bluuebunny/crossref_metadata_2025 huggingface dataset:
Administration of depot GnRH agonist prior to programmed frozen-thawed embryo transfer does not improve the live birth rate in ovulatory women: A large, multi-center retrospective study
Authors: Wu Hongbo , Wei Fu , Tan Weihong , Dong Mei , Tan Ying , Zhang Xiqian , Song Ge , Liu Liling
Published: October 2022

Despite that gonadotropin-releasing hormone (GnRH) agonist pretreatment has been widely used before programmed frozen-thawed transfer (FET), its impact on live birth rates in ovulatory women remains uncertain. In the present study, we aim to determine if GnRH agonists pretreatment before FET improves live birth rates in women undergoing in vitro fertilization with FET. Programmed FET cycles conducted in four infertility centers were retrospectively collected and reviewed for eligibility from January 2016 and December 2017. Patient’s demographics, ovarian stimulation parameters, and pregnancy outcomes were compared between those given GnRH agonist pretreatment versus no pretreatment in ovulatory women undergoing FET cycles. A total of 6397 programmed cycles were screened for eligibility, of which 5049 cycles were included in the study for analysis. Compared with the group of no GnRH agonist pretreatment (n = 4143), women in the GnRH agonist group (n = 906) were older (33.0 vs 34.0, P < .001), had a higher proportion of subjects with previous transfer attempts and had a higher number of embryos transferred. After controlling for confounders, the logistic regression results showed that GnRH agonist pretreatment did not increase the odds of both clinical pregnancy (OR 0.92, 95% CI [0.70–1.20]), ongoing pregnancy (OR 0.91, 95% CI [0.69–1.19]) and live birth rates (OR 0.84, 95% CI [0.64–1.10]). However, when restricted to women who had no previous transfer attempts, women in the GnRH pretreatment group had lower odds of achieving live birth (OR 0.49, 95% CI [0.30–0.79]). Sensitivity analysis performed in patients with male factor infertility causes showed GnRH agonist pretreated group had lower live birth rates compared to no GnRH agonist pretreatment group (OR = 0.65, 95% CI [0.43–0.97]). Our findings suggested that GnRH agonist pretreatment does not bring additional benefits in live birth rate improvements for ovulatory women undergoing FET cycles. Therefore, the pros of using GnRH agonist to reduce premature ovulation should be weighed against the cons of prolonged time to pregnancy, discomforts resulting from pituitary suppression, and increased medical costs associated with GnRH agonist use.
Efficacy and safety of acupuncture in the treatment of foot drop in post-stroke: A protocol for systematic review and meta-analysis
Authors: Gao Ying , Gang Xiaochao , Yuan Yue , Yin Kai , Gong Xiaoyan
Published: October 2022

Background:

Foot drop is a common complication in post-stroke. Patients with foot drop are at high risk for falls and fall-related injuries. Accordingly, it can reduce independence and quality of life in patients. Clinical studies have confirmed that acupuncture is effective in treating foot drop in post-stroke. However, there is a lack of systematic review exploring the efficacy and safety of acupuncture treatment. This study aims to assess the efficacy and safety of acupuncture in the treatment of foot drop in poststroke from the results of randomized controlled trials.

Methods:

We will search articles in 8 electronic databases including the Cochrane Central Register of Controlled Trials, the Web of Science, PubMed, Embase, the China National Knowledge Infrastructure, the Chinese Biomedical Literature Database, Wanfang Data Database, and the Chinese Scientific Journal Database for RCTs of acupuncture treated foot drop in post-stroke from their inception to 10 August 2022. We will analyze the data meeting the inclusion criteria with the RevMan V.5.4 software. Two authors will assess the quality of the study with the Cochrane collaborative risk bias tool. We will evaluate the certainty of the estimated evidence with the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) method. Data analysis will be performed using STATA 16.0.

Results:

This study will review and evaluate the available evidence for the treatment of foot drop in post-stroke using acupuncture.

Conclusion subsections:

This study will determine the efficacy and safety of acupuncture applied to post-stroke individuals with foot drop.
Importance of eosinophilic infiltration of the colonic mucosa in ulcerative colitis patients who are refractory to maintenance therapy: A prospective, single-center study
Authors: Miyazu Takahiro , Ishida Natsuki , Asai Yusuke , Tamura Satoshi , Tani Shinya , Yamade Mihoko , Hamaya Yasushi , Iwaizumi Moriya , Osawa Satoshi , Furuta Takahisa , Baba Satoshi , Sugimoto Ken
Published: October 2022

Eosinophilic infiltration is sometimes observed histologically in ulcerative colitis (UC), but the effect of the degree of infiltration on the treatment course for UC is not completely understood. We investigated whether short-term steroid administration in UC patients refractory to maintenance therapy, with high eosinophilic infiltration in the colonic mucosa, contributed to the clinical and endoscopic improvement. Ten patients with endoscopically active and pathologically high eosinophilic infiltration, based on pathological examination using endoscopic biopsy, were examined for the clinical background when starting steroid treatment. The clinical and endoscopic improvement before and after steroid use were assessed prospectively. The average initial steroid dosage and duration of use were 21.0 mg and 102.7 days, respectively. The mean values before and after steroid use of the clinical activity index, the Mayo endoscopic subscore, and the UC endoscopic index of severity were 2.4 and 1.0, 1.8 and 0.7, and 3.9 and 1.1, respectively. All scores improved significantly after steroid use (P = .042, P = .002, P = .002, respectively). Steroids were discontinued in all patients; no patients required steroid re-administration. There may be cases of UC with eosinophilic infiltration into the colonic mucosa and resistance to maintenance treatment, suggesting that short-term steroid administration may contribute to clinical and endoscopic improvements.
Use of PDSA Cycles to Increase Aspiration Risk and Swallow Screening Documentation in the Hospitalized General Medical Patient Care Population
Authors: Jaekel Camilla , Becker Denise Peters , Voss Yvonne
Published: October 2022

Background:

Aspiration, while hospitalized, can lead to increases in length of stay and health care costs. Nurses must identify patients at risk of aspiration early to initiate appropriate precautions.

Local Problem:

An increase in-hospital patient aspirations at a Midwestern hospital prompted a review of events, which identified opportunities to improve identification of patients' risk factors and completion of the bedside swallow screening.

Methods:

Interventions were identified via a causal factor tree analysis and an impact-effort grid then deployed using the Plan-Do-Study-Act (PDSA) methodology.

Interventions:

Interventions deployed included game based-learning, a unit-based champion, and the use of visual cues to identify patients at risk for aspiration.

Results:

After 3 PDSA cycles, documentation of patients' aspiration risk factors on admission increased by 40%, with a 51.3% increase in bedside swallow screening results.

Conclusion:

Iterative PDSA cycles successfully tested staff engagement strategies to improve aspiration risk and swallow screening documentation compliance.
Who Are the Local Policy Innovators? Cluster Analysis of Municipal Tobacco Control Policies in Massachusetts
Authors: Feng Wenhui , Lischko Amy , Martin Erika G. , Skeer Margie , Kaplan Anna , Wang Yihua , Stopka Thomas J.
Published: October 2022

Context:

Tobacco use is a leading cause of preventable death, yet it is challenging to establish public policy to reduce tobacco use. Massachusetts has been a national leader in tobacco control, and its policy-making patterns can be informative to the country.

Objective:

To identify factors associated with the adoption of tobacco policy within 351 Massachusetts municipalities.

Design:

We obtained the 2019 Massachusetts municipality-level tobacco control policy information from Massachusetts' Tobacco Automated Fact Sheet Information system and compiled it with data from American Community Survey, Massachusetts Municipal Association, and Massachusetts state government's Web sites. We used k-means clustering method to identify statistical clustering patterns and hotspot analysis (Getis-Ord Gi*) and Local Indicators of Spatial Association to identify geographic clustering patterns. We then performed multinomial logistic regression to identify factors associated with policy clusters.

Setting:

Massachusetts.

Participants:

Three hundred fifty-one municipalities in Massachusetts.

Main Outcome Measure:

Policy clusters—groups of municipalities with similar tobacco control policy behaviors.

Results:

Based on the k-means analyses, we identified 3 clusters in Massachusetts municipal tobacco control policy behaviors: 54% (N = 191) of municipalities were “Policy Leaders” with a high adoption rate of the 6 tobacco control policies; 18% (N = 63) were “Peer-Influenced Actors” focused on tobacco purchase restrictions for individuals younger than 21 years; and 28% (N = 97) were “Policy Non-Actors,” with no tobacco control policies in place. Policy Leaders were geographically clustered in larger cities and the MetroWest region. Policy Non-Actors were clustered in rural areas of Western and Central Massachusetts. Larger municipal population size, higher municipal tax income, and higher percentages of residents voting Democratic were associated with higher policy adoption activities.

Conclusions:

Local variation in the adoption of tobacco policies may exacerbate inequities in tobacco use and population health. Opportunities remain to implement additional tobacco control regulations at the local level to promote public health.
Pregnancy Outcomes Among Perinatally HIV-Infected Women in Spain
Authors: Nogueira López Javier , Prieto-Tato Luis , Escosa-García Luis , Bernardino José I. , Muñoz Eloy , Díez Cristina , Carrasco Itzíar , Ryan Pablo , Guillén-Martín Sara , Ramos-Amador José Tomás , Navarro María Luisa , Holguín Africa , Sainz Talía ,   The CoRISpe Group
Published: October 2022

Background:

An increasing number of women living with perinatally acquired HIV are reaching adulthood and becoming pregnant. Achieving viral suppression is challenging in this population frequently exposed to numerous antiretroviral regimens. This study describes the long-term outcomes of pregnant women living with perinatally acquired HIV in Spain.

Methods:

Descriptive, retrospective, multicenter study of the women living with perinatally acquired HIV who gave birth between January 2000 and December 2019 in Madrid. Epidemiological, clinical, and HIV-related data were collected from the first delivery to the end of the study period, including antiretroviral therapy, prevention strategies, and outcomes.

Results:

Sixty-three live births in 33 women were included. The mean number of pregnancies per women was 1.9 (range: 1–6). At first delivery, women's median age was 20 years (interquartile range: 18–23), 11 (33.3%) had been previously diagnosed with AIDS and 6 (18%) with mental health disorders. Forty percent became pregnant unsuppressed, whereas 81% achieved viral suppression at delivery. Treatment interruptions were common after delivery, as were losses to follow-up, with no positive effect of pregnancy on retention to care or the immune virological situation. Five women (15%) experienced a new AIDS event, and there were 2 deaths (6%) during follow-up. There was 1 case of mother-to-child transmission in a nonadherent woman in whom preventive measures could not be implemented.

Conclusions:

Pregnancy in this unique population of women living with perinatally acquired HIV poses particular challenges. Specific strategies, including a multidisciplinary approach, are needed to minimize perinatal transmission risks and improve outcomes during the postpartum period.
Impact of COVID-19 on HIV Testing Among AIDS Institute–Funded Providers in New York State–A Time Series Analysis
Authors: O'Grady Thomas J. , Yuan Yingchao , Harris Julie M. , Massaroni Ronald J. , Fuller John A. , Tesoriero James M.
Published: October 2022

Background:

New York State (NYS) was at the intersection of the HIV epidemic and coronavirus disease 2019 (COVID-19) pandemic leading to a disruption in HIV-preventive services. This study sought to determine the impact of the COVID-19 pandemic and mitigation efforts on HIV-testing trends in NYS among AIDS Institute (AI)-funded providers.

Methods:

We analyzed weekly testing data from the AI Reporting System from January 1, 2017, to June 27, 2021, to fit an interrupted time series model that predicted the expected number of HIV tests among AI-funded providers in NYS had the COVID-19 pandemic not occurred. The actual observed numbers of HIV testing that occurred from weeks beginning March 15, 2020, to June 30, 2021, were compared with the number of HIV tests predicted by the model.

Results:

In the absence of the COVID-19 pandemic, our model predicted that there would have been 45,605 HIV tests among AI-funded providers between the weeks beginning March 15, 2020, to June 27, 2021. We observed 20,742 HIV tests, representing a 54.5% reduction. We observed percent decreases of greater than 50% for HIV testing among AI-funded providers for New York City (52.9%) and rest of state (59.8%) regions, male (50.6%) and female (66.8%) genders, as well as Black (59.2%), Hispanic (52.8%), mixed race (57.5%), other (50.3%), and White (50.1%) race and ethnicities.

Conclusion:

HIV testing among AI-funded providers in NYS has declined substantially following the COVID-19 pandemic, reflecting decreased access to, and/or demand for, testing among persons at elevated risk for HIV. Initiatives to increase HIV testing and maintain access to HIV prevention services need to be explored following COVID-19.
Fin whale singalong: evidence of song conformity
Authors: Romagosa Miriam , Nieukirk Sharon , Cascão Irma , Marques Tiago A. , Dziak Robert , Royer Jean-Yves , O’Brien Joanne , Mellinger David K. , Pereira Andreia , Ugalde Arantza , Papale Elena , Aniceto Sofia , Buscaino Giuseppa , Rasmussen Marianne , Matias Luis , Prieto Rui , Silva Mónica A.
Published: October 2022

Mechanisms driving song learning and conformity are still poorly known yet fundamental to understand the behavioural ecology of animals. Broadening the taxonomic range of these studies and interpreting song variation under the scope of cultural evolution will increase our knowledge on vocal learning strategies. Here, we analysed changes in fin whale (Balaenoptera physalus) songs recorded over two decades across the Central and Northeast Atlantic Ocean. We found a rapid (over 4 years) replacement of fin whale song types (different inter-note intervals - INIs) that co-existed with hybrid songs during the transition period and showed a clear geographic pattern. We also revealed gradual changes in INIs and note frequencies over more than a decade with all males adopting both rapid and gradual changes. These results provide evidence of vocal learning of rhythm in fin whale songs and conformity in both song rhythm and note frequencies.
Multidisciplinary approach to the study of artworks: environmental conditions, color palette, microbial colonization and nannofossils inLas Musaspainting
Authors: Calderón-Mesén P. , Jaikel-Víquez D. , Barrantes-Madrigal M.D. , Sánchez-Solís J. , Mena-Vega J. , Arguedas-Molina J. , Ureña-Alvarado K. , Maynard-Hernández G. , Santamaría-Montero L. , Cob-Delgado M. , Angulo-Pardo E. , Vallejo Felipe , Sandoval-Gutiérez M. , Durán-Quesada A. M. , Redondo-Solano M. , Herrera-Sancho O.A.
Published: October 2022

Over time, cultural heritage has become a key for comprehending and developing our society at an individual and group level, as it provides fundamental information about our origins, specific temporary space, materials’ availability using current technology, artist’s intention, and site weather conditions. Here, we investigated the physical characteristics of an Italian large-format artwork diptych, located on the ceiling of the National Theater of Costa Rica, to evaluate its pictorial palette as well as the tropical climatological conditions and the fungal aerial spore concentration. We characterized the role of two innovative software tools, as they have direct connection with an effective microbiological sampling and description of secrets encompassed in each pictorial layer during the process of creation and intention. We further found that eight genera of calcareous nannofossils could be associated with the optical properties of the artwork and the effects that the artist wanted to portray through his creative process.
Escaping antibody responses to bacteriolytic enzymes Pal and Cpl-1 by epitope scanning and engineering
Authors: Harhala Marek , Gembara Katarzyna , Rybicka Izabela , Kaźmierczak Zuzanna , Miernikiewicz Paulina , Majewska Joanna , Budziar Wiktoria , Nasulewicz-Goldeman Anna , Nelson Daniel C. , Owczarek Barbara , Dąbrowska Krystyna
Published: October 2022

Bacteriolytic enzymes are promising antibacterial agents, but they can cause a typical immune responsein vivo. In this study, we used a targeted modification of two antibacterial endolysins, Pal and Cpl-1. We identified the key immunogenic amino-acids, and designed and tested new, bacteriolytic variants with altered immunogenicity. One new variant of Pal (257-259 MKS → TFG) demonstrated decreased immunogenicity while a similar mutant (257-259 MKS → TFK) demonstrated increased immunogenicity. A third variant (280-282 DKP → GGA) demonstrated significantly increased antibacterial activity and it was not cross-neutralized by antibodies induced by the wild-type enzyme. We propose this variant as a new engineered endolysin with increased antibacterial activity that is capable of escaping cross-neutralization by antibodies induced by wild-type Pal. We show that efficient antibacterial enzymes that avoid cross-neutralization by IgG can be developed by epitope scanning,in silicomodelling, and substitutions of identified key amino acids with a high rate of success. Importantly, this universal approach can be applied to many proteins beyond endolysins and has the potential for design of numerous biological drugs.
Intestinal myofibroblasts regulate intestinal epithelial cell plasticity via YAP/TAZ
Authors: Pastuła Agnieszka , Janssen Klaus-Peter , Steiger Katja , Slotta-Huspenina Julia , Friedman Richard A. , Hauck Stefanie M. , Ruiz-Fernandez Mauricio J. A. , Fottner Maximilian , Borgmann Martin , Ehmer Ursula , Schmid Roland M. , Wang Timothy C. , Quante Michael
Published: October 2022

Intestinal stromal cells play a key role as the crypt niche cells during epithelial homeostasis and tumor initiation. However, the underlying cellular and molecular mechanisms remain unclear. We developed various types of three-dimensional (3D) tissue culture models to culture small intestinal myofibroblasts (SI MFs) together with enteroids. SI MFs significantly enhanced self-renewal, lumen formation and survival of enteroids, that was mediated via a paracrine mechanism in a Wnt-independent manner. Such co-cultured enteroids resembled SI organoids derived from Apc+/1638N tumors. Microarray analysis showed upregulation of genes associated with YAP signaling in enteroids co-cultured with SI MFs, which was confirmed by protein quantification by mass spectrometry and could be correlated with findings from human colorectal tumor specimens. Mass spectrometric analysis of conditioned media and inhibitor studies pointed to a role for TGF-β in the SI MF-SI epithelium cross-talk. Altogether, utilizing different 3D stroma-epithelium co-culture models, we demonstrate here that SI MFs have the potential to induce a tumor-like phenotype in the intestinal crypts via a paracrine mechanism, that involves YAP and TGF-β, but not canonical Wnt signaling.
2D-QSAR and Molecular Docking based virtual screening of the herbal molecules against Alzheimer’s Disorder: An approach to predict CNS activity
Authors: Thakur Aman , Parashar Arun , Sharma Vivek , Kumar Ajay , Mehta Vineet
Published: October 2022

Acetylcholinesterase (AChE) is one of the key enzyme targets that have been used clinically for the management of Alzheimer’s Disorder (AD). Numerous reports in the literature predict and demonstratein-vitro, andin-silicoanticholinergic activity of synthetic and herbal molecules, however, the majority of them failed to reproduce the results in preclinical or clinical settings. To address these issues, we developed a 2D-QSAR model that could not only efficiently predict the AChE inhibitory activity of herbal molecules but also predicted their potential to cross BBB to exert their beneficial effects during AD. Applying this model, virtual screening of the herbal molecules was performed and amentoflavone, asiaticoside, astaxanthin, bahouside, biapigenin, glycyrrhizin, hyperforin, hypericin, and tocopherol were predicted as the most promising herbal molecules for inhibiting AChE. Results were validated through molecular docking studies against human AChE (PDB ID: 4EY7). To determine whether or not these molecules can cross BBB to inhibit AChE within the CNS for being beneficial for the management of AD, we determined a CNS PPO score, which was found in the range of 1 to 3.76. Overall, the best results were observed for amentoflavone and our results demonstrated a PIC50value of 7.377 nM, molecular docking score of −11.5 kcal/mol, and CNS MPO score of 3.76. In conclusion, we successfully developed a reliable and efficient 2D-QSAR model and predicted amentoflavone to be the most promising molecule that could inhibit human AChE enzyme within the CNS and could prove beneficial for the management of AD.
Genealogical inference and more flexible sequence clustering using iterative PopPUNK
Authors: Zhao Bin , Lees John A. , Wu Hongjin , Yang Chao , Falush Daniel
Published: October 2022

Bacterial genome data are accumulating at an unprecedented speed due the routine use of sequencing in clinical diagnoses, public health surveillance and population genetics studies. Genealogical reconstruction is fundamental to many of these uses, however, inferring genealogy from large-scale genome datasets quickly, accurately, and flexibly is still a challenge. Here, we extend an alignment- and annotation-free method, PopPUNK, to increase its flexibility and interpretability across datasets. Our method, iterative-PopPUNK, rapidly produces multiple consistent cluster assignments across a range of sequence identities. By constructing a partially resolved genealogical tree with respect to these clusters, users can select a resolution most appropriate for their needs. We demonstrated the accuracy of clusters at all levels of similarity and genealogical inference of iterative-PopPUNK based on simulated data and obtained phylogenetically-concordant results in real datasets from seven bacterial species. Using two example sets ofEscherichia/Shigellagenomes andVibrio parahaemolyticusgenomes we show that iterative-PopPUNK can achieve cluster resolutions ranging from phylogroup down to sequence typing (ST). The iterative-PopPUNK algorithm is implemented in the ‘PopPUNK_iterate’ program, available as part of PopPUNK package.
Identifying Regulation with Adversarial Surrogates
Authors: Teichner Ron , Shomar Aseel , Barak O. , Brenner N. , Marom S. , Meir R. , Eytan D.
Published: October 2022

Homeostasis, the ability to maintain a relatively constant internal environment in the face of perturbations, is a hallmark of biological systems. It is believed that this constancy is achieved through multiple internal regulation and control processes. Given observations of a system, or even a detailed model of one, it is both valuable and extremely challenging to extract the control objectives of the homeostatic mechanisms. In this work, we develop a robust data-driven method to identify these objectives, namely to understand: “what does the system care about?”. We propose an algorithm, Identifying Regulation with Adversarial Surrogates (IRAS), that receives an array of temporal measurements of the system, and outputs a candidate for the control objective, expressed as a combination of observed variables. IRAS is an iterative algorithm consisting of two competing players. The first player, realized by an artificial deep neural network, aims to minimize a measure of invariance we refer to as the coefficient of regulation. The second player aims to render the task of the first player more difficult by forcing it to extract information about the temporal structure of the data, which is absent from similar ‘surrogate’ data. We test the algorithm on two synthetic and one natural data set, demonstrating excellent empirical results. Interestingly, our approach can also be used to extract conserved quantities, e.g., energy and momentum, in purely physical systems, as we demonstrate empirically.
GABA decrease is associated with degraded neural specificity in the visual cortex of glaucoma patients
Authors: Bang Ji Won , Parra Carlos , Yu Kevin , Wollstein Gadi , Schuman Joel S. , Chan Kevin C.
Published: October 2022

Glaucoma is an age-related neurodegenerative disease of the visual system, affecting both the eye and the brain. Yet its underlying metabolic mechanisms and neurobehavioral relevance remain largely unclear. Here, using proton magnetic resonance spectroscopy and functional magnetic resonance imaging, we investigated the GABAergic and glutamatergic systems in the visual cortex of glaucoma patients, as well as neural specificity, which is shaped by GABA and glutamate signals and underlies efficient sensory and cognitive functions. Our study showed that among the older adults, both GABA and glutamate levels decrease with increasing glaucoma severity regardless of age. Further, the reduction of GABA but not glutamate predicted the neural specificity. This association was independent of the impairments on the retina structure and age. Our results suggest that glaucoma-specific decline of GABA undermines neural specificity in the visual cortex and that targeting GABA could improve the neural specificity in glaucoma.
A cell size threshold triggers commitment to stomatal fate inArabidopsis
Authors: Gong Yan , Dale Renee , Fung Hannah F. , Amador Gabriel O. , Smit Margot E. , Bergmann Dominique C.
Published: October 2022

How flexible developmental programs integrate information from internal and external factors to modulate stem cell behavior is a fundamental question in developmental biology. Cells of theArabidopsisstomatal lineage modify the balance of stem cell proliferation and differentiation to adjust the size and cell type composition of mature leaves. Here, we report that meristemoids, one type of stomatal lineage stem cell, trigger the transition from asymmetric self-renewing divisions to commitment and terminal differentiation by crossing a critical cell size threshold. Through computational simulation, we demonstrate that this cell size-mediated transition allows robust, yet flexible termination of stem cell proliferation and we observe adjustments in the number of divisions before the differentiation threshold under several genetic manipulations. We experimentally evaluate several mechanisms for cell size sensing, and our data suggest that cell size is sensed via a chromatin ruler acting in the nucleus.
ASCL1 interacts with the mSWI/SNF at distal regulatory elements to regulate neural differentiation
Authors: Păun Oana , Tan Yu Xuan , Patel Harshil , Strohbuecker Stephanie , Ghanate Avinash , Cobolli-Gigli Clementina , Sopena Miriam Llorian , Gerontogianni Lina , Goldstone Robert , Ang Siew-Lan , Guillemot François , Dias Cristina
Published: October 2022

Abstract

Pioneer transcription factors are thought to play pivotal roles in developmental processes by binding nucleosomal DNA to activate gene expression. The role of neurogenic pioneer factor ASCL1 in shaping chromatin landscape in human neurogenesis remains unclear. Here we show that ASCL1 acts as a pioneer transcription factor in a transient population of progenitors. Using anin vitroASCL1 knockout model we show it drives progenitor differentiation by cis-regulation both as a classical pioneer factor and as a non-pioneer remodeler, where ASCL1 binds permissive chromatin to induce chromatin conformation changes. We find ASCL1 directly interacts with mammalian BAF SWI/SNF chromatin remodeling complexes, essential for neurogenesis and involved in multiple neurodevelopmental disorders. ASCL1 acts as a non-pioneer chromatin remodeler to regulate gene expression at a subset of loci, requiring mBAF SWI/SNF’s ATPase activity for cis-regulation of gene expression. Our findings demonstrate that ASCL1 is a key chromatin remodeler in human neurogenesis, uncovering an alternative mechanism of remodeling function dependent on partner ATPase activity.
Single-cell DNA methylation sequencing by combinatorial indexing and enzymatic DNA methylation conversion
Authors: Chatterton Zac , Lamichhane Praves , Rastegar Diba Ahmadi , Fitzpatrick Lauren , Lebhar Hélène , Marquis Christopher , Halliday Glenda , Kwok John B
Published: October 2022

DNA methylation is a critical molecular mark involved in cellular differentiation and cell-specific processes. Single-cell whole genome DNA methylation profiling methods hold great potential to resolve the DNA methylation profiles of individual cell-types. Here we present a method that couples single-cell combinatorial indexing (sci) with enzymatic conversion (sciEM) of unmethylated cytosines. The method facilitates single-base resolution DNA methylation profiling of single-cells that is highly correlated with single-cell bisulfite-based workflows (r2>0.99) whilst improving sequencing alignment rates, reducing adapter contamination and over-estimation of DNA methylation levels (CpG and non-CpG). As proof-of-concept we perform sciEM analysis of the temporal lobe, motor cortex, hippocampus and cerebellum of the human brain to resolve single-cell DNA methylation of all major cell-types.
Differences in activity and stability drive transposable element variation in tropical and temperate maize
Authors: Ou Shujun , Collins Tyler , Qiu Yinjie , Seetharam Arun S. , Menard Claire C. , Manchanda Nancy , Gent Jonathan I. , Schatz Michael C. , Anderson Sarah N. , Hufford Matthew B. , Hirsch Candice N.
Published: October 2022

Much of the profound interspecific variation in genome content has been attributed to transposable elements (TEs). To explore the extent of TE variation within species, we developed an optimized open-source algorithm, panEDTA, tode novoannotate TEs in a pan-genome context. We then generated a unified TE annotation for a maize pan-genome derived from 26 reference-quality genomes, which revealed an excess of 35.1 Mb of TE sequences per genome in tropical maize relative to temperate maize. A small number (n = 216) of TE families, mainly LTR retrotransposons, drive these differences. Evidence from the methylome, transcriptome, LTR age distribution, and LTR insertional polymorphisms revealed that 64.7% of the variability was contributed by LTR families that were young, less methylated, and more expressed in tropical maize, while 18.5% was driven by LTR families with removal or loss in temperate maize. This study demonstrates the use of a comprehensive pan-TE annotation to reveal the driving role of TEs in within-species genomic variation via their ongoing amplification and purging.
Geographically Weighted Linear Combination Test for Gene Set Analysis of a Continuous Spatial Phenotype as applied to Intratumor Heterogeneity
Authors: Amini Payam , Hajihosseini Morteza , Pyne Saumyadipta , Dinu Irina
Published: October 2022

Background

The impact of gene-sets on phenotype is not necessarily uniform across different locations of a cancer tissue. This study introduces a computational platform, GWLCT, for combining gene set analysis with spatial data modeling to provide a new statistical test for association of phenotypes and molecular pathways in spatial single-cell RNA-seq data collected from an input tumor sample.

Methods

At each location, the most significant linear combination is found using a geographically weighted shrunken covariance matrix and kernel function. Whether a fixed or adaptive bandwidth is determined based on a cross validation procedure. Our proposed method is compared to the global version of linear combination test (LCT), bulk and random-forest based gene-set enrichment analyses using data created by the Visium Spatial Gene Expression technique on an invasive breast cancer tissue sample, as well as 144 different simulation scenarios.

Results

In an illustrative example, the new geographically weighted linear combination test, GWLCT, identifies the cancer hallmark gene-sets that are significantly associated at each location with the five spatially continuous phenotypic contexts in the tumors defined by different well-known markers of cancer-associated fibroblasts. Scan statistics revealed clustering in the number of significant gene-sets. A spatial heatmap of combined significance over all selected gene-sets is also produced. Extensive simulation studies demonstrate that our proposed approach outperforms other methods in the considered scenarios, especially when the spatial association increases.

Conclusions

Our proposed approach considers the spatial covariance of gene expression to detect the most significant gene-sets affecting a continuous phenotype. It reveals spatially detailed information in tissue space and can thus play a key role in understanding contextual heterogeneity of cancer cells.
Insulin-like growth factor receptor / mTOR signaling elevates global translation to accelerate zebrafish fin regenerative outgrowth
Authors: Lewis Victor M. , Le Bleu Heather K. , Henner Astra L. , Markovic Hannah , Robbins Amy E. , Stewart Scott , Stankunas Kryn
Published: October 2022

Zebrafish robustly regenerate fins, including their characteristic bony ray skeleton. Amputation activates intra-ray fibroblasts and dedifferentiates osteoblasts that migrate under a wound epidermis to establish an organized blastema. Coordinated proliferation and re-differentiation across lineages then sustains progressive outgrowth. We generate a single cell transcriptome dataset to characterize regenerative outgrowth and explore coordinated cell behaviors. We computationally identify sub-classes of fibroblast-lineage cells and describe novel markers of intra- and inter-ray fibroblasts and growth-promoting distal blastema cells. A pseudotemporal trajectory and in vivo photoconvertible lineage tracing indicate distal blastemal mesenchyme generates both re-differentiated intra- and inter-ray fibroblasts. Gene expression profiles across this trajectory suggest elevated protein translation in the blastemal mesenchyme state. O-propargyl-puromycin incorporation and small molecule inhibition identify insulin growth factor receptor (IGFR) / mechanistic target of rapamycin kinase (mTOR)-dependent elevated bulk translation in blastemal mesenchyme and differentiating osteoblasts. We test candidate cooperating differentiation factors identified from the osteoblast trajectory, finding IGFR/mTOR signaling expedites glucocorticoid-promoted osteoblast differentiationin vitro. Concordantly, mTOR inhibition slows but does not prevent fin regenerative outgrowthin vivo. IGFR/mTOR may elevate translation in both fibroblast- and osteoblast-lineage cells during the outgrowth phase as a tempo-coordinating rheostat.
Controlling Neocortical Epileptic Seizures using Forced Temporal Spike-Time Stimulation: AnIn SilicoComputational Study
Authors: Schmalz Joseph , Quinarez Rachel V. , Kothare Mayuresh V. , Kumar Gautam
Published: October 2022

Epileptic seizure is typically characterized by highly synchronized episodes of neural activity. Existing stimulation therapies focus purely on suppressing the pathologically synchronized neuronal firing patterns during the ictal (seizure) period. While these strategies are effective in suppressing seizures when they occur, they fail to prevent the re-emergence of seizures once the stimulation is turned off. Previously, we developed a novel neurostimulation motif, which we refer to as “Forced Temporal Spike-Time Stimulation” (FTSTS) [1] that has shown remarkable promise in long-lasting desynchronization of excessively synchronized neuronal firing patterns by harnessing synaptic plasticity. In this paper, we build upon this prior work [1] by optimizing the parameters of the FTSTS protocol in order to efficiently desynchronize the pathologically synchronous neuronal firing patterns that occur during epileptic seizures using a recently published computational model of neocortical-onset seizures [2]. We show that the FTSTS protocol applied during the ictal period can modify the excitatory-to-inhibitory synaptic weight in order to effectively desynchronize the pathological neuronal firing patterns even after the ictal period. Our investigation opens the door to a possible new neurostimulation therapy for epilepsy.
PRAMEL7/CUL2 axis regulates NuRD stability to establish ground-state pluripotency in embryonic stem cells
Authors: Rupasinghe Meneka , Bersaglieri Cristiana , Leslie Pedrioli Deena M , Pedrioli Patrick G. A. , Hottiger Michael O. , Cinelli Paolo , Santoro Raffaella
Published: October 2022

Pluripotency is established in E4.5 preimplantation epiblast. Embryonic stem cells (ESCs) represent the immortalization of pluripotency, however, they only partially resemble the gene expression signature of developmental ground-state. Induced PRAMEL7 expression, a protein highly expressed in the ICM but lowly expressed in ESCs, reprograms developmentally advanced ESC+serum into ground-state pluripotency by causing DNA hypomethylation and gene expression signature close to developmental ground-state. However, how PRAMEL7 reprograms gene expression remains elusive. Here we show that PRAMEL7 associates with Cullin2 (CUL2) and this interaction is required to establish ground-state gene expression. PRAMEL7 recruits CUL2 to chromatin and targets for proteasomal degradation regulators of repressive chromatin, including NuRD complex. PRAMEL7 antagonizes NuRD-mediated repression of genes implicated in pluripotency by decreasing NuRD stability and promoter association in a CUL2-dependent manner. Our data link proteasome degradation pathways to ground-state gene expression, offering insights to generatein vitromodels to reproduce thein vivoground-state pluripotency.
PTH regulates osteogenesis and suppresses adipogenesis through Zfp 467 in a feed-forward, cyclic AMP-dependent manner
Authors: Liu Hanghang , Wada Akane , Le Isabella , Le Phuong T , Lee Andrew WF , Zhou Jun , Gori Francesca , Baron Roland , Rosen Clifford J.
Published: October 2022

Conditional deletion of the PTH1R in mesenchymal progenitors reduces osteoblast differentiation, enhances marrow adipogenesis and increases zinc finger protein 467 (Zfp467) expression. In contrast, genetic loss ofZfp467increasedPth1rexpression and shifts mesenchymal progenitor cell fate towards osteogenesis and higher bone mass. In this study we hypothesized that PTH1R and ZFP467 could constitute a feedback loop that facilitates PTH-induced osteogenesis and that conditional deletion ofZfp467in osteogenic precursors would lead to high bone mass. We report thatPrrxCre Zfp467but notAdipoCre Zfp467mice exhibit an identical phenotype to theZfp467-/-mice with high bone mass and greater osteogenic differentiation We also found that PTH suppressedZfp467expression primarily via the cyclic AMP/PKA pathway. Not surprisingly, PKA activation inhibited the expression ofZfp467and gene silencing ofPth1rcaused an increase inZfp467mRNA transcription. Dual fluorescence reporter assays and confocal immunofluorescence demonstrated that genetic deletion ofZfp467resulted in higher nuclear translocation of p50 that binds to the P2 promoter of thePth1rand increased its transcription. As expected,Zfp467-/-cells had enhanced production of cyclic AMP and increased glycolysis in response to exogenous PTH. Additionally, the osteogenic response to PTH was also enhanced inZfp467-/-calvarial osteoblasts, and the pro-osteogenic effect ofZfp467deletion was blocked by gene silencing ofPth1ror a PKA inhibitor. In conclusion, our findings suggest that loss or PTH1R-mediated repression ofZfp467results in a pathway that increasesPth1rtranscription via p50 and thus cellular responsiveness to PTH, ultimately leading to enhanced bone formation.
Relative efficiencies of the state universities in Sri Lanka: can they enroll more students?
Authors: Wijesundara W.M.T.H. , Prabodanie R.A. Ranga
Published: October 2022

Purpose

This study aimed to evaluate the relative efficiencies of the state universities in Sri Lanka from 2017 to 2019 and their capacity to enroll more students.

Design/methodology/approach

Data envelopment analysis (DEA) method was used to measure the relative efficiencies. Annual data on expenditure, academic staff, non-academic staff, student enrollments, graduate output and publications in indexed journals were used.

Findings

Results from both input oriented DEA and output oriented DEA showed that seven out of 15 (47%) state universities were constantly performing efficiently from 2017 to 2019. Well-established universities are apparently more efficient than emerging universities. Six universities were constantly inefficient. Excess staff and the deficiencies in enrollments, graduate output and publications were the main causes of the inefficiencies. In particular, the total enrollments can be increased by 23%.

Research limitations/implications

The outcomes are thoroughly based on DEA with a selected set of variables and data. Owing to the limitations in the DEA method, variables and data, the results may not reflect the actual efficiencies of the universities. However, this study indicates that the universities can improve their relative efficiencies by accommodating more students and increasing research output.

Originality/value

This study is the first proper investigation of the relative efficiencies of the state universities in Sri Lanka using DEA. This is also the first quantitative assessment of the capacity of Sri Lankan Universities to increase student enrollments.
Fostering individual behavior through quality of life variables: the role of Islamic work ethics
Authors: Zia Muhammad Qamar , Naveed Muhammad , Fasih Tayyaba , Meero Abdul Rehman
Published: October 2022

Purpose

The increasing ethical misconduct at job place demands to understand the role of ethics in a wide variety of disciplines. This paper aims to empirically investigate the mediating mechanism of life satisfaction and subjective happiness between Islamic work ethics – innovative work behavior (IWB) and organizational citizenship behavior (OCB).

Design/methodology/approach

The sample comprised 296 employees and 58 head of departments (HODs) of top 11 business schools in Pakistan. The data of the study were collected in three waves and from two different sources (faculty members and their HODs) through questionnaire. The statistical technique SEM analysis was applied to inspect the proposed direct and mediating hypotheses.

Findings

Taken together, the findings revealed that Islamic work ethics (IWE) improves quality of life and by following IWE at workplace, employees feel pleasure and show satisfaction from life. The results supported the mediating role of both life satisfaction and subjective happiness between IWE-IWB and IWE-OCB.

Practical implications

This study provides practical insight that Islamic business ethics plays an important role at workplace and improves quality of life and individual behavior.

Originality/value

The current research is unique, as it empirically investigates the mechanism quality of life phenomena which connects IWE and individual behavior (innovative and citizenship). The mechanism quality of life is less studied, and therefore this study fills the gap of scant literature.
Product as a service (PaaS) for traditional product companies: an automotive lease practice evaluation
Authors: Kesavapanikkar Pradeep , Amit R.K. , Ramu Palaniappan
Published: October 2022

Purpose

Product as a service (PaaS) is a method of business innovation for traditional product companies to make their offerings more attractive, move up the value chain and find more customers. However, the customer acceptance of PaaS depends on the market in which it operates. The purpose of this study is to understand, through an automotive lease PaaS evaluation and from an outside-in user perspective, the effects of the main intrinsic and extrinsic factors of a product, its design and brand, on the lease versus buy decision of automobiles by consumers in an emerging market, to help companies transition to a PaaS business model.

Design/methodology/approach

A survey of actual car owners and lease car users was conducted. Confirmatory factor analysis was used to test the measurement model, followed by logistic regression for statistical modeling. As a practice evaluation of an existing PaaS example, this study further explored the expectations and experience of automotive lease users to link practical insights to analytical results and help businesses make a successful transition to PaaS.

Findings

The results of the study showed the effect of the brand as significant in lease versus buy decisions. Brand loyalty is more important when leasing than when buying a car. However, brand awareness/association is less important for leasing than buying. There was no significant difference in consumer expectations of product design in automotive lease PaaS. Customers who buy and lease cars have the same expectations of the overall product in terms of its key design attributes.

Originality/value

The literature on PaaS has mostly focused on strategies, frameworks and guidelines for implementation and empirical studies are limited. Comparative analyses between PaaS and traditional ownership models are also limited. It is unclear how consumers’ expectations differ between PaaS and traditional ownership models, especially in emerging markets, because PaaS’s success depends on the market in which it operates. This study addresses this gap in the literature.