bluuebunny/crossref_metadata_2025 huggingface dataset:
Axial and Rotational Malreduction (Golf Club Deformity) in Distal Femur Fractures
Authors: Lowe Jason , Alhandi Ali , Manoharan Aditya , Ouellette Elizabeth , Kaimrajh David , Milne Edward , Latta Loren
Published: April 2022

Objectives:

To describe malreduction of supracondylar distal femur fractures stabilized with lateral femoral locking plates and determine whether a mismatch in axial lateral distal femur anatomy and lateral distal femoral plate design contributes to supracondylar distal femoral fracture malreduction.

Materials and Methods:

OTA/AO 33A were simulated in 7 cadaver femurs and fixed with a lateral distal locking femoral plate placed flush to the lateral femoral condyle (group 1). In group 2, the anterior flange of the plate was externally rotated 10 degrees in relation to the lateral condyle. A motion capture system measured translation and rotation of the articular segment as shaft screws were applied, reducing plate to femoral diaphysis. Articular segment movement was compared between groups using paired Student t test, P < 0.05. A large database of 3D scans of 800 femurs was used to define the relationship of the lateral femoral condyle to the lateral cortical surface of the human femur.

Results:

Malreduction was observed with anatomic plate application results from medial translation (17 mm) and external rotation (12.2 degrees) (group 1). Modifying plate geometry to match lateral femur anatomy (group 2) improved medial translation by 46% and external rotation by 80%. An analysis of the shape of the 800 distal femurs showed that the average posterior anterior inclination is 16.5 degrees.

Conclusions:

Anatomic application of distal femoral plates results in significant malreduction. Modifying the plate design to accommodate 10 degrees slope of lateral distal femur results in partial correction of deformity. Future studies should investigate other means of correcting the malalignment, especially considering the 16.5-degree posterior anterior inclination of the condyle.
Palatoplasty Using Alveolar Ridge Incisions: A Novel Approach for Addressing Cleft Palate Deformities
Authors: Khetpal Sumun , Patel Harsh , DeLong Michael , Liu Mengyuan T. , Ozaki Wayne H.
Published: April 2022

Background:

Traditionally, plastic surgeons have performed palatoplasties using mucoperiosteal flaps with lateral incisions that are medial to the alveolar ridge. However, narrow flaps can cause limitations in some cases. To construct larger and wider flaps and minimize exposed bone after closure, we propose a novel technique that entails creating the lateral incisions at the top of the alveolar ridge, instead of the base of the alveolar ridge, to capture more tissue when repairing the hard palate.

Methods:

A retrospective chart review was conducted for patients undergoing cleft palate repair with the aforementioned technique. Information collected included basic demographic and diagnostic factors related to cleft palate deformity and history of previous facial surgeries. Operative report details and postoperative complications were analyzed.

Results:

Nineteen patients with hard palate clefts were included in the analysis, with the majority being women (68%). There was a balanced representation of patients with Veau classifications of II (47%) and III (42%). The majority of patients had an isolated cleft palate (74%) and incomplete deformity (63%), with no other craniofacial deformities. One (5%) had postoperative self-limited oronasal fistula managed conservatively.

Conclusions:

We present a novel approach for repairing cleft palate deformities by extending the lateral incision to the top of the alveolar ridge to create larger mucosal flaps. Further longitudinal studies are needed to evaluate how this unique approach compares to traditional methods—with respect to impact on maxillary growth processes, requirement for subsequent surgeries beyond two years of follow-up, and ultimately normalized speech over time.
The Holistic Philosophy of Traditional Chinese Medicine and Conflicts With Modern Medicine
Authors: Chien Tsai-Ju
Published: April 2022

Traditional Chinese medicine (TCM) has sparked the public's attention for its potential in new drug development and its holistic view toward health, which is totally different from the reductionistic science of modern medicine. Although many scholars try to connect TCM with precision medicine or apply new methods and technology to integrate TCM with modern medicine, the misunderstandings and gap between TCM and modern medicine limit the development of evidence-based TCM. Traditional Chinese medicine is actually a medical science encompassing not only medicine but also philosophy and art in direct contrast to molecular-based modern medicine. As more and more multidisciplinary studies are being published, finding ways to integrate TCM with modern or precision medicine through artificial intelligence, new study design and technology may become a critical issue. This article aims to briefly review the unique philosophy of TCM and its conflicts with modern medicine, with a focus on the potential integration of TCM and modern medicine. We also provide insight for the key attributes of TCM and the associated investigation with Western research approaches.
Evaluation of a Brief Stress Management Workshop for Incoming Nursing Students
Authors: Windle Stephanie , Musselman Elaine
Published: April 2022

The purpose of this study was to evaluate the effectiveness of a brief stress management workshop on nursing students' perceived stress and resilience. Students who received the stress management intervention during orientation had significantly higher resilience scores and lower stress scores 1 year later during COVID-19 than the comparison group.
The Effect of Distant Reiki on the Stress and Fatigue Levels of Nurses Working in COVID-19 Clinics
Authors: Bektaş Akpınar Nilay , Özcan Yüce Ulviye , Yurtsever Sabire
Published: April 2022

The study was conducted using a pre/posttest, randomized-controlled, single-blind trial method. After the pretest, a survey was administered and, distant Reiki was applied to nurses in the intervention group (n = 30) for 20 minutes a day for 4 consecutive days at a usual time. No intervention was made in the control group (n = 32). On the second day after the fourth Reiki session, a posttest survey was administered to nurses in the intervention group. The control group, on the other hand, was administered the posttest survey together with the last intervention group. As a result, in the intervention group, there was a decrease in the mean scores of the Helpless Approach subdimension on the Coping Style Scale and an increase in the mean scores of the Optimistic Approach and Social Support subdimensions (P < .05). In the Visual Analog Scale for Fatigue, the mean Fatigue score in the intervention group decreased and there was an increase in the Energy subdimension mean score (P < .05).
AMNIOTIC MEMBRANE GRAFT FOR THE TREATMENT OF LARGE REFRACTORY MACULAR HOLE
Authors: Khaqan Hussain Ahmad , Sahyoun Jean-Yves , Haider Muhammad Ali , Buksh Hasnain Muhammad
Published: April 2022

PURPOSE:

Study off-label human amniotic membrane use outcomes for giant refractory macular hole closure.

Materials and Methods:

The study was performed at Lahore General Hospital, Lahore, over 52 months on patients who had undergone standard macular hole surgical procedures for treatment, but the hole failed to close. Refractory macular hole dimensions ranged from 824 µm to 1,568 µm. Before surgery, patients underwent slit-lamp examination, fundus photography, and optical coherence tomography for macular scan. Amniotic membrane graft (AMG) used in surgery was harvested from a human placenta 24 hours before. Before AMG application, enough internal limiting membrane peeling was performed to ensure perfect fitting and recovery. All holes were plugged with AMG and SF6 gas tamponade.

Results:

Twenty-nine patients, 20 men and nine women, were included in this study. Mean age of patients was 58 ± 6. Patients had refractory holes of average 1,237.48 ± 151.25 µm. Post-op, 100% macular hole closure was achieved in all patients. Type 1 closure was found in patients (37.93%) who underwent AMG surgery within 3 months after primary surgical failure. Type 2 closure was found in patients (62.07%) who were operated on 3 months after primary surgical failure.

Conclusion:

Refractory macular holes treated by AMG with SF6 gas tamponade achieve anatomical Type 1 closure if performed within 3 months of primary surgical repair.
Functional Status Change Among Infants, Children, and Adolescents Following Extracorporeal Life Support: a Multicenter Report
Authors: Beshish Asaad G. , Rodriguez Zahidee , Hani Farhat Mohamed , Newman Jordan W. , Jahadi Ozzie , Baginski Matthew , Bradley Jeffrey , Rao Nikita , Figueroa Janet , Viamonte Heather , Chanani Nikhil K. , Owens Gabe E. , Barbaro Ryan , Yarlagadda Vamsi , Ryan Kathleen R.
Published: April 2022

In our retrospective multicenter study of patients 0 to 18 years of age who survived extracorporeal life support (ECLS) between January 2010 and December 2018, we sought to characterize the functional status scale (FSS) of ECLS survivors, determine the change in FSS from admission to discharge, and examine risk factors associated with development of new morbidity and unfavorable outcome. During the study period, there were 1,325 ECLS runs, 746 (56%) survived to hospital discharge. Pediatric patients accounted for 56%. Most common ECLS indication was respiratory failure (47%). ECLS support was nearly evenly split between veno-arterial and veno-venous (51% vs. 49%). Median duration of ECLS in survivors was 5.5 days. Forty percent of survivors had new morbidity, and 16% had an unfavorable outcome. In a logistic regression, African American patients (OR 1.68, p = 0.01), longer duration of ECLS (OR 1.002, p = 0.004), mechanical (OR 1.79, p = 0.002), and renal (OR 1.64, p = 0.015) complications had higher odds of new morbidity. Other races (Pacific Islanders, and Native Americans) (OR 2.89, p = 0.013), longer duration of ECLS (OR 1.002, p = 0.002), and mechanical complications (OR 1.67, p = 0.026) had higher odds of unfavorable outcomes. In conclusion, in our multi-center 9-year ECLS experience, 56% survived, 40% developed new morbidity, and 84% had favorable outcome. Future studies with larger populations could help identify modifiable risk factors that could help guide clinicians in this fragile patient population.
Hypoxia and Polycythemia
Authors: Oren Shachar , Brenner Galit , Garty Yael , Scheier Eric
Published: April 2022

Point of care ultrasound (POCUS) can be useful in the differentiation between cardiac and pulmonary etiologies of hypoxia. Here, we present a child with signs of chronic hypoxia, found on POCUS to have multiple pulmonary arteriovenous malformations. A combination of POCUS and history supported a presumptive pediatric emergency department diagnosis of hereditary hemorrhagic telangiectasia. This case is the first case of a pulmonary arteriovenous malformation found on POCUS and reinforces the importance of POCUS as a first-line examination in the evaluation of chronic hypoxia in the pediatric emergency department.
Four-Quadrant Approach Squared: Ethical Analysis of Living Donation in Vascularized Composite Allotransplantation
Authors: Beederman Maureen , Teven Chad M. , Gottlieb Lawrence J.
Published: April 2022

Vascularized composite allotransplantation has become a widely accepted method for reconstruction or restoration of body parts, and the various ethical dilemmas that accompany vascularized composite allotransplantation have been widely discussed. As advancements in immunosuppression and tolerance continue to be made, the concept of living donor vascularized composite allotransplantation will likely become a popular option of the “reconstructive elevator.” In this article, the authors discuss the various ethical implications of living donor vascularized composite allotransplantation.
Assessment of Gender Disparities and Geographic Variations in Payments from Industry among Plastic Surgeons in the United States
Authors: Cunning Jessica R. , Rios-Diaz Arturo J. , Othman Sammy , Rappaport Gal , Gaughan John P. , Matthews Martha S.
Published: April 2022

Background:

Various medical specialties have demonstrated gender disparities involving industry-supported payments. The authors sought to determine whether such disparities exist within plastic surgery.

Methods:

Industry contributions to plastic surgeons practicing in the United States were extracted from the Centers for Medicare and Medicaid Services Open Payments 2013 to 2017 databases. Specialists’ gender was obtained through online searches. Kruskal-Wallis tests compared payments (in U.S. dollars) by gender (overall and by payment category). Linear regression estimated the independent association of female gender with increased/reduced payments while controlling for state-level variations.

Results:

Of 1518 plastic surgeons, 13.4 percent were female. Of $44.4 million total payments from the industry, $3.35 million were made to female plastic surgeons (p < 0.01). During the study period, female plastic surgeons received lower overall payments than male plastic surgeons [median, $3500 (interquartile range, $800 to $9500) versus $4160.60 (interquartile range, $1000 to $19,728.20); p < 0.01]. This trend persisted nationwide after normalizing for year [$2562.50/year (interquartile range, $770 to $5916.25/year) versus $3200/year (interquartile range, $955 to $8715.15/year); p = 0.02] and at the state level in all 38 states where there was female representation. Analysis of payment categories revealed that honoraria payments were significantly higher for male plastic surgeons [$4738 (interquartile range, $1648 to $16,100) versus $1750 (interquartile range, $750 to $4100); p = 0.02]. Within risk-adjusted analysis, female plastic surgeons received $3473.21/year (95 percent CI, $671.61 to $6274.81; p = 0.02) less than male plastic surgeons.

Conclusions:

Gender disparities involving industry payments exist in plastic surgery at both national and state levels. Factors contributing to this phenomenon must be explored to understand implications of this gap.
Working Smarter, Not Harder: Using Data-Driven Strategies to Generate Front-End Cost Savings through Price Negotiation and Supply Chain Optimization
Authors: Reece Edward M. , Davis Matthew J. , Abu-Ghname Amjed , Castanon Joe M. , Voris Matthew , Hoxworth Ron , Winocour Sebastian , Buchanan Edward P.
Published: April 2022

Background:

Supply chain optimization is an effective method of generating front-end cost savings and increasing hospital profits. Through the negotiation and renegotiation of supply chain contracts, plastic surgeons can dramatically change the price at which they purchase surgical supplies and implants. This study characterizes the potential impact of supply chain optimization and puts forth a generalizable, systematic approach for successful sourcing.

Methods:

From October of 2017 to September of 2018, the authors examined all patients taken to the operating room for either a facial fracture or a hand fracture. Cost data were collected, Supply Chain Information Management numbers were used to determine whether each item used during the study period was under contract, and cost savings based on contract negotiation were calculated. Potential cost savings were calculated using the BillOnly calculator.

Results:

For the 77 facial trauma cases and 63 hand trauma cases performed, a total of 330 items (70 distinct items) were used, 47 percent of which were under contract (47 percent contract use), with an average negotiated discount of 49 percent. Based on BillOnly material cost estimates, the authors’ institution would need to increase its contract use to 70 percent to achieve a net savings of 19 percent, and to 90 percent to achieve a net savings of 39 percent. The authors also estimated that if contract use increased to 90 percent, net savings would increase commensurately with increases in the average discount negotiated.

Conclusion:

Supply chain optimization offers plastic surgeons the potential to significantly decrease surgical costs while maintaining surgical quality.
The apportionment of citations: a scientometric analysis of Lewontin 1972
Authors: Carlson Jedidiah , Harris Kelley
Published: April 2022

‘The apportionment of human diversity’ (1972) is the most highly cited research article published by geneticist Richard Lewontin in his career. This study's primary result—that most genetic diversity in humans can be accounted for by within-population differences, not between-population differences—along with Lewontin's outspoken, politically charged interpretations thereof, has become foundational to the scientific and cultural discourse pertaining to human genetic variation. The article has an unusual bibliometric trajectory in that it is much more salient in the bibliographic record today compared to the first 20 years after its publication. Here, we highlight four factors that may have played a role in shaping the paper's fame: (i) citations in influential publications across several disciplines; (ii) Lewontin's own popular books and media appearances; (iii) the renaissance of population genetics research of the early 1990s; and (iv) the serendipitous collision of scientific progress, influential books and papers, and heated controversies around the year 1994. We conclude with an analysis of Twitter data to characterize the communities and conversations that continue to keep this study at the centre of discussions about race and genetics, prompting new challenges for scientists who have inherited Lewontin's legacy.

This article is part of the theme issue ‘Celebrating 50 years since Lewontin's apportionment of human diversity’.
A geometric relationship of
F
2
,
F
3
and
F
4
-statistics with principal component analysis
Authors: Peter Benjamin M.
Published: April 2022

Principal component analysis (PCA) and
F
-statistics
sensu
Patterson are two of the most widely used population genetic tools to study human genetic variation. Here, I derive explicit connections between the two approaches and show that these two methods are closely related.
F
-statistics have a simple geometrical interpretation in the context of PCA, and orthogonal projections are a key concept to establish this link. I show that for any pair of populations, any population that is admixed as determined by an
F
3
-statistic will lie inside a circle on a PCA plot. Furthermore, the
F
4
-statistic is closely related to an angle measurement, and will be zero if the differences between pairs of populations intersect at a right angle in PCA space. I illustrate my results on two examples, one of Western Eurasian, and one of global human diversity. In both examples, I find that the first few PCs are sufficient to approximate most
F
-statistics, and that PCA plots are effective at predicting
F
-statistics. Thus, while
F
-statistics are commonly understood in terms of discrete populations, the geometric perspective illustrates that they can be viewed in a framework of populations that vary in a more continuous manner.

This article is part of the theme issue ‘Celebrating 50 years since Lewontin's apportionment of human diversity’.
Covariance of pairwise differences on a multi-species coalescent tree and implications forFST
Authors: Guerra Geno , Nielsen Rasmus
Published: April 2022

The multi-species coalescent (MSC) provides a theoretical foundation for modern phylogenetics and comparative population genetics. Its theoretical properties have been heavily studied but there are still aspects of the MSC that are largely unknown, including the covariances in pairwise coalescence times, which are fundamental for understanding the properties of statistics that combine data from multiple species, such as the fixation index (FST). The major contribution of this study is the derivation and implementation of exact expressions for the covariances of pairwise coalescence times under phylogenetic models with piecewise constant changes in population size, assuming no gene flow after species divergence. We use these expressions to derive the variance in average pairwise differences within and between populations. We then derive approximations for the expectation and bias of a sequence-based estimator ofFST, a commonly used genetic measurement of population differentiation, when it is applied to a non-recombining region of the genome. We show that the estimator ofFSTis generally biased downward. A freely available software package is provided, STCov, to calculate the mean, variances and covariances in coalescence times presented here under user-defined piecewise-constant species trees.

This article is part of the theme issue ‘Celebrating 50 years since Lewontin's apportionment of human diversity’.
Population differentiation of polygenic score predictions under stabilizing selection
Authors: Yair Sivan , Coop Graham
Published: April 2022

Given the many small-effect loci uncovered by genome-wide association studies (GWAS), polygenic scores have become central to genomic medicine, and have found application in diverse settings including evolutionary studies of adaptation. Despite their promise, polygenic scores have been found to suffer from limited portability across human populations. This at first seems in conflict with the observation that most common genetic variation is shared among populations. We investigate one potential cause of this discrepancy: stabilizing selection on complex traits. Counterintuitively, while stabilizing selection constrains phenotypic evolution, it accelerates the loss and fixation of alleles underlying trait variation within populations (GWAS loci). Thus even when populations share an optimum phenotype, stabilizing selection erodes the variance contributed by their shared GWAS loci, such that predictions from GWAS in one population explain less of the phenotypic variation in another. We develop theory to quantify how stabilizing selection is expected to reduce the prediction accuracy of polygenic scores in populations not represented in GWAS samples. In addition, we find that polygenic scores can substantially overstate average genetic differences of phenotypes among populations. We emphasize stabilizing selection around a common optimum as a useful null model to connect patterns of allele frequency and polygenic score differentiation.

This article is part of the theme issue ‘Celebrating 50 years since Lewontin's apportionment of human diversity’.
How methodological changes have influenced our understanding of population structure in threatened species: insights from tiger populations across India
Authors: Aylward Megan , Sagar Vinay , Natesh Meghana , Ramakrishnan Uma
Published: April 2022

Unprecedented advances in sequencing technology in the past decade allow a better understanding of genetic variation and its partitioning in natural populations. Such inference is critical to conservation: to understand species biology and identify isolated populations. We review empirical population genetics studies of Endangered Bengal tigers within India, where 60–70% of wild tigers live. We assess how changes in marker type and sampling strategy have impacted inferences by reviewing past studies, and presenting three novel analyses including a single-nucleotide polymorphism (SNP) panel, genome-wide SNP markers, and a whole-mitochondrial genome network. At a broad spatial scale, less than 100 SNPs revealed the same patterns of population clustering as whole genomes (with the exception of one additional population sampled only in the SNP panel). Mitochondrial DNA indicates a strong structure between the northeast and other regions. Two studies with more populations sampled revealed further substructure within Central India. Overall, the comparison of studies with varied marker types and sample sets allows more rigorous inference of population structure. Yet sampling of some populations is limited across all studies, and these should be the focus of future sampling efforts. We discuss challenges in our understanding of population structure, and how to further address relevant questions in conservation genetics.

This article is part of the theme issue ‘Celebrating 50 years since Lewontin's apportionment of human diversity’.
The genetic legacy of the Manila galleon trade in Mexico
Authors: Rodríguez-Rodríguez Juan Esteban , Ioannidis Alexander G. , Medina-Muñoz Santiago G. , Barberena-Jonas Carmina , Blanco-Portillo Javier , Quinto-Cortés Consuelo D. , Moreno-Estrada Andrés
Published: April 2022

The population of Mexico has a considerable genetic substructure due to both its pre-Columbian diversity and due to genetic admixture from post-Columbian trans-oceanic migrations. The latter primarily originated in Europe and Africa, but also, to a lesser extent, in Asia. We analyze previously understudied genetic connections between Asia and Mexico to infer the timing and source of this genetic ancestry in Mexico. We identify the predominant origin within Southeast Asia—specifically western Indonesian and non-Negrito Filipino sources—and we date its arrival in Mexico to approximately 13 generations ago (1620 CE). This points to a genetic legacy from the seventeenth century Manila galleon trade between the colonial Spanish Philippines and the Pacific port of Acapulco. Indeed, within Mexico we observe the highest level of this trans-Pacific ancestry in Acapulco, located in the state of Guerrero. This colonial Spanish trade route from East Asia to Europe was centred on Mexico and appears in historical records, but its legacy has been largely ignored. Identities and stories were suppressed due to slavery, assimilation of the immigrants as ‘Indios’ and incomplete historical records. Here we characterize this understudied Mexican ancestry.

This article is part of the theme issue ‘Celebrating 50 years since Lewontin's apportionment of human diversity’.
Polygenic risk, population structure and ongoing difficulties with race in human genetics
Authors: Kaplan Jonathan Michael , Fullerton Stephanie M.
Published: April 2022

‘The Apportionment of Human Diversity’ stands as a noteworthy intervention, both for the field of human population genetics as well as in the annals of public communication of science. Despite the widespread uptake of Lewontin's conclusion that racial classification is of ‘virtually no genetic or taxonomic significance’, the biomedical research community continues to grapple with whether and how best to account for race in its work. Nowhere is this struggle more apparent than in the latest attempts to translate genetic associations with complex disease risk to clinical use in the form of polygenic risk scores, or PRS. In this perspective piece, we trace current challenges surrounding the appropriate development and clinical application of PRS in diverse patient cohorts to ongoing difficulties deciding which facets of population structure matter, and for what reasons, to human health. Despite numerous analytical innovations, there are reasons that emerge from Lewontin's work to remain sceptical that accounting for population structure in the context of polygenic risk estimation will allow us to more effectively identify and intervene on the significant health disparities which plague marginalized populations around the world.

This article is part of the theme issue ‘Celebrating 50 years since Lewontin's apportionment of human diversity’.
A comprehensive study of mRNA and long noncoding RNAs in Indian Breast cancer patients using transcriptomics approach
Authors: Manjunath Meghana , Nirgude Snehal , Mhatre Anisha , Gayatri Sai Vemuri , Nataraj Mallika , Thumsi Jayanti , choudhary Bibha
Published: April 2022

Background

Breast cancer (BC) is one of the leading causes of cancer-associated death in women. Despite the progress in therapeutic regimen, resistance and recurrence of Breast cancer have impacted Overall Survival. Transcriptomic profiling of tumour samples has led to identifying subtype-specific differences, identifying biomarkers, and designing therapeutic strategies. Although there are multiple transcriptomic studies on breast cancer patients from different geographical regions, a comprehensive study on long noncoding RNA (lncRNA) and mRNA in Indian Breast cancer patients in multiple subtypes are very limited. This study aims to understand the subtype-specific alterations and mRNA-lncRNA gene sets.

Method

We have performed transcriptome analysis of 17 Indian breast cancer patients and matched normal belonging to 6 different subtypes, i.e., four patients in triple positive, three patients in estrogen receptor-positive (ER+ve), three patients in estrogen and progesterone receptor-positive (ER+ve, PR+ve), two patients in Human epidermal growth factor receptor (Her2+ve), three patients in triple-negative and one patient in ER+ve and Her2 +ve subtypes. Hierarchical clustering and principal component analysis were performed using R packages to derive gene sets. Univariate and multivariate Cox analyses were performed for survival analysis.

Results

mRNA and lncRNA expression profiles segregated Indian Breast cancer subtypes with minimum overlap. We have identified a 25mRNA-27 lncRNA gene set, which displayed proper segregation of the subtypes in our data. The same gene set also segregated premenopausal women samples in The Cancer Genome Atlas (TCGA) data. Pathway analysis of the differentially expressed genes revealed unique pathways for premenopausal and postmenopausal women. Kaplan-Meier survival analysis revealed menopausal status, grade of the tumour, and hormonal status displayed statistically significant effects (p < 0.05) on the risk of mortality due to breast cancer. Her2+ve patients showed low overall survival

Conclusion

This is the first study describing subtype-specific mRNA and lncRNA gene expression in Indian Breast Cancer patients with unique pathway signatures for premenopausal and postmenopausal breast cancer patients. Additionally, our data identified an mRNA-lncRNA gene set that could segregate pre and postmenopausal women with Breast Cancer. Although the sample size is small, results from this study could be a foundation that could be validated further in a larger dataset to establish an mRNA-lncRNA signature specific to the Indian population which might, in turn, improve therapeutic decisions.
The Decision of the Optimal Rank of a Non-negative Matrix Factorization Model for Gene Expression Datasets Utilizing Unit Invariant Knee Method
Authors: Güven Emine
Published: April 2022

Background

There is a great need to develop a computational approach to analyze and exploit the information contained in gene expression data. Recent utilization of non-negative matrix factorization (NMF) in computational biology has served its capability to derive essential details from a high amount of data in particular gene expression microarrays.

Objective

A common problem in NMF is finding the proper number rank (r) of factors. Thus, various techniques have been suggested to select the optimal value of rank factorization (r).

Method

This study focused on the unit invariant knee (UIK) method to calculate factorization rank (basis vector) of the non-negative matrix factorization (NMF) of gene expression data sets is employed. Because the UIK method requires an extremum distance estimator (EDE) that is eventually employed for inflection and identification of a knee point, this study finds the first inflection point of curvature of RSS of the proposed algorithms using the UIK method on gene expression datasets as a target matrix.

Results

Computation was conducted for the UIK task using the esGolub data set of R studio, and consequently, the distinct results of NMF was subjected to compare on different algorithms. The proposed UIK method is easy to perform, free of a priori rank value input, and does not require initial parameters that significantly influence the model’s functionality.

Conclusion

This study demonstrates that the UIK method provides a credible prediction for both gene expression data and precisely estimating of simulated mutational processes data with known dimensions.
ScisorWiz: Visualizing Differential Isoform Expression in Single-Cell Long-Read Data
Authors: Stein Alexander N. , Joglekar Anoushka , Poon Chi-Lam , Tilgner Hagen U.
Published: April 2022

RNA isoforms contribute to the diverse functionality of the proteins they encode within the cell. Visualizing how isoform expression differs across cell types and brain regions can inform our understanding of disease and gain or loss of functionality caused by alternative splicing with potential negative impacts. However, the extent to which this occurs in specific cell types and brain regions is largely unknown. This is the kind of information that ScisorWiz plots can provide in an informative and easily communicable manner. ScisorWiz affords its user the opportunity to visualize specific genes across any number of cell types, and provides various sorting options for the user to gain different ways to understand their data. ScisorWiz provides a clear picture of differential isoform expression through various clustering methods and highlights features such as alternative exons and Single Nucleotide Variants (SNVs). Tools like Scisor-Wiz are key for interpreting single-cell isoform sequencing data. This tool applies to any single-cell long-read RNA sequencing data in any cell type, tissue, or species.
Somatosensory Cortical Signature of Facial Nociception and Vibrotactile Touch Induced Analgesia
Authors: Lu Jinghao , Chen Bin , Levy Manuel , Xu Peng , Han Bao-Xia , Takatoh Jun , Thompson P. M. , He Zhigang , Prevosto Vincent , Wang Fan
Published: April 2022

Pain relief by vibrotactile touch is a common human experience. Previous neurophysiological investigations in animals focused on spinal mechanisms while human studies suggested the involvement of supraspinal mechanisms. Here we asked whether and how the primary somatosensory cortex (S1) is involved in touch induced analgesia. We discovered that in mice, vibrotactile reafferent signals from self-generated whisking significantly reduce facial nociception, which is abolished by specifically blocking touch transmission from thalamus to the barrel cortex (S1B). The presence of whisking altered nociceptive signal processing in S1B neurons. Intrinsic manifold analysis of S1B population activity revealed that whisking pushes the transition of neural state induced by noxious stimuli towards the state encoding non-nocifensive actions. Thus, S1B integrates facial tactile and noxious signals to enable touch mediated analgesia.

Teaser

Vibrotactile signals modulate barrel cortex population dynamics during touch mediated facial analgesia
PvC3H29 interacts with and inhibits DNA binding of PvNAPs to finetune leaf senescence in switchgrass (Panicum virgatum)
Authors: Xie Zheni , Yu Guohui , Lei Shanshan , Wang Hui , Xu Bin
Published: April 2022

Finetuning the progression of leaf senescence is important for plant’s fitness in nature, while ‘staygreen’ with delayed leaf senescence has been considered as a valuable agronomic trait in crop genetic improvement. In this study, a switchgrass CCCH-type Zinc finger gene, PvC3H29, was characterized as a suppressor of leaf senescence that over-expressing or suppressing the gene led to delayed or accelerated leaf senescence, respectively. Transcriptomic analysis marked that chlorophyll catabolic pathway genes were involved in the PvC3H29-regulated leaf senescence. PvC3H29 was a nucleus-localized protein with no transcriptional activity. By Y2H screening, we identified its interacting proteins, including a pair of paralogous transcription factors, PvNAP1&2. Over-expressing the PvNAPs led to precocious leaf senescence at least partially by directly targeting and transactivating chlorophyll catabolic genes to promote chlorophyll degradation. PvC3H29, through protein-protein interaction, repressed the DNA-binding efficiency of PvNAPs and alleviated its transactivating effect on downstream genes, thereby functioned as a ‘brake’ in the progression of leaf senescence. Moreover, over-expressing PvC3H29 resulted in up to 47% higher biomass yield and improved biomass feedstock quality, reiterating the importance of leaf senescence regulation in the genetic improvement of switchgrass and other feedstock crops.

One-sentence summary

PvC3H29 interacts with transcription factors, PvNAP1&2, to inhibit their transactivation on chlorophyll catabolism and leaf senescence in switchgrass.
Supervised spatial inference of dissociated single-cell data with SageNet
Authors: Heidari Elyas , Lohoff Tim , Tyser Richard C. V. , Marioni John C. , Robinson Mark D. , Ghazanfar Shila
Published: April 2022

Spatially-resolved transcriptomics uncovers patterns of gene expression at supercellular, cellular, or subcellular resolution, providing insights into spatially variable cellular functions, diffusible morphogens, and cell-cell interactions. However, for practical reasons, multiplexed single cell RNA-sequencing remains the most widely used technology for profiling transcriptomes of single cells, especially in the context of large-scale anatomical atlassing. Devising techniques to accurately predict the latent physical positions as well as the latent cell-cell proximities of such dissociated cells, represents an exciting and new challenge. Most of the current approaches rely on an ‘autocorrelation’ assumption, i.e., cells with similar transcriptomic profiles are located close to each other in physical space and vice versa. However, this is not always the case in native biological contexts due to complex morphological and functional patterning. To address this challenge, we developed SageNet, a graph neural network approach that spatially reconstructs dissociated single cell data using one or more spatial references. SageNet first estimates a gene-gene interaction network from a reference spatial dataset. This informs the structure of the graph on which the graph neural network is trained to predict the region of dissociated cells. Finally, SageNet produces a low-dimensional embedding of the query dataset, corresponding to the reconstructed spatial coordinates of the dissociated tissue. Furthermore, SageNet reveals spatially informative genes by extracting the most important features from the neural network model. We demonstrate the utility and robust performance of SageNet using molecule-resolved seqFISH and spot-based Spatial Transcriptomics reference datasets as well as dissociated single-cell data, across multiple biological contexts. SageNet is provided as an open-source python software package at https://github.com/MarioniLab/SageNet.
Rare Monoclonal Antibody Discovery Based on Indirect Competitive Screening of Single Hapten-specific Rabbit Antibody Secreting Cell
Authors: Li Yuan , Li Peipei , Ke Yuebin , Yu Xuezhi , Yu Wenbo , Wen Kai , Shen Jianzhong , Wang Zhanhui
Published: April 2022

Rare antibody that is able to tolerate physio-chemical factors is preferred and highly demanded in diagnosis and therapy. Rabbit monoclonal antibodies (RmAbs) are distinguished owing to their high affinity and stability. However, the efficiency and availability of traditional methods for RmAb discovery are limited, especially for small molecules. Here, we present an indirect competitive screening method in nanowells, named CSMN, for single rabbit antibody secreting cells (ASCs) selection with 20.6 h and proposed an efficient platform for RmAb production against small molecule with 5.8 days for the first time. Chloramphenicol (CAP) as an antibacterial agent has the great threats for public health. We applied the CSMN to select CAP-specific ASCs and produced one high affinity RmAb, surprisingly showing extremely halophilic properties with an IC50of 0.08 ng mL-1in saturated salt solution which has as yet not been shown by other antibodies. Molecular dynamic simulation showed that the negatively charged surface improved the stability of the RmAb structure with additional disulfide bonds compared with mouse antibody. Moreover, the reduced solvent accessible surface area of the binding pocket increased the interactions of RmAb with CAP in a saturated salt solution. Furthermore, the RmAb was used to develop an immunoassay for the detection of CAP in real biological samples with simple pretreatment, shorter assay time, and higher sensitivity. The results demonstrated that the practical and efficient CSMN is suitable for rare RmAb discovery against small molecules.
Biological misinterpretation of transcriptional signatures in tumour samples can unknowingly undermine mechanistic understanding and faithful alignment with preclinical data
Authors: Fisher Natalie C , Byrne Ryan M , Leslie Holly , Wood Colin , Legrini Assya , Cameron Andrew J , Ahmaderaghi Baharak , Corry Shania , Malla Sudhir , Amirkhah Raheleh , McCooey Aoife , Rogan Emily , Redmond Keara L , Sakhnevych Svetlana , Domingo Enric , Jackson James , Loughrey Maurice B , Leedham Simon , Maughan Tim , Lawler Mark , Sansom Owen J , Lamrock Felicity , Koelzer Viktor H , Jamieson Nigel , Dunne Philip D
Published: April 2022

Precise mechanism-based gene expression signatures (GESs) have been developed in appropriate in vitro and in vivo model systems, to identify important cancer-related signalling processes. However, some GESs originally developed to represent specific disease processes, primarily with an epithelial cell focus, are being applied to heterogeneous tumour samples where the expression of the genes in the signature may no longer be epithelial-specific. Therefore, unknowingly, even small changes in tumour stroma percentage can directly influence GESs, undermining the intended mechanistic signalling.

Using colorectal cancer as an exemplar, we deployed numerous orthogonal profiling methodologies, including laser capture microdissection, flow cytometry, bulk and multiregional biopsy clinical samples, single cell RNAseq and finally spatial transcriptomics, to perform a comprehensive assessment of the potential for the most widely-used GESs to be influenced, or confounded, by stromal content in tumour tissue. To complement this work, we generated a freely-available resource, ConfoundR; https://confoundr.qub.ac.uk/, that enables users to test the extent of stromal influence on an unlimited number of the genes/signatures simultaneously across colorectal, breast, pancreatic, ovarian and prostate cancer datasets.

Findings presented here demonstrate the clear potential for misinterpretation of the meaning of GESs, due to widespread stromal influences, which in-turn can undermine faithful alignment between clinical samples and preclinical data/models, particularly cell lines and organoids, or tumour models not fully recapitulating the stromal and immune microenvironment. As such, efforts to faithfully align preclinical models of disease using phenotypically-designed GESs must ensure that the signatures themselves remain representative of the same biology when applied to clinical samples.
Chloroplasts in plant cells show active glassy behavior under low light conditions
Authors: Schramma Nico , Israëls Cintia Perugachi , Jalaal Maziyar
Published: April 2022

Plants have developed intricate mechanisms to adapt to changing light conditions. Besides photo- and heliotropism (the differential growth towards light and the diurnal motion with respect to sunlight), chloroplast motion acts as a fast mechanism to change the intracellular structure of leaf cells. While chloroplasts move towards the sides of the plant cell to avoid strong light, they accumulate and spread out into a layer on the bottom of the cell at low light to increase the light absorption efficiency. Although the motion of chloroplasts has been studied for over a century, the collective organelle-motion leading to light adapting self-organized structures remains elusive. Here, we study the active motion of chloroplasts under dim light conditions, leading to an accumulation in a densely packed quasi-2D layer. We observe burst-like re-arrangements and show that these dynamics resemble systems close to the glass transition by tracking individual chloroplasts. Furthermore, we provide a minimal mathematical model to uncover relevant system parameters controlling the stability of the dense configuration of chloroplasts. Our study suggests that the meta-stable caging close to the glass-transition in the chloroplast mono-layer serves a physiological relevance: chloroplasts remain in a spread-out configuration to increase the light uptake, but can easily fluidize when the activity is increased to efficiently rearrange the structure towards an avoidance state. Our research opens new questions about the role that dynamical phase transitions could play in self-organized intracellular responses of plant cells towards environmental cues.
3DPolyS-LE: an accessible simulation framework to model the interplay between chromatin and loop extrusion
Authors: Gitchev Todor , Zala Gabriel , Meister Peter , Jost Daniel
Published: April 2022

Motivation

Recent studies suggest that the loop extrusion activity of Structural Maintenance of Chromosomes complexes is central to proper organization of genomes in vivo. Polymer physics-based modeling of chromosome structure has been instrumental to assess which structures such extrusion can create. Only few laboratories however have the technical and computational expertise to create in silico models combining dynamic features of chromatin and loop extruders.

Results

Here we present 3DPolyS-LE, a self-contained, easy to use modeling and simulation framework allowing non-specialists to ask how specific properties of loop extruders and boundary elements impact on 3D chromosome structure. 3DPolyS-LE also provides algorithms to compare predictions with experimental Hi-C data.

Availability and implementation

Software available at https://gitlab.com/togop/3DPolyS-LE ; implemented in Python and Fortran 2003 and supported on any Unix-based operating system (Linux, Mac OS).

Contact

peter.meister@unibe.ch and daniel.jost@ens-lyon.fr

Supplementary Information

Supplemental data are available at Bioinformatics online
Meta-analysis using new methods for three-stressor combinations reveal substantial higher-order interactions and emergent properties
Authors: Diamant Eleanor S. , Boyd Sada , Lozano-Huntelman Natalie Ann , Enriquez Vivien , Kim Alexis R. , Savage Van M. , Yeh Pamela J.
Published: April 2022

Although natural populations are typically subjected to multiple stressors, most past research has focused on single stressors and two-stressor interactions, with little attention paid to higher-order interactions among three or more stressors. However, higher-order interactions increasingly appear to be widespread. Consequently, we used a recently introduced and improved framework to re-analyze higher-order ecological interactions. We conducted a literature review of the last 100 years (1920-2020) and reanalyzed 151 ecological three-stressor interactions from 45 published papers. We found that 89% (n=134) of the three-stressor combinations resulted in new or different interactions than previously reported. We also found substantial levels of emergent properties— interactions that are only revealed when all three stressors are present. Antagonism was the most prevalent net interaction whereas synergy was the most prevalent emergent interaction. Understanding multiple stressor interactions is crucial for fundamental questions in ecology and also has implications for conservation biology and population management.