bluuebunny/crossref_metadata_2025 huggingface dataset:
Can a Situational Judgment Test Identify Trainees at Risk of Professionalism Issues? A Multi-Institutional, Prospective Cohort Study
Authors: Cullen Michael J. , Zhang Charlene , Sackett Paul R. , Thakker Krima , Young John Q.
Published: May 2022

Purpose

To determine whether overall situational judgment test (SJT) scores are associated with programs’ clinical competency committee (CCC) ratings of trainee professionalism, any concerning behavior, and concerning behavior requiring active remediation at 2 time periods.

Method

In fall 2019, trainees from 17 U.S. programs (16 residency, 1 fellowship) took an online 15-scenario SJT developed to measure 7 dimensions of professionalism. CCC midyear and year-end (6 months and 1 year following SJT completion, respectively) professionalism scores and concern ratings were gathered for academic year 2019–2020. Analyses were conducted to determine whether overall SJT scores related to overall professionalism ratings, trainees displaying any concerns, and trainees requiring active remediation at both time periods.

Results

Overall SJT scores correlated positively with midyear and year-end overall professionalism ratings (r = .21 and .14, P < .001 and = .03, respectively). Holding gender and race/ethnicity constant, a 1 standard deviation (SD) increase in overall SJT score was associated with a .20 SD increase in overall professionalism ratings at midyear (P = .005) and a .22 SD increase at year-end (P = .001). Holding gender and race/ethnicity constant, a 1 SD increase in overall SJT score decreased the odds of a trainee displaying any concerns by 37% (odds ratio [OR] 95% confidence interval [CI]: [.44, .87], P = .006) at midyear and 34% (OR 95% CI: [.46, .95], P = .025) at year-end and decreased the odds of a trainee requiring active remediation by 51% (OR 95% CI: [.25, .90], P = .02) at midyear.

Conclusions

Overall SJT scores correlated positively with midyear and year-end overall professionalism ratings and were associated with whether trainees exhibited any concerning behavior at midyear and year-end and whether trainees needed active remediation at midyear. Future research should investigate whether other potential professionalism measures are associated with concerning trainee behavior.
Early Neurodevelopmental Outcomes Following Exposure to General Anesthesia in Infancy: EGAIN, a Prospective Cohort Study
Authors: Bong Choon Looi , Ho Duncun , Allen John Carson , Lim Gillian Si-Min , Tan Hong-Kuang , Broekman Birit F.P. , Fabila Teddy , Reddy Satish , Koh Woon-Puay , Swee-Kim Tan Josephine , Meaney Michael , Rifkin-Graboi Anne
Published: May 2022

Background:

General anesthesia (GA) is known to worsen neural outcomes in animals, but human research assessing early-life GA exposure and neurodevelopment show inconsistent findings. We investigated the effects of a single GA exposure for minor surgery on the neurodevelopment of healthy children at multiple time-points, using clinical assessments along with behavioral and neurophysiological measures rarely used in human research.

Methods:

GA-exposed children were a prospective cohort of 250 full-term, healthy infants who underwent GA for minor surgery before 15 months. Nonexposed children were from a separate cohort of similar age, sex, ethnicity, and maternal education. In both cohorts, clinical measures (Bayley Scales of Infant and Toddler Development-III [BSID-III] and Child Behavior Checklist [CBCL1½-5]) were assessed at 24 months, and experimental tests (memory and attentional) and neurophysiology (event-related potentials) at 6 and 18 months.

Results:

At 24 months, there were no differences between GA-exposed and nonexposed children in the cognitive, language, motor, and socioemotional domains of the BSDI-III; however, GA-exposed children had poorer parental-reported scores in BSID-III general adaptability (94.2 vs. 99.0 [mean difference, 4.77; 97.3% confidence interval, −9.29, −0.24]; P=0.020) and poorer internalizing behavior scores on CBCL1½-5 (52.8 vs. 49.4 [mean difference, 3.35; 97.3% confidence interval, 0.15-6.55]; P=0.021). For experimental measures, GA-exposed children showed differences in 4 tests at 6 and 18 months.

Conclusions:

GA-exposed children did not differ from unexposed children in cognitive, language or motor outcomes at 24 months, but exhibited poorer parent-reported behavior scores. Differences in infant behavior and neurophysiology were detected at 6 and 18 months. Neurophysiological assessments may complement clinically relevant assessments to provide greater insights into neurodevelopment following early GA exposure.
Proteomics of Coagulopathy Following Injury Reveals Limitations of Using Laboratory Assessment to Define Trauma-Induced Coagulopathy to Predict Massive Transfusion
Authors: Moore Hunter B. , Neal Matthew D. , Bertolet Marnie , Joughin Brian A. , Yaffe Michael B. , Barrett Christopher D. , Bird Molly A. , Tracy Russell P. , Moore Ernest E , Sperry Jason L. , Zuckerbraun Brian S. , Park Myung S. , Cohen Mitchell J. , Wisniewski Stephen R. , Morrissey James H. ,   TACTIC Investigators
Published: May 2022

Objective:

Trauma-induced coagulopathy (TIC) is provoked by multiple mechanisms and is perceived to be one driver of massive transfusions (MT). Single laboratory values using prothrombin time (INR) or thrombelastography (TEG) are used to clinically define this complex process. We used a proteomics approach to test whether current definitions of TIC (INR, TEG, or clinical judgment) are sufficient to capture the majority of protein changes associated with MT.

Methods:

Eight level I trauma centers contributed blood samples from patients available early after injury. TIC was defined as INR >1.5 (INR-TIC), TEG maximum amplitude <50 mm (TEG-TIC), or clinical judgment (Clin-TIC) by the trauma surgeon. MT was defined as >10 units of red blood cells in 24 hours or >4 units RBC/hour during the first 4 hours. SomaLogic proteomic analysis of 1305 proteins was performed. Pathways associated with proteins dysregulated in patients with each TIC definition and MT were identified.

Results:

Patients (n = 211) had a mean injury severity score of 24, with a MT and mortality rate of 22% and 12%, respectively. We identified 578 SOMAscan analytes dysregulated among MT patients, of which INR-TIC, TEG-TIC, and Clin-TIC patients showed dysregulation only in 25%, 3%, and 4% of these, respectively. TIC definitions jointly failed to show changes in 73% of the protein levels associated with MT, and failed to identify 26% of patients that received a massive transfusion. INR-TIC and TEG-TIC patients showed dysregulation of proteins significantly associated with complement activity. Proteins dysregulated in Clin-TIC or massive transfusion patients were not significantly associated with any pathway.

Conclusion:

These data indicate there are unexplored opportunities to identify patients at risk for massive bleeding. Only a small subset of proteins that are dysregulated in patients receiving MT are statistically significantly dysregulated among patients whose TIC is defined based solely on laboratory measurements or clinical assessment.
The utility of routine dual-energy x-ray absorptiometry scans in matched-pair cadaveric biomechanical trauma research
Authors: Black Natalie R. , Morris Randal P. , Chen Jie
Published: May 2022

Background:

Performing cadaveric dual-energy x-ray absorptiometry (DEXA) scanning is a routine part of orthopaedic biomechanical research, but it is not without cost. Matched pairs are often used in biomechanical studies to further equalize comparison groups. Despite the widespread use of matched-pair analysis, the practical utility of obtaining routine DEXA scans remains unknown. The authors’ objective was to determine the value of DEXA scans in biomechanical cadaveric trauma studies.

Methods:

The authors identified 10 sequential journal articles from the Journal of Orthopaedic Trauma from February 2013 to February 2019 that were biomechanical studies with two comparison groups using matched pairs, which were DEXA-scanned prior to experimentation. For each study, the authors determined the number of pairs used, number of pairs discarded, any significant differences in bone density between groups compared, and how density results were reported for individual specimens or pairs.

Results:

None of the 113 matched pairs reported in these studies were discarded because of DEXA scan results. There were inconsistencies between studies on reported units of measurement and how the specimens were compared. No significant differences in density between the compared groups were reported in the 10 studies. No studies disclosed the bone density for any individual specimen or score difference for any individual pair.

Conclusions:

As currently used in the literature, routine DEXA scans of cadaveric matched-pair specimens do not typically lead to any modification of experimental design or reporting of results.

Level of Evidence:

Level IV.
Percutaneous Reduction and Provisional Pinning of the Distal Fibula: A Novel Way to Maintain Fibular Length in Temporary Stabilization
Authors: Roper Brennan , Ahmad Heba , Gary Joshua L.
Published: May 2022

Summary:

Ankle fractures are commonly observed by orthopaedic trauma surgeons, foot and ankle surgeons, and general orthopaedists with more than 135,000 fractures surgically treated every year in the United States.
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The soft tissue envelope surrounding the osseous anatomy of the ankle is limited and many injuries, including those that result from higher injury mechanisms and/or those occurring in hosts with vascular and metabolic comorbidities may benefit from a delay in definitive fixation; this may minimize risks of wound healing issues and fracture-related infection.
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Open fractures may benefit from temporizing fixation after debridement and irrigation for the same reasons.
4–6

The benefits of temporizing external fixation in pilon fractures has been recognized for decades.
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The use of ankle-spanning external fixation for ankle fractures and dislocations has become more frequently used to maintain coronal and sagittal alignment of the ankle mortise as a bridge to definitive fixation.
8–10

However, standard ankle-spanning external fixation techniques do not always directly restore fibular length and rotation, especially in fracture patterns with syndesmotic disruption and/or segmental fibular comminution. Some authors have advocated for limited internal fixation of fibula fractures at time of external fixation application to address this problem,
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but this still necessitates a surgical approach through a traumatized soft tissue envelope and potentially compromises posterolateral and anterolateral approaches that could be used to address associated Volkman or Chaput fragments. Delayed distal fibular open reduction and internal fixation of shortened fractures has frustrated orthopaedic surgeons for decades and techniques such as “push–pull” screws
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and extensive soft tissue dissection
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are often necessary to restore anatomic fibular reduction of length and rotation. Given these challenges, the senior author began to use a technique of percutaneous reduction and buried provisional pinning of the distal fibula to the talus for fibula fractures with persistent shortening after ankle-spanning external fixation of injuries not deemed appropriate for immediate open reduction and internal fixation. We aim to report early results and describe this novel, low-cost surgical technique.
Where Are the New Federally Qualified Health Center Sites? Uncovering FQHC Expansion and Ambulatory Care Policy Implications
Authors: Choi Seongwon , Davlyatov Ganisher , Opoku-Agyeman William
Published: May 2022

So-called “geographic expansion race,” health care organizations expand physical facilities to different geographical locations as a way to foster growth. This study furthers knowledge on Federally Qualified Health Centers' (FQHCs') geographical expansion in relation to the local market's payer mix. The results indicated that areas with a higher proportion of Medicaid patients with fewer uninsured are more likely to see new FQHC sites opening. The findings are consistent with previous literature on the health care organization's geographical expansion and also indicated that some areas might lack proper FQHC services despite the high needs.
Addressing Medical and Social Needs to Reduce Unnecessary Health Care Utilization and Costs
Authors: Liss David T. , Guzman Adriana , Walsh Emily E. , Shaunfield Sara , Brown Tiffany
Published: May 2022

This study explored the goals, and care delivery approaches, of 14 interventions to address patients' medical and social needs. In qualitative interviews with clinicians and researchers, several themes emerged. Participants frequently described their overall goal as meeting patients' diverse needs to prevent avoidable acute care utilization. Medical needs were addressed by ensuring patients received primary care and actively coordinating care across clinical settings. Participants perceived social needs as tightly linked with medical needs, as well as a need for interpersonal skills among intervention staff. Descriptions of overall approaches to meeting patients' needs frequently aligned with principles of trauma-informed care and patient-centered care.
Factors Associated With Patient-Centered Medical Home Teams' Use of Resources for Identifying and Approaches for Managing Patients With Complex Needs
Authors: Stockdale Susan E. , Rose Danielle E. , McClean Michael , Rosland Ann-Marie , Chang Evelyn T. , Zulman Donna M. , Stewart Gregory , Nelson Karin M.
Published: May 2022

Using data from a Veterans Health Administration national primary care survey, this study identified the most highly rated tools and care approaches for patients with complex needs and how preferences varied by professional role, staffing, and training. Nurses were significantly more likely to rate most tools as very important as compared with primary care providers. Having a fully staffed team was also significantly associated with a very important rating on all tools. Nurses and fully staffed teams reported a greater likeliness to use most care approaches, and those with perceived need for training reporting a lower likeliness to use.
Employers' Perspectives on the Use of Medical Assistant Apprenticeships
Authors: Jopson Andrew D. , Cummings Allison G. , Frogner Bianca K. , Skillman Susan M.
Published: May 2022

Medical assistants (MAs) are among the fastest-growing occupations in the United States, yet health care employers report high turnover rates and difficulty filling MA positions. Employers are increasingly using apprenticeship to meet emerging workforce needs. This qualitative study examined the perspectives of 14 employers using registered MA apprenticeships in 8 states. The findings revealed motivations for using apprenticeship, perceived benefits to the organization, challenges with implementation, and reflections on successful implementation. We detail how MA apprenticeship is successfully meeting recruitment and training needs in a variety of health care organizations, especially where program support resources are available.
Update in Management of Craniosynostosis
Authors: Xue Amy S. , Buchanan Edward P. , Hollier Larry H.
Published: May 2022

Learning Objectives:

After studying this article, the participant should be able to: 1. Understand the craniofacial dysmorphology of craniosynostosis, and the variation of each type. 2. Identify the functional concerns and learn the rationale behind timing of operative intervention. 3. Approach each dysmorphology critically and identify the operative intervention needed to improve form and function 4. Understand and address the specific issues related to syndromic craniosynostosis and be able to delineate management plan.

Craniosynostosis is a condition in which premature fusion of one or more cranial sutures lead to abnormal head shape and growth restriction of the brain. Nonsyndromic craniosynostosis occurs in isolation, and usually involves a single suture, whereas syndromic craniosynostosis may involve multiple sutures and is associated with extracraniofacial findings. Although surgical management can be similar, the treatment plan must take into consideration issues specific to the syndromes. This article aims to provide a concise overview of the authors’ current understanding regarding the presentation, treatment principle, surgical option, and debates in craniosynostosis.
Nonreplantable Total Scalp Avulsion Reconstruction with Acellular Biologic Matrix and Long-Term Outcome
Authors: Anderson Spencer R. , Gupta Nishtha , Johnson R. Michael
Published: May 2022

Total scalp avulsion is a significant injury typically occurring as a result of industrial accidents involving high-speed rotary machines. Although ideal, scalp replantation is uncommon secondary to the nature of the injury and lack of viable microvas-cular anastomosis targets. Therefore, these defects are often reconstructed with microvascular free tissue transfer, with or without skin grafting. We present a unique case of a patient with total scalp avulsion achieving complete, stable skin coverage over partially intact periosteum using only spare parts of the amputated scalp as a temporary full-thickness graft and porcine urinary bladder matrix, thus, avoiding significant donor site morbidity or extensive surgery. At 4 years postoperative, the scalp coverage remains stable.
Burn Injury-Induced Extracellular Vesicle Production and Characteristics
Authors: Yang Xiaoyuan , Chatterjee Victor , Zheng Ethan , Reynolds Amanda , Ma Yonggang , Villalba Nuria , Tran Thanh , Jung Michelle , Smith David J. , Wu Mack H. , Yuan Sarah Y.
Published: May 2022

Extracellular vesicles (EVs) are nano-sized membrane-bound particles containing biologically active cargo molecules. The production and molecular composition of EVs reflect the physiological state of parent cells, and once released into the circulation, they exert pleiotropic functions via transferring cargo contents. Thus, circulating EVs not only serve as biomarkers, but also mediators in disease processes or injury responses. In the present study, we performed a comprehensive analysis of plasma EVs from burn patients and healthy subjects, characterizing their size distribution, concentration, temporal changes, cell origins, and cargo protein contents. Our results indicated that burn injury induced a significant increase in circulating EVs, the response peaked at the time of admission and declined over the course of recovery. Importantly, EV production correlated with injury severity, as indicated by the total body surface area and depth of burn, requirement for critical care/ICU stay, hospitalization length, wound infection, and concurrence of sepsis. Burn patients with inhalation injury showed a higher level of EVs than those without inhalation injury. We also evaluated patient demographics (age and sex) and pre-existing conditions (hypertension, obesity, and smoking) and found no significant correlation between these conditions and overall EV production. At the molecular level, flow cytometric analysis showed that the burn-induced EVs were largely derived from leukocytes and endothelial cells (ECs), which are known to be activated postburn. Additionally, a high level of zona-occludens-1 (ZO-1), a major constituent of tight junctions, was identified in burn EV cargos, indicative of injury in tissues that form barriers via tight junctions. Moreover, when applied to endothelial cell monolayers, burn EVs caused significant barrier dysfunction, characterized by decreased transcellular barrier resistance and disrupted cell–cell junction continuity. Taken together, these data suggest that burn injury promotes the production of EVs containing unique cargo proteins in a time-dependent manner; the response correlates with injury severity and worsened clinical outcomes. Functionally, burn EVs serve as a potent mediator capable of reducing endothelial barrier resistance and impairing junction integrity, a pathophysiological process underlying burn-associated tissue dysfunction. Thus, further in-depth characterization of circulating EVs will contribute to the development of new prognostic tools or therapeutic targets for advanced burn care.
Critical roles for EGFR and EGFR–HER2 clusters in EGF binding of SW620 human carcinoma cells
Authors: Wollman Adam J. M. , Fournier Charlotte , Llorente-Garcia Isabel , Harriman Oliver , Payne-Dwyer Alex L. , Shashkova Sviatlana , Zhou Peng , Liu Ta-Chun , Ouaret Djamila , Wilding Jenny , Kusumi Akihiro , Bodmer Walter , Leake Mark C.
Published: May 2022

Epidermal growth factor (EGF) signalling regulates normal epithelial and other cell growth, with EGF receptor (EGFR) overexpression reported in many cancers. However, the role of EGFR clusters in cancer and their dependence on EGF binding is unclear. We present novel single-molecule total internal reflection fluorescence microscopy of (i) EGF and EGFR in living cancer cells, (ii) the action of anti-cancer drugs that separately target EGFR and human EGFR2 (HER2) on these cells and (iii) EGFR–HER2 interactions. We selected human epithelial SW620 carcinoma cells for their low level of native EGFR expression, for stable transfection with fluorescent protein labelled EGFR, and imaged these using single-molecule localization microscopy to quantify receptor architectures and dynamics upon EGF binding. Prior to EGF binding, we observe pre-formed EGFR clusters. Unexpectedly, clusters likely contain both EGFR and HER2, consistent with co-diffusion of EGFR and HER2 observed in a different model CHO-K1 cell line, whose stoichiometry increases following EGF binding. We observe a mean EGFR : EGF stoichiometry of approximately 4 : 1 for plasma membrane-colocalized EGFR–EGF that we can explain using novel time-dependent kinetics modelling, indicating preferential ligand binding to monomers. Our results may inform future cancer drug developments.
A combination of red structural and pigmentary coloration in the eyespot of a copepod
Authors: Justyn Nicholas M. , Heine Kyle B. , Hood Wendy R. , Peteya Jennifer A. , Vanthournout Bram , Debruyn Gerben , Shawkey Matthew D. , Weaver Ryan J. , Hill Geoffrey E.
Published: May 2022

While the specific mechanisms of colour production in biological systems are diverse, the mechanics of colour production are straightforward and universal. Colour is produced through the selective absorption of light by pigments, the scattering of light by nanostructures or a combination of both. WhenTigriopus californicuscopepods were fed a carotenoid-limited diet of yeast, their orange-red body coloration became faint, but their eyespots remained unexpectedly bright red. Raman spectroscopy indicated a clear signature of the red carotenoid pigment astaxanthin in eyespots; however, refractive index matching experiments showed that eyespot colour disappeared when placed in ethyl cinnamate, suggesting a structural origin for the red coloration. We used transmission electron microscopy to identify consecutive nanolayers of spherical air pockets that, when modelled as a single thin film layer, possess the correct periodicity to coherently scatter red light. We then performed microspectrophotometry to quantify eyespot coloration and confirmed a distinct colour difference between the eyespot and the body. The observed spectral reflectance from the eyespot matched the reflectance predicted from our models when considering the additional absorption by astaxanthin. Together, this evidence suggests the persistence of red eyespots in copepods is the result of a combination of structural and pigmentary coloration.
Two Nobel laureates in conversation: Robert Robinson listens to Dorothy Hodgkin's account of her life scientific
Authors: Butler Stella V. F.
Published: May 2022

In 1974 the Nobel laureate Sir Robert Robinson OM PRS (1886–1975) was gathering information for the memoirs he was writing. As part of his research, he recorded a conversation with his former student, fellow Nobel laureate Professor Dorothy Hodgkin OM FRS (1910–1994), during which she outlined the key stages of her career. She explained the principles underlying crystallography and described her work on the structure of biological molecules including penicillin and vitamin B
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—for which she received the Nobel Prize—and on insulin. This paper includes a verbatim transcript of the conversation, which reveals the key figures in Hodgkin's career and the technical breakthroughs which underlay the elucidation of the structure of very large complex molecules. The paper includes a commentary on the value of oral accounts and concludes on the issues raised and not raised during the conversation. Sir Robert was President of the Royal Society between 1945 and 1950 when women were first elected Fellows. Hodgkin was elected in 1947. However, no mention is made of the challenges facing women developing a scientific career in the first half of the twentieth century.
A toy model for the effective density of acoustic metamaterials
Authors: Pierre Juliette , Leroy Valentin , Dollet Benjamin
Published: May 2022

We propose a simple mechanical system that can be used as a toy model for calculating the effective density of acoustic metamaterials. Through analytical calculations, it gives a better understanding of how the effective density can become negative, when the system responds elastically instead of inertially. We show that this toy model can reproduce, qualitatively, the acoustical behaviour of some real acoustic metamaterials.
Regional mortality variations among older adults in India: Evidence from Demographic Health Survey
Authors: Akhtar Saddaf Naaz , Saikia Nandita
Published: May 2022

Background

Studies on regional mortality variations among older adults in India are poorly documented. Therefore, we intend to estimate the impact of individual and district level determinants on regional mortality variations among the older adults in India. Additionally, we have performed decomposition analysis to evaluate the contribution of socioeconomic and demographic factors in the inter-regional mortality variations among older adults in India.

Methods

We performed a two-level logistic regression model using data from Demographic Health Survey (2015-16) for India to quantify the impact of socio-demographic and ecomonic characteristics. We have also analyzed multivariate decomposition approach to determine the role of determinants in regional mortality variations among older adults.

Results

The multilevel analyses results revealed that regional mortality variations exist at both individual and district levels among older adults in India. Our finding identified that older adults living in the Central region have a higher mortality risk than in Northern regions. The decomposition results showed that the Central, Eastern and North-eastern regions have significantly higher average number of excess mortality compared to other regions among older adults. The district-level literacy, insurance coverage, electricity supply and public health facilities also showed a significant impact on district level mortality among older adults in India.

Conclusion

Our study insights extremely important determinants for India’s public health. In order to eliminate these mortality gaps, there is a need for solid support from the state and central government to bridge the socio-demographic and economic development in India at the regional level. As a result, policy should include efforts to improve health outcomes among older adults at early stages.
Genome-wide analyses of early-onset acute myocardial infarction identify 29 novel loci by whole genome sequencing
Authors: Jeon Yeonsu , Jeon Sungwon , Choi Whan-Hyuk , An Kyungwhan , Choi HanSol , Kim Byoung-Chul , Kim Weon , Lee Sang Yeob , Bae Jang-Whan , Hwang Jin-Yong , Kang Min Gyu , Kim Yeonkyung , Kang Younghui , Kim Yeo Jin , Kim Byung Chul , Bhak Jong , Shin Eun-Seok
Published: May 2022

Early-onset acute myocardial infarction (AMI) may have a higher genetic predisposition than late-onset AMI does. The present study aimed to identify and characterize germline variants that affect early-onset AMI using whole-genome sequencing (WGS). We performed a genome-wide association study based on WGS of 1,239 Koreans, including 596 early-onset AMI patients and 643 healthy individuals. Patients with AMI who underwent percutaneous coronary intervention (PCI) caused by atherothrombotic occlusive lesions were included in the study. A total of 29 novel loci were found to be associated with early-onset AMI. These loci are involved in thrombosis, fibrinolysis, inflammation, and lipid metabolism. One of the associated single nucleotide variants (SNVs), rs1614576, located upstream of PRKCB, is known to be associated with thrombus formation. Additionally, the results revealed a novel locus, rs78631167, located upstream of PLAUR which plays a critical role in regulating plasminogen activation and is related to fibrinolysis. The association between early-onset AMI and rs9357455, which is located upstream of PHACTR1 that regulates inflammation in AMI, was found. Moreover, we could identify a lipid metabolism related genetic risk locus, rs5072, in the APOA1-AS gene. This study provides new evidence supporting the genetic association between early-onset AMI and thrombosis and fibrinolysis, as well as inflammation and lipid metabolism, by analyzing the whole-genome of 596 patients with early-onset AMI who have been treated with PCI. Our findings highlight potential genetic markers for the prediction and management of AMI, as well as for understanding the etiology of AMI.
Predicting recognition between T cell receptors and epitopes using contextualized motifs
Authors: Jokinen Emmi , Dumitrescu Alexandru , Huuhtanen Jani , Gligorijević Vladimir , Mustjoki Satu , Bonneau Richard , Heinonen Markus , Lähdesmäki Harri
Published: May 2022

We introduce TCRconv, a deep learning model for predicting recognition between T-cell receptors and epitopes. TCRconv uses a deep protein language model and convolutions to extract contextualized motifs and provides state-of-the-art TCR-epitope prediction accuracy. Using TCR repertoires from COVID-19 patients, we demonstrate that TCRconv can provide insight into T-cell dynamics and phenotypes during the disease.
Machine learning for lumbar and pelvis kinematics clustering
Authors: Higgins Seth , Dutta Sandipan , Kakar Rumit Singh
Published: May 2022

Clustering algorithms such as k-means and agglomerative hierarchical clustering (HCA) may provide a unique opportunity to analyze time-series kinematic data. Here we present an approach for determining number of clusters and which clustering algorithm to use on time-series lumbar and pelvis kinematic data. Cluster evaluation measures such as silhouette coefficient, elbow method, Dunn Index, and gap statistic were used to evaluate the quality of decision making. The result show that multiple clustering evaluation methods should be used to determine the ideal number of clusters and algorithm suitable for clustering time-series data for each dataset being analyzed.
Porcine placenta extract upregulates ceramide synthase 3 expression via the PPARδ/ILK/Akt/mTOR/STAT3 pathway
Authors: Aioi Akihiro , Muromoto Ryuta , Kashiwakura Jun-ichi , Mogami Sho , Nishikawa Megumi , Ogawa Shigeyuki , Matsuda Tadashi
Published: May 2022

Porcine placenta extract (PPE) is widely accepted as an ingredient in complementary and alternative medicine and previous studies have reported its availability, however, its underlying action mechanism remains unclear. In this study, we investigated the underlying mechanism of porcine placenta extract-induced ceramide synthase 3 upregulation. PPE enhanced the expression of ceramide synthase 3 at both the mRNA and protein levels in HaCaT cells. Moreover, porcine placenta extract-induced ceramide synthase3 upregulation was suppressed by the Akt inhibitor, suggesting the involvement of Akt in the underlying mechanism. As the PI3K inhibitor did not affect porcine placenta extract-induced ceramide synthase 3 upregulation, the factors upstream of Akt were estimated. Inhibition and small interfering RNA experiments demonstrated that the peroxisome proliferator-activated receptors δ (PPAR δ) and integrin-linked kinase (ILK) are involved in the phosphorylation of Akt. Next, we explored the factors downstream of Akt and found that porcine placenta extract induced phosphorylation of the STAT3 while porcine placenta extract-induced upregulation of ceramide synthase 3 was significantly suppressed by the inhibitor of the mTOR, suggesting that the mTOR/STAT3 pathway is involved in the downstream of Akt. These results demonstrate that porcine placenta extract upregulates CerS3 expression via the PPARδ/ILK/Akt/mTOR/STAT3 pathway.
Selective detection of m6A derived from mRNA using the Phospho-tag m6A assay
Authors: Mirza Aashiq H. , Attarwala Nabeel , Gross Steven S. , Chen Qiuying , Jaffrey Samie R.
Published: May 2022

N6-methyladenosine (m6A) is a modified nucleotide found in mRNA, ribosome RNA (rRNA) and small nuclear RNA (snRNA). m6A in mRNA has important roles in regulating mRNA stability, splicing, and other processes. Numerous studies have described m6A as a dynamic modification using mass spectrometry-based quantification of m6A in mRNA samples prepared from different cellular conditions. However, these results have been questioned based on the finding that the mRNA purification protocols often result in varying levels of rRNA contamination. Additionally, mRNA purification protocols disproportionately enrich for the 3’ ends of mRNA, a region that is enriched in m6A. To address these problems, we developed the Phospho-tag m6A assay, a highly efficient method for quantifying m6A specifically from mRNA. In this assay, a series of selective RNase digestion steps is performed, which results in m6A from rRNA and snRNA being liberated as m6A monophosphate, while m6A from mRNA is mostly liberated as m6A nucleoside. m6A levels are normalized to transcript levels, using m7G monophosphate liberated by yDcpS decapping enzyme as a surrogate for mRNA levels. Notably, this approach uses total cellular RNA, rather than purified mRNA, which simplifies the steps for m6A detection and overcomes the 3’-end biases associated with mRNA purification. Overall, the Phospho-tag m6A provides a simple and efficient method for quantification of mRNA-derived m6A from total RNA samples.
Modulation of I-wave generating pathways with repetitive paired-pulse transcranial magnetic stimulation: A TMS-EEG study
Authors: Sasaki Ryoki , Hand Brodie J. , Semmler John G. , Opie George M.
Published: May 2022

Objectives

Repetitive paired-pulse transcranial magnetic stimulation (iTMS) at indirect (I) wave intervals increases motor-evoked potentials (MEPs) produced by TMS to primary motor cortex (M1). However, the effects of iTMS at early and late intervals on the plasticity of specific I-wave circuits remains unclear. The current study therefore aimed to assess how the timing of iTMS influences intracortical excitability within early and late I-wave circuits. To investigate the cortical effects of iTMS more directly, changes due to the intervention were also assessed using combined TMS-electroencephalography (EEG).

Material and Methods

Eighteen young adults (24.6 ± 4.2 years) participated in four sessions in which iTMS targeting early (1.5 ms interval; iTMS1.5) or late (4.0 ms interval; iTMS4.0) I-waves was applied over M1. Neuroplasticity was assessed using both posterior-to-anterior (PA) and anterior-to-posterior (AP) stimulus directions to record MEPs and TEPs before and after iTMS. SICF at inter-stimulus intervals of 1.5 and 4.0 ms was also used to index I-wave activity.

Results

MEP amplitude was increased after iTMS (P < 0.01) and this was greater for PA responses (P < 0.01), but not different between iTMS intervals (P = 0.9). Irrespective of iTMS interval and coil current, SICF was facilitated after the intervention (P < 0.01). While the N45 produced by AP stimulation was reduced by iTMS1.5 (P = 0.04), no other changes in TEP amplitude were observed.

Conclusion

The timing of iTMS failed to influence which I-wave circuits were potentiated by the intervention. In contrast, reductions in the N45 suggest that the neuroplastic effects of iTMS may include disinhibition of intracortical inhibitory processes.
MADET: A Manually Curated Knowledgebase for Microbiomic Effects on Efficacy and Toxicity of Anticancer Treatments
Authors: Zhang Jie , Chen Xiqian , Zou Jiaxin , Li Chen , Kang Wanying , Guo Yang , Liu Sheng , Zhao Wenjing , Mou Xiangyu , Huang Jiayuan , Ke Jia
Published: May 2022

A plethora of studies have reported the associations between microbiota and multiple diseases, leading to at least four databases to demonstrate microbiota-disease associations, i.e., gutMDisorder, mBodyMap, GMrepo and Amadis. Moreover, gut microbiota also mediates drug efficacy and toxicity, whereas a comprehensive database to elucidate the microbiota-drug associations is lacking. Here we report an open-access knowledgebase, MADET (Microbiomics of Anticancer Drug Efficacy and Toxicity), which harbors 453 manually annotated microbiota-drug associations from 24 papers. MADET provides user-friendly functions allowing users to freely browse, search, and download the data conveniently from the database. Users can customize their search filters in MADET using different types of keywords, including bacterial name (e.g., Akkermansia muciniphila), anticancer treatment (e.g., anti-PD-1 therapy) or cancer type (e.g., lung cancer) with different types of experimental evidence of microbiota-drug association and causation. We have also enabled user submission to further enrich the data document in MADET. The MADET database is freely available at https://www.madet.info. We anticipate that MADET will serve as a useful resource for a better understanding of the microbiota-drug associations and facilitate the future development of novel biomarkers and live biotherapeutic products for anticancer therapies.
Combined omic analyses reveal novel loss-of-function NLGN3 variants in GnRH deficiency and autism
Authors: Oleari Roberto , Lettieri Antonella , Manzini Stefano , Paganoni Alyssa , André Valentina , Grazioli Paolo , Busnelli Marco , Duminuco Paolo , Vitobello Antonio , Philippe Christophe , Bizaoui Varoona , Storr Helen L. , Amoruso Federica , Memi Fani , Vezzoli Valeria , Massa Valentina , Scheiffele Peter , Howard Sasha R. , Cariboni Anna
Published: May 2022

Gonadotropin releasing hormone (GnRH) deficiency is a disorder characterized by absent or delayed puberty, with largely unknown genetic causes. The purpose of this study was to obtain and exploit gene expression profiles of GnRH neurons during development to unveil novel biological mechanisms and genetic determinants underlying GnRH deficiency (GD). Here, we combined bioinformatic analyses of primary embryonic and immortalized GnRH neuron transcriptomes with exome sequencing from GD patients to identify candidate causative genes. Among differentially expressed and filtered transcripts, we found loss-of-function (LoF) variants of the autism-linked Neuroligin 3 (NLGN3) gene in two unrelated patients co- presenting with GD and neurodevelopmental traits. We demonstrated that NLGN3 is upregulated in maturing GnRH neurons and that NLGN3 wild type, but not mutant proteins, promotes neuritogenesis when overexpressed in developing GnRH cells. Our data represent proof-of-principle that this complementary approach can identify novel candidate GD genes and demonstrate that LoF NLGN3 variants may contribute to GD. This novel genotype- phenotype correlation implies common genetic mechanisms underlying neurodevelopmental disorders, such as GD and autistic spectrum disorder.
Single-cell profiling identifies a spectrum of human unconventional intraepithelial T lineage cells
Authors: Billiet Lore , De Cock Laurenz , Sanchez Guillem Sanchez , Mayer Rupert L. , Goetgeluk Glenn , De Munter Stijn , Pille Melissa , Ingels Joline , Jansen Hanne , Weening Karin , Pascal Eva , Raes Killian , Bonte Sarah , Kerre Tessa , Vandamme Niels , Seurinck Ruth , Roels Jana , Lavaert Marieke , Van Nieuwerburgh Filip , Leclercq Georges , Taghon Tom , Impens Francis , Menten Björn , Vermijlen David , Vandekerckhhove Bart
Published: May 2022

In the human thymus, a CD10+PD-1+TCRαβ+differentiation pathway diverges from the conventional single positive T cell lineages at the early double positive stage. These cells are phenotypically and functionally similar to murine unconventional intraepithelial lymphocyte (uIEL) precursors. Here, the progeny of the human uIEL lineage was identified in antigen-inexperienced blood. The uIELs in thymus and peripheral blood share a transcriptomic profile, characterized by hallmark transcription factors (i.e.ZNF683andIKZF2), and polyclonal TCR repertoire with autoreactive features, exhibiting a bias towards early TCR alpha chain rearrangements. Single-cell RNA sequencing confirmed a common developmental trajectory between the thymic and peripheral uIELs, and clearly delineated this unconventional lineage in peripheral blood. This population is phenotypically defined as CD3+TCRαβ+CD4-CCR7-CD26-. It contains CD10+recent thymic emigrants, Helios+KIR+CD8+Tregs and CD8αα+T cells. Thus, the uIEL lineage represents a well-defined but heterogeneous, unconventional TCRαβ+lineage mostly confined in human within the CD8 single positive T cells.

Billiet et al. identify the postthymic progeny of the intraepithelial lymphocyte precursors in human based on shared characteristics of the T cell receptor repertoire and the transcriptome. This lineage represents a well-defined but heterogeneous, unconventional TCRαβ+lineage mostly confined within the CD8 single positive T cells.
Improving sequence alignments with AlphaFold2 regardless of structural modeling accuracy
Authors: Baltzis Athanasios , Mansouri Leila , Jin Suzanne , Langer Björn E. , Erb Ionas , Notredame Cedric
Published: May 2022

Protein sequence alignments are essential to structural, evolutionary and functional analysis but their accuracy is often limited by sequence similarity unless molecular structures are available. Protein structures predicted at experimental grade accuracy, as achieved by AlphaFold2, could therefore have a major impact on sequence analysis. Here, we find that multiple sequence alignments estimated on AlphaFold2 predictions are almost as accurate as alignments estimated on experimental structures and significantly superior to sequence-based alignments. We also show that AlphaFold2 structural models of relatively low quality can be used to obtain highly accurate alignments. These results suggest that, besides structure modeling, AlphaFold2 encodes higher-order dependencies that can be exploited for sequence analysis.
Single-Cell RNA Sequencing Reveals the Effects of Chemotherapy on Human Pancreatic Adenocarcinoma and its Tumor Microenvironment
Authors: Werba Gregor , Weissinger Daniel , Kawaler Emily A. , Zhao Ende , Kalfakakou Despoina , Dhara Surajit , Oh Grace , Jing Xiaohong , Beri Nina , Khanna Lauren , Gonda Tamas , Oberstein Paul , Hajdu Cristina , Loomis Cynthia , Heguy Adriana , Sherman Mara H. , Lund Amanda W. , Welling Theodore H. , Dolgalev Igor , Tsirigos Aristotelis , Simeone Diane M.
Published: May 2022

The tumor microenvironment (TME) in pancreatic ductal adenocarcinoma (PDAC) is a complex ecosystem that drives tumor progression; however, in-depth single cell characterization of the PDAC TME and its role in response to therapy is lacking. We performed single-cell RNA sequencing on freshly collected human PDAC samples either before or after chemotherapy. Overall, we found a heterogeneous mixture of basal and classical cancer cell subtypes, along with distinct cancer-associated fibroblast and macrophage subpopulations. Strikingly, classical and basal-like cancer cells exhibited similar transcriptional responses to chemotherapy, and did not demonstrate a shift towards a basal-like transcriptional program among treated samples. We observed decreased ligand-receptor interactions in treated samples, particularly TIGIT on CD8+ T cells and its receptor on cancer cells, and identified TIGIT as the major inhibitory checkpoint molecule of CD8+ T cells. Our results suggest that chemotherapy profoundly impacts the PDAC TME and may promote resistance to immunotherapy.
To β or not to β: Lack of correlation between APC mutation and β-catenin nuclear localization in colorectal cancer
Authors: Bala Pratyusha , Kavadipula Padmavathi , Sarkar Sanjana , Bashyam Murali Dharan
Published: May 2022

Colorectal cancer (CRC) appears to arise from sequential genetic lesions in tumor suppressor genes (APC, SMAD4 and TP53) and oncogenes (KRAS) leading to the classical adenoma to carcinoma progression. Biallelic APC inactivating genetic aberrations are detected in about 70% of early microadenomas implicating APC inactivation as the first genetic hit in CRC. APC is an essential protein of the Wnt ‘destruction complex’; APC inactivation is believed to cause disruption of the complex allowing stabilization and nuclear translocation of β-catenin, resulting in transcriptional activation of cancer-promoting genes. Here, we provide evidence for a surprising lack of correlation between APC mutation and β-catenin nuclear localization in early-onset sporadic rectal cancer samples. β-catenin nuclear localization and APC mutation were validated from serial FFPE sections representing same tumor regions. Several factors including status of KRAS mutation could not explain the absence of β-catenin nuclear localization in tumor samples harboring APC mutation. This lack of correlation was validated in CRC cell lines harboring various APC mutations. Our results provide evidence directly from tumor samples for possible non-canonical role(s) for mutant APC.
Peripheral membrane proteins modulate stress tolerance by safeguarding cellulose synthases
Authors: Kesten Christopher , García-Moreno Álvaro , Amorim-Silva Vítor , Menna Alexandra , Castillo Araceli G. , Percio Francisco , Armengot Laia , Ruiz-Lopez Noemi , Jaillais Yvon , Sánchez-Rodríguez Clara , Botella Miguel A
Published: May 2022

Controlled primary cell wall remodeling adapts plant growth under stressful conditions, but how these changes are conveyed to adjust cellulose synthesis is unknown. Here, we identify the Tetratricopeptide Thioredoxin-Like (TTL) proteins as new members of the cellulose synthase complex (CSC) and describe their unique and hitherto unknown dynamic association with the CSC under cellulose-deficient conditions. We find that TTLs are essential for maintaining cellulose synthesis under salinity stress, establishing a stress-resilient cortical microtubule array, and stabilizing CSCs at the plasma membrane. To fulfill these functions, TTLs interact with Cellulose Synthase1 (CESA1) and engage with cortical microtubules to promote their polymerization. We propose that TTLs function as bridges connecting stress perception with dynamic regulation of cellulose biosynthesis at the plasma membrane.

One Sentence Summary

TTLs are peripheral membrane proteins that maintain the integrity of the cellulose synthase complex upon adverse conditions.