bluuebunny/crossref_metadata_2025_split huggingface dataset:
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

AbstractBackgroundThe 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.ResultsWe 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.ConclusionsWe 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

ABSTRACTNuclear 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

ABSTRACTCovalent 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

AbstractTissue-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.SummaryThe 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

AbstractThe 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

AbstractSome 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

ABSTRACTRapid 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.
PQM-1 controls hypoxic survival via regulation of lipid metabolism
Authors: Heimbucher Thomas , Hog Julian , Murphy Coleen T. 
Published: September 2019

AbstractAnimals 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.
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

Abstract

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

AbstractPrevious 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

AbstractWe 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

SummaryWAP‐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

BackgroundCertain 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.MethodsThe 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.Results467 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).ConclusionsUHR first‐generation migrants may be under‐accessing mental health services.