bluuebunny/crossref_metadata_2025_split huggingface dataset:
Inhibiting Spinal Cord-Specific Hsp90 Isoforms Reveals a Novel Strategy to Improve the Therapeutic Index of Opioid Treatment
Authors: Duron David I. , Campbell Christopher S. , Chou Kerry , Tanguturi Parthasaradhireddy , Bejarano Paul , Gabriel Katherin A. , Bowden Jessica L. , Mishra Sanket , Brackett Christopher , Barlow Deborah , Houseknecht Karen L. , Blagg Brian S.J. , Streicher John M. 
Published: April 2021

AbstractOpioid drugs like morphine are the gold standard for the treatment of chronic pain, but are limited by adverse side effects, such as tolerance, constipation, and reward/addiction. In our earlier work, we showed that Heat shock protein 90 (Hsp90) has a crucial role in regulating opioid signaling that differs between brain and spinal cord; Hsp90 inhibition in brain blocks opioid pain relief, while inhibition in the spinal cord enhances it. Building on these findings here, we injected the non-selective Hsp90 inhibitor KU-32 directly into the spinal cord of male and female CD-1 mice, showing that morphine anti-nociceptive potency was boosted by 1.9-3.5 fold in the pain models of tail flick, post-surgical paw incision, and HIV peripheral neuropathy. At the same time, morphine tolerance was reduced from 21 fold to 2.9 fold and established tolerance was rescued, while the potency of constipation and reward (as measured by conditioned place preference) was unchanged. These results demonstrate that spinal Hsp90 inhibition can improve the therapeutic index of morphine. However, we also found that systemic non-selective Hsp90 inhibition resulted in a brain-like effect, blocking opioid pain relief. We thus sought a way to circumvent the effects of brain Hsp90 inhibition by investigating the molecular Hsp90 isoforms active in regulating opioid signaling in both regions. Using selective small molecule inhibitors and CRISPR gene editing, we found that 3 Hsp90 isoforms regulated spinal cord opioid signaling (Hsp90α, Hsp90β, and Grp94) while our previous work showed only Hsp90α was active in brain. We thus hypothesized that a systemically delivered selective inhibitor to Hsp90β or Grp94 could selectively inhibit spinal cord Hsp90 activity, resulting in enhanced opioid pain relief and decreased side effects. We tested this hypothesis using intravenous delivery of KUNB106 (Hsp90β) and KUNG65 (Grp94), showing that both drugs enhanced morphine potency in tail flick and paw incision pain while rescuing anti-nociceptive tolerance. We also found that intravenous KUNA115 (Hsp90α) fully blocked morphine anti-nociception. Together, these results suggest that selective inhibition of spinal cord Hsp90 isoforms is a novel, translationally feasible strategy to improve the therapeutic index of opioids.
Reduced graphene oxide membrane as supporting film for high-resolution cryo-EM
Authors: Liu Nan , Zheng Liming , Xu Jie , Wang Jia , Hu Cuixia , Lan Jun , Zhang Xing , Zhang Jincan , Xu Kui , Cheng Hang , Yang Zi , Gao Xin , Wang Xinquan , Peng Hailin , Chen Yanan , Wang Hong-Wei 
Published: April 2021

AbstractAlthough single-particle cryogenic electron microscopy (cryo-EM) has been applied extensively for elucidating many crucial biological mechanisms at the molecular level, this technique still faces critical challenges, the major one of which is to prepare the high-quality cryo-EM specimen. Aiming to achieve a more reproducible and efficient cryo-EM specimen preparation, novel supporting films including graphene-based two-dimensional materials have been explored in recent years. Here we report a robust and simple method to fabricate EM grids coated with single- or few-layer reduced graphene oxide (RGO) membrane in large batch for high-resolution cryo-EM structural determination. The RGO membrane has decreased interlayer space and enhanced electrical conductivity in comparison to regular graphene oxide (GO) membrane. Moreover, we found that the RGO supporting film exhibited nice particle-absorption ability, thus avoiding the air-water interface problem. More importantly, we found that the RGO supporting film is particularly useful in cryo-EM reconstruction of sub-100 kDa biomolecules at near-atomic resolution, as exemplified by the study of RBD-ACE2 complex and other small protein molecules. We envision that the RGO membranes can be used as a robust graphene-based supporting film in cryo-EM specimen preparation.
Generation of guard cell RNA-seq transcriptomes during progressive drought and recovery using an adapted INTACT protocol forArabidopsis thalianashoot tissue
Authors: van Weringh Anna , Pasha Asher , Esteban Eddi , Gamueda Paul J. , Provart Nicholas J. 
Published: April 2021

AbstractDrought is an important environmental stress that limits crop production. Guard cells (GC) act to control the rate of water loss. To better understand how GCs change their gene expression during a progressive drought we generated guard cell-specific RNA-seq transcriptomes during mild, moderate, and severe drought stress. We additionally sampled re-watered plants that had experienced severe drought stress. These transcriptomes were generated using the INTACT system to capture the RNA from GC nuclei. We optimized the INTACT protocol forArabidopsis thalianaleaf tissue, incorporating fixation to preserve RNA during nuclear isolation. To be able to identify gene expression changes unique to GCs, we additionally generated transcriptomes from all cell types, using a 35S viral promoter to capture the nuclei of all cell types in leaves. These data sets highlight shared and unique gene expression changes between GCs and the bulk leaf tissue. The timing of gene expression changes is different between GCs and other cell types: we found that only GCs had detectable gene expression changes at the earliest drought time point. The drought responsive GC and leaf RNA-seq transcriptomes are available in the Arabidopsis ePlant at the Bio-Analytic Resource for Plant Biology website.
Phosphorylation of phosphoglucomutase 1 on a peripheral site tunes its activity to regulate glycogen metabolism
Authors: Doello Sofía , Neumann Niels , Forchhammer Karl 
Published: April 2021

AbstractRegulation of glycogen metabolism is of vital importance in organisms of all three kingdoms of life. Although the pathways involved in glycogen synthesis and degradation are well known, many regulatory aspects around the metabolism of this polysaccharide remain undeciphered. Here, we used the unicellular cyanobacteriumSynechocystisas a model to investigate how glycogen metabolism is regulated in nitrogen-starved dormant cells, which entirely rely on glycogen catabolism to resume growth upon nitrogen repletion. We identified phosphoglucomutase 1 (PGM1) as a key regulatory point in glycogen metabolism, and post-translational modification as an essential mechanism for controlling its activity. We could show that PGM1 is phosphorylated at a peripheral residue (Ser 47) during nitrogen starvation, which inhibits its activity. Inactivation of PGM1 by phosphorylation at Ser 47 prevents premature degradation of the glycogen stores and appears to be essential for survival ofSynechocystisin the dormant state. Remarkably, this regulatory mechanism seems to be evolutionary conserved in PGM1 enzymes, from bacteria to humans.Significance statementIn this study, we identified phosphoglucomutase 1 (PGM1) as a central metabolic valve that regulates the utilization of the glycogen reserves. We showed that post-translational modification of PGM1 via phosphorylation at a peripheral residue is a key, evolutionary-conserved regulatory mechanism that controls PGM1 activity and the mobilization of the glycogen stores.
Deep mutational scanning of the plasminogen activator inhibitor-1 functional landscape
Authors: Huttinger Zachary M. , Haynes Laura M. , Yee Andrew , Kretz Colin A. , Siemieniak David R. , Lawrence Daniel A. , Ginsburg David 
Published: April 2021

ABSTRACTThe serine protease inhibitor (SERPIN) plasminogen activator inhibitor-1 (PAI-1) is a key regulator of the fibrinolytic system, inhibiting the serine proteases tissue- and urokinase-type plasminogen activator (tPA and uPA, respectively). Missense variants may render PAI-1 non-functional through misfolding, leading to its turnover as a protease substrate, or to a more rapid transition to the latent/inactive state. Deep mutational scanning was performed to evaluate the impact of amino acid sequence variation on PAI-1 inhibition of uPA using an M13 filamentous phage display system. The effects of single amino acid substitutions on PAI-1’s functional inhibition of its canonical target proteases, tPA and uPA, have been determined for only a small fraction of potential mutations. To construct a more comprehensive dataset, a mutagenized PAI-1 library, encompassing ∼70% of potential single amino acid substitutions, was displayed on M13 filamentous phage. From this library, the relative effects of 27% of all possible missense variants on PAI-1 inhibition of urokinase-type plasminogen activator were determined using high-throughput DNA sequencing with 826 missense variants demonstrating conserved inhibitory activity and 1137 resulting in loss of PAI-1 function. Comparison of these deep mutational scanning results to predictions from PolyPhen-2 and SIFT demonstrate the limitations of these algorithms, consistent with similar reports for other proteins. Comparison to common human PAI-1 gene variants present in the gnomAD database is consistent with evolutionary selection against loss of PAI-1 function. These findings provide insight into structure-function relationships for PAI-1 and other members of the SERPIN superfamily.
Kheyti: Product and Business Development at an AgTech Social Enterprise
Authors: Sawhney Mohanbir , Saumya  
Published: April 2021

In early 2017, after launching its successful “Greenhouse-in-a-Box” pilot project in India with fifteen smallholder farmers, Kheyti, a non-profit agricultural technology (AgTech) social enterprise, was struggling with several decisions in developing and growing its business. Kheyti was launched in 2015 to help smallholder farmers battle poverty and income variability by providing affordable technologies bundled with services. Over eighteen months, the team had developed a low-cost and modular greenhouse product to which it added financing, inputs, training, and market linkages to create a comprehensive “full-stack” solution for small farmers. The pilot project was a success in many ways, but Saumya, Kheyti's co-founder and head of product, was concerned that it revealed shortcomings that could severely affect the viability and scalability of Kheyti's solution.
Saumya had some important decisions to make. Should Kheyti redesign the product from scratch, or find other ways to reduce the cost for early adopters? Should it rely on upfront revenues from sales of the greenhouse, or consider developing an innovative financing or contract farming model? Kheyti's dwindling cash reserves meant that these decisions were urgent and critical. The path chosen now would determine whether the startup would move beyond the pilot stage and achieve its vision of serving 1 million farmers by 2025.
CEMEX: Information Technology, an Enabler for Building the Future
Authors: Walker Russell 
Published: April 2021

The case examines the role of IT in CEMEX, a giant Mexican building materials manufacturer in an industry categorized by low margins and high costs. In the early 1990s, CEMEX made significant investments in its IT systems, resulting in a data-based management operation that put it at the forefront of the industry. As the company grew through acquisitions, it integrated IT through “The CEMEX Way,” a set of standardized processes, organizations, and systems implemented on a common IT platform.
In 2007, when CEMEX acquired Rinker, a major Australian concrete company, aligning Rinker with CEMEX IT systems was critical to quickly streamline operations and realize efficiencies. The CIO of CEMEX had developed a new integration process called Processes & IT (P&IT) that he was considering using for the Rinker integration. However, P&IT required additional resources, including significant upfront fixed costs and investment in new personnel teams at a time when the company was already struggling with the integration of another acquisition. CEMEX could either align Rinker to The CEMEX Way or use the opportunity to invest significantly more in evolving to the new P&IT approach that focused on business process management.
Pregnancy outcomes following different protocols of controlled ovarian hyperstimulation in couples undergoing intrauterine insemination
Authors: Taiyeb Ahmed M. , Haji Azheen I. , Ibraheem Zaid O. , Alsakkal Ghada S. 
Published: April 2021

AbstractClomiphene citrate (CC), letrozole and cetrorelix acetate are frequently used agents in controlled ovarian hyperstimulation (COH). However, these three agents have not yet been compared to one another regarding their pregnancy outcomes. The present study was designed to retrospectively compare pregnancy outcomes among the three aforementioned agents. This study involved infertile couples with an infertility duration of at least 2 years, ages 18 to 42 years and who were referred to have their first intrauterine insemination (IUI) treatment cycle. All patients underwent COH with recombinant follicle‐stimulating hormone (rFSH) plus CC (n = 118), letrozole (n = 81), or cetrorelix acetate (n = 62), followed by IUI. Using the one‐way multivariate analysis of covariance to control female patients’ ages, patients stimulated with cetrorelix acetate/rFSH or CC/rFSH had higher numbers of preovulatory follicles than women stimulated with letrozole/rFSH (P < .02), whereas women stimulated with cetrorelix acetate/rFSH had a thicker endometrium than women stimulated with CC/rFSH (P < .0005). Biochemical pregnancy rates were similar among the three protocols of COH. However, women stimulated with letrozole/rFSH showed clinical pregnancy rates higher than those stimulated with CC/rFSH (P = .003) or cetrorelix acetate/rFSH (P = .03) and subclinical abortion rates lower than those stimulated with CC/rFSH or cetrorelix acetate/rFSH (P = .009). Of the different protocols of COH, the odds of having a clinical pregnancy was 3.1 times greater for women stimulated with letrozole/rFSH than women stimulated with CC/rFSH (P = .004) and 2.8 times greater for women stimulated with letrozole/rFSH than women stimulated with cetrorelix acetate/rFSH (P = .03). Our observations show that increased numbers of preovulatory follicles or endometrium thickness do not necessarily improve pregnancy outcomes, because pregnancy outcomes are also subjected to the type of COH used agent. In this regard, letrozole produced fewer preovulatory follicles and did not significantly increase endometrium thickness, but significantly improved pregnancy outcomes in comparison to CC and cetrorelix acetate.
Reassessing the magnitude of housing price declines and the use of leverage in the Depressions of the 1890s and 1930s
Authors: Rose Jonathan D. 
Published: April 2021

AbstractThis paper presents the first repeat sales index for residential housing in any U.S. city spanning the late 19th and early 20th centuries, covering Baltimore from 1880 to 1953. Compared to previous data, the index shows larger declines in housing prices during the Depressions of the 1890s and 1930s. I also find higher leverage entering into those periods than previously understood. I conclude that negative equity in the 1930s was a bigger problem than implied by existing data, rationalizing the extent of foreclosures that occurred.
Dosimetric and clinical outcomes of SpaceOAR in men undergoing external beam radiation therapy for localized prostate cancer: A systematic review
Authors: Babar Mustufa , Katz Alan , Ciatto Michael 
Published: April 2021

AbstractSpaceOAR, an absorbable polyethylene glycol hydrogel, increases the space between the prostate and rectum to reduce the radiation received by the rectum during prostate cancer radiation therapy. The objective of this systematic review was to evaluate controlled studies on the dosimetric and clinical outcomes of SpaceOAR in men undergoing external beam radiation therapy for localized prostate cancer. Eight studies were included in the review. All of the studies showed SpaceOAR to reduce the radiation dose volume to the rectum over numerous dosimetry levels. Of the four studies that assessed toxicity, one reported SpaceOAR to significantly decrease acute Grade 1 diarrhoea and two reported SpaceOAR to significantly decrease late Grade 1 and Grade ≥2 rectal toxicities. Two studies assessed cumulative incidence of toxicity at 3 years in which one reported SpaceOAR to significantly decrease urinary incontinence and Grade ≥1 and Grade ≥2 rectal toxicities, and the other reported SpaceOAR to significantly decrease Grade 1 diarrhoea and Grade 2 proctitis. Moreover, one study reported that fewer SpaceOAR patients experienced 10‐point declines in bowel quality of life at 3 years, but another study reported no significant difference in 10‐point declines in bowel quality of life between the SpaceOAR and control groups at 5 years. With the current research available, SpaceOAR may be beneficial to those who did not meet the standard rectal dose‐volume criteria, have higher risk factors of developing rectal toxicities post‐radiation, or wish to decrease the length and costs of radiotherapy by increasing the dose of radiation per fraction.
Association between deficient levels of circulating vitamin D, dietary intake of vitamin D, calcium and retinol, and risk of colorectal cancer in an Iranian population: A case control study
Authors: Abbasnezhad Amir , Falahi Ebrahim , Ghavamzadeh Saeid , Beiranvand Ramin , Talaiezadeh Abdolhassan , Hasanvand Amin , Angali Kambiz Ahmadi , Choghakhori Razieh 
Published: April 2021

AbstractAimWe aimed to assess the association between deficient levels of circulating vitamin D, dietary intake of vitamin D, calcium and retinol, and risk of colorectal cancer in an Iranian population.MethodsIn this retrospective case‐control study that was conducted between 2012 and 2015, 278 first incident colorectal cancer cases (colon cancer = 103; rectal cancer = 175), and 278 sex and age matched healthy controls (HCs) were recruited. Serum 25(OH)D, dietary vitamin D, and calcium intake were assessed. Logistic regression was used to estimate the odds ratio (OR) between studied factors and colorectal cancer. Estimates of OR were calculated according to both bivariate analyses based on the matching factors and multivariate analyses, with additional adjustment for potential confounders.ResultsA strong inverse linear dose‐response association was seen between serum 25(OH)D and colorectal cancer (P for trend = .002). In comparison to serum 25(OH)D more than 40 nmol/L, lower serum concentrations were significantly associated with an increased OR of colorectal cancer. When analyzing anatomical subsites separately, lower circulating 25(OH)D was associated with higher OR for both colon and rectum cancers. Dietary vitamin D and calcium intake were not associated with colorectal cancer. Interaction analysis between serum 25(OH)D and the amount of calcium intake demonstrated that the lowest level of both factors was associated with an increased OR of colorectal cancer. The highest OR of colorectal cancer that was associated with lowest circulating 25(OH)D was stronger at the highest retinol intakes.ConclusionThis study demonstrated an inverse strong association between 25(OH)D concentration and colorectal cancer in an Iranian population.
Vaginal NOTES surgery in patients with prior hysterectomy: A first case series
Authors: Vanhooren Emma , Baekelandt Jan 
Published: April 2021

AbstractThis is a first feasibility on vaginal natural orifice transluminal endoscopic surgery (vNOTES) in patients with prior hysterectomy. Our aim was to gain initial experience on performing vNOTES surgery on prior hysterectomy cases, whereby the main concern is that pelvic adhesions may impede safe transvaginal access. Between January 2017 and February 2020, a single surgeon (J.B.) performed vNOTES surgery on nine patients with a history of hysterectomy. Conventional laparoscopic instruments were inserted transvaginally through a vNOTES port. No abdominal incisions were made. Patient data and perioperative data were analyzed. Mean operating time was 38 minutes and there were no operative complications. Postoperative pain scores were low. The mean size of the adnexal cysts that were removed was 26 mm. In this study, vNOTES surgery was successfully performed in nine patients with prior hysterectomy. Following the IDEAL principles, it is important to report on our initial findings of this IDEAL stage 1 study. The results warrant further investigation in IDEAL stage 2 studies but do not validate the widespread use of this approach.
Prenatal tobacco and postbirth second‐hand smoke exposure and dental caries in children
Authors: Dearing Bianca A. , Katz Ralph V. , Weitzman Michael 
Published: April 2021

AbstractObjectivesSecond‐hand smoke (SHS) exposure has been identified as a risk factor for several childhood health problems including dental caries. The purpose of this study was to examine the association of postbirth SHS exposure and dental caries and to determine whether the association is independent of prenatal tobacco exposure, sugar consumption and dental utilization.MethodsNHANES 2013‐2014 and 2015‐2016 were used to examine the research question in 1733 children, 4‐11 years old with full primary or mixed dentition and serum cotinine levels below 10 ng/mL. Weighted multivariable logistic regression models were developed to examine the independent association between SHS exposure and the prevalence of (i) any dental caries experience and (ii) any decayed teeth.ResultsChildren exposed to postbirth SHS differed from children not exposed regarding decayed teeth prevalence in the total sample (OR = 1.80, 95% CI: 1.20, 2.71) and mixed dentition (OR = 1.86, 95% CI: 1.20, 2.90) after confounder adjustment. However, no association was found in the primary dentition or between SHS exposure and total caries experience.ConclusionsThe findings partially show that postbirth SHS is associated with dental caries in children. However, the inconsistencies in findings across the three samples and between the two outcome measures, dental caries experience and decayed teeth prevalence raise questions regarding the validity of the hypothesis. Further, the findings suggest that postbirth SHS is likely a marker for true causes of dental caries and the association is likely confounded with other factors associated with dental caries.