene signature comprising LAMA1, ITGB1, ITGA2, CXCR4 and VEGFA has negative predictive value in colon cancer.

Conclusions

Together, we have identified VEGFA, CXCR4 and α2β1 integrin downstream of LMα1 in colon cancer as of bad prognostic value for patient survival.

Significance

This information opens novel opportunities for diagnosis and treatment of colon cancer.
Ultrasound detection of insulin‐induced lipohypertrophy in Type 1 and Type 2 diabetes
Authors: Kapeluto J. E. , Paty B. W. , Chang S. D. , Meneilly G. S.
Published: June 2018

Aims

To define standard criteria for the detection of lipohypertrophy using ultrasonography and to determine the accuracy of this method.

Method

Individuals using insulin therapy for ≥2 years with unknown lipohypertrophy status were enrolled at a diabetes education centre. A team of diabetes educator nurses performed a clinical examination for evidence of lipohypertrophy and a separate team of ultrasonographers examined participants in a blinded fashion.

Results

The echo signature for lipohypertrophy consisted of location in the subcutaneous layer and lesions that were 1) well circumscribed either by hyperechoic foci with defined borders or a nodular shape with a hypoechoic halo, 2) heterogeneous in echotexture compared with surrounding tissue, 3) associated with distortion of surrounding connective tissue with 4) absence of vascularity and 5) absence of capsule. Ultrasonography identified individuals with lipohypertrophy significantly more frequently than inspection or palpation (P<0.0001). Inter‐observer agreement was moderate (κ=0.50) and limited by the presence of subclinical lesions in 73% of the participants.

Conclusions

The ultrasound detection of lipohypertrophy is consistent with clinical examination and is reproducible using a defined echo signature.

(ClinicalTrials.gov registration no: NCT02348099).
Sunsets and Solidarity: Overcoming Sacramental Shame in Conservative Christian Churches to Forge a Queer Vision of Love and Justice
Authors: Moon Dawne , Tobin Theresa W.
Published: June 2018

Drawing from our interdisciplinary qualitative study of LGBTI conservative Christians and their allies, we name an especially toxic form of shame—what we call sacramental shame—that affects the lives of LGBTI and other conservative Christians. Sacramental shame results from conservative Christianity's allegiance to the doctrine of gender complementarity, which elevates heteronormativity to the level of the sacred and renders those who violate it as not persons, but monsters. In dispensing shame as a sacrament, nonaffirming Christians require constant displays of shame as proof that LGBTI church members love God and belong in the community. Part of what makes this shame so harmful is that parents and pastors often dispense it with sincere expressions of care and affection, compounding the sense that one's capacity to give and receive love is damaged. We foreground LGBTI Christian movements to overcome sacramental shame by cultivating nonhubristic pride, and conclude by discussing briefly their new understandings of love and justice that could have far‐reaching benefits.
The Shame of Shamelessness
Authors: Weiss Gail
Published: June 2018

An important question that is often raised, whether directly or indirectly, in philosophical discussions of shame‐inducing behavior concerns whether the experience of shame has unique moral value. Despite the fact that shame is strongly associated with negative affective responses, many people have argued that the experience of being ashamed plays an important motivating role, rather than being an obstacle, in living a moral life. These discussions, however, tend to take for granted two interrelated assumptions that I will be problematizing: 1) that the subject's shame is warranted; 2) that the shame is directly attributable to the subject's own actions. I challenge these assumptions by turning to a phenomenon I call secondhand shame, namely, shame that is induced by another person's shameless behavior. This essay examines the gender and racial dynamics that so frequently intensify secondhand shame, and suggests that this troubling phenomenon, when shared as a group experience, can be morally transformative, particularly when it leads to unified public resistance to shameless conduct.
Quality evaluation of biscuits produced from composite blends of pumpkin seed oil press cake and wheat flour
Authors: Jukić Marko , Lukinac Jasmina , Čuljak Jaka , Pavlović Mateja , Šubarić Drago , Koceva Komlenić Daliborka
Published: June 2018

Pumpkin seed oil press cake (PSOPC) is a by‐product of pumpkin oil production, and after cold pressing, a significant amount of oil still remains in the press cake. The aim of this study was to investigate the possible use of PSOPC flour as a substitute for wheat flour in biscuit production and, consequently, for reducing shortening usage. Biscuits have been produced from composite blends of plain white flour and PSOPC flour in ratios 100:0, 80:20, 60:40 and 40:60, respectively. Shortening addition was gradually reduced depending on the PSOPC flour addition. Biscuit baking quality was determined by width, thickness, spread factor, volume and textural properties. Computer vision was used to evaluate biscuit colour, and sensory evaluation was conducted for colour, taste, texture and overall acceptance. Results showed that PSOPC flour decreased biscuit diameter, height and volume and also caused a softer texture of biscuit. PSOPC flour contributed to the greenish colour of biscuits and the pleasant taste of roasted pumpkin seed. PSOPC flour can be successfully used as a functional and nutritionally valuable substitute for wheat flour and shortening, even in quantities up to 60%, without significant deterioration of the technological quality of biscuits.
Fifteen years of LIFE (Losartan Intervention for Endpoint Reduction in Hypertension)—Lessons learned for losartan: An “old dog playing good tricks”
Authors: Katsiki Niki , Tsioufis Konstantinos , Ural Dilek , Volpe Massimo
Published: June 2018

There is an unmet need to prevent cardiovascular disease and chronic kidney disease development and progression worldwide. Losartan, the first angiotensin receptor blocker, was shown to exert significant cardioprotective and renoprotective effects in the LIFE (Losartan Intervention for Endpoint Reduction in Hypertension) and RENAAL (Reduction of Endpoints in NIDDM With the Angiotensin II Antagonist Losartan) trials. Losartan significantly prevented stroke and decreased serum uric acid levels and the rates of new‐onset diabetes mellitus and atrial fibrillation. The present review discusses the LIFE (and its subanalyses) and RENAAL trials and the translation of their results to clinical practice. The place of losartan in the current guidelines for hypertension management is also discussed. Losartan still represents an efficacious, safe, and cost‐effective therapeutic option in patients with hypertension who have left ventricular hypertrophy. Losartan is a useful antihypertensive agent for stroke prevention and in the management of patients with chronic kidney disease, atrial fibrillation, diabetes mellitus, albuminuria, and hyperuricemia.
Melatonin induces mechanisms of brain resilience against neurodegeneration
Authors: Corpas Rubén , Griñán‐Ferré Christian , Palomera‐Ávalos Verónica , Porquet David , García de Frutos Pablo , Franciscato Cozzolino Silvia M. , Rodríguez‐Farré Eduard , Pallàs Mercè , Sanfeliu Coral , Cardoso Bárbara R.
Published: June 2018

Melatonin is an endogenous pleiotropic molecule which orchestrates regulatory functions and protective capacity against age‐related ailments. The increase in circulating levels of melatonin through dietary supplements intensifies its health benefits. Investigations in animal models have shown that melatonin protects against Alzheimer's disease (AD)‐like pathology, although clinical studies have not been conclusive. We hypothesized that melatonin induces changes in the brain that prevent or attenuate AD by increasing resilience. Therefore, we treated healthy nontransgenic (NoTg) and AD transgenic (3xTg‐AD) 6‐month‐old mice with a daily dose of 10 mg/kg of melatonin until 12 months of age. As expected, melatonin reversed cognitive impairment and dementia‐associated behaviors of anxiety and apathy and reduced amyloid and tau burden in 3xTg‐AD mice. Remarkably, melatonin induced cognitive enhancement and higher wellness level‐related behavior in NoTg mice. At the mechanism level, NF‐κB and proinflammatory cytokine expressions were decreased in both NoTg and 3xTg‐AD mice. The SIRT1 pathway of longevity and neuroprotection was also activated in both mouse strains after melatonin dosing. Furthermore, we explored new mechanisms and pathways not previously associated with melatonin treatment such as the ubiquitin‐proteasome proteolytic system and the recently proposed neuroprotective Gas6/TAM pathway. The upregulation of proteasome activity and the modulation of Gas6 and its receptors by melatonin were similarly displayed by both NoTg and 3xTg‐AD mice. Therefore, these results confirm the potential of melatonin treatment against AD pathology, by way of opening new pathways in its mechanisms of action, and demonstrating that melatonin induces cognitive enhancement and brain resilience against neurodegenerative processes.
Validity of hip‐worn inertial measurement unit compared to jump mat for jump height measurement in adolescents
Authors: Rantalainen Timo , Hesketh Kylie D. , Rodda Christine , Duckham Rachel L.
Published: June 2018

Jump tests assess lower body power production capacity, and can be used to evaluate athletic ability and development during growth. Wearable inertial measurement units (IMU) seem to offer a feasible alternative to laboratory‐based equipment for jump height assessments. Concurrent validity of these devices for jump height assessments has only been established in adults. Therefore, the purpose of this study was to evaluate the concurrent validity of IMU‐based jump height estimate compared to contact mat‐based jump height estimate in adolescents. Ninety‐five adolescents (10‐13 years‐of‐age; girls N = 41, height = 154 (SD 9) cm, weight = 44 (11) kg; boys N = 54, height = 156 (10) cm, weight = 46 (13) kg) completed 3 counter‐movement jumps for maximal jump height on a contact mat. Inertial recordings (accelerations, rotations) were concurrently recorded with a hip‐worn IMU (sampling at 256 Hz). Jump height was evaluated based on flight time. The mean IMU‐derived jump height was 27.1 (SD 3.8) cm, and the corresponding mean jump‐mat‐derived value was 21.5 (3.4) cm. While a significant 26% mean difference was observed between the methods (5.5 [95% limits of agreement 2.2 to 8.9] cm, P = 0.006), the correspondence between methods was excellent (ICC = 0.89). The difference between methods was weakly positively associated with jump height (r = 0.28, P = 0.007). Take‐off velocity‐derived jump height was also explored but produced only fair congruence. In conclusion, IMU‐derived jump height exhibited excellent congruence to contact mat‐based jump height and therefore presents a feasible alternative for jump height assessments in adolescents.