bluuebunny/crossref_metadata_2025_split huggingface dataset:
Diversity Matters: A 21-Year Review of Trends in Resident Recruitment into Surgical Specialties
Authors: Mohan Anita T. , Banuelos Joseph , Cespedes-Gomez Omar , Kapoor Trishul , Moran Steven L. , Heller Stephanie F. , Dozois Eric J. , Nelson Heidi , Stulak John M. , Martinez-Jorge Jorys 
Published: October 2021

Background:
Diversity within the healthcare workforce is essential to improve quality of care, although evaluation of diversity within surgical training remains limited. This study analyzed diversity in recruitment of residents into surgical subspecialties at a large academic medical institution and national trends.

Methods:
A 21-year cross-sectional study of medical school graduates accepted into all surgical subspecialty training programs was performed. The institutional cohort was divided into two groups (1997–2006, 2007–2017). Subspecialty acceptance rates were determined between 2011 and 2018. Data on candidate demographics including gender, race, ethnicity, citizenship, and origin of medical education at a single institution and nationally were extracted.

Results:
Two thousand found hundred seventy-two residents were included in this study. From 1997 to 2018, female acceptances increased from 21.1% to 29.7% (p < 0.01), non-White increased from 27.9% to 31.8% (p = 0.01), and international medical graduates decreased from 28.8% to 25.5% (p = 0.02). There was no significant change in accepted Hispanic and Non-US candidates. Female subspecialty rates for subspecialties increased nationally and was comparable to our cohort, except in general surgery. Hispanic subspecialty acceptance rates were less than 10% and Black/African American acceptance rates remained less than 5% across subspecialties nationally and at our institution.

Conclusion:
Diversity in surgical training has modestly progressed over the last two decades, but the degree of positive change has not been universal and highlights the critical need for improvement and action. Continued institution driven and collaborative strategies are essential to promote diversity in recruitment across all surgical specialties that has implications on our future workforce and surgical leadership.
Elimination of hepatitis B virus infection in children: experience and challenge in China
Authors: Tang Jie , Luo Yu-Qian , Zhou Yi-Hua 
Published: October 2021

Abstract
Chronic hepatitis B virus (HBV) infection is a serious health issue because of its severe sequelae. Prevention of mother-to-child transmission (MTCT) of HBV is critical to eliminate chronic HBV infection. Here, we reviewed the progress toward the elimination of HBV infection in children in China in the recent decade. A universal hepatitis B vaccination program started from 2002 has been intensified, with the coverage of timely birth dose >95% of all newborn infants from 2012. Since 2011, China has taken a nationwide program to administer hepatitis B immunoglobulin (HBIG) with free of charge in all neonates of HBV-infected mothers, leading to a significant increment of timely use of HBIG. The prevalence of hepatitis B surface antigen (HBsAg) was declined from around 10% among children in 1980s to <0.5% among children born after 2011. Administration of oral antiviral agents in HBV-infected pregnant women with HBV DNA >2 × 105 U/mL during the third trimester is increasing, which will further reduce MTCT of HBV. However, there are some challenges in the elimination of HBV infection in children, which need to overcome by the concerted efforts. Nevertheless, it is anticipated that China will achieve the goal set by the World Health Organization that the prevalence of HBsAg in children aged <5 years is ≤0.1% by 2030.
Risk factors of sudden cardiac death in hypertrophic cardiomyopathy
Authors: Hong Ying , Su Wilber W. , Li Xiaoping 
Published: October 2021

Purpose of review
Hypertrophic cardiomyopathy (HCM) is one of the leading causes of sudden cardiac death (SCD) in younger people and athletes. It is crucial to identify the risk factors for SCD in individuals with HCM. This review, based on recent systematic literature studies, will focus on the risk factors for SCD in patients with HCM.

Recent findings
An increasing number of studies have further explored the risk factors for SCD in patients with HCM, and new risk markers have emerged accordingly. In addition, more accurate SCD risk estimation and stratification methods have been proposed and continuously improved.

Summary
The identification of independent risk factors for HCM-related SCD would likely contribute to risk stratification. However, it is difficult to predict SCD with absolute certainty, as the annual incidence of SCD in adult patients with HCM is approximately 1%. The review discusses the established risk factors, such as a family history of SCD, unexplained syncope and some new risk factors. Taken together, the findings of this review demonstrate that there is a need for further research on individual risk factors and that SCD risk stratification in HCM patients remains a clinical challenge.
Total Intravenous Anesthesia in a Malignant Hyperthermia-Susceptible Patient with Klinefelter Syndrome Undergoing Orthognathic Surgery
Authors: Lee Ju-Young , Choi Min Ho , Park Je-Uk 
Published: October 2021

Abstract
A patient with Klinefelter syndrome and skeletal Class III malocclusion experienced a malignant hyperthermia-like reaction while undergoing orthognathic surgery. The patient fully recovered after prompt diagnosis and management, and surgery was reattempted under total intravenous anesthesia. The patient was discharged without any anesthetic complications and was satisfied with the surgical results. This is the first described case of a malignant hyperthermia-like event in a patient with Klinefelter syndrome. Total intravenous anesthesia may be safely administered in malignant hyperthermia-susceptible patients who require orthognathic surgery.
Time-based binding as a solution to and a limitation for flexible cognition
Authors: Senoussi Mehdi , Verbeke Pieter , Verguts Tom 
Published: October 2021

AbstractWhy can’t we keep as many items as we want in working memory? It has long been debated whether this resource limitation is a bug (a downside of our fallible biological system) or instead a feature (an optimal response to a computational problem). We propose that the resource limitation is a consequence of a useful feature. Specifically, we propose that flexible cognition requires time-based binding, and time-based binding necessarily limits the number of (bound) memoranda that can be stored simultaneously. Time-based binding is most naturally instantiated via neural oscillations, for which there exists ample experimental evidence. We report simulations that illustrate this theory and that relate it to empirical data. We also compare the theory to several other (feature and bug) resource theories.
Environmentally dependent and independent control of cell shape determination by Rho GTPase regulators in melanoma
Authors: Dent L. G. , Curry N. , Sparks H. , Bousgouni V. , Maioli V. , Kumar S. , Munro I. , Dunsby C. , Bakal C. 
Published: October 2021

AbstractIn order to invade 3D tissues, cancer cells dynamically change cell morphology in response to geometric and mechanical cues in the environment. But how cells determine their shape in 3D versus 2D environments is poorly understood. Studying 2D versus 3D single cell shape determination has historically been technically difficult due to the lack of methodologies to directly compare the two environments. We developed an approach to study cell shape in 2D versus 3D by measuring cell shape at different depths in collagen using stage-scanning oblique plane microscopy (ssOPM). We find characteristic shape changes occur in melanoma cells depending on whether a cell is attached to a 2D surface or 3D environment, and that these changes can be modulated by Rho GTPase regulatory proteins. Our data suggest that regulation of cell protrusivity undergoes a ‘switch’ of control between different Rho GTPase regulators depending on the physical microenvironment.
A functionally conserved STORR gene fusion in Papaver species that diverged 16.8 million years ago
Authors: Catania Theresa , Li Yi , Winzer Thilo , Harvey David , Meade Fergus , Caridi Anna , Larson Tony R. , Ning Zemin , Graham Ian A 
Published: October 2021

AbstractThe STORR gene fusion event is considered a key step in the evolution of benzylisoquinoline alkaloid (BIA) metabolism in opium poppy as the resulting bi-modular protein performs the isomerization of (S)- to (R)-reticuline which is required for morphinan biosynthesis. Our previous analysis of the opium poppy genome suggested the STORR gene fusion event occurred before a whole genome duplication event 7.2 million years ago. Here we use a combination of phylogenetic, transcriptomic, metabolomic, biochemical and genomic analysis to investigate the origin of the STORR gene fusion across the Papaveraceae family. The pro-morphinan/morphinan subclass of BIAs was present in a subset of 10 Papaver species including P. somniferum (opium poppy) and this correlated with the presence of the STORR gene fusion with one important exception. P. californicum does not produce morphinans but it does contain a STORR gene fusion that epimerizes (S)- to (R)-reticuline when heterologously expressed in yeast. The high similarity of the amino acid sequence linking the two modules of STORR along with phylogenetic gene tree analysis strongly suggests the gene fusion occurred only once and between 17-25 million years ago before the separation of P. californicum from the other Papaver species. We discovered that the most abundant BIA in P. californicum is (R)-glaucine, a member of the aporphine subclass of BIAs. Only the (S) isomer of this compound has previously been reported from nature. These results lead us to conclude that the function of the STORR gene fusion is not exclusive to morphinan production in the Papaveraceae.
Coincident Fluorescence Burst Analysis of dUTP-Loaded Exosome-Mimetic Nanovesicles
Authors: Sanaee Maryam , Sandberg Elin , Ronquist K. Göran , Morrell Jane M. , Widengren Jerker , Gallo Katia 
Published: October 2021

AbstractThe targeting functionality and low immunogenicity of exosomes and exosome-mimetic nanovesicles make them promising as drug-delivery carriers. To tap into this potential, accurate non-destructive methods to load them and characterize their contents are of utmost importance. However, their small size, polydispersity and aggregation in solution make quantitative characterizations of their loading particularly challenging. Here we develop an ad-hoc methodology based on a burst analysis of dual-color confocal fluorescence microscopy experiments, suited for quantitative characterizations of exosome-like nanovesicles and of their loading. We apply it to study bioengineered nanovesicles, loaded with dUTP cargo molecules, synthetized from detergent-resistant membranes of animal extracellular vesicles and human red blood cells. For both classes of bioengineered nanovesicles we prove, by means of dual-color fluorescence cross-correlation spectroscopy (FCCS), successful loading. Furthermore, by a dual-color coincident fluorescence burst (DC-CFB) analysis of the experimental data, we retrieve size and loading statistics for both types of nanovesicles. The procedure affords single-vesicle characterizations, which are essential for reliable quantitative studies of loading processes in exosomes and exosome-mimetic nanovesicles, especially in light of the typically high heterogeneity of their populations. Moreover, the method implementation can be easily adapted to the investigation of a variety of combinations of different cargo molecules and biological nanovesicles besides the proof-of-principle demonstrations considered in this study. The results provide a powerful characterization tool, well-suited for the optimization of loading processes of biomimetic nanovesicles and their advanced engineering for therapeutic drug delivery.
Application of synthetic peptide CEP1 increases nutrient uptake rates along plant roots
Authors: Roy Sonali , Griffiths Marcus , Torres-Jerez Ivone , Sanchez Bailey , Antonelli Elizabeth , Jain Divya , Krom Nicholas , Zhang Shulan , York Larry M. , Scheible Wolf-Rüdiger , Udvardi Michael K. 
Published: October 2021

AbstractThe root system of a plant provides vital functions including resource uptake, storage, and anchorage in soil. Uptake from the soil of macro-nutrients like nitrogen (N), phosphorus (P), potassium (K), and sulphur (S) is critical for plant growth and development. Small signaling peptide (SSP) hormones are best known as potent regulators of plant growth and development with a few also known to have specialized roles in macronutrient utilization. Here we describe a high-throughput screen of SSP effects on root uptake of multiple nutrients. The SSP, MtCEP1 enhanced nitrate uptake rate per unit root length in Medicago truncatula plants deprived of N. MtCEP1 and AtCEP1 enhanced uptake not only of nitrate, but also phosphate and sulfate in both Medicago and Arabidopsis. Transcriptome analysis of Medicago roots treated with different MtCEP1 encoded peptide domains revealed that hundreds of genes respond to these peptides, including several nitrate transporters and a sulfate transporter that may mediate the uptake of these macronutrients downstream of CEP1 signaling. Likewise, several putative signaling pathway genes were induced in roots by CEP1 treatment. Thus, a scalable method has been developed for screening synthetic peptides of potential use in agriculture, with CEP1 shown to be one such peptide.
Sparse Representation Learning Derives Biological Features with Explicit Gene Weights from the Allen Mouse Brain Atlas
Authors: Abbasi Mohammad , Sanderford Connor R , Raghu Narendiran , Pasha Mirjeta , Bartelle Benjamin B 
Published: October 2021

ABSTRACTUnsupervised learning methods are commonly used to detect features within transcriptomic data and ultimately derive meaningful representations of biology. Contributions of individual genes to any feature however becomes convolved with each learning step, requiring followup analysis and validation to understand what biology might be represented by a cluster on a low dimensional plot. We sought learning methods that could preserve the gene information of detected features, using the spatial transcriptomic data and anatomical labels of the Allen Mouse Brain Atlas as a test dataset with verifiable ground truth. We established metrics for accurate representation of molecular anatomy to find sparse learning approaches were uniquely capable of generating anatomical representations and gene weights in a single learning step. Fit to labeled anatomy was highly correlated with intrinsic properties of the data, offering a means to optimize parameters without established ground truth. Once representations were derived, complementary gene lists could be further compressed to generate a low complexity dataset, or to probe for individual features with >95% accuracy. We demonstrate the utility of sparse learning as a means to derive biologically meaningful representations from transcriptomic data and reduce the complexity of large datasets while preserving intelligible gene information throughout the analysis.
The mechanochemical origins of the microtubule sliding motility within the kinesin-5 domain organization
Authors: Nithianantham Stanley , Iwanski Malina K. , Gaska Ignas , Pandey Himanshu , Bodrug Tatyana , Inagaki Sayaka , Major Jennifer , Brouhard Gary J. , Gheber Larissa , Rosenfeld Steven S. , Forth Scott , Hendricks Adam G. , Al-Bassam Jawdat 
Published: October 2021

AbstractThe conserved kinesin-5 bipolar tetrameric motors slide apart microtubules during mitotic spindle assembly and elongation. Kinesin-5 bipolar organization originates from its conserved tetrameric helical minifilament, which position the C-terminal tail domains of two subunits near the N-terminal motor domains of two anti-parallel subunits (Scholey et al, 2014). This unique tetrameric structure enables kinesin-5 to simultaneously engage two microtubules and transmit forces between them, and for multiple kinesin-5 motors to organize via tail to motor interactions during microtubule sliding (Bodrug et al, 2020). Here, we show how these two structural adaptations, the kinesin-5 tail-motor domain interactions and the length of the tetrameric minifilament, determine critical aspects of kinesin-5 motility and sliding mechanisms. An x-ray structure of the 34-nm kinesin-5 minifilament reveals how the dual dimeric N-terminal coiled-coils emerge from the tetrameric central bundle. Using this structure, we generated active bipolar mini-tetrameric motors from Drosophila and human orthologs, which are half the length of native kinesin-5. Using single-molecule motility assays, we show that kinesin-5 tail domains promote mini-tetramers static pauses that punctuate processive motility. During such pauses, kinesin-5 mini-tetramers form multi-motor clusters mediated via tail to motor domain cross-interactions. These clusters undergo slow and highly processive motility and accumulate at microtubule plus-ends. In contrast to native kinesin-5, mini-tetramers require tail domains to initiate microtubule crosslinking. Although mini-tetramers are highly strained in initially aligning microtubules, they slide microtubules more efficiently than native kinesin-5, due to their decreased minifilament flexibility. Our studies reveal that the conserved kinesin-5 motor-tail mediated clustering and the length of the tetrameric minifilament are key features for sliding motility and are critical in organizing microtubules during mitotic spindle assembly and elongation.
Requirements for mammalian promoters to decode transcription factor dynamics
Authors: Antwi Enoch B. , Marrakchi Yassine , Çiçek Özgün , Brox Thomas , Di Ventura Barbara 
Published: October 2021

AbstractIn response to different stimuli many transcription factors (TFs) display different activation dynamics that trigger the expression of specific sets of target genes, suggesting that promoters have a way to decode them. Combining optogenetics, deep learning-based image analysis and mathematical modeling, we find that decoding of TF dynamics occurs only when the coupling between TF binding and transcription pre-initiation complex formation is inefficient and that the ability of a promoter to decode TF dynamics gets amplified by inefficient translation initiation. Furthermore, we propose a theoretical mechanism based on phase separation that would allow a promoter to be activated better by pulsatile than sustained TF signals. These results provide an understanding on how TF dynamics are decoded in mammalian cells, which is important to develop optimal strategies to counteract disease conditions, and suggest ways to achieve multiplexing in synthetic pathways.
Differential growth rates and in vitro drug susceptibility to currently used drugs for multiple isolates of Naegleria fowleri
Authors: Russell A. Cassiopeia , Kyle Dennis E. 
Published: October 2021

AbstractThe free-living amoeba, Naegleria fowleri, which typically dwells within warm, freshwater environments, can opportunistically cause Primary Amoebic Meningoencephalitis (PAM), a disease with a mortality rate of >98%, even with the administration of the best available drug regimens. The lack of positive outcomes for PAM has prompted a push for the discovery and development of more effective therapeutics, but most studies only utilize one or two clinical isolates in their drug discovery assays. The inability to assess possible heterogenic responses to drugs among isolates from varying geographical regions hinders progress in the field due to a lack of proven universal efficacy for novel therapeutics. Herein we conducted drug efficacy and growth rate determinations for 11 different clinical isolates, including one obtained from a successful treatment outcome, by applying a previously developed CellTiter-Glo 2.0 screening technique and flow cytometry. We found some significant differences in the susceptibility of these isolates to 7 of 8 different drugs tested, all of which comprise the cocktail that is recommended to physicians by the Centers for Disease Control. We also discovered significant variances in growth rates among isolates which draws attention to the dissidence among the amoebae populations collected from different patients. The findings of this study reiterate the need for inclusion of additional clinical isolates of varying genotypes in drug assays and highlight the necessity for more targeted therapeutics with universal efficacy across N. fowleri isolates. Our data establishes a needed baseline for drug susceptibility among clinical isolates and provides a segue for future combination therapy studies as well as research related to phenotypic or genetic differences that could shed light on mechanisms of action or predispositions to specific drugs.
APOBEC mutagenesis is low in most types of non-B DNA structures, unlike other types of cancer mutagenesis
Authors: Ponomarev Gennady V. , Fatykhov Bulat , Nazarov Vladimir A. , Abasov Ruslan , Shvarov Evgeny , Landik Nina-Vicky , Denisova Alexandra A. , Chervova Almira A. , Gelfand Mikhail S. , Kazanov Marat D. 
Published: October 2021

AbstractWhile somatic mutations are known to be enriched in genome regions with non-canonical DNA secondary structure, the impact of particular mutagens still needs to be elucidated. Here, we demonstrate that in human cancers, the APOBEC mutagenesis is not enriched in direct repeats, mirror repeats, short tandem repeats, and G-quadruplexes, and even decreased below its level in B-DNA for cancer samples with very high APOBEC activity. In contrast, we observe that the APOBEC-induced mutational density is positively associated with APOBEC activity in inverted repeats (cruciform structures), where the impact of cytosine at the 3’-end of the hairpin loop is substantial. Surprisingly, the APOBEC-signature mutation density per TC motif in the single-stranded DNA of a G-quadruplex (G4) is lower than in the four-stranded part of G4 and in B-DNA. The APOBEC mutagenesis, as well as the UV-mutagenesis in melanoma samples are absent in Z-DNA regions, due to depletion of their mutational signature motifs.
Nephronectin-Integrin α8 signaling is required for proper migration of periocular neural crest cells during chick corneal development
Authors: Ma Justin , Bi Lian , Spurlin James , Lwigale Peter 
Published: October 2021

ABSTRACTDuring development, cells aggregate at tissue boundaries to form normal tissue architecture of organs. However, how cells are segregated into tissue precursors remains largely unknown. Cornea development is a perfect example of this process whereby neural crest cells aggregate in the periocular region prior to their migration and differentiation into corneal cells. Our recent RNA-Seq analysis identified upregulation of Nephronectin (Npnt) transcripts during early stages of corneal development where its function has not been investigated. We found that Npnt mRNA and protein are expressed by various ocular tissues including the migratory periocular neural crest (pNC), which also express the integrin alpha 8 (Itgα8) receptor. Knockdown of either Npnt or Itgα8 attenuated cornea development, whereas overexpression of Npnt resulted in cornea thickening. Moreover, overexpression of Npnt variants lacking RGD binding sites did not affect corneal thickness. Neither the knockdown or augmentation of Npnt caused significant changes in cell proliferation, suggesting that Npnt directs pNC migration into the cornea. In vitro analyses showed that Npnt promotes pNC migration from explanted periocular mesenchyme, which requires Itgα8. Combined, these findings show that Npnt specifies and tunes cell migration into the presumptive cornea ECM by providing a substrate for Itgα8-positive pNC cells.