bluuebunny/crossref_metadata_2025_split huggingface dataset:
The West Coast Plastic Surgery Mentorship Program
Authors: Reghunathan Meera , Llaneras Jason , Segal Rachel , Gosman Amanda 
Published: April 2023

Background
Students who are underrepresented in medicine experience limited access to mentorship throughout medical school and when applying to plastic surgery residency. This study describes the creation, growth, and results of the multi-institutional West Coast Plastic Surgery Mentorship Program (WCPSMP), specifically reflecting on barriers to implementation and room for future improvement.

Methods
Students were eligible to apply to the plastic surgery mentorship program if they were first-, second-, or third-year medical students in a US medical school interested in plastic surgery. Preference was given to students who are (1) underrepresented-in-medicine racial/ethnic minorities; (2) first generation, low income; (3) lesbian, gay, bisexual, transgender, queer; and/or (4) without a home integrated plastic surgery program. Preprogram and postprogram surveys were analyzed.

Results
The 2021–2022 cycle of the WCPSMP included 30 resident mentors and 30 resident mentees, with a 1:1 mentor-to-mentee relationship. The second annual Mentor-Mentee Day was hosted on June 25, 2022, in San Diego, California, with attendance from 18 mentees. There was a 63% response rate in the presurvey and postsurvey. Most students endorsed gaining didactic skills, technical skills, and networking, but only a few gained research opportunities.

Conclusion
The WCPSMP is a promising venue to offer underrepresented medical students valuable resident mentorship, as well as acquire surgical knowledge and skills. Further development of the program includes implementing a curriculum for residents on how to be an effective mentor and offering more research opportunities.
Multicenter, Prospective Cohort Study of Oesophageal Injuries and Related Clinical Outcomes (MUSOIC study)
Authors: Owen Richard P. , Chidambaram Swathikan , Griffiths Ewen A , Sultan Javed , Phillips Alexander W , Vohra Ravindra , Preston Shaun , Gossage James , Hanna George B. , Underwood Tim J. , Maynard Nick , Markar Sheraz R. ,   on behalf of the MUSOIC study group
Published: April 2023

Objective:
To identify prognostic factors associated with 90-day mortality in patients with oesophageal perforation (OP), and characterize the specific timeline from presentation to intervention, and its relation to mortality.

Background:
OP is a rare gastro-intestinal surgical emergency with a high mortality rate. However, there is no updated evidence on its outcomes in the context of centralized esophago-gastric services; updated consensus guidelines; and novel non-surgical treatment strategies.

Methods:
A multi-center, prospective cohort study involving eight high-volume esophago-gastric centers (January 2016 to December 2020) was undertaken. The primary outcome measure was 90-day mortality. Secondary measures included length of hospital and ICU stay, and complications requiring re-intervention or re-admission. Mortality model training was performed using random forest, support-vector machines, and logistic regression with and without elastic net regularisation. Chronological analysis was performed by examining each patient’s journey timepoint with reference to symptom onset.

Results:
The mortality rate for 369 patients included was 18.9%. Patients treated conservatively, endoscopically, surgically, or combined approaches had mortality rates of 24.1%, 23.7%, 8.7%, and 18.2%, respectively. The predictive variables for mortality were Charlson comorbidity index, haemoglobin count, leucocyte count, creatinine levels, cause of perforation, presence of cancer, hospital transfer, CT findings, whether a contrast swallow was performed, and intervention type. Stepwise interval model showed that time to diagnosis was the most significant contributor to mortality.

Conclusion
Non-surgical strategies have better outcomes and may be preferred in selected cohorts to manage perforations. Outcomes can be significantly improved through better risk-stratification based on afore-mentioned modifiable risk factors.
Enhancing CAR T cell therapy using Fab-Based Constitutively Heterodimeric Cytokine Receptors
Authors: Righi Matteo , Gannon Isaac , Robson Matthew , Srivastava Saket , Kokalaki Evangelia , Grothier Thomas , Nannini Francesco , Allen Christopher , Yuchen Bai , Sillibourne James , Cordoba Shaun , Thomas Simon , Pule Martin 
Published: April 2023

AbstractAdoptive T cell therapy aims to achieve lasting tumour clearance, requiring enhanced engraftment and survival of the immune cells. Cytokines are paramount modulators of T cell survival and proliferation. Cytokine receptors signal via ligand-induced dimerization, and this principle has been hijacked utilising non-native dimerization domains. A major limitation of current technologies resides in the absence of a module that recapitulates the natural cytokine receptor heterodimeric pairing. To circumvent this, we created a new engineered cytokine receptor able to constitutively recreate receptor-heterodimer utilising the heterodimerization domain derived from the IgG1 antibody (dFab_CCR). We found that the signal delivered by the dFab_CCR-IL2 proficiently mimics the cytokine receptor heterodimerization, with transcriptomic signatures similar to that obtained by the activation of IL2 native receptor. Importantly, we found that this dimerization structure is agnostic, efficiently activating signaling through four cytokine receptor families.Using a combination ofin vivoandin vitroscreening approaches, we characterized a library of 18 dFab_CCRs co-expressed with a clinically relevant solid tumor-specific GD2 CAR. Based on this characterization we suggest that the co-expression of either the common β-chain GMCSF or the IL18 dFab_CCRs is optimal to improve CAR T cell expansion, engraftment, and efficacy.Our results demonstrate how the Fab dimerization is efficient and versatile in recapitulating a cytokine receptor heterodimerization signal. This module could be applied for the enhancement of adoptive T cell therapies, and therapies based on other immune cell types. Furthermore, these results provide a choice of cytokine signal to incorporate with adoptive T cells therapies.
Chimeric protein EWS-FLI1 drives cell proliferation in Ewing Sarcomaviaoverexpression ofKCNN1
Authors: Dupuy Maryne , Gueguinou Maxime , Postec Anaïs , Brion Régis , Tesfaye Robel , Mullard Mathilde , Regnier Laura , Amiaud Jérôme , Potier-Cartereau Marie , Chantôme Aurélie , Royer Bénédicte Brounais-Le , Baud’huin Marc , Georges Steven , Lamoureux François , Ory Benjamin , Delattre Olivier , Rédini Françoise , Vandier Christophe , Verrecchia Franck 
Published: April 2023

AbstractEwing sarcoma (ES) is characterized by chimeric fusion proteins, which act as oncogenes. Over the last decade, patient survival has not increased, especially for high risk patients. Knowing that ion channels are studied for their implication in tumorigenesis, the aim of this work is to study the involvement of the SK1 potassium channels in ES. RNA-Seq analyses showed a high restricted expression ofKCNN1, the gene encoding SK1, only in ES patients, and its expression is inversely correlated with patient survival. EWS-FLI1 silencing demonstrated the regulation ofKCNN1by these fusion proteins, which bind at GGAA microsatellites nearKCNN1promoter. In addition,KCNN1has been shown to be involved in the regulation of ES cell proliferation, its silencing being associated with a slowing of the cell cycle. Finally,KCNN1expression modulates membrane potential and calcium flux suggesting the role of calcium inKCNN1driving cell proliferation. These results highlight thatKCNN1is a direct EWS-FLI1 and EWS-ERG target, and is involved in the regulation of ES cell proliferation, making it an interesting therapeutic target in ES.
Spatial transcriptomics reveal pitfalls and opportunities for the detection of rare high-plasticity breast cancer subtypes
Authors: Coutant Angèle , Cockenpot Vincent , Muller Lauriane , Degletagne Cyril , Pommier Roxane , Tonon Laurie , Ardin Maude , Michallet Marie-Cécile , Caux Christophe , Laurent Marie , Morel Anne-Pierre , Saintigny Pierre , Puisieux Alain , Ouzounova Maria , Martinez Pierre 
Published: April 2023

AbstractBreast cancer is one of the most prominent types of cancers, in which therapeutic resistance is still a major clinical hurdle. Specific subtypes like Claudin-low (CL) and metaplastic breast cancers (MpBC) have been associated with high non-genetic plasticity, which can facilitate resistance. The overlaps and differences between these orthogonal subtypes, respectively identified by molecular and histopathological analyses, are however still insufficiently characterised. Adequate methods to identify high-plasticity tumours to better anticipate resistance are furthermore still lacking. Here we analysed 11 triple negative breast tumours, including 3 CL and 4 MpBC samples,viahigh-resolution spatial transcriptomics. We combined pathological annotations and deconvolution approaches to precisely identify tumour spots, on which we performed signature enrichment, differential expression and copy-number analyses. We used the TCGA and CCLE public databases for external validation of expression markers. By levying spatial transcriptomics to focus analyses only to tumour cells in MpBC samples, and therefore bypassing the negative impact of stromal contamination, we could identify specific markers that are not expressed in other subtypes nor stromal cells. Three markers (BMPER, POPDC3andSH3RF3) could furthermore be validated in external expression databases encompassing bulk tumour material and stroma-free cell lines. We find that existing bulk expression signatures of high-plasticity breast cancers are relevant in mesenchymal transdifferentiated compartments but can be hindered by stromal cell prevalence in tumour samples, negatively impacting their clinical applicability. Spatial transcriptomics analyses can however help identify more specific expression markers, and could thus enhance diagnosis and clinical care of rare high-plasticity breast cancers.
Analysis of Gene Expression Differences Between Eastern and Western Loblolly Pine Seed Sources
Authors: Festa Adam R , Whetten Ross 
Published: April 2023

AbstractThe selection of an appropriate seed source for a given geographic region is critical to ensuring prosperous southern pine plantations. The observed variation between eastern and western loblolly pine seed sources has shown differences in economically advantageous traits such as drought tolerance, growth rates, and disease resistance. Understanding what drives these local adaptations is of interest, given that current forecasted climate modeling suggests there will be increased temperatures and changes to precipitation by the year 2050. The objectives of this experiment were to 1) identify differentially expressed transcripts between eastern and western loblolly pine sources; 2) link these transcripts toArabidopsisorthologs; 3) compare GO categories of differentially-expressed transcripts. The findings highlighted include interesting pathways and genes that are related to the known differences among eastern and western seed provenances. Additionally, they represent fundamental differences in the beginning of seedling development without any treatment or disease pressure applied, showing that there are detectable differences between these two provenances at a young age. Overall, this experiment contributes to the body of literature on fundamental differences between loblolly pine seed sources.
Identification of allele-specific KIV-2 repeats and impact on Lp(a) measurements for cardiovascular disease risk
Authors: Behera S. , Belyeu J. R. , Chen X. , Paulin L. F. , Nguyen N.Q.H. , Newman E. , Mahmoud M. , Menon V. K. , Qi Q. , Joshi P. , Marcovina S. , Rossi M. , Roller E. , Han J. , Onuchic V. , Avery C. L. , Ballantyne C.M. , Rodriguez C. J. , Kaplan R. C. , Muzny D. M. , Metcalf G. A. , Gibbs R. , Yu B. , Boerwinkle E. , Eberle M. A. , Sedlazeck F. J. 
Published: April 2023

AbstractThe abundance of Lp(a) protein holds significant implications for the risk of cardiovascular disease (CVD), which is directly impacted by the copy number (CN) of KIV-2, a 5.5 kbp sub-region. KIV-2 is highly polymorphic in the population and accurate analysis is challenging. In this study, we present the DRAGEN KIV-2 CN caller, which utilizes short reads. Data across 166 WGS show that the caller has high accuracy, compared to optical mapping and can further phase ∼50% of the samples. We compared KIV-2 CN numbers to 24 previously postulated KIV-2 relevant SNVs, revealing that many are ineffective predictors of KIV-2 copy number. Population studies, including USA-based cohorts, showed distinct KIV-2 CN, distributions for European-, African-, and Hispanic-American populations and further underscored the limitations of SNV predictors. We demonstrate that the CN estimates correlate significantly with the available Lp(a) protein levels and that phasing is highly important.
High throughput intracellular delivery by viscoelastic mechanoporation
Authors: Sevenler Derin , Toner Mehmet 
Published: April 2023

AbstractBrief and intense electric fields (electroporation) and/or tensile stresses (mechanoporation) have been used to temporarily permeabilize the plasma membrane of mammalian cells for the purpose of delivering materials to the cytosol. However, electroporation can be harmful to cells, while efficient mechanoporation strategies have not been scalable due to the use of narrow constrictions or needles which are susceptible to clogging. Here we report a method of mechanoporation in which cells were stretched and permeabilized by viscoelastic flow forces without surface contact. Inertio-elastic cell focusing aligned cells to the center of the device, avoiding direct contact with walls and enabling efficient (95%) intracellular delivery to over 200 million cells per minute. Functional biomolecules such as proteins, RNA, and ribonucleoprotein complexes were successfully delivered to Jurkat cells. Efficient intracellular delivery to HEK293T cells and primary activated T cells was also demonstrated. Contact-free mechanoporation using viscoelastic fluid forces appears to be feasible method for efficient and high throughput intracellular delivery of biomolecules to mammalian cellsex vivo.
Interfacial residues in protein-protein complexes are in the eyes of the beholder
Authors: Parvathy Jayadevan , Yazhini Arangasamy , Srinivasan Narayanaswamy , Sowdhamini Ramanathan 
Published: April 2023

AbstractInteractions between proteins are vital in almost all biological processes. The characterization of protein-protein interactions helps us understand the mechanistic basis of biological processes, thereby enabling the manipulation of proteins for biotechnological and clinical purposes. The interface residues of a protein-protein complex are assumed to have the following two properties: a) they always interact with a residue of a partner protein, which forms the basis for distance-based interface residue identification methods, and b) they are solvent-exposed in the isolated form of the protein and become buried in the complex form, which forms the basis for Accessible Surface Area (ASA)-based methods. The study interrogates this popular assumption by recognizing interface residues in protein-protein complexes through these two methods. The study shows that a few residues are identified uniquely by each method, and the extent of conservation, propensities and their contribution to the stability of protein-protein interaction varies substantially between these residues. The case study analyses showed that interface residues, unique to distance, participate in crucial interactions that hold the proteins together, whereas the interface residues unique to the ASA method have a potential role in the recognition, dynamics and specificity of the complex and can also be a hotspot. Overall, the study recommends applying both distance and ASA methods so that some interface residues missed by either method but crucial to the stability, recognition, dynamics and function of protein-protein complexes are identified in a complementary manner.
A Common Cause for Nystagmus in Different Congenital Stationary Night Blindness Mouse Models
Authors: Hölzel Maj-Britt , Winkelman Beerend H. J. , Howlett Marcus H. C. , Kamermans Wouter , De Zeeuw Chris I. , Kamermans Maarten 
Published: April 2023

AbstractInNyxnobmice, a model for congenital nystagmus associated with congenital stationary night blindness (CSNB), synchronous oscillating retinal ganglion cells (RGCs) lead to oscillatory eye movements, i.e., nystagmus. Given the distribution ofmGluR6andCav1.4in the retina as well as their clinical association with CSNB, we hypothesize thatmGluR6-/-andCav1.4-/-mutants show, like theNyxnobmouse, oscillations that originate in the AIIamacrine cells (AIIACs). Using eye movement and multi-electrode array (MEA) recordings of RGCs we show that the nystagmus as well as the underlying RGC oscillations are also present inmGluR6-/-andCav1.4-/-mice. Yet, we find that the oscillations in themGluR6-/-andCav1.4-/-mutants slightly differ from each other and also from those of theNyxnobmice. Moreover, each of the three mutations likely impacts the membrane potential of the AIIACs differently. Together our results indicate that nystagmus and oscillating RGCs are generalizable features associated with CSNB mutations localized at the photoreceptor-bipolar cell synapse.
Identifying the multiple drivers of Cactus diversification
Authors: Thompson Jamie B. , Hernández-Hernández Tania , Keeling Georgia , Priest Nicholas K. 
Published: April 2023

AbstractMany drivers of diversification have been identified across the angiosperm Tree of Life, ranging from abiotic factors, such as climate change, to biotic factors such as key adaptations. While this provides invaluable evolutionary insight into the rise of major angiosperm lineages, our understanding of the complexity underlying this remains incomplete. In species-rich families such as Cactaceae, simple explanations of triggers of diversification are insufficient. Their sheer morphological and ecological diversity, and wide distribution across heterogeneous environments, render the identification of key forces difficult. Cactus diversification is likely shaped by multiple drivers, which themselves interact in complex ways. This complexity is extremely difficult to disentangle, but applying modern analytical methods to extensive datasets offers a solution. Here, we investigate the heterogeneous diversification of the iconic Cactus family. We reconstruct a comprehensive phylogeny, build a dataset of 39 abiotic and biotic variables, and predict the variables of central importance to tip-speciation rate variation using Machine Learning. State-dependent diversification models confirm that a rich range of eleven abiotic and biotic variables filtered as important by Machine Learning shape Cactus diversification. Of highest importance is an atypical latitudinal gradient in speciation rates, which is spatially decoupled from richness hotspots. Of medium importance is plant size, shaped by growth form. Of lesser, but significant, importance is soil composition, bioclimate, topography, geographic range size, and chromosome count. However, it is unlikely that any one of these eleven variables is of primary importance without the complex interactions formed with others. Our results contribute to our understanding of one of the most iconic angiosperm families, while revealing the need to account for the complexity underlying macroevolution.
Dietary zinc protects against methotrexate-induced neurotoxicity in rats via modulation of oxidative stress, inflammation and neuronal energy metabolism
Authors: Onaolapo Adejoke Y. , Okunola Olufemi B , Olofinnade Anthony T. , Onaolapo Olakunle J. 
Published: April 2023

AbstractBackgroundIncreasing incidence of cancers and cancer chemotherapy-induced neurotoxicities makes it imperative to research compounds with neuroprotective potential that can do not impede therapy.ObjectiveTo examine the effect of dietary zinc supplementation on methotrexate-induced changes in neurobehaviour and neurochemistry and hippocampal morphology in rats.MethodsAdult male rats were assigned into five groups of twelve animals each. Group were normal control and methotrexate control fed standard rodent chow and three groups of rats fed zinc supplemented diet at 25, 50 and 100 mg/kg of feed respectively. Standard and zinc supplemented diet were administered daily for 21 days. Animals in the normal control were administered intraperitoneal injection (i.p) of normal saline at 2ml/kg, while those in the methotrexate and zinc groups were administered i.p methotrexate at 20 mg/kg/day on days 19-21. On day 22, animals were exposed to behavioural paradigm (open field, Y-maze, radial arm maze, elevated plus maze and behavioural despair test). After the last behavioural test, animals were sacrificed and blood taken for the assessment of Tumour necrosis factor-α, interleukin 1β and interleukin 10), malondialdehyde levels and total antioxidant capacity. The hippocampus was either homogenised for the assessment of dopamine, serotonin, acetylcholine and brain derived neurotropic factor levels or processed for histological study.ResultsDietary zinc protected against methotrexate-induced changes in weight, food intake, cognition, hippocampal histomorphology and neuron specific enolase immunohistochemistry.ConclusionDietary zinc supplementation protects against methotrexate induced neurotoxicities by modulating oxidative stress, inflammatory markers brain neurotransmitters and metabolism in rats.
Stent For Life Initiative in Portugal: progress through years and Covid-19 Impact
Authors: Pereira Ernesto , Calé Rita , Pereira Angela Maria , Pereira Hélder , Martins Luís Dias 
Published: April 2023

AbstractBackgroundDuring Stent for Life Initiative in Portugal lifetime, positive changes in ST elevation myocardial infarction treatment were observed, by the increase of Primary Angioplasty numbers and improvements in patients’ behaviour towards myocardial infarction, with an increase in those who called 112 and the lower proportion attending non primary percutaneous coronary intervention centres. Despite public awareness campaigns and system educational programmes, patient and system delay did not change significantly over this period. The aim of this study was to address the public awareness campaign effectiveness on peoples’ behaviour facing STEMI, and how Covid-19 has affected STEMI treatment.MethodsData from 1381 STEMI patients were collected during a one-month period each year, from 2011 to 2016, and during one and a half month, matching first lockdown in Portugal 2020. Four groups were constituted: Group A (2011); Group B (2012&2013); Group C (2015&2016) and group D (2020).ResultsThe proportion of patients who called 112, increased significantly (35.2% Group A; 38.7% Group B; 44.0% Group C and 49.6% Group D, p=0.005); significant reduction was observed in the proportion of patients who attended healthcare centres without PPCI (54.5% group A; 47.6% Group B; 43.2% Group C and 40.9% Group D, p=0.016), but there were no differences on groups comparison. Total ischemic time, measured from symptoms onset to reperfusion increased progressively from group A [250.0 (178.0-430.0)] to D [296.0 (201.0 – 457.5.8)] p=0.012, with statistically significant difference between group C and D (p=0.034).ConclusionsDuring the term of SFL initiative in Portugal, patients resorted less to primary health centres and called more to 112. These results can be attributed the public awareness campaign. Nevertheless, patient and system delays did not significantly change over this period, mainly in late years of SFL, probably for low efficacy of campaigns and in 2020 due to Covid-19 pandemic.