bluuebunny/crossref_metadata_2025 huggingface dataset:
ASlive: a database for alternative splicing atlas in livestock animals
Authors: Liu Jinding , Tan Suxu , Huang Shuiqing , Huang Wen
Published: September 2019

We present in this study the development and implementation of a database for alternative splicing atlas in livestock animals (ASlive.org). Alternative splicing is an important biological process whose precision must be tightly regulated during growth and development. Using publicly available RNASeq data sets across many tissues, cell types, and biological conditions totaling 28.6 tera bases, we built a database of alternative splicing events in five major livestock animal species (cattle, sheep, pigs, horses, and chickens). The database contains many types of information on alternative splicing events, including basic information such as genomic locations, genes, and event types, quantitative measurements of alternative splicing in the form of percent spliced in (PSI), overlap with known DNA variants, as well as orthologous events across different lineage groups. This database, the first of its kind in livestock animals, will provide a useful exploratory tool to assist functional annotation of animal genomes.
miRCoop: Identifying Cooperating miRNAs via Kernel Based Interaction Tests
Authors: Olgun Gulden , Tastan Oznur
Published: September 2019

Although miRNAs can cause widespread changes in expression programs, single miRNAs typically induce mild repression on their targets. Cooperativity is reported as one strategy to overcome this constraint. Expanding the catalog of synergistic miRNAs is critical for understanding gene regulation and for developing miRNA-based therapeutics. In this study, we develop miRCoop to identify synergistic miRNA pairs that have weak or no repression on the target mRNA, but when bound together, induce strong repression. miRCoop uses kernel-based interaction tests together with miRNA and mRNA target information. We apply our approach to kidney tumor patient data and identify 66 putative triplets. For 64 of these triplets, there is at least one common transcription factor that potentially regulates all participating RNAs of the triplet, supporting a functional association among them. Furthermore, we find that triplets are enriched for certain biological processes that are relevant to kidney cancer. Some of the synergistic miRNAs are very closely encoded in the genome, hinting a functional association among them. We believe miRCoop can aid our understanding of the complex regulatory interactions in different health and disease states of the cell and can help in designing miRNA-based therapies. Matlab code for the methodology is provided inhttps://github.com/guldenolgun/miRCoop.
Brain dynamics for confidence-weighted learning
Authors: Meyniel Florent
Published: September 2019

Learning in a changing and uncertain environment is a difficult problem. A popular solution is to predict future observations and then use surprising outcomes to update those predictions. However, humans also have a sense of confidence that characterizes the precision of their predictions. Bayesian models use this confidence to regulate learning: for a given surprise, the update is smaller when confidence is higher. We explored the human brain dynamics sub-tending such a confidence-weighting using magneto-encephalography. During our volatile probability learning task, subjects’ confidence reports conformed with Bayesian inference. Several stimulus-evoked brain responses reflected surprise, and some of them were indeed further modulated by confidence. Confidence about predictions also modulated pupil-linked arousal and beta-range (15-30 Hz) oscillations, which in turn modulated specific stimulus-evoked surprise responses. Our results suggest thus that confidence about predictions modulates intrinsic properties of the brain state to amplify or dampen surprise responses evoked by discrepant observations.
Dissociable neural effects of temporal expectations due to passage of time and contextual probability
Authors: Todorovic Ana , Auksztulewicz Ryszard
Published: September 2019

The human brain is equipped with complex mechanisms to track the changing probability of events in time. While the passage of time itself usually leads to a mounting expectation, context can provide additional information about when events are likely to happen. In this study we dissociate these two sources of temporal expectation in terms of their neural correlates and underlying brain connectivity patterns. We analysed magnetoencephalographic (MEG) data acquired from N=24 healthy participants listening to auditory stimuli. These stimuli could be presented at different temporal intervals but occurred most often at intermediate intervals, forming a contextual probability distribution. Evoked MEG response amplitude was sensitive to both passage of time and contextual probability, albeit at different latencies: the effects of passage of time were observed earlier than the effects of context. The underlying sources of MEG activity were also different across the two types of temporal prediction: the effects of passage of time were localised to early auditory regions and superior temporal gyri, while context was additionally linked to activity in inferior parietal cortices. Finally, these differences were modelled using biophysical (dynamic causal) modelling: passage of time was explained in terms of widespread gain modulation and decreased prediction error signalling at lower levels of the hierarchy, while contextual expectation led to more localised gain modulation and decreased prediction error signalling at higher levels of the hierarchy. These results present a comprehensive account of how independent sources of temporal prediction may be differentially expressed in cortical circuits.

HIGHLIGHTS

- Predictability of tone onset times affects auditory network connectivity

- Foreperiod and distribution of events in time have dissociable neural substrates

- Decreased prediction error at different levels of cortical hierarchy
Green, orange, red, and far-red optogenetic tools derived from cyanobacteriochromes
Authors: Jang Jaewan , McDonald Sherin , Uppalapati Maruti , Woolley G. Andrew
Published: September 2019

Existing optogenetic tools for controlling protein-protein interactions are available in a limited number of wavelengths thereby limiting opportunities for multiplexing. The cyanobacteriochrome (CBCR) family of photoreceptors responds to an extraordinary range of colors, but light-dependent binding partners for CBCR domains are not currently known. We used a phage-display based approach to develop small (~50-residue) monomeric binders selective for the green absorbing state (Pg), or for the red absorbing state (Pr) of the CBCR Am1_c0023g2 with a phycocyanobilin chromophore and also for the far-red absorbing state (Pfr) of Am1_c0023g2 with a biliverdin chromophore. These bind in a 1:1 mole ratio with KDs for the target state from 0.2 to 2 μM and selectivities from 10 to 500-fold. We demonstrate green, orange, red, and far-red light-dependent control of protein-protein interactions in vitro and also in vivo where these multicolor optogenetic tools are used to control transcription in yeast.
A Framework for Transcriptome-Wide Association Studies in Breast Cancer in Diverse Study Populations
Authors: Bhattacharya Arjun , García-Closas Montserrat , Olshan Andrew F. , Perou Charles M. , Troester Melissa A. , Love Michael I.
Published: September 2019

Background

The relationship between germline genetic variation and breast cancer survival is largely unknown, especially in understudied minority populations who often have poorer survival. Genome-wide association studies (GWAS) have interrogated breast cancer survival but often are underpowered due to subtype heterogeneity and many clinical covariates and detect loci in non-coding regions that are difficult to interpret. Transcriptome-wide association studies (TWAS) show increased power in detecting functionally-relevant loci by leveraging expression quantitative trait loci (eQTLs) from external reference panels in relevant tissues. However, ancestry- or race-specific reference panels may be needed to draw correct inference in ancestrally-diverse cohorts. Such panels for breast cancer are lacking.

Results

We provide a framework for TWAS for breast cancer in diverse populations, using data from the Carolina Breast Cancer Study (CBCS), a North Carolina population-based cohort that oversampled black women. We perform eQTL analysis for 406 breast cancer-related genes to train race-stratified predictive models of tumor expression from germline genotypes. Using these models, we impute expression in independent data from CBCS and TCGA, accounting for sampling variability in assessing performance. These models are not applicable across race, and their predictive performance varies across tumor subtype. Within CBCS (N = 3,828), at a false discovery-adjusted significance of 0.10 and stratifying for race, we identify associations in black women nearAURKA, CAPN13, PIK3CA, and SERPINB5via TWAS that are underpowered in GWAS.

Conclusions

We show that carefully implemented and thoroughly validated TWAS is an efficient approach for understanding the genetics underpinning breast cancer outcomes in diverse populations.
Proteomic-based evaluation of nuclear transport of NLS-tagged trastuzumab-emtansine with enhanced cytotoxic potency
Authors: Lacasse Vincent , Beaudoin Simon , Jean Steve , Leyton Jeffrey V.
Published: September 2019

Nuclear transport receptors (NTRs) are the only proteins able to transport large molecular weight payloads into the nucleus. A dominant area of molecular therapeutic research is the extension of the use of NTRs to target the nucleus for the development of pharmaceuticals or as tools for investigating fundamental biological questions. Although several examples of synthesized peptides harbouring nuclear localization signal (NLS) sequences conjugated to various payloads exist in the literature, the assumption has been that transport occurs by classical nuclear localization via the NTRs importin-α and importin-β. This assumption is relevant to nuclear-targeted therapeutics that aim for full potential clinical impact. In addition, fundamental research can benefit from unbiased approaches to investigate the role of NTRs. Herein, we report the construction of a novel NLS-modified agent composed of trastuzumab-emtansine (T-DM1) coupled to cell accumulator (Accum), a technology that enables monoclonal antibodies to escape endosome entrapment and accumulate conjugated payloads in the nucleus without abrogating affinity or specificity to target antigens. Accum harbours a classical NLS sequence from SV-40 large T-antigen. We demonstrate that routing T-DM1 to the nucleus successfully increased cytotoxic potency in the HER2-positive cell line SKBR3. More importantly, through the development of a novel bait-prey proteomic approach, we show that the non-classical NTR importin 7 and not importin-α/importin-β was required for the cytotoxicity effect. This result was validated by siRNA knock down. Our findings also indicate that by discovering an unanticipated NTR regulator of an NLS-modified agent, this study demonstrates the utility of combining an unbiased proteomic approach to probe NTR function in mammalian cell system and, is a foresight for future NLS-based development initiatives.
Defining and targeting adaptations to oncogenic KRASG12Cinhibition using quantitative temporal proteomics
Authors: Santana-Codina Naiara , Chandhoke Amrita Singh , Yu Qijia , Małachowska Beata , Kuljanin Miljan , Gikandi Ajami , Stańczak Marcin , Gableske Sebastian , Jedrychowski Mark P. , Scott David A. , Aguirre Andrew J. , Fendler Wojciech , Gray Nathanael S. , Mancias Joseph D.
Published: September 2019

Covalent inhibitors of the KRASG12Concoprotein have recently been developed and are being evaluated in clinical trials. Resistance to targeted therapies is common and likely to limit long-term efficacy of KRAS inhibitors (KRASi). To identify pathways of adaptation to KRASi and to predict drug combinations that circumvent resistance, we used a mass spectrometry-based quantitative temporal proteomics and bioinformatics workflow to profile the temporal proteomic response to KRASG12Cinhibition in pancreatic and lung cancer 2D and 3D cellular models. We quantified 10,805 proteins across our datasets, representing the most comprehensive KRASi proteomics effort to date. Our data reveal common mechanisms of acute and long-term response between KRASG12C-driven tumors. To facilitate discovery in the cancer biology community, we generated an interactive ‘KRASi proteome’ website (https://manciaslab.shinyapps.io/KRASi/). Based on these proteomic data, we identified potent combinations of KRASi with PI3K, HSP90, CDK4/6, and SHP2 inhibitors, in some instances converting a cytostatic response to KRASi monotherapy to a cytotoxic response to combination treatment. Overall, using our quantitative temporal proteomics-bioinformatics platform, we have comprehensively characterized the proteomic adaptations to KRASi and identified combinatorial regimens to induce cytotoxicity with potential therapeutic utility.
Cervicovaginal tissue residence imprints a distinct differentiation program upon memory CD8 T cells
Authors: Davé Veronica , Cardozo-Ojeda E. Fabian , Mair Florian , Erickson Jami , Woodward-Davis Amanda S. , Koehne Amanda , Soerens Andrew , Czartoski Julie , Teague Candice , Potchen Nicole , Oberle Susanne , Zehn Dietmar , Schiffer Joshua T. , Lund Jennifer M. , Prlic Martin
Published: September 2019

Tissue-resident memory CD8 T cells (CD8 TRM) are critical for maintaining barrier immunity. CD8 TRM have been mainly studied in the skin and gut with recent studies suggesting that the signals that control tissue-residence and phenotype are highly tissue-dependent. We examined the T cell compartment in healthy human cervicovaginal tissue (CVT) and found that most CD8 T cells were granzyme B+ and TCF-1-. To address if this phenotype is driven by CVT tissue-residence, we used a mouse model to control for environmental factors. Using localized and systemic infection models, we found that CD8 TRM in the mouse CVT gradually acquired a granzyme B+, TCF-1- phenotype as seen in human CVT. In contrast to CD8 TRM in the gut, these CD8 TRM were not stably maintained regardless of the initial infection route, which led to reductions in local immunity. Our data show that residence in the CVT is sufficient to progressively shape the size and function of its CD8 TRM compartment.

The tissue-resident memory (TRM) CD8 T cell compartment in human and mouse cervicovaginal tissue (CVT) is remarkably similar. The CVT TRM compartment is maintained autonomously and does not reach phenoypical or numerical equilibrium. The numerical decline leads to impaired viral control in a secondary challenge.
More than Two Populations of Microtubules Comprise the Dynamic Mitotic Spindle
Authors: Tipton Aaron R. , Gorbsky Gary J.
Published: September 2019

The microtubules of the mitotic spindle mediate chromosome alignment to the metaphase plate, then sister chromatid segregation to the spindle poles in anaphase. Previous analyses of spindle microtubule kinetics utilizing fluorescence dissipation after photoactivation described two main populations, a slow and a fast turnover population, and these were ascribed to reflect kinetochore versus non-kinetochore microtubules, respectively. Here, we test this categorization by disrupting kinetochores through depletion of the Ndc80 complex. In the absence of functional kinetochores, microtubule dynamics still exhibit slow and fast turnover populations, though the proportion of each population and the timings of turnover are altered. Importantly, the data obtained following Hec1/Ndc80 depletion suggests other sub-populations, in addition to kinetochore microtubules, contribute to the slow turnover population. Further manipulation of spindle microtubules revealed a complex landscape. Dissection of the dynamics of microtubule populations provides a greater understanding of mitotic spindle kinetics and insight into roles in facilitating chromosome attachment, movement, and segregation during mitosis.
Pain Stickiness in Complex Regional Pain Syndrome: A role for the Nucleus Accumbens
Authors: Youssef Andrew M. , Peng Ke , Kim Pearl Kijoo , Lebel Alyssa , Sethna Navil F. , Kronman Corey , Zurakowski David , Borsook David , Simons Laura E.
Published: September 2019

Some individuals with chronic pain experience improvement in their pain with treatment, whereas others do not. The neurobiological reason is unclear, but an understanding of brain structure and functional patterns may provide insights into pain’s responsivity to treatment. In this investigation, we used magnetic resonance imaging (MRI) techniques to determine grey matter density alterations on resting functional connectivity (RFC) strengths between pain responders and nonresponders. Brain metrics of pediatric patients at admission to an intensive pain rehabilitative treatment program were evaluated. Pain responders reported significant pain improvement at discharge and/or follow-up whereas nonresponders reported no improvements, increases in pain, or emergence of new pain symptoms. The pain (responder/nonresponder) groups were compared with pain-free healthy controls to examine predictors of pain responder status via brain metrics. Our results show: (1) on admission, pain nonresponders had decreased grey matter density (GMD) within the nucleus accumbens (NAc) and reduced RFC strength between the NAc and the dorsolateral prefrontal cortex vs. responders; (2) Connectivity strength was positively correlated with change in pain intensity from admission to discharge; (3) Compared with pain-free controls, grey matter and RFC differences emerged only among pain nonresponders; and (4) Using a discriminative model, combining GMD and RFC strengths assessed at admission showed the highest prediction estimate (87%) on potential for pain improvement, warranting testing in a de novo sample. Taken together, these results support the idea that treatment responsiveness on pain is underpinned by concurrent brain structure and resting brain activity.
Suppression gene drive in continuous space can result in unstable persistence of both drive and wild-type alleles
Authors: Champer Jackson , Kim Isabel , Champer Samuel E. , Clark Andrew G. , Messer Philipp W.
Published: September 2019

Rapid evolutionary processes can produce drastically different outcomes when studied in panmictic population models versus spatial models where the rate of evolution is limited by dispersal. One such process is gene drive, which allows “selfish” genetic elements to quickly spread through a population. Engineered gene drive systems are being considered as a means for suppressing disease vector populations or invasive species. While laboratory experiments and modeling in panmictic populations have shown that such drives can rapidly eliminate a population, it is not yet clear how well these results translate to natural environments where individuals inhabit a continuous landscape. Using spatially explicit simulations, we show that instead of population elimination, release of a suppression drive can result in what we term “chasing” dynamics. This describes a condition in which wild-type individuals quickly recolonize areas where the drive has locally eliminated the population. Despite the drive subsequently chasing the wild-type allele into these newly re-colonized areas, complete population suppression often fails or is substantially delayed. This delay increases the likelihood that the drive becomes lost or that resistance evolves. We systematically analyze how chasing dynamics are influenced by the type of drive, its efficiency, fitness costs, as well as ecological and demographic factors such as the maximal growth rate of the population, the migration rate, and the level of inbreeding. We find that chasing is generally more common for lower efficiency drives and in populations with low dispersal. However, we further find that some drive mechanisms are substantially more prone to chasing behavior than others. Our results demonstrate that the population dynamics of suppression gene drives are determined by a complex interplay of genetic and ecological factors, highlighting the need for realistic spatial modeling to predict the outcome of drive releases in natural populations.
Recent hybrids recapitulate ancient hybrid outcomes
Authors: Chaturvedi Samridhi , Lucas Lauren K. , Buerkle C. Alex , Fordyce James A. , Forister Matthew L. , Nice Chris C. , Gompert Zachariah
Published: September 2019

Genomic outcomes of hybridization depend on selection and recombination in hybrids. Whether these processes have similar effects on hybrid genome composition in contemporary hybrid zones versus ancient hybrid lineages is unknown. Here we show that patterns of introgression in a contemporary hybrid zone inLycaeidesbutterflies predict patterns of ancestry in geographically adjacent, older hybrid populations. We find a particularly striking lack of ancestry from one of the hybridizing taxa,Lycaeides melissa, on the Z chromosome in both the old and contemporary hybrids. The same pattern of reducedL. melissaancestry on the Z chromosome is seen in two other ancient hybrid lineages. More generally, we find that patterns of ancestry in old or ancient hybrids are remarkably predictable from contemporary hybrids, which suggests selection and recombination affect hybrid genomes in a similar way across disparate time scales and during distinct stages of speciation and species breakdown.
PQM-1 controls hypoxic survival via regulation of lipid metabolism
Authors: Heimbucher Thomas , Hog Julian , Murphy Coleen T.
Published: September 2019

Animals have evolved responses to low oxygen conditions to ensure their survival. Here we have identified theC. eleganszinc finger transcription factor PQM-1 as a regulator of the hypoxic stress response. PQM-1 is required for the longevity of insulin signaling mutants, but surprisingly, loss of PQM-1 increases survival under hypoxic conditions. PQM-1 functions as a metabolic regulator by controlling oxygen consumption rates, suppressing hypoxic glycogen levels, and inhibiting the expression of the sorbitol dehydrogenase-1 SODH-1, a crucial enzyme for sugar metabolism. PQM-1 promotes intestinal fat metabolism by activating the expression of the stearoyl-CoA desaturase FAT-7, an oxygen consuming, rate-limiting enzyme in fatty acid biosynthesis. PQM-1 activity enhances fat accumulation in embryos under hypoxic conditions, thereby increasing survival rates of arrested progeny during hypoxia. Thus, whilepqm-1mutants increase survival of mothers, ultimately this loss is detrimental to progeny survival. Our data support a model in which PQM-1 controls a trade-off between lipid metabolic activity in the mother and her progeny to promote the survival of the species under hypoxic conditions.
Nascent transcript analysis of glucocorticoid crosstalk with TNF defines primary and cooperative inflammatory repression
Authors: Sasse Sarah K. , Gruca Margaret , Allen Mary A. , Kadiyala Vineela , Song Tengyao , Gally Fabienne , Gupta Arnav , Pufall Miles A. , Dowell Robin D. , Gerber Anthony N.
Published: September 2019

The glucocorticoid receptor (NR3C1, also known as GR) binds to specific DNA sequences and directly induces transcription of anti-inflammatory genes that contribute to cytokine repression, frequently in cooperation with NF-kB. Whether inflammatory repression also occurs through local interactions between GR and inflammatory gene regulatory elements has been controversial. Here, using global run-on sequencing (GRO-seq) in human airway epithelial cells, we show that glucocorticoid signaling represses transcription within 10 min. Many repressed regulatory regions reside within “hyper-ChIPable” genomic regions that are subject to dynamic, yet nonspecific, interactions with some antibodies. When this artifact was accounted for, we determined that transcriptional repression does not require local GR occupancy. Instead, widespread transcriptional induction through canonical GR binding sites is associated with reciprocal repression of distal TNF-regulated enhancers through a chromatin-dependent process, as evidenced by chromatin accessibility and motif displacement analysis. Simultaneously, transcriptional induction of key anti-inflammatory effectors is decoupled from primary repression through cooperation between GR and NF-kB at a subset of regulatory regions. Thus, glucocorticoids exert bimodal restraints on inflammation characterized by rapid primary transcriptional repression without local GR occupancy and secondary anti-inflammatory effects resulting from transcriptional cooperation between GR and NF-kB.
Temperature thresholds for black mangrove (Avicennia germinans) freeze damage, mortality and recovery in North America: Refining tipping points for range expansion in a warming climate
Authors: Osland Michael J. , Day Richard H. , Hall Courtney T. , Feher Laura C. , Armitage Anna R. , Cebrian Just , Dunton Kenneth H. , Hughes A. Randall , Kaplan David A. , Langston Amy K. , Macy Aaron , Weaver Carolyn A. , Anderson Gordon H. , Cummins Karen , Feller Ilka C. , Snyder Caitlin M.
Published: September 2019

Near the tropical‐temperate transition zone, warming winter temperatures are expected to facilitate the poleward range expansion of freeze‐sensitive tropical organisms. In coastal wetlands of eastern and central North America, freeze‐sensitive woody plants (mangroves) are expected to expand northward into regions currently dominated by freeze‐tolerant herbaceous salt marsh plants. To advance understanding of mangrove range expansion, there is a need to refine temperature thresholds for mangrove freeze damage, mortality and recovery.

We integrated data from 38 sites spread across the mangrove range edge in the Gulf of Mexico and Atlantic coasts of North America, including data from a regional collaborative network – the Mangrove Migration Network. In 2018, an extreme freeze event affected 60% of these sites, with minimum temperatures ranging from 0 to −7°C.

We used temperature and vegetation data from before and after the freeze to quantify temperature thresholds for leaf damage, mortality and biomass recovery of the black mangrove (Avicennia germinans) – the most freeze‐tolerant mangrove species in North America.

For A. germinans individuals near their northern range limit, our results indicate that temperature thresholds for leaf damage are close to −4°C, but temperature thresholds for mortality are closer to −7°C. Thresholds are expected to be warmer for more southern A. germinans individuals and for the other two common mangrove species in the region (Laguncularia racemosa and Rhizophora mangle). Regenerative buds allowed A. germinans to resprout and recover quickly from above‐ground freeze damage. Hence, biomass recovery levels during the first post‐freeze growing season were 90%, 78%, 62% and 45% for temperatures of −4, −5, −6 and −7°C, respectively. Due to a combination of vigorous resprouting and new recruitment from propagules, we expect full recovery at most sites within 1–3 years, assuming no further freeze events.

Synthesis. To improve predictions of tropical range expansion in response to climate change, there is a need to better understand tropical species’ responses to winter temperature extremes. Collectively, our results refine temperature thresholds for A. germinans freeze damage, mortality and recovery, which can improve predictions of mangrove range expansion and coastal wetland ecological transformations in a warming climate.
Pyrroloquinoline quinone delays inflammaging induced by TNF‐α through the p16/p21 and Jagged1 signalling pathways
Authors: Hao Jingjing , Ni Xiushi , Giunta Sergio , Wu Junzhen , Shuang Xiaoping , Xu Kangqiao , Li Rui , Zhang Wei , Xia Shijin
Published: September 2019

Previous studies on the longevity effect of pyrroloquinoline quinine (PQQ) on nematode worms have revealed that PQQ can enhance the antioxidant capacity of nematode worms, thus extending the lifespan of the worms. The induction and development of cellular senescence are closely connected with inflammatory reactions. The aim of this study was to determine the effect of PQQ and ageing factors on senescent cells. To this end, we cultivated human embryonic lung fibroblasts in nutrient solution with or without tumour necrosis factor‐alpha (TNF‐α) to establish an inflammaging model in vitro. The cells were preincubated with or without PQQ to determine if PQQ had any anti‐inflammaging effect. More senescent cells were detected with the addition of TNF‐α than without (P < .01). The ratio of senescent cells to non‐senescent cells in the TNF‐α group was greater than that in the control group (P < .01). When cells were preincubated with PQQ prior to TNF‐α treatment, there were fewer senescent cells than those in the control group, which was not pretreated with PQQ (P < .05). The same tendency was noted with regard to p21, p16, and Jagged1. In summary, we used TNF‐α, a well‐known pro‐inflammatory cytokine associated with inflammaging, to establish an in vitro inflammaging model and provided evidence that PQQ delays TNF‐α –induced cellular senescence and has anti‐inflammaging properties.
Foreclosure Externalities and Home Liquidity
Authors: Bian Xun , Brastow Raymond , Waller Bennie , Wentland Scott
Published: September 2019

We study the external impact of foreclosures, exploring how foreclosed properties affect the liquidity of nearby homes. Empirically, we find a foreclosure increases a nearby home's time‐on‐market by approximately 30% on average, which is primarily driven by a disamenity effect. There is evidence that this delay comes from surprises or information shocks to nearby sellers, as foreclosures that come on and/or leave the market after a nearby home's listing date have the largest adverse liquidity effects. However, when there is no surprise and a nearby foreclosure remains through the entire marketing period, sellers discount list prices more steeply, effectively counteracting these liquidity effects. The results suggest that information, pricing and expectations play key roles in how this externality is absorbed by the real estate market.
Systematic optimization for production of the anti‐MRSA antibiotics WAP‐8294A in an engineered strain of Lysobacter enzymogenes
Authors: Chen Xusheng , Li Shanren , Yu Lingjun , Miller Amanda , Du Liangcheng
Published: September 2019

WAP‐8294A is a group of cyclic lipodepsipeptides and considered as the first‐in‐class new chemical entity with potent activity against methicillin‐resistant Staphylococcus aureus. One of the roadblocks in developing the WAP‐8294A antibiotics is the very low yield in Lysobacter. Here, we carried out a systematic investigation of the nutritional and environmental conditions in an engineered L. enzymogenes strain for the optimal production of WAP‐8294A. We developed an activity‐based simple method for quick screening of various factors, which enabled us to optimize the culture conditions. With the method, we were able to improve the WAP‐8294A yield by 10‐fold in small‐scale cultures and approximately 15‐fold in scale‐up fermentation. Additionally, we found the ratio of WAP‐8294A2 to WAP‐8294A1 in the strains could be manipulated through medium optimization. The development of a practical method for yield improvement in Lysobacter will facilitate the ongoing basic research and clinical studies to develop WAP‐8294A into true therapeutics.
Migrant status and identification as ultra‐high risk for psychosis and transitioning to a psychotic disorder
Authors: Geros H. , Sizer H. , Mifsud N. , Reynolds S. , Kim D. J. , Eaton S. , McGorry P. , Nelson B. , O’Donoghue B.
Published: September 2019

Background

Certain migrant groups are more likely to develop a psychotic disorder compared to the native‐born populations, and a younger age at migration is associated with greater risk. However, it is not known at which stage migration has an effect on the development of psychotic disorders. We examined whether migrants were more likely to be identified as ultra‐high risk for psychosis (UHR) compared to native‐born young people and whether migrant status was associated with the risk of transition to a full‐threshold psychotic disorder.

Methods

The cohort included all young people aged 15–24 who were identified as UHR at a specialist clinic over a five‐year period (2012–16). Australian census data were used to obtain the at‐risk population. Poisson regression was used to calculate rate ratios and Cox regression analysis determined hazard ratios.

Results

467 young people were identified as UHR, of which 13.5% (n = 63) were born overseas. First‐generation migrants were 2.6‐fold less likely to be identified as UHR compared to Australian‐born young people (IRR = 0.39, 95% CI [0.30, 0.51], P < 0.001). There was no difference between migrant and native‐born young people in their risk of transitioning to a psychotic disorder (HR = 0.90, 95% CI [0.39, 2.08], P = 0.81).

Conclusions

UHR first‐generation migrants may be under‐accessing mental health services.
Energetics suggest cause for even further conservation concern for Temminck’s ground pangolin
Authors: Boyles J. G. , Swart J. M. , Bennett N. C. , Ferguson W. , Speakman J. R. , Scantlebury D. M.
Published: September 2019

Conservation of rare and declining species requires reliable information about life‐history traits and population growth characteristics. Unfortunately, long‐term studies necessary to obtain such data are often difficult or impossible for species of concern. In such cases, data that can be collected during limited capture events can serve as valuable proxies. We measured metabolic characteristics of Temminck’s ground pangolin Smutsia temminckii because metabolic traits provide clues about relative gestation length, reproductive output and population growth, all of which were largely unknown for this species. As expected, both basal and field metabolic rates are considerably lower than would be predicted from body mass alone, suggesting pangolins are likely to have slow life histories and low intrinsic population growth. Such characteristics suggest Temminck’s ground pangolins (and likely all pangolins) are less able to persist under heavy poaching and trafficking than other similarly sized mammals and will likely recover slowly even if poaching and trafficking are stopped. While physiological data cannot be used to directly calculate population growth rates, we believe they may provide a tangible data source to inform management decisions for critically endangered, difficult‐to‐study species.
The theory of Rational Addiction
Authors: Rogeberg Ole
Published: September 2019

The Theory of Rational Addictions, by Gary Becker & Kevin Murphy (1988), was a rational choice model that became a standard tool for economists modeling addictive behavior. The approach differs from other theories of addiction by modeling addictive behavior as the gradual implementation of a rational, forward‐looking plan, where consumption at any point in time is partly motivated by the immediate payoff of consumption and partly by the effects this consumption has on the individual in the future. This makes addictive behavior a subset of rational behavior, requiring no more specific government policies or attention than any other consumption choice. Later work by economists extended the theory in different ways, allowing it to match an increasing number of consumption patterns, and searched for ways to test the forward‐looking assumption in different types of market data. While the work was successful as a contribution to rational choice theory, with possible statistical applications, there are several reasons to dismiss its usefulness as an explanation of real‐world addictive behavior and its ability to assess the welfare effects of addictions.
Metabolomics analysis of seminal plasma in patients with idiopathic Oligoasthenoteratozoospermia using high‐resolution NMR spectroscopy
Authors: Mumcu A. , Karaer A. , Dogan B. , Tuncay G.
Published: September 2019

Background

Male infertility is a global health issue caused by a combination of different factors. Specialists generally rely on semen analysis to diagnose male infertility. However, it is known that diagnostic semen analysis fails to identify about 50% of male infertility disorders. Recently, metabolomics has been proven to be a powerful technique for the diagnosis of different diseases.

Objective

To determine whether metabolites could be used as potential biomarkers for the diagnosis of male factor infertility through comparing seminal plasma samples from infertile men with oligoasthenoteratozospermia (OAT) and samples from normozoospermic controls.

Materials and methods

This study utilized high‐resolution 1H NMR spectroscopy to reveal whether the metabolomic changes of seminal plasma obtained from 31 patients with oligoasthenoteratozospermia (OAT) are different from the ones obtained from 28 normozoospermic controls.

Results

Multivariate statistical analysis of NMR data concluded that the metabolomic profile of samples from patients with OAT exhibits statistically significant differences when compared to the controls. The differences were based on the metabolites lactate, citrate, lysine, arginine, valine, glutamine, creatinine, α‐ketoglutaric acid, spermine, putrescine, and tyrosine. Except the tyrosine, levels of the above metabolites were significantly decreased in patients with OAT compared to the controls. The levels of citrate, choline, spermine, putrescine, α‐ketoglutaric acid, valine, and tyrosine were significantly different (p < 5 × 10−4) between two groups. On the other hand, levels of lactate, creatinine, lysine, arginine, and glutamine were also statistically significant (0.001 < p < 0.05). However, considering the p‐values, the physiological relevance of these metabolites may be lower when compared to the others. A PLS‐DA model built on the NMR data achieved 89.29% sensitivity and 93.55% specificity results in a leave‐one‐out cross‐validation process.

Discussion and conclusion

1H NMR spectroscopy‐based metabolomic analysis could be used as a diagnostic tool for the diagnosis of oligoasthenoteratozospermia.
Women undergoing peripartum hysterectomy due to obstetric hemorrhage: A prospective population‐based study
Authors: Maraschini Alice , Lega Ilaria , D'Aloja Paola , Buoncristiano Marta , Dell'Oro Stefania , Donati Serena ,   the Regional Obstetric Surveillance System Working Group
Published: September 2019

Introduction

Peripartum hysterectomy is usually undertaken in cases of life‐threatening obstetric hemorrhage to prevent the death of the mother. Near‐miss events are still under‐researched and inappropriate care continues to be a critical issue, even in countries with advanced obstetric surveillance systems. The aim of the present study was to estimate the prevalence, associated factors, management and intraoperative and postoperative complications of peripartum hysterectomy due to obstetric hemorrhage.

Material and methods

A prospective population‐based study has been conducted in six Italian regions covering 49% of births in Italy. The study population comprised all women aged 11‐59 years undergoing peripartum hysterectomy, from September 2014 to August 2016, due to obstetric hemorrhage within 7 days of delivery. In each maternity unit a trained reference person reported incident cases using electronic data collection forms. The background population comprised all women who delivered in the participating regions during the study period.

Results

The overall peripartum hysterectomy prevalence was 1.09 per 1000 maternities, with a large variability among regions, ranging from 0.52 to 1.60. Previous cesarean section (relative risk [RR] 4.97, 95% CI 4.13‐5.96), assisted reproductive technology (RR 5.99, 95% CI 4.42‐8.11) multiple pregnancy (RR 5.03, 95% CI 3.57‐7.09) and maternal age ≥35 years (RR 2.69, 95% CI 2.25‐3.21) were the main associated factors for hysterectomy. The most common causes of peripartum hysterectomy were uterine atony (45.1%) and abnormally invasive placentation (40.2%). Intensive care unit admission was reported in 49.9% of cases, 16.8% of women suffered severe morbidity and 5 women died.

Conclusions

The rate of peripartum hysterectomy in Italy was three times higher compared with the UK, the Netherlands and the Nordic countries. The wide difference may be associated with women's characteristics, such as age at delivery and previous cesarean section, and with different management options leading to peripartum hysterectomy.
Effect of the expression of CD62P and thrombin generation on patients using central venous catheters for hemodialysis
Authors: Lucas Thabata Coaglio , Carvalho Maria das Graças , Duarte Rita Carolina Figueiredo , Haniel Jonathas , Trindade Sissy Araújo , Ottoni Marcelo Henrique Fernandes , dos Santos Luara Isabela , Brito Alvim de Melo Gustavo Eustáquio , Huebner Rudolf
Published: September 2019

The formation of thrombi in medical devices that come into contact with blood is a common cause of increased morbidity and mortality. Prolonged use of central venous catheters (CVCs) may cause high infection rates or compromise CVC patency due to thrombus development. In this study, we sought insights into possible changes in the hemostatic system during prolonged use of inserted CVCs for hemodialysis by assessing platelets by CD62P and CD41a expression and the potential for thrombin generation (TG). This study included patients with chronic renal failure who were undergoing hemodialysis three times a week using a CVC, and healthy subjects as controls. The participants were distributed into three groups: Group 1: clinically and laboratorially healthy individuals matched by sex and age to the patients (controls); Group II: patients who had completed 1 month of CVC insertion; and Group III: the same patients after they had completed 4 months of CVC insertion. Platelet activation analysis and TG evaluation were performed using blood samples obtained through two different accesses, that is, through a peripheral vein and directly from the CVC lumen. The data showed platelet activation and an increase in the generation of thrombin, particularly after 4 months of CVC use. The results also indicated that insertion of the catheter into the blood stream stimulated the intrinsic rather than the extrinsic pathway. Taken together, the data showed a direct relationship between the use of CVCs in hemodialysis patients and a state of hypercoagulability, most likely associated with endothelial damage and the contact of the medical device with blood components such as platelets and coagulation factors.
A Starling‐like total work controller for rotary blood pumps: An in vitro evaluation
Authors: Wu Eric L. , Stevens Michael C. , Nestler Frank , Pauls Jo P. , Bradley Andrew P. , Tansley Geoff , Fraser John F. , Gregory Shaun D.
Published: September 2019

Due to improved durability and survival rates, rotary blood pumps (RBPs) are the preferred left ventricular assist device when compared to volume displacement pumps. However, when operated at constant speed, RBPs lack a volume balancing mechanism which may result in left ventricular suction and suboptimal ventricular unloading. Starling‐like controllers have previously been developed to balance circulatory volumes; however, they do not consider ventricular workload as a feedback and may have limited sensitivity to adjust RBP workload when ventricular function deteriorates or improves. To address this, we aimed to develop a Starling‐like total work controller (SL‐TWC) that matched the energy output of a healthy heart by adjusting RBP hydraulic work based on measured left ventricular stroke work and ventricular preload. In a mock circulatory loop, the SL‐TWC was evaluated using a HeartWare HVAD in a range of simulated patient conditions. These conditions included changes in systemic hypertension and hypotension, pulmonary hypertension, blood circulatory volume, exercise, and improvement and deterioration of ventricular function by increasing and decreasing ventricular contractility. The SL‐TWC was compared to constant speed control where RBP speed was set to restore cardiac output to 5.0 L/min at rest. Left ventricular suction occurred with constant speed control during pulmonary hypertension but was prevented with the SL‐TWC. During simulated exercise, the SL‐TWC demonstrated reduced LVSW (0.51 J) and greater RBP flow (9.2 L/min) compared to constant speed control (LVSW: 0.74 J and RBP flow: 6.4 L/min). In instances of increased ventricular contractility, the SL‐TWC reduced RBP hydraulic work while maintaining cardiac output similar to the rest condition. In comparison, constant speed overworked and increased cardiac output. The SL‐TWC balanced circulatory volumes by mimicking the Starling mechanism, while also considering changes in ventricular workload. Compared to constant speed control, the SL‐TWC may reduce complications associated with volume imbalances, adapt to changes in ventricular function and improve patient quality of life.
Epidemiology of Kawasaki disease before and after universal Bacille Calmette‐Guérin vaccination program was discontinued
Authors: Pasma Hanna , Honkila Minna , Pokka Tytti , Renko Marjo , Salo Eeva , Tapiainen Terhi
Published: September 2019

Aim

Bacille Calmette‐Guérin (BCG) vaccine (BCG) has been suggested to induce the primary immunity needed for the subsequent Kawasaki disease (KD). We studied the epidemiology of KD before and after the universal BCG vaccination ended in Finland in September 2006.

Methods

Kawasaki disease cases were retrieved from national health registries from 1996 to 2016 for annual incidence rates. We then compared 612 433 children born in the BCG vaccination era, from 1 January 1996 to 30 August 2006, to 604 163 born after BCG era, from 1 September 2006 to 31 December 2016.

Results

The annual incidence rates did not change after the BCG vaccination stopped. We found 370 first visits for KD by children born in the BCG era and 341 after universal BCG vaccination ended. The mean age at diagnosis increased from 2.6 years to 3.0 years (95% CI−0.64 to −0.012, P = .04) and the proportion of children with Kawasaki disease under 5 years decreased from 87% to 81% (95% CI 1%‐12%, P = .02).

Conclusion

Discontinuing the universal BCG vaccination programme did not change the incidence rates of KD. The increased age at diagnosis could suggest that the pathogenesis of KD may be associated with the immunological pathways primed by BCG immunisation.
Hidden sources like saline flushes make a significant contribution to the fluid intake of very low birthweight infants during the first postnatal week
Authors: Mäkelä Pauliina M. , Immeli Lotta , Leskinen Markus , Rinta‐Koski Olli‐Pekka , Sund Reijo , Andersson Sture , Luukkainen Päivi
Published: September 2019

Aim

We examined actual fluid intake, and routes of administration, in very low birthweight (VLBW) infants during the first week of life in a neonatal intensive care unit.

Methods

This retrospective cohort study comprised 953 infants born at <32 weeks and 1500 g and treated at Helsinki University Children's Hospital from 2005 to 2013. All parenterally and enterally administered fluids, and their sources, were obtained from our patient information system. Infants were divided into three groups according to their gestational age: 23‐26, 27‐29 and 30‐31 weeks.

Results

Fluid intake exceeded European guidelines during the first 3 days. On days 1‐7, total fluid intake was highest in the most premature group (P < .001) and the median total fluid intake in this group peaked at 177 mL/kg/d (IQR 154‐209) on day three. Intravascular flushes provided a considerable source of fluids, with the median intake in the most preterm group peaking at 26.4 mL/kg/d, which represented 15.6% of total fluid intake.

Conclusion

During the first 3 days of life, our VLBW infants had a higher total fluid intake than the European guidelines. A considerable percentage came from hidden sources, such as saline flushes, which should be taken into account when prescribing fluids.