bluuebunny/crossref_metadata_2025 huggingface dataset:
Senescent cell turnover slows with age providing an explanation for the Gompertz law
Authors: Karin Omer , Agrawal Amit , Porat Ziv , Krizhanovsky Valery , Alon Uri
Published: December 2019

A causal factor in mammalian aging is the accumulation of senescent cells (SnCs). SnCs cause chronic inflammation, and removing SnCs decelerates aging in mice. Despite their importance, turnover rates of SnCs are unknown, and their connection to aging dynamics is unclear. Here we use longitudinal SnC measurements and induction experiments to show that SnCs turn over rapidly in young mice, with a half-life of days, but slow their own removal rate to a half-life of weeks in old mice. This leads to a critical-slowing-down that generates persistent SnC fluctuations. We further demonstrate that a mathematical model, in which death occurs when fluctuating SnCs cross a threshold, quantitatively recapitulates the Gompertz law of mortality in mice and humans. The model can go beyond SnCs to explain the effects of lifespan-modulating interventions in Drosophila and C. elegans, including scaling of survival-curves and rapid effects of dietary shifts on mortality.
Carrier multiplication in van der Waals layered transition metal dichalcogenides
Authors: Kim Ji-Hee , Bergren Matthew R. , Park Jin Cheol , Adhikari Subash , Lorke Michael , Frauenheim Thomas , Choe Duk-Hyun , Kim Beom , Choi Hyunyong , Gregorkiewicz Tom , Lee Young Hee
Published: December 2019

Carrier multiplication (CM) is a process in which high-energy free carriers relax by generation of additional electron-hole pairs rather than by heat dissipation. CM is promising disruptive improvements in photovoltaic energy conversion and light detection technologies. Current state-of-the-art nanomaterials including quantum dots and carbon nanotubes have demonstrated CM, but are not satisfactory owing to high-energy-loss and inherent difficulties with carrier extraction. Here, we report CM in van der Waals (vdW) MoTe2 and WSe2 films, and find characteristics, commencing close to the energy conservation limit and reaching up to 99% CM conversion efficiency with the standard model. This is demonstrated by ultrafast optical spectroscopy with independent approaches, photo-induced absorption, photo-induced bleach, and carrier population dynamics. Combined with a high lateral conductivity and an optimal bandgap below 1 eV, these superior CM characteristics identify vdW materials as an attractive candidate material for highly efficient and mechanically flexible solar cells in the future.
DNA methylation in AgRP neurons regulates voluntary exercise behavior in mice
Authors: MacKay Harry , Scott C. Anthony , Duryea Jack D. , Baker Maria S. , Laritsky Eleonora , Elson Amanda E. , Garland Theodore , Fiorotto Marta L. , Chen Rui , Li Yumei , Coarfa Cristian , Simerly Richard B. , Waterland Robert A.
Published: December 2019

DNA methylation regulates cell type-specific gene expression. Here, in a transgenic mouse model, we show that deletion of the gene encoding DNA methyltransferase Dnmt3a in hypothalamic AgRP neurons causes a sedentary phenotype characterized by reduced voluntary exercise and increased adiposity. Whole-genome bisulfite sequencing (WGBS) and transcriptional profiling in neuronal nuclei from the arcuate nucleus of the hypothalamus (ARH) reveal differentially methylated genomic regions and reduced expression of AgRP neuron-associated genes in knockout mice. We use read-level analysis of WGBS data to infer putative ARH neural cell types affected by the knockout, and to localize promoter hypomethylation and increased expression of the growth factor Bmp7 to AgRP neurons, suggesting a role for aberrant TGF-β signaling in the development of this phenotype. Together, these data demonstrate that DNA methylation in AgRP neurons is required for their normal epigenetic development and neuron-specific gene expression profiles, and regulates voluntary exercise behavior.
Unveiling how intramolecular stacking modes of covalently linked dimers dictate photoswitching properties
Authors: Lu Ru-Qiang , Yan Xiao-Yun , Zhu Lei , Yang Lin-Lin , Qu Hang , Wang Xin-Chang , Luo Ming , Wang Yu , Chen Rui , Wang Xiao-Ye , Lan Yu , Pei Jian , Weng Wengui , Xia Haiping , Cao Xiao-Yu
Published: December 2019

Covalently linked π-stacked dimers represent the most significant platform for elucidating the relationship between molecular alignments and their properties. Here, we present the one-pot synthesis of two intramolecularly π-stacked dimers and disclose how intramolecular stacking modes dictate photoswitching properties. The dimer, which features cofacially stacked chromophores and geometrically favours intramolecular photochemical [2 + 2] cycloadditions, displays a nearly irreversible photoswitching behaviour. By contrast, the dimer, bearing crosswise stacked chromophores, is geometrically unfavourable for the cycloaddition and exhibits a highly reversible photoswitching process, in which the homolysis and reformation of carbon−carbon single bonds are involved. Moreover, the chiral carbon centres of both dimers endow these photoswitches with chirality and the separated enantiomers exhibit tuneable chiroptical properties by photoswitching. This work reveals that intramolecular stacking modes significantly influence the photochemical properties of π-stacked dimers and offers a design strategy toward chiral photoswitchable materials.
Single phase charge ordered stoichiometric CaFe3O5 with commensurate and incommensurate trimeron ordering
Authors: Cassidy Simon J. , Orlandi Fabio , Manuel Pascal , Clarke Simon J.
Published: December 2019

Mixed-valent transition metal compounds display complex structural, electronic and magnetic properties which can often be exquisitely tuned. Here the charge-ordered state of stoichiometric CaFe3O5 is probed using neutron powder diffraction, Monte Carlo simulation and symmetry analysis. Magnetic ordering is dominated by the formation of ferromagnetic Fe3+–Fe2+–Fe3+ trimers which are evident above the magnetic ordering transition. Between TN = 289 K and 281 K an incommensurate magnetically ordered phase develops due to magnetic frustration, but a spin Jahn-Teller distortion lifts the frustration and enables the magnetic ordering to lock in to a charge-ordered commensurate state at lower temperatures. Stoichiometric CaFe3O5 exhibits single phase behaviour throughout and avoids the phase separation into two distinct crystallographic phases with different magnetic structures and Fe valence distributions reported recently, which likely occurs due to partial Fe2+ for Ca2+ substitution. This underlines the sensitivity of the magnetism and chemistry of these mixed-valent systems to composition.
LRIG1 is a pleiotropic androgen receptor-regulated feedback tumor suppressor in prostate cancer
Authors: Li Qiuhui , Liu Bigang , Chao Hsueh-Ping , Ji Yibing , Lu Yue , Mehmood Rashid , Jeter Collene , Chen Taiping , Moore John R. , Li Wenqian , Liu Can , Rycaj Kiera , Tracz Amanda , Kirk Jason , Calhoun-Davis Tammy , Xiong Jie , Deng Qu , Huang Jiaoti , Foster Barbara A. , Gokhale Abhiram , Chen Xin , Tang Dean G.
Published: December 2019

LRIG1 has been reported to be a tumor suppressor in gastrointestinal tract and epidermis. However, little is known about the expression, regulation and biological functions of LRIG1 in prostate cancer (PCa). We find that LRIG1 is overexpressed in PCa, but its expression correlates with better patient survival. Functional studies reveal strong tumor-suppressive functions of LRIG1 in both AR+ and AR− xenograft models, and transgenic expression of LRIG1 inhibits tumor development in Hi-Myc and TRAMP models. LRIG1 also inhibits castration-resistant PCa and exhibits therapeutic efficacy in pre-established tumors. We further show that 1) AR directly transactivates LRIG1 through binding to several AR-binding sites in LRIG1 locus, and 2) LRIG1 dampens ERBB expression in a cell type-dependent manner and inhibits ERBB2-driven tumor growth. Collectively, our study indicates that LRIG1 represents a pleiotropic AR-regulated feedback tumor suppressor that functions to restrict oncogenic signaling from AR, Myc, ERBBs, and, likely, other oncogenic drivers.
A High Throughput Isolation Method for Phosphate-Accumulating Organisms
Authors: Anand Ajeeta , Aoyagi Hideki
Published: December 2019

Hyperphosphatemia is a secondary issue associated with chronic kidney disorder. Use of phosphate binders and dialysis are the treatments for hyperphosphatemia, albeit with harmful side effects and high cost, respectively. A safer and healthier approach is attempted to administer phosphate-accumulating organisms (PAOs) from probiotics to prevent hyperphosphatemia. However, screening and isolation of PAOs are limited by inefficient enrichment of relevant metabolism and contamination. Therefore, we devised a novel strategy to isolate elite PAOs from Lactobacillus casei JCM 1134 and Bifidobacterium adolescentis JCM 1275 (previously reported PAOs). PAOs were first enriched for phosphate uptake and incubated in low-pH phosphate-free media to dormant non-PAOs, and then purified using Percoll density gradient centrifugation. Subsequently, elite PAOs were isolated from centrifuged pellet on a toluidine blue O-supplemented agar-based media. Using this technique, elite PAOs could not only be isolated, but also semi-quantitatively scored for their phosphate accumulation capabilities. Additionally, these scores correlated well with their accumulated phosphate values. The elite PAOs isolated from L. casei and B. adolescentis showed 0.81 and 0.70 [mg-phosphate/mg-dry cell], respectively (23- and 4.34-fold increase, respectively). Thus, our method can be used to successfully isolate elite PAOs, which might be of use to prevent hyperphosphatemia at early stages.
Study on Chemical Modifications of Glutathione by Cold Atmospheric Pressure Plasma (Cap) Operated in Air in the Presence of Fe(II) and Fe(III) Complexes
Authors: Śmiłowicz Dariusz , Kogelheide Friederike , Stapelmann Katharina , Awakowicz Peter , Metzler-Nolte Nils
Published: December 2019

Cold atmospheric pressure plasma is an attractive new research area in clinical trials to treat skin diseases. However, the principles of plasma modification of biomolecules in aqueous solutions remain elusive. It is intriguing how reactive oxygen and nitrogen species (RONS) produced by plasma interact on a molecular level in a biological environment. Previously, we identified the chemical effects of dielectric barrier discharges (DBD) on the glutathione (GSH) and glutathione disulphide (GSSG) molecules as the most important redox pair in organisms responsible for detoxification of intracellular reactive species. However, in the human body there are also present redox-active metals such as iron, which is the most abundant transition metal in healthy humans. In the present study, the time-dependent chemical modifications on GSH and GSSG in the presence of iron(II) and iron(III) complexes caused by a dielectric barrier discharge (DBD) under ambient conditions were investigated by IR spectroscopy, mass spectrometry and High Performance Liquid Chromatography (HPLC). HPLC chromatograms revealed one clean peak after treatment of both GSH and GSSH with the dielectric barrier discharge (DBD) plasma, which corresponded to glutathione sulfonic acid GSO3H. The ESI-MS measurements confirmed the presence of glutathione sulfonic acid. In our experiments, involving either iron(II) or iron(III) complexes, glutathione sulfonic acid GSO3H appeared as the main oxidation product. This is in sharp contrast to GSH/GSSG treatment with DBD plasma in the absence of metal ions, which gave a wild mixture of products. Also interesting, no nitrosylation of GSH/GSSG was oberved in the presence of iron complexes, which seems to indicate a preferential oxygen activation chemistry by this transition metal ion.
Genomewide Gene-by-Sex Interaction Scans Identify ADGRV1 for Sex Differences in Opioid Dependent African Americans
Authors: Yang Bao-Zhu , Zhou Hang , Cheng Zhongshan , Kranzler Henry R. , Gelernter Joel
Published: December 2019

Sex differences in opioid dependence (OD) are genetically influenced. We conducted genomewide gene-by-sex interaction scans for the DSM-IV diagnosis of OD in 8,387 African-American (AA) or European-American subjects (43.6% women; 4,715 OD subjects). Among AAs, 9 SNPs were genome-wide significant at ADGRV1 (adhesion G-protein-coupled receptor V1, lead-SNP rs2366929*(C/T), p = 1.5 × 10−9) for sex-different risk of OD, with the rs2366929*C-allele increasing OD risk only for men. The top co-expressions in brain were between ADGRV1 and GRIK2 in substantia nigra and medullary inferior olivary nucleus, and between ADGRV1 and EFHC2 in frontal cortex and putamen. Significant sex-differential ADGRV1 expression from GTEx was detected in breast (Bonferroni-corrected-p < 0.002) and in heart (p < 0.0125), with nominal significance identified in brain, thyroid, lung, and stomach (p < 0.05). ADGRV1 co-expression and disease-enrichment analysis identifying the top 10 diseases showed strikingly sexually dimorphic risks. The enrichment and transcriptome analyses provided convergent support that ADGRV1 exerts a sex-different effect on OD risk. This is the first study to identify genetic variants contributing to sex differences in OD. It shows that ADGRV1 contributes to OD risk only in AA men, a finding that warrants further study.
Mitochondrial Dysfunction and Changes in High-Energy Compounds in Different Cellular Models Associated to Hypoxia: Implication to Schizophrenia
Authors: e Silva Luiz Felipe Souza , Brito Mariana Dutra , Yuzawa Jéssica Mayumi Camargo , Rosenstock Tatiana Rosado
Published: December 2019

Schizophrenia (SZ) is a multifactorial mental disorder, which has been associated with a number of environmental factors, such as hypoxia. Considering that numerous neural mechanisms depends on energetic supply (ATP synthesis), the maintenance of mitochondrial metabolism is essential to keep cellular balance and survival. Therefore, in the present work, we evaluated functional parameters related to mitochondrial function, namely calcium levels, mitochondrial membrane potential, redox homeostasis, high-energy compounds levels and oxygen consumption, in astrocytes from control (Wistar) and Spontaneously Hypertensive Rats (SHR) animals exposed both to chemical and gaseous hypoxia. We show that astrocytes after hypoxia presented depolarized mitochondria, disturbances in Ca2+ handling, destabilization in redox system and alterations in ATP, ADP, Pyruvate and Lactate levels, in addition to modification in NAD+/NADH ratio, and Nfe2l2 and Nrf1 expression. Interestingly, intrauterine hypoxia also induced augmentation in mitochondrial biogenesis and content. Altogether, our data suggest that hypoxia can induce mitochondrial deregulation and a decrease in energy metabolism in the most prevalent cell type in the brain, astrocytes. Since SHR are also considered an animal model of SZ, our results can likewise be related to their phenotypic alterations and, therefore, our work also allow an increase in the knowledge of this burdensome disorder.
Fluctuating thermal environments of shallow-water rocky reefs in the Gulf of California, Mexico
Authors: Galland Grantly R. , Hastings Philip A. , Leichter James J.
Published: December 2019

As part of a broad-scale study of the biogeography of rocky reefs in the Gulf of California, Mexico (GOC), we collected a continuous 1-yr temperature time series at ~5 m water depth at 16 sites spanning 5° of latitude and ~700 km along the western boundary of the basin. Throughout the region, thermal conditions were most variable in summer with fluctuations concentrated at diurnal and semi-diurnal frequencies, likely associated with solar and wind forcing and vertical water column oscillations forced by internal waves. Temperatures in winter were less variable than in summer, and minimum temperatures also differed among sites. Thermal variability integrated across the diurnal and semi-diurnal frequency bands was greatest near the Midriff Islands in the northern GOC and decreased toward the southern sites. Diurnal variability was greater than semi-diurnal variability at 13 of the 16 sites. A statistic-of-extremes analysis indicated shortest return times for cooling events in summer, and reef organisms at many of the sites may experience anomalous 2 to 5 °C cooling events multiple times per month. The significant extent of local temperature variability may play important roles in limiting species occurrences among sites across this biogeographic region.
Glacial lakes exacerbate Himalayan glacier mass loss
Authors: King Owen , Bhattacharya Atanu , Bhambri Rakesh , Bolch Tobias
Published: December 2019

Heterogeneous glacier mass loss has occurred across High Mountain Asia on a multi-decadal timescale. Contrasting climatic settings influence glacier behaviour at the regional scale, but high intra-regional variability in mass loss rates points to factors capable of amplifying glacier recession in addition to climatic change along the Himalaya. Here we examine the influence of surface debris cover and glacial lakes on glacier mass loss across the Himalaya since the 1970s. We find no substantial difference in the mass loss of debris-covered and clean-ice glaciers over our study period, but substantially more negative (−0.13 to −0.29 m w.e.a−1) mass balances for lake-terminating glaciers, in comparison to land-terminating glaciers, with the largest differences occurring after 2000. Despite representing a minor portion of the total glacier population (~10%), the recession of lake-terminating glaciers accounted for up to 32% of mass loss in different sub-regions. The continued expansion of established glacial lakes, and the preconditioning of land-terminating glaciers for new lake development increases the likelihood of enhanced ice mass loss from the region in coming decades; a scenario not currently considered in regional ice mass loss projections.
Geography is essential for reproductive isolation between florally diversified morning glory species from Amazon canga savannahs
Authors: Babiychuk Elena , Teixeira Juliana Galaschi , Tyski Lourival , Guimaraes José Tasso Felix , Romeiro Luiza Araújo , da Silva Edilson Freitas , dos Santos Jorge Filipe , Vasconcelos Santelmo , da Silva Delmo Fonseca , Castilho Alexandre , Siqueira José Oswaldo , Fonseca Vera Lucia Imperatriz , Kushnir Sergei
Published: December 2019

The variety, relative importance and eco-evolutionary stability of reproductive barriers are critical to understanding the processes of speciation and species persistence. Here we evaluated the strength of the biotic prezygotic and postzygotic isolation barriers between closely related morning glory species from Amazon canga savannahs. The flower geometry and flower visitor assemblage analyses supported pollination by the bees in lavender-flowered Ipomoea marabaensis and recruitment of hummingbirds as pollinators in red-flowered Ipomoea cavalcantei. Nevertheless, native bee species and alien honeybees foraged on flowers of both species. Real-time interspecific hybridization underscored functionality of the overlap in flower visitor assemblages, questioning the strength of prezygotic isolation underpinned by diversification in flower colour and geometry. Interspecific hybrids were fertile and produced offspring in nature. No significant asymmetry in interspecific hybridization and hybrid incompatibilities among offspring were found, indicating weak postmating and postzygotic isolation. The results suggested that despite floral diversification, the insular-type geographic isolation remains a major barrier to gene flow. Findings set a framework for the future analysis of contemporary evolution of plant-pollinator networks at the population, community, and ecosystem levels in tropical ecosystems that are known to be distinct from the more familiar temperate climate models.
An electronic medical records-based approach to identify idiosyncratic drug-induced liver injury in children
Authors: Sandritter Tracy L. , Goldman Jennifer L. , Habiger Clayton J. , Daniel James F. , Lowry Jennifer , Fischer Ryan T.
Published: December 2019

Drug-induced liver injury (DILI) is the leading cause of liver failure in the United States and the most common cause of drug recall. As opposed to the recognized direct toxicity of super-therapeutic acetaminophen or chemotherapeutic agents in children, limited data exists for pediatric populations on the incidence of idiosyncratic DILI (iDILI) that may develop independently of drug dose or duration of administration. To improve the detection of adverse drug reactions at our hospital, we utilized electronic medical records-based automated trigger tools to alert providers of potential iDILI. Clinical criteria concerning for iDILI were defined as serum ALT > 5x or serum bilirubin > 1.5x upper limit of normal in the setting of medication exposure. Over a two year period, 12 patients were identified as having possible or probable iDILI. Out of the identified patients, three were males, and the mean age was 10.8 years. Implicated agents included eight antibiotics, two anti-epileptics, one anti-psychotic, and one anti-inflammatory medication. Roussel-Uclaf Causality Assessment Methods identified one “possible” case, 11 “probable” cases, and one “highly probable” case of iDILI. Improved awareness and more vigilant programming can generate better data on iDILI and improve our understanding of the condition and its incidence in children.
Mechanics of very slow human walking
Authors: Wu Amy R. , Simpson Cole S. , van Asseldonk Edwin H. F. , van der Kooij Herman , Ijspeert Auke J.
Published: December 2019

Human walking speeds can be influenced by multiple factors, from energetic considerations to the time to reach a destination. Neurological deficits or lower-limb injuries can lead to slower walking speeds, and the recovery of able-bodied gait speed and behavior from impaired gait is considered an important rehabilitation goal. Because gait studies are typically performed at faster speeds, little normative data exists for very slow speeds (less than 0.6 ms$${}^{-1}$$−1). The purpose of our study was to investigate healthy gait mechanics at extremely slow walking speeds. We recorded kinematic and kinetic data from eight adult subjects walking at four slow speeds from 0.1 ms$${}^{-1}$$−1   to 0.6 ms$${}^{-1}$$−1   and at their self-selected speed. We found that known relations for spatiotemporal and work measures are still valid at very slow speeds. Trends derived from slow speeds largely provided reasonable estimates of gait measures at self-selected speeds. Our study helps enable valuable comparisons between able-bodied and impaired gait, including which pathological behaviors can be attributed to slow speeds and which to gait deficits. We also provide a slow walking dataset, which may serve as normative data for clinical evaluations and gait rehabilitative devices.
Early life nutrition influences susceptibility to chronic inflammatory colitis in later life
Authors: Ley Delphine , Desseyn Jean-Luc , Gouyer Valérie , Plet Ségolène , Tims Sebastian , Renes Ingrid , Mischke Mona , Gottrand Frédéric
Published: December 2019

The first thousand days of life are a critical time of development in humans during which the risk profile for diseases in later life can be modified. Nevertheless, long-term consequences of early environment on susceptibility to intestinal diseases have not yet been assessed. Using a mouse model of postnatal growth restriction (PNGR), we showed that early life nutrition influences intestinal maturation and gut health in later life. PNGR induced an alteration of the intestinal barrier in pups at weaning, resulting in increased intestinal permeability, and affected gut bacterial colonization. Specifically, pups with PNGR harbored a decreased bacterial diversity, higher Enterococcus spp., Staphylococcus spp., and Escherichia-Shigella spp., and lower Odoribacter spp. and several members of the Lachnospiraceae family. The lack of an efficient intestinal barrier in early life and the dysbiosis induced by PNGR were associated with a higher susceptibility to chronic colitis in adulthood.
Light therapy with boxes or glasses to counteract effects of acute sleep deprivation
Authors: Comtet Henri , Geoffroy Pierre A. , Kobayashi Frisk Mio , Hubbard Jeffrey , Robin-Choteau Ludivine , Calvel Laurent , Hugueny Laurence , Viola Antoine U. , Bourgin Patrice
Published: December 2019

Sleep deprivation, in the context of shift work, is an increasing major public health issue. We aimed to determine whether early light administration can counteract sleep deprivation effects, and to compare LED-glasses with a traditional light therapy box. This cross-over design study included 18 individuals exposed to light therapy for 30 minutes at 5 am after one night of complete sleep deprivation, to mimic the night shift condition. Individuals were randomly exposed to 10,000 Lux light box, 2,000 Lux LED blue-enriched glasses, and control (ambient dim-light at 8 lux). Alertness, cognition and mood were assessed throughout the night and following morning. Five women and 13 men (mean 24.78 year old) presented with a progressive and increasing alteration of alertness, cognition, and mood during each sleep deprivation. A rebound was observed at 8 am resulting from the circadian drive overriding cumulative sleep homeostatic effects. Morning light significantly improved sleepiness and sustained attention from 5 to 7 am. These effects were comparable between devices and significantly different from control. Both devices were overall well and similarly tolerated. Early morning light therapy in the condition of sleep loss may have broad practical applications to improve sleepiness, sustained attention and subsequent risk of accidents.
Real-world Treatment Patterns and Outcomes in HR+/HER2+ Metastatic Breast Cancer Patients: A National Cancer Database Analysis
Authors: Statler Abby B. , Hobbs Brian P. , Wei Wei , Gupta Annie , Blake Cassann N. , Nahleh Zeina A.
Published: December 2019

Treatment patterns and outcomes are unclear for metastatic breast cancer (MBC) patients diagnosed with hormone receptor-positive (HR+), human epidermal growth factor 2-positive (HER2+) disease. This study aimed to: (1) examine the utilization of first-line therapy among HR+/HER2+/MBC patients and (2) compare overall survival (OS) between the identified regimens. We analyzed National Cancer Database patients (HR+/HER2+/MBC) who were treated between 2010 and 2015. Multivariable logistic and Cox regression were used to: (1) identify independent predictors of treatment receipt and (2) determine significant prognostic factors for OS. Kaplan-Meier method and log-rank test were used to estimate and evaluate OS, respectively. Propensity scores were added to all multivariate OS models, thereby accounting for bias in treatment receipt. Of 6,234 patients analyzed, 3770 (60.5%) received hormonal therapy and 2464 (39.5%) received chemotherapy. Receipt of hormonal therapy was associated with older age, grade 1/grade 2 disease, no visceral involvement, higher comorbidity scores, and being white. Multivariate analysis suggest patients receiving hormonal therapy + anti-HER2 experienced improved OS, when compared to chemotherapy + anti-HER2 (HR: 0.74, p = 0.004). Overall, the cohort receiving hormonal therapy + anti-HER2 reported the highest 5-year OS (hormonal + anti-HER2: 47.5% vs. chemotherapy + anti-HER2: 39.8% vs. hormonal: 38.5% vs. chemotherapy: 36.3%, p < 0.001). Our findings suggest de-escalated therapy may be the preferred and potentially more effective care path for HR+/HER2+/MBC patients, signaling a need for randomized studies.
Demonstration of critical coupling in an active III-nitride microdisk photonic circuit on silicon
Authors: Tabataba-Vakili Farsane , Doyennette Laetitia , Brimont Christelle , Guillet Thierry , Rennesson Stéphanie , Damilano Benjamin , Frayssinet Eric , Duboz Jean-Yves , Checoury Xavier , Sauvage Sébastien , El Kurdi Moustafa , Semond Fabrice , Gayral Bruno , Boucaud Philippe
Published: December 2019

On-chip microlaser sources in the blue constitute an important building block for complex integrated photonic circuits on silicon. We have developed photonic circuits operating in the blue spectral range based on microdisks and bus waveguides in III-nitride on silicon. We report on the interplay between microdisk-waveguide coupling and its optical properties. We observe critical coupling and phase matching, i.e. the most efficient energy transfer scheme, for very short gap sizes and thin waveguides (g = 45 nm and w = 170 nm) in the spontaneous emission regime. Whispering gallery mode lasing is demonstrated for a wide range of parameters with a strong dependence of the threshold on the loaded quality factor. We show the dependence and high sensitivity of the output signal on the coupling. Lastly, we observe the impact of processing on the tuning of mode resonances due to the very short coupling distances. Such small footprint on-chip integrated microlasers providing maximum energy transfer into a photonic circuit have important potential applications for visible-light communication and lab-on-chip bio-sensors.
Oxygen consumption in seasonally stratified lakes decreases only below a marginal phosphorus threshold
Authors: Müller Beat , Steinsberger Thomas , Schwefel Robert , Gächter René , Sturm Michael , Wüest Alfred
Published: December 2019

Areal oxygen (O2) consumption in deeper layers of stratified lakes and reservoirs depends on the amount of settling organic matter. As phosphorus (P) limits primary production in most lakes, protective and remediation efforts often seek to reduce P input. However, lower P concentrations do not always lead to lower O2 consumption rates. This study used a large hydrochemical dataset to show that hypolimnetic O2 consumption rates in seasonally stratified European lakes remain consistently elevated within a narrow range (1.06 ± 0.08 g O2 m−2 d−1) as long as areal P supply (APS) exceeded 0.54 ± 0.06 g P m−2 during the productive season. APS consists of the sum of total P present in the productive top 15 m of the water column after winter mixing plus the load of total dissolved P imported during the stratified season, normalized to the lake area. Only when APS sank below this threshold, the areal hypolimnetic mineralization rate (AHM) decreased in proportion to APS. Sediment trap material showed increasing carbon:phosphorus (C:P) ratios in settling particulate matter when APS declined. This suggests that a decreasing P load results in lower P concentration but not necessarily in lower AHM rates because the phytoplankton community is able to maintain maximum biomass production by counteracting the decreasing P supply by a more efficient P utilization. In other words, in-lake organic matter production depends only on APS if the latter falls below the threshold of 0.54 g P m−2 and correspondingly, the atomic C:P ratio of the settling material exceeds ~155.
Fluctuating renal function and the risk of incident atrial fibrillation: a nationwide population-based study
Authors: Kwon Soonil , Lee So-Ryoung , Choi Eue-Keun , Han Kyung-Do , Yang Seokhun , Lee Seo-Young , Lee Hyun-Jung , Moon Inki , Lee Euijae , Cha Myung-Jin , Lim Woo-Hyun , Oh Seil , Lip Gregory Y. H.
Published: December 2019

Although chronic kidney disease is known to increase the risk of atrial fibrillation (AF), the impact of the variability of renal function on the risk of incident AF is unknown. We aimed to evaluate the association between variability of renal function and the risk of developing AF among the general population. We evaluated a total of 3,551,249 adults who had three annual health check-ups provided by the National Health Insurance Service. The variability of renal function was defined as GFR-VIM, which is variability independent of the mean (VIM) of creatinine-based estimated glomerular filtration rate (eGFR). The study population was divided into four groups (Q1-4) based on the quartiles of GFR-VIM, and the risks of incident AF by each group were compared. During a mean of 3.2 ± 0.5 years follow-up, incident AF occurred in 15,008 (0.42%) subjects. The incidence rates of AF increased from Q1 to Q4 (0.98, 1.42, 1.27, and 1.63 per 1,000 person-years, respectively). Adjusting with multiple variables, Q4 showed an increased risk of incident AF compared to Q1 (hazard ratio (HR) 1.125, 95% confidence interval (CI) 1.071–1.181). Variability of serum creatinine or other definitions of variability showed consistent results. On subgroup analyses, Q4 in males or those with a decreasing trend of eGFR had significantly increased risks of incident AF compared to Q1 (HR 1.127, 95% CI 1.082–1.175; and HR 1.115, 95% CI 1.059–1.173, respectively). High variability of eGFR was associated with an increased risk of incident AF, particularly in males or those with decreasing trends of eGFR during follow-up.
Modeling reservoir management for malaria control in Ethiopia
Authors: Kibret Solomon , Ryder Darren , Wilson G. Glenn , Kumar Lalit
Published: December 2019

This study investigated how changes in reservoir water level affect mosquito abundance and malaria transmission in Ethiopia. Digital elevation models of three Ethiopian dams at lowland, midland and highland elevations were used to quantify water surface area and wetted shoreline at different reservoir water levels (70, 75, 80, 85, 90, 95 and 100% full capacity) to estimate surface area of potential mosquito breeding habitat. Reservoir water level drawdown rates of 10, 15 and 20 mm.day−1 were applied as scenarios to model larval abundance, entomological inoculation rate (EIR) and malaria prevalence at each dam. Malaria treatment cost and economic cost in terms of lost working days were calculated for each water level scenario and dam. At the lowland dam, increased larval abundances were associated with increasing reservoir water level and wetted shoreline area. In contrast, both larval abundances and area of wetted shoreline declined with increasing reservoir water level at the midland and highland dams. Estimated EIR, malaria prevalence, malaria treatment cost and economic cost generally decreased when the water level drawdown rate increased from 10 to 15 and 20 mm.day−1 irrespective of reservoir water level. Given the expansion of dam construction in sub-Saharan Africa, incorporating malaria control measures such as manipulating drawdown rates into reservoir management has the potential to reduce the malaria burden and health care costs in communities near reservoirs.
Inhibitory characteristics of flavonol-3-O-glycosides from Polygonum aviculare L. (common knotgrass) against porcine pancreatic lipase
Authors: Park Jun-Young , Kim Chung Sun , Park Kyung-Min , Chang Pahn-Shick
Published: December 2019

Pancreatic lipase (PL) is an enzyme that plays an essential role in the digestion of dietary lipids and is a suitable target for an anti-obesity dietary supplement. The objective of this study was to find a novel source of PL inhibitors from Korean medicinal plants and investigate the PL-inhibitory properties of the active constituents. From among 34 kinds of methanolic crude extracts, Polygonum aviculare L. showed the highest PL-inhibitory activity (63.97 ± 0.05% of inhibition). Solvent fractionation and liquid chromatography/mass spectrometry (LC/MS) analysis identified flavonol-3-O-glycosides, flavonol-3-O-(2″-galloyl)-glycosides, and flavonol aglycones as active constituents. Furthermore, the inhibitory characteristics of the major compounds were investigated in terms of enzyme kinetics and fluorescence quenching. The results suggested that the inhibitory activity of the major compounds is closely related to the tertiary structural change in PL, and that differences in inhibitory activity occurred due to slight discrepancies in their chemical structure.
Optimal gestational weight gain for underweight pregnant women in Japan
Authors: Shindo Ryosuke , Aoki Mihoko , Yamamoto Yuriko , Misumi Toshihiro , Miyagi Etsuko , Aoki Shigeru
Published: December 2019

We aimed to investigate the optimal range of gestational weight gain (GWG) for Japanese underweight (body mass index <18.5 kg/m2) women using the Japanese Birth Registry System. The study subjects included underweight women who were divided into groups according to the GWG recommendations of the Ministry of Health, Labour and Welfare (MHLW) (9–12 kg): <9.0 kg, group A; 9–12 kg, group B; and >12 kg, group C. The subjects were then classified according to the recommendations of the Institute of Medicine (IOM) (12.7–18.1 kg): <12.7 kg, group D; 12.7–18.1 kg, group E; and >18.1 kg, group F. In total, 148,135 cases were analysed. The frequencies of small for gestational age, preterm delivery, and caesarean delivery were as follows: 19.3%, 22.7%, and 28.5% for group A; 11.7%, 8.7%, and 22.8% for group B; 8.0%, 4.9%, and 21.5% for group C; 15.0%, 14.7%, and 25.2% for group D; 8.0%, 5.3%, and 21.5% for group E; and 7.0%, 5.5%, and 25.0% for group F, respectively. These results indicated that groups C and E had the best outcomes. Therefore, the IOM guidelines seem more appropriate than the MHLW guidelines. Therefore, the MHLW recommended GWG guidelines require revision.
The Effect of pH on Antibiotic Efficacy against Coxiella burnetii in Axenic Media
Authors: Smith Cody B. , Evavold Charles , Kersh Gilbert J.
Published: December 2019

Coxiella burnetii, the etiologic agent of Q fever, replicates in an intracellular phagolysosome with pH between 4 and 5. The impact of this low pH environment on antimicrobial treatment is not well understood. An in vitro system for testing antibiotic susceptibility of C. burnetii in axenic media was set up to evaluate the impact of pH on C. burnetii growth and survival in the presence and absence of antimicrobial agents. The data show that C. burnetii does not grow in axenic media at pH 6.0 or higher, but the organisms remain viable. At pH of 4.75, 5.25, and 5.75 moxifloxacin, doxycycline, and rifampin are effective at preventing growth of C. burnetii in axenic media, with moxifloxacin and doxycycline being bacteriostatic and rifampin having bactericidal activity. The efficacy of doxycycline and moxifloxacin improved at higher pH, whereas rifampin activity was pH independent. Hydroxychloroquine is thought to inhibit growth of C. burnetii in vivo by raising the pH of typically acidic intracellular compartments. It had no direct bactericidal or bacteriostatic activity on C. burnetii in axenic media, suggesting that raising pH of acidic intracellular compartments is its primary mechanism of action in vivo. The data suggest that doxycycline and hydroxychloroquine are primarily independent bacteriostatic agents.
Projecting the impact of variable MDR-TB transmission efficiency on long-term epidemic trends in South Africa and Vietnam
Authors: Salvatore Phillip P. , Kendall Emily A. , Seabrook Dena , Brown Jessie , Durham George H. , Dowdy David W.
Published: December 2019

Whether multidrug-resistant tuberculosis (MDR-TB) is less transmissible than drug-susceptible (DS-)TB on a population level is uncertain. Even in the absence of a genetic fitness cost, the transmission potential of individuals with MDR-TB may vary by infectiousness, frequency of contact, or duration of disease. We used a compartmental model to project the progression of MDR-TB epidemics in South Africa and Vietnam under alternative assumptions about the relative transmission efficiency of MDR-TB. Specifically, we considered three scenarios: consistently lower transmission efficiency for MDR-TB than for DS-TB; equal transmission efficiency; and an initial deficit in the transmission efficiency of MDR-TB that closes over time. We calibrated these scenarios with data from drug resistance surveys and projected epidemic trends to 2040. The incidence of MDR-TB was projected to expand in most scenarios, but the degree of expansion depended greatly on the future transmission efficiency of MDR-TB. For example, by 2040, we projected absolute MDR-TB incidence to account for 5% (IQR: 4–9%) of incident TB in South Africa and 14% (IQR: 9–26%) in Vietnam assuming consistently lower MDR-TB transmission efficiency, versus 15% (IQR: 8–27%)and 41% (IQR: 23–62%), respectively, assuming shrinking transmission efficiency deficits. Given future uncertainty, specific responses to halt MDR-TB transmission should be prioritized.
Simple oral mucosal epithelial transplantation in a rabbit model
Authors: Inamochi Aya , Tomioka Akiko , Kitamoto Kohdai , Miyai Takashi , Usui Tomohiko , Aihara Makoto , Yamagami Satoru
Published: December 2019

This study investigated a rabbit model of autologous simple oral mucosal epithelium transplantation (SOMET) for limbal stem cell deficiency (LSCD). LSCD was created in the SOMET group and the Control group. In the SOMET group, oral mucosa harvested from the buccal region was treated with dispase, cut into small pieces, and placed on the exposed corneal stroma without using graft sutures, amniotic membrane, and/or glue. A soft contact lens was positioned and tarsorrhaphy was performed in both groups. Postoperative corneal neovascularization and fluorescein staining scores were evaluated by slit lamp microscopy in both groups. At 2 weeks postoperatively, eyes were excised and subjected to immunohistochemical staining for CK3, CK13, CK15, and p63. In the SOMET group, transplantation of oral mucosa led to complete recovery of LSCD, as indicated by low neovascularization scores, low fluorescein staining scores, and detection of stratified K3/K13-positive cells on the stroma at 2 weeks after surgery. In contrast, corneal epithelial defects persisted in the Control group at 2 weeks. SOMET achieved re-epithelialization of the corneal surface in this rabbit LSCD model. It is a simple technique that does not require culture and could be a promising option for ocular surface reconstruction in bilateral LSCD.
6-Bromoindirubin-3′-oxime intercepts GSK3 signaling to promote and enhance skeletal muscle differentiation affecting miR-206 expression in mice
Authors: Ragozzino Elvira , Brancaccio Mariarita , Di Costanzo Antonella , Scalabrì Francesco , Andolfi Gennaro , Wanderlingh Luca G. , Patriarca Eduardo J. , Minchiotti Gabriella , Altamura Sergio , Summa Vincenzo , Varrone Francesca
Published: December 2019

Dystrophies are characterized by progressive skeletal muscle degeneration and weakness as consequence of their molecular abnormalities. Thus, new drugs for restoring skeletal muscle deterioration are critically needed. To identify new and alternative compounds with a functional role in skeletal muscle myogenesis, we screened a library of pharmacologically active compounds and selected the small molecule 6-bromoindirubin-3′-oxime (BIO) as an inhibitor of myoblast proliferation. Using C2C12 cells, we examined BIO’s effect during myoblast proliferation and differentiation showing that BIO treatment promotes transition from cell proliferation to myogenic differentiation through the arrest of cell cycle. Here, we show that BIO is able to promote myogenic differentiation in damaged myotubes in-vitro by enriching the population of newly formed skeletal muscle myotubes. Moreover, in-vivo experiments in CTX-damaged TA muscle confirmed the pro-differentiation capability of BIO as shown by the increasing of the percentage of myofibers with centralized nuclei as well as by the increasing of myofibers number. Additionally, we have identified a strong correlation of miR-206 with BIO treatment both in-vitro and in-vivo: the enhanced expression of miR-206 was observed in-vitro in BIO-treated proliferating myoblasts, miR-206 restored expression was observed in a forced miR-206 silencing conditions antagomiR-mediated upon BIO treatment, and in-vivo in CTX-injured muscles miR-206 enhanced expression was observed upon BIO treatment. Taken together, our results highlight the capacity of BIO to act as a positive modulator of skeletal muscle differentiation in-vitro and in-vivo opening up a new perspective for novel therapeutic targets to correct skeletal muscle defects.
Fluorescence imaging reversion using spatially variant deconvolution
Authors: Anastasopoulou Maria , Gorpas Dimitris , Koch Maximilian , Liapis Evangelos , Glasl Sarah , Klemm Uwe , Karlas Angelos , Lasser Tobias , Ntziachristos Vasilis
Published: December 2019

Fluorescence imaging opens new possibilities for intraoperative guidance and early cancer detection, in particular when using agents that target specific disease features. Nevertheless, photon scattering in tissue degrades image quality and leads to ambiguity in fluorescence image interpretation and challenges clinical translation. We introduce the concept of capturing the spatially-dependent impulse response of an image and investigate Spatially Adaptive Impulse Response Correction (SAIRC), a method that is proposed for improving the accuracy and sensitivity achieved. Unlike classical methods that presume a homogeneous spatial distribution of optical properties in tissue, SAIRC explicitly measures the optical heterogeneity in tissues. This information allows, for the first time, the application of spatially-dependent deconvolution to correct the fluorescence images captured in relation to their modification by photon scatter. Using experimental measurements from phantoms and animals, we investigate the improvement in resolution and quantification over non-corrected images. We discuss how the proposed method is essential for maximizing the performance of fluorescence molecular imaging in the clinic.
Synthesis and biological activities of two camptothecin derivatives against Spodoptera exigua
Authors: Yang Fulai , Wang Liping , Zhang Lan , Zhang Yanning , Mao Liangang , Jiang Hongyun
Published: December 2019

Camptothecin (CPT), a natural alkaloid isolated from Camptotheca acuminata Decne, is found to show potential insecticidal activities with unique action mechanisms by targeting at DNA-topoisomease I (Top1) complex and inducing cell apoptosis. To improve the efficacy against insect pests, two camptothecin (CPT) derivatives were synthesized through introducing two functional groups, 2-nitroaminoimidazoline and 1-chloro-2-isocyanatoethane by esterification reaction. The insecticidal activities of these two derivatives were evaluated at contact toxicity, cytotoxicity and topoisomerase I (Top1) inhibitory activities comparing with CPT and hydroxyl-camptothecin (HCPT). Results showed that compound a, synthesized by introducing 2-nitroaminoimidazoline to CPT, apparently increased contact toxicity to the third larvae of beet armyworm, Spodoptera exigua, and cytotoxicity to IOZCAS-Spex-II cells isolated from S. exigua. However, the inhibition on DNA relaxation activity of Top1 was reduced to less than 5 percentage even at high concentrations (50 and 100 μM). For introducing 1-chloro-2-isocyanatoethane to HCPT, the contact toxicity, cytotoxicity and Top1 inhibitory activity of synthesized compound b were increased significantly compared to CPT and HCPT. These results suggested that both synthesized compounds possessed high efficacy against S. exigua by targeting at Top1 (compound b) or novel mechanism of action (compound a).