bluuebunny/crossref_metadata_2025 huggingface dataset:
Structural basis of unisite catalysis of bacterial F0F1-ATPase
Authors: Nakano Atsuki , Kishikawa Jun-ichi , Nakanishi Atsuko , Mitsuoka Kaoru , Yokoyama Ken
Published: July 2022

Adenosine triphosphate (ATP) synthases (F0F1-ATPases) are crucial for all aerobic organisms. F1, a water-soluble domain, can catalyze both the synthesis and hydrolysis of ATP with the rotation of the central γε rotor inside a cylinder made of α3β3 in three different conformations (referred to as βE, βTP, and βDP). In this study, we determined multiple cryo-electron microscopy structures of bacterial F0F1 exposed to different reaction conditions. The structures of nucleotide-depleted F0F1 indicate that the ε subunit directly forces βTP to adopt a closed form independent of the nucleotide binding to βTP. The structure of F0F1 under conditions that permit only a single catalytic β subunit per enzyme to bind ATP is referred to as unisite catalysis and reveals that ATP hydrolysis unexpectedly occurs on βTP instead of βDP, where ATP hydrolysis proceeds in the steady-state catalysis of F0F1. This indicates that the unisite catalysis of bacterial F0F1 significantly differs from the kinetics of steady-state turnover with continuous rotation of the shaft.
Understanding and Improving the Collection and Use of Diagnostic Test Validation Data: Reflections and Next Steps
Authors: Harrison Catherine , Agstner Barbara , Tomlinson Jenny , Macarthur Roy , van den Berg Femke
Published: July 2022

Although the importance of test validation in a plant health context is widely recognized, it is arguably not yet used to its full potential. This concept note describes the basic concepts underlying test performance and validation, as well as their current interpretation and use by key stakeholder groups. It is argued that, due to a number of communication pitfalls and associated limitations, current approaches are too fragmented and could lead to suboptimal results. Recommendations on how to improve the collection and use of validation data are based on work conducted in the EU VALITEST project (2018 to 2021). A key output of the project is its contribution to the standardization of test performance studies from sample selection and testing to interpreting and communicating test results. In addition, a prototype mathematical framework has been developed, which enables users to more easily consider and communicate trade-offs in test selection and development. The framework provides the basis for a more holistic approach, aiming to streamline collaboration between stakeholder groups.

[Formula: see text] Copyright © 2023 The Author(s). This is an open access article distributed under the CC BY-NC-ND 4.0 International license .
A Primer on Monkeypox Virus for Obstetrician–Gynecologists
Authors: Meaney-Delman Dana M. , Galang Romeo R. , Petersen Brett W. , Jamieson Denise J.
Published: July 2022

Since May 2022, more than 6,900 cases of monkeypox virus infection have been reported in 52 countries. The World Health Organization is planning to rename the virus and its clades to reduce stigma. As of July 5, 2022, 556 cases have been reported in 33 U.S. states and the District of Columbia. The initial cases were travel-associated; however, person-to-person transmission is now occurring domestically. Close, sustained skin-to-skin contact, including during sexual activity, appears to be the primary mode of transmission. The risk of widespread community transmission remains low; however, rapid identification of monkeypox virus infection and isolation of affected individuals is critical to prevent further transmission. Most but not all cases have occurred in males; some infections have started with anogenital lesions and can be mistaken for common sexually transmitted infections. To facilitate rapid, accurate diagnosis of monkeypox virus infection, obstetrician–gynecologists (ob-gyns) in the United States should ask about recent travel history and new ulcers or lesions and perform a thorough visual inspection of skin and mucosal sites (oral, genital, perianal area) in patients presenting with new rash. Obstetrician–gynecologists should become familiar with the appearance of monkeypox lesions and know whom to call to report a suspected case, how and when to test for monkeypox virus, and how to counsel patients. In the event of a suspected case, ob-gyns should follow infection-control guidelines to prevent transmission and make recommendations to prevent further community spread. This article outlines the diagnosis, prevention, and treatment of monkeypox virus infection, monkeypox virus infection during pregnancy, and implications for practicing ob-gyns in the United States.
Adverse Events of Non-Invasive Body Contouring: Analysis of the Food and Drug Administration Manufacturer and User Facility Device Experience Database
Authors: Nguyen Christopher N. , Nguyen Quoc-Bao D. , Hebert Adelaide A. , Gold Michael H.
Published: July 2022

BACKGROUND

Multiple non-invasive modalities have become popular alternatives to surgical procedures for body contouring.

OBJECTIVE

To analyze adverse events (AEs) associated with non-invasive body contouring devices reported through the Manufacturer and User Facility Device Experience (MAUDE) database.

METHODS AND MATERIALS

The MAUDE database were queried for AEs associated with non-invasive body contouring devices between January 2011 and June 2021. An extensive list of keywords and brand and manufacturer names was used.

RESULTS

A total of 1,325 reports with 1,590 AEs were identified among 6 modalities. More than 70% were reported in the past 5 years. Cryolipolysis made up 38.3% reports, which mostly pertained to paradoxical hyperplasia and hernias. Radiofrequency had the most reports (41.9%). Like laser devices, most of their reports described burns. Focused ultrasound was commonly associated with unintentional fat loss and surface irregularities. Focused electromagnetic field resulted in only 7 reports.

CONCLUSION

The analysis of present study supports previous studies concerning common local symptoms caused by these devices, but it also reveals complications not reported in previous device studies. This study highlights the importance of proper technique and adherence to device guidelines. Practitioners should be knowledgeable of potential complications from each device to both prevent and manage them accordingly.
Complex Eyelid Reconstruction: A Practical Guide for the Mohs Surgeon
Authors: Blumenthal Shoshana R. , Swick Marki , Bayan Claire-Audrey , Ramanathan Diya , Maher Ian
Published: July 2022

BACKGROUND

A growing body of literature suggests that Mohs micrographic surgeons can safely and successfully perform complex eyelid reconstruction. Given that up to 10 percent of all skin cancers occur on the periorbital skin, it is imperative that Mohs surgeons understand form and function to properly assess the defect and select the appropriate reconstruction method for a variety of eyelid defects.

OBJECTIVE

Our objective is to provide a thorough understanding of eyelid anatomy with an emphasis on form and function, provide a framework for defect analysis, and an algorithmic approach to defect analysis and appropriate selection of repair.

METHODS AND MATERIALS

A review of the literature on eyelid reconstruction was performed with specific reference to defect analysis and appropriately choosing repairs that are applicable to Mohs micrographic surgeons.

CONCLUSION

Mohs micrographic surgeons can safely and successfully perform complex eyelid repairs. An understanding of eyelid anatomy is the first step toward the best surgical outcome, and there are various methods for reconstructing eyelid defects. Defect size, location and analysis of the anterior lamella, posterior lamella, and the canthal regions helps to create an organized operative plan.
COMPARISON OF PAIN EXPERIENCE IN PATIENTS UNDERGOING SUB-TENON'S ANESTHESIA VERSUS PERIBULBAR ANESTHESIA DURING ELECTIVE VITREORETINAL SURGERY
Authors: Ripa Matteo , Schipa Chiara , Kopsacheilis Nikolaos , Nomikarios Mikes , De Rosa Carlo , De Rosa Pasquale , Motta Lorenzo
Published: July 2022

Purpose:

To assess and compare the patients' discomfort and pain experienced during anesthesia, pars plana vitrectomy, and 24 hours postoperatively after sub-Tenon's injection (STI) versus peribulbar block (PB) in elective vitreoretinal surgery.

Methods:

Retrospective study involving 80 patients who underwent elective vitreoretinal surgery receiving either PB (Group 1, n = 40) or STI (Group 2, n= 40) between January 2021 and March 2022. Patients' pain experienced during the procedure and 24 hours postoperatively were assessed using a pain scale and a two-section questionnaire. One hour postoperatively, patients were asked to rate the level of pain they felt during the entire procedure by pointing at a 0 to 100 Visual Analog Scale. Subsequently, patients answered a two-section questionnaire regarding pain and discomfort felt 24 hours postoperatively.

Results:

According to Visual Analog Scale measurements, patients experienced significantly more pain during PB than during STI 1 hour after surgery. Patients undergoing PB experienced more pain than those who underwent STI, experiencing burning and discharge feeling. Patients undergoing STI had a lower pain level score 24 hours postoperatively despite similar discomfort.

Conclusion:

Sub-Tenon's injection has a lower pain score than PB during the procedure and 24 hours postoperatively, representing a valuable procedure to deliver analgesia in vitreoretinal surgery.
SARS-CoV-2 vaccines in children and adolescents: Can immunization prevent hospitalization?
Authors: Liang Kung-Hao , Hung Kai-Feng , Wang Mong-Lien , Chang Tai-Jay , Cheng Yen-Fu , Chiang Su-Hua , Chen Mei-Fang , Liao Yi-Ting , Chiou Shih-Hwa , Yang De-Ming
Published: July 2022

The SARS-CoV-2 coronavirus and its variants of concern can infect people of all ages and can cause severe diseases in children, such as encephalitis, which require intensive care. Therefore, vaccines are urgently required to prevent severe disease in all age groups. We reviewed the safety and efficacy profiles of mRNA vaccines—BNT162b2 and mRNA-1273—demonstrated by clinical trials or observed in the real world. mRNA-1273 is effective in preventing SARS-CoV-2 infection in preschool children (6 months-6 years old). Both BNT162b2 and mRNA-1273 are effective in preventing SARS-CoV-2 infection in school-aged children and adolescents, thereby preventing post-COVID conditions. The common side effects of vaccination are pain at the injection site, fatigue, and headache. Myocarditis and pericarditis are uncommon. Monitoring post-vaccination troponin levels may help prevent severe cardiac events. The SARS-CoV-2 coronavirus mutates its genome to overcome the herd immunity provided by mass vaccinations; therefore, we may need to develop new generations of vaccines, such as those using viral nucleocapsid proteins as antigens. In conclusion, the mRNA vaccines are generally safe and effective in preventing severe diseases and hospitalization among children and adolescents.
Assessing Harmful Bias and Celebrating Strength Through the Narratives of Black/African American Physician Assistant Students
Authors: Bester Vanessa S. , Bradley-Guidry Carolyn
Published: July 2022

Introduction

Two national crises, the COVID-19 pandemic and systemic racism, have drawn nationwide attention to the disparities that exist in our society today. The American healthcare system, including physician assistant (PA) education, is not exempt from the impact of harmful bias and discrimination. The purpose of this study was to explore narratives recounting the experiences of Black/African Americans who have successfully completed their PA education in an attempt to understand how PA educators can better support students of color.

Methods

Qualitative, semi-structured interviews, guided by a critical race theory framework, were conducted with 6 Black/African American PAs who had graduated within the last 5 years. Trustworthiness was ensured through member checking, triangulation, peer debriefing during the coding and analysis process, and autoethnographic reflection.

Results

Themes of mentorship and cultural capital, including aspirations, family, social support, and resistance to an oppressive system, highlight the strengths present in Black/African American students. Additional themes surrounding stress related to race, including a pressure to prove, isolation and anxiety, and imposter phenomenon, all pointed toward the need for honest and safe dialogue among individuals with racial differences.

Discussion

This research article presents key findings and opportunities for PA educators to emphasize cultural capital to enable Black/African American PA students to thrive. Communicating across racial differences and intentional engagement are imperative for PA educators to successfully support Black/African American students.
The Role of Interpersonal Toxicity on Healthcare Students’ Well-Being
Authors: Sierra Talia , McCall Timothy C. , Brown Heidi , Smith Noël E.
Published: July 2022

Introduction

Nearly half of all medical students suffer from burnout, which not only has detrimental effects on the students themselves but can transfer into the clinical realm. Yet, studies exploring burnout and interpersonal toxicity in physician assistant (PA) students are rare. This study examined the role that interpersonal toxicity and abuse play in PA student burnout.

Methods

Nearly 2500 PA students in the United States responded to a survey about well-being, stress, and experiences with interpersonal toxicity in PA school as part of a larger cross-sectional study on PA student experiences in their didactic and clinical years. The present research focuses on overall measures among all PA students, as well as differences between didactic and clinical students, including the extent to which experiences of interpersonal toxicity predict symptoms associated with burnout.

Results

Overall, PA students reported high levels of satisfaction and happiness in school and life, but enthusiasm for school decreased for clinical students. More than two-thirds of students reported moderate to high levels of life stress, and more than 9 in 10 reported moderate to high levels of school stress. Symptoms of burnout were reported by many students, with clinical students reporting interpersonal toxicity exposure more often than didactic students. Experiencing interpersonal toxicity or abuse predicted symptoms of burnout.

Discussion

While PA students report high levels of life and school satisfaction, given the high levels of stress also reported, burnout metrics and well-being programs are needed. PA programs should work to create a supportive and engaging educational environment to ensure students’ long-term career success.
Prognostic value of GRACE risk score in patients hospitalized for coronavirus disease 2019
Authors: Dönmez Esra , Özcan Sevgi , Tuğrul Sevil , Ziyrek Murat , İnce Orhan , Nar Sagir Gurur , Baran Yavuz Mustafa , Gungor Baris , Okuyan Ertugrul , Sahin Irfan
Published: July 2022

Objective

COVID-19 pandemic continues to threaten human health as novel mutant variants emerge and disease severity ranges from asymptomatic to fatal. Thus, studies are needed to identify the patients with ICU need as well as those who have subsequent mortality. Global Registry of Acute Coronary Events (GRACE) risk score is a validated score in acute coronary syndrome. We aimed to evaluate if GRACE score can indicate adverse outcomes and major ischemic events in hospitalized COVID-19 patients.

Methods

All hospitalized patients due to COVID-19 at our institution between March 2020 and September 2020 were included in this retrospective study. Patients were grouped according to GRACE risk scores: low risk 0–108 points, intermediate risk 109–140 and high risk ≥141.

Results

A total of 787 patients were enrolled; 434 patients formed group 1. One-hundred forty-one patients in group 2 and 212 patients formed group 3. We found that inhospital mortality, length of hospital stay, ICU and advanced ventilatory support need were associated with increasing GRACE risk score. In addition, major ischemic events were more frequently observed in higher risk groups and strong positive correlations between GRACE risk score and pro-BNP, procalcitonin and moderate positive correlation with D-dimer, CRP, NLR was found. Regression analysis showed that only GRACE risk score was an independent risk factor associated with inhospital mortality, major ischemic events, advanced ventilatory support and ICU need.

Conclusion

The GRACE risk score is easy to apply on hospital admission and useful for classifying those in medium-high-intensity care units and to raise the assignments of sources.
Progression to Anti-TNF Treatment in Very Early Onset Inflammatory Bowel Disease Patients
Authors: Eindor-Abarbanel Adi , Meleady Laura , Lawrence Sally , Hamilton Zachary , Krikler Gena , Lakhani Alam , Zhang Qian , Jacobson Kevan
Published: July 2022

Objectives:

Limited data are currently available regarding anti-tumor necrosis factor (TNF) use and outcomes in very early onset inflammatory bowel disease (VEOIBD) patients. We aimed to assess the long-term outcomes and time to progression to anti-TNF treatment in VEOIBD patients.

Methods:

We retrospectively reviewed IBD patients diagnosed under 6 years of age, between January 2005 and December 2019, from the British-Columbia (BC) Pediatric IBD database. Demographic data, disease characteristics, disease location and severity were documented. Data on anti-TNF treatment at initiation and during follow up including type of biologic, dosing, and response were collected. Kaplan-Meier curves were used to assess the number of years to progression to anti-TNF treatment and the parameters influencing commencement.

Results:

Eighty-nine patients with VEOIBD were diagnosed during the study period. Median age at diagnosis was 3.8 years [interquartile range (IQR) 2.6–5.1], 45.3% had Crohn disease (CD) and 62.8% were males. Median duration of follow up was 6.39 years (IQR 3.71–10.55). Anti-TNF treatment was started on 39.5% of patients and 7.0% underwent surgery. Rapid progression to biologic treatment was associated with Perianal fistulizing disease or stricturing disease in CD patients (P = 0.026, P = 0.033, respectively), and disease severity (P = 0.017) in ulcerative colitis

(UC) patients. The median dose of infliximab at 1 year was 10 mg/kg (IQR 7.5–11) and a median dose interval of 4.5 weeks (IQR 4–6). Clinical remission was reported in 61.8% of patients on their first biologic agent.

Conclusions:

The response rate was higher than previously reported and might be due to higher infliximab dosing with shorter infusion intervals than standard dosing.
An Innovative Workforce Initiative to Support New Graduate Nurses: Clinical Nurse Transition Coaches
Authors: Beckman Beth P. , Bronsord Jeannette L. , Ghidini Jennifer L. , Williams Ena M.
Published: July 2022

Nursing leaders at Yale New Haven Health System identified a need among new-graduate nurses for further support beyond their accredited new-graduate residency program. The Clinical Nurse Transition Coach (CNTC) program focused on moving from individual tasks to caring for the entire patient, fostered by focused mentoring and education. The CNTC nurses were experienced and worked with a team of 10 new-graduate nurses.
How Long Can a Dead Body Remain Infectious?
Authors: Ventura Francesco , Drommi Martina , Barranco Rosario , Balbo Arianna , Errico Stefano , Mangioni Manuela , Molinari Giulia , Di Biagio Antonio , De Pace Vanessa , Lai Alessia , Bruzzone Bianca
Published: July 2022

The SARS-CoV-2 pandemic involved several changes and difficulties in the work of forensic pathologists. Postmortem nasopharyngeal swabs for the diagnosis of the SARS-CoV-2 infection are recommended before an autopsy examination by the Centers for Disease Control and Prevention.

Autopsy examinations must not be performed for SARS-CoV-2 infection cases when airborne infection isolation rooms or other suitable spaces are unavailable. However, it has not yet been reported whether the presence of SARS-CoV-2 at a low viral load may be enough to infect and disseminate the contagion.

Here, we report the case of a 67-year-old man found dead at home on November 9, 2020, and transferred immediately after to the Genova District Mortuary. As the first postmortem molecular nasopharyngeal swab resulted positive, a weekly sampling was carried until February 4, 2021. All the molecular tests were positive for SARS-CoV-2, including the last swab performed 87 days after the arrival of the corpse at the morgue. Virus isolation conducted on VERO E6 cells revealed no cytopathic effect indicating no viral replication as early as 18 days after the corpse's arrival at the morgue and until January 2021.

Our findings suggest that the presence of the genome of SARS-CoV-2 at low viral load should not be considered a sign of an active infection but a trace of a remaining viral genome from a previous infection. Then, if the virus shows no replication activity, its molecular detection should not constitute a threat to public health. Further studies are required to establish the infection's potential and its correlation with viral load.
Risk factors and the epidemiology of surgical-site infections at a tertiary care medical center in Mexico, the experience at the National Institute of Medical Sciences and Nutrition Salvador Zubirán: A 6-month-prospective cohort study; carried out during the first decade of the XXI century. Untitled Item
Authors: Delgado-Hachmeister Jorge , Mercado-Joffre Irene , Jimenez Martha Huertas , Ponce de Leon Rosales Samuel , Rangel-Frausto Sigfrido
Published: July 2022

In the data isq, means surgical site infection. We also provide the name of the surgeons for surgeons to check their personal infection rates to improve outcomes. Stata 8.2 version is used, College Station, TX, USA. Most are categorical variables, or converted to categorical variables, or need to be converted to categorical variables, for example to set up a cut of value for albumin < 3g/dl. The same as the body mass index >= 27. 
A Systematic Review of Operative Team Familiarity on Metrics of Efficiency, Patient Outcomes, Cost, and Team Satisfaction
Authors: Witmer Hunter D.D. , Dhiman Ankit , Jones Alonzo D. , Laffan Alison M. , Adelman Dan , Turaga Kiran K.
Published: July 2022

Objective:

This study seeks to systematically review the current literature on how surgical team familiarity relates to metrics of operative efficiency.

Background:

The operating room (OR) is a complex environment involving numerous multidisciplinary interactions that must interface precisely to achieve a successful outcome.

Methods:

A systematic search of the PubMed database was prospectively registered in the National Institute for Health Research PROSPERO database (CRD 42020181046) and performed according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Exposure variable was team familiarity and outcome measures included operative efficiency, patient outcomes, costs, and/or team satisfaction.

Results:

Of 1123 articles screened, 15 studies involving 24,340 operations met inclusion criteria. All studies were limited to an individual specialty, procedure, or both. The effects of more familiar teams were most pronounced in decreasing operative times [standardized mean difference of −0.51 (95% confidence interval: −1.00, −0.02), P=0.04], whereas the reported impacts on patient clinical outcomes, material waste, and team satisfaction were much more heterogenous.

Conclusions:

Improving OR team familiarity is associated with superior operative efficiency and may be associated with other favorable measures. Further inferences are limited by literature heterogeneity, yet could be a novel focus for improving OR performance.
Interplay between the oxytocin and opioid systems in regulating social behaviour
Authors: Putnam Philip T. , Chang Steve W. C.
Published: July 2022

The influence of neuromodulators on brain activity and behaviour is undeniably profound, yet our knowledge of the underlying mechanisms, or ability to reliably reproduce effects across varying conditions, is still lacking. Oxytocin, a hormone that acts as a neuromodulator in the brain, is an example of this quandary; it powerfully shapes behaviours across nearly all mammalian species, yet when manipulated exogenously can produce unreliable or sometimes unexpected behavioural results across varying contexts. While current research is rapidly expanding our understanding of oxytocin, interactions between oxytocin and other neuromodulatory systems remain underappreciated in the current literature. This review highlights interactions between oxytocin and the opioid system that serve to influence social behaviour and proposes a parallel-mechanism hypothesis to explain the supralinear effects of combinatorial neuropharmacological approaches.

This article is part of the theme issue ‘Interplays between oxytocin and other neuromodulators in shaping complex social behaviours’.
Oxytocin—a social peptide? Deconstructing the evidence
Authors: Leng Gareth , Leng Rhodri I. , Ludwig Mike
Published: July 2022

In this paper, we analyse the claim that oxytocin is a ‘social neuropeptide’. This claim originated from evidence that oxytocin was instrumental in the initiation of maternal behaviour and it was extended to become the claim that oxytocin has a key role in promoting social interactions between individuals. We begin by considering the structure of the scientific literature on this topic, identifying closely interconnected clusters of papers on particular themes. We then analyse this claim by considering evidence of four types as generated by these clusters: (i) mechanistic studies in animal models, designed to understand the pathways involved in the behavioural effects of centrally administered oxytocin; (ii) evidence from observational studies indicating an association between oxytocin signalling pathways and social behaviour; (iii) evidence from intervention studies, mainly involving intranasal oxytocin administration; and (iv) evidence from translational studies of patients with disorders of social behaviour. We then critically analyse the most highly cited papers in each segment of the evidence; we conclude that, if these represent the best evidence, then the evidence for the claim is weak.

This article is part of the theme issue ‘Interplays between oxytocin and other neuromodulators in shaping complex social behaviours’.
The role of oxytocin in shaping complex social behaviours: possible interactions with other neuromodulators
Authors: Paletta Pietro , Bass Noah , Kavaliers Martin , Choleris Elena
Published: July 2022

This review explores the role of oxytocin in the mediation of select social behaviours, with particular emphasis on female rodents. These behaviours include social recognition, social learning, pathogen detection and avoidance, and maternal care. Specific brain regions where oxytocin has been shown to directly mediate various aspects of these social behaviours, as well as other proposed regions, are discussed. Possible interactions between oxytocin and other regulatory systems, in particular that of oestrogens and dopamine, in the modulation of social behaviour are considered. Similarities and differences between males and females are highlighted.

This article is part of the theme issue ‘Interplays between oxytocin and other neuromodulators in shaping complex social behaviours’.
Distinct Streptococcus pneumoniae cause invasive disease in Papua New Guinea
Authors: Mellor Kate C. , Lo Stephanie , Yoannes Mition , Michael† Audrey , Orami Tilda , Greenhill Andrew R. , Breiman Robert F. , Hawkins Paulina , McGee Lesley , Bentley Stephen D. , Ford Rebecca L. , Lehmann Deborah
Published: July 2022

Streptococcus pneumoniae

is a key contributor to childhood morbidity and mortality in Papua New Guinea (PNG). For the first time, whole genome sequencing of 174 isolates has enabled detailed characterisation of diverse

S. pneumoniae

causing invasive disease in young children in PNG, 1989-2014. This study captures the baseline

S. pneumoniae

population prior to the introduction of 13-valent pneumococcal conjugate vaccine (PCV13) into the national childhood immunisation programme in 2014. Relationships amongst lineages, serotypes and antimicrobial resistance traits were characterised, and the population was viewed in the context of a global collection of isolates. The analyses highlighted adiverse

S. pneumoniae

population associated with invasive disease in PNG, with 45 unique Global Pneumococcal Sequence Clusters (GPSCs) observed amongst the 174 isolates reflecting multiple lineages observed in PNG that have not been identified in other geographic locations. The majority of isolates were from children with meningitis, of which 52% (n=72) expressed non-PCV13 serotypes. Over a third of isolates were predicted to be resistant to at least one antimicrobial. PCV13 serotype isolates had 10.1 times the odds of being multidrug-resistant (MDR) compared to non-vaccine serotype isolates, and no isolates with GPSCs unique to PNG were MDR. Serotype 2 was the most commonly identified serotype; we identified a highly clonal cluster of serotype 2 isolates unique to PNG, and a distinct second cluster indicative of long-distance transmission. Ongoing surveillance, including whole-genome sequencing, is needed to ascertain the impact of the national PCV13 programme upon the

S. pneumoniae

population, including serotype replacement and antimicrobial resistance traits.
Single Cell RNA Sequencing Driven Characterization of Pediatric Mixed Phenotype Acute Leukemia
Authors: Mumme Hope L. , Raikar Sunil S. , Bhasin Swati S. , Thomas Beena E. , DeRyckere Deborah , Wechsler Daniel S. , Porter Christopher C. , Castellino Sharon M. , Graham Douglas K. , Bhasin Manoj K.
Published: July 2022

Background

Mixed phenotype acute leukemia (MPAL) is a rare subgroup of leukemia characterized by blast cells that display both myeloid and lymphoid lineage features, making this cancer difficult to diagnose and treat. A deeper characterization of MPAL at the molecular level is essential to better understand similarities/differences to the more common and better-studied leukemias, acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL). Therefore, we performed single-cell RNA sequencing (scRNAseq) on MPAL bone marrow (BM) samples in an attempt to develop a more granular map of the MPAL microenvironment landscape.

Methods

We analyzed ∼16,000 cells from five pediatric MPAL BM samples collected at diagnosis to generate a single-cell transcriptomic landscape of B/Myeloid (B/My) and T/Myeloid (T/My) MPAL blasts and associated microenvironment cells. Cell clusters were identified using principal component analysis and uniform manifold approximation and projection (UMAP). Unsupervised analysis was performed to determine the overall relationship among B/My MPAL, T/My MPAL, and other acute leukemias – B-ALL, T-ALL, and AML. Supervised differentially expressed gene (DEG) analysis was performed to identify B/My and T/My MPAL blast-specific signatures. MPAL sample transcriptome profiles were compared with normal BM stem and immune cells to identify MPAL-specific dysregulation. Gene set enrichment analysis (GSEA) was performed, and significantly enriched pathways were compared in MPAL subtypes. Comparative analysis was performed on diagnostic samples based on their future minimal residual disease (MRD) and relapse status.

Results

B/My MPAL and T/My MPAL blasts displayed distinct subtype-specific blast signatures. UMAP analysis revealed that B/My MPAL samples had greater overlap with B-ALL samples, while T/My MPAL samples clustered separately from other acute leukemia subtypes. Genes overexpressed in both MPAL subtypes’ blasts compared to other leukemias and healthy controls includedPLIN2, CD81, andUBE2S. B/My MPAL blast-specific genes includedIRS2, SMIM3, andHBEGF, whereas T/My MPAL blast-overexpressed genes includedIER5, BOD1L1, andHPGD. Sirtuin signaling, p38 MPAK signaling, and PI3K signaling pathways were upregulated in B/My MPAL blasts while oxidative phosphorylation and Rho family GTPases signaling pathways were upregulated in T/My MPAL blasts. Transcriptomic, pathways, and cell communication level differences were observed in the MPAL samples based on future MRD and clinical outcome status.

Conclusions

We have for the first time described the single-cell landscape of pediatric MPAL and demonstrate that B/My and T/My MPAL have unique scRNAseq profiles distinct from each other as well as from ALL and AML.
TGFB1 rs8179181 polymorphism is reproducibly associated with Parkinson’s disease in a Spanish population
Authors: Comino Alicia , Antolín-Vallespín Mónica , López-Benito Azahara , Muñoz Gloria , del Castillo Francisco Javier , Vela Lydia , Martínez-Castrillo Juan Carlos , Sánchez-Capelo Amelia
Published: July 2022

There is evidence that transforming growth factor (TGF)-β signaling participates in the pathology of Parkinson’s disease (PD). Dampened TGF-β signaling in Smad3- or TβRII-deficient mice leads to the appearance of α-synuclein inclusions in the brain, as well as dopaminergic, motor, and cognitive deficits. Accordingly, we hypothesized that genetic variants of TGFB/SMAD could be risk factors for PD in humans. Here, we present two independent case-control studies aimed at evaluating the association between genetic variants of six genes related to TGF-β signaling (TGFB1, TGFB2, TGFBRI, TGFBRII, SMAD3 and SMAD2) and the development of sporadic PD. A total of 275 unrelated Spanish Caucasian individuals were included in the study (141 cases and 134 controls), with 132 individuals in the discovery phase and 143 individuals in the replication phase. Next-generation sequencing identified a total of 409 variants in the coding, splicing, and untranslated regions of these genes. Analysis of common variants in the discovery phase revealed an association between PD and the TGFB1 rs8179181 variant, which was further confirmed in the replication phase [odds ratio (OR) 0.48, 95% confidence interval (CI) 0.32–0.73, p = 0.00057). A weak association of the SMAD3 rs11556089 polymorphism with PD was also detected (OR 0.49, 95% CI 0.26–0.93, p = 0.0375). Seven haplotypes were identified; however, there were no significant differences in their frequencies between patients with PD and controls. In conclusion, both the discovery and replication phases of this study suggest that the rs8179181 variant of TGFB1 represents a novel susceptibility locus for PD.

HIGHLIGHTS

Deficient TGF-β signalling via Smad3 induces the formation of α-synuclein aggregates and a parkinsonian pathology in mice.

TGFB1, TGFB2, TGFBRI, TGFBRII, SMAD3 and SMAD2 genes were sequenced to search for associations of their allelic variants with idiopathic PD.

Two independent case-control studies of Spanish Caucasian individuals identified 409 genetic variants in their coding, splicing and UTR regions.

The rs8179181 SNP in TGFB1 was reproducibly associated with idiopathic PD, representing a novel PD susceptibility locus.
The genome of Gynandropsis gynandra provides insights into whole-genome duplications and the evolution of C4 photosynthesis in Cleomaceae
Authors: Hoang Nam V. , Sogbohossou E. O. Deedi , Xiong Wei , Simpson Conor J. C. , Singh Pallavi , van den Bergh Erik , Zhu Xin-Guang , Brautigam Andrea , Weber Andreas P. M. , van Haarst Jan C. , Schijlen Elio G. W. M. , Hendre Prasad S. , Deynze Allen Van , Achigan-Dako Enoch G. , Hibberd Julian M. , Schranz M. Eric
Published: July 2022

Gynandropsis gynandra (Cleomaceae) is a cosmopolitan leafy vegetable and medicinal plant, which has also been used as a model to study C4 photosynthesis due to its evolutionary proximity to Arabidopsis. Here, we present a high-quality genome sequence of G. gynandra, anchored onto 17 main super- scaffolds with a total length of 740 Mb, an N50 of 42 Mb and 30,933 well-supported gene models. The G. gynandra genome and previously released genomes of C3 relatives in the Cleomaceae and Brassicaceae make an excellent model for studying the role of genome evolution in the transition from C3 to C4 photosynthesis. We revealed that G. gynandra and its C3 relative Tarenaya hassleriana shared a whole-genome duplication event (Gg-α), then an addition of a third genome (Th-α, +1x) took place in T. hassleriana but not in G. gynandra. Analysis of syntenic copy number of C4 photosynthesis-related gene families indicates that G. gynandra generally retained more duplicated copies of these genes than C3 T. hassleriana, and also that the G. gynandra C4 genes might have been under positive selection pressure. Both whole-genome and single-gene duplication were found to contribute to the expansion of the aforementioned gene families in G. gynandra. Collectively, this study enhances our understanding of the impact of gene duplication and gene retention on the evolution of C4 photosynthesis in Cleomaceae.
Neuromechanical Coupling is Reflected in the Spatial Organization of the Spinal Motoneuron Pools
Authors: Taitano Rachel I. , Yakovenko Sergiy , Gritsenko Valeriya
Published: July 2022

Recent advances in neuroprosthetics have shown that activating the surviving spinal circuitry below the level of spinal damage can produce complex movements and restore function. This is because the spinal cord circuitry plays an important role in the control of complex movements by integrating descending execution-related signals with feedback sensory signals. To generate efficient movements through muscle contractions, the nervous system embeds the anatomical and dynamical properties of the controlled body parts, a concept termed neuromechanical tuning. The motoneurons innervating the skeletal muscles of the body form complex spatial structures that span multiple segments. The goal of this study is to determine if these structures can support neuromechanical tuning. We performed a comparative analysis of the spatial organization of the motoneuron pools and the functional organization of the muscles they innervate. We developed a three-dimensional model of the spatial organization of motoneuron pools innervating upper limb muscles in the macaque and quantified their relative distances. We then utilized a musculoskeletal model of the macaque upper extremity to characterize the functional relationship between the muscles innervated by the motoneuron pools. We found that the distances between motoneuron pools mimicked the agonistic or antagonistic actions of muscles they innervate. This shows that the spatial organization of the motoneuron pools embeds the functional musculoskeletal anatomy evolved to support the large repertoire of upper limb movements in primates. This spinal anatomy may play an important role in the neuromechanical tuning and simplify the sensorimotor control of the arm.
Signal Alignment Enables Analysis of DIA Proteomics Data from Multisite Experiments
Authors: Gupta Shubham , Sing Justin C. , Röst Hannes L.
Published: July 2022

DIA has become a mainstream method for quantitative proteomics, however consistent quantification across multiple LC-MS/MS instruments remains a bottleneck in parallelizing the data-acquisition. To produce a highly consistent and quantitatively accurate data matrix, we have developed DIAlignR which uses raw fragment-ion chromatograms for cross-run alignment. Its performance on a gold standard annotated dataset, demonstrates a threefold reduction in the identification error-rate when compared to standard non-aligned DIA results. A similar performance is achieved for a dataset of 229 runs acquired using 11 different LC-MS/MS setups. Finally, the analysis of 949 plasma runs with DIAlignR increased the number of statistically significant proteins by 43% and 62% for insulin resistant (IR) and respiratory viral infection (RVI), respectively compared to prior analysis without it. Hence, DIAlignR fills a gap in analyzing DIA runs acquired in-parallel using different LC-MS/MS instrumentation.
Targeting Acid Ceramidase Ameliorates Fibrosis in Mouse Models of Nonalcoholic Steatohepatitis
Authors: Yu Amy , Cable Carson , Shihan Mahbubul H. , Sharma Sachin , Mattis Aras N. , Mileva Izolda , Hannun Yusuf A. , Duwaerts Caroline C. , Chen Jennifer Y.
Published: July 2022

1)

Nonalcoholic fatty liver disease (NAFLD) is a common cause of liver disease worldwide, and is characterized by the accumulation of fat in the liver. Nonalcoholic steatohepatitis (NASH), an advanced form of NAFLD, is a leading cause of liver transplantation. Fibrosis is the histologic feature most associated with liver-related morbidity and mortality in patients with NASH, and treatment options remain limited. In previous studies, we discovered that acid ceramidase (aCDase) is a potent antifibrotic target using human hepatic stellate cells (HSCs) and models of hepatic fibrogenesis. Using two dietary mouse models, we demonstrate that depletion of aCDase in HSC reduces fibrosis without worsening metabolic features of NASH, including steatosis, inflammation, and insulin resistance. Consistently, pharmacologic inhibition of aCDase ameliorates fibrosis but does not alter metabolic parameters. The findings suggest that targeting aCDase is a viable therapeutic option to reduce fibrosis in patients with NASH.
Tumor subclones, where are you?
Authors: Su Xianbin , Bai Shihao , Xie Gangcai , Shi Yi , Zhao Linan , Yang Guoliang , Tian Futong , He Kun-Yan , Wang Lan , Li Xiaolin , Long Qi , Han Ze-Guang
Published: July 2022

Introduction

Tumor clonal structure is closely related to future progression, which has been mainly investigated via mutation abundance clustering in bulk sample. With limited studies at single-cell resolution, a systematic comparison of the two approaches is still lacking.

Methods

Here, using bulk and single-cell mutational data from liver and colorectal cancers, we would like to check the possibility of obtaining accurate tumor clonal structures from bulk-level analysis. We checked whether co-mutations determined by single-cell analysis had corresponding bulk variant allele frequency (VAF) peaks. We examined VAF ranges for different groups of co-mutations, and also the possibility of discriminating them.

Results

While bulk analysis suggested absence of subclonal peaks and possibly neutral evolution in some cases, single-cell analysis identified co-existing subclones. The overlaps of bulk VAF ranges for co-mutations from different subclones made it difficult to separate them, even with other parameter introduced. The difference between mutation cluster and tumor subclone is accountable for the challenge in bulk clonal deconvolution, especially in case of branched evolution as shown in colorectal cancer.

Conclusion

Complex subclonal structures and dynamic evolution are hidden under the seemingly clonal neutral pattern at bulk level, suggesting single-cell analysis will be needed to avoid under-estimation of tumor heterogeneity.

Research Highlights

Bulk-level mutation abundance clusters are not equal to tumor subclones.

Different groups of co-mutations could not be discriminated at bulk-level.

Single-cell mutational analysis can identify rather than infer tumor subclones.

Co-existing tumor subclones may have clonal neutral appearance at bulk-level.

Lay summary

Systematic comparison of tumor clonal structure differences between bulk and single-cell mutational analysis is lacking. Here we performed such as study and found that complex subclonal structures and dynamic evolution are hidden under clonal neutral appearance at bulk level in liver and colorectal cancers, suggesting single-cell analysis will be needed to avoid under-estimation of tumor heterogeneity.
Longitudinal Urine Metabolic Profiling and Gestational Age Prediction in Pregnancy
Authors: Chen Songjie , Shen Xiaotao , Liang Liang , Avina Monika , Zackriah Hanyah , Jelliffe-Pawlowski Laura , Rand Larry , Snyder Michael
Published: July 2022

Pregnancy is a critical time that has long-term impacts on both maternal and fetal health. During pregnancy, the maternal metabolome undergoes dramatic systemic changes, although correlating longitudinal changes in maternal urine remain largely unexplored. We applied an LCMS-based untargeted metabolomics profiling approach to analyze 346 longitudinal maternal urine samples collected throughout pregnancy for 36 women from diverse ethnic backgrounds with differing clinical characteristics. We detected 20,314 metabolic peaks and annotated 875 metabolites. Altered metabolites include a broad panel of glucocorticoids, lipids, and amino acid derivatives, which revealed systematic pathway alterations during pregnancy. We also developed a machine-learning model to precisely predict gestational age (GA) at time of sampling using urine metabolites that provides a non-invasive method for pregnancy dating. This longitudinal maternal urine study demonstrates the clinical utility of using untargeted metabolomics in obstetric settings.

One Sentence Summary

Machine-learning based gestational age and due date using longitudinal urine samples of pregnancy.
Phosphorylation of light-harvesting complex II controls excitation energy spillover between photosystems
Authors: Tokutsu Ryutaro , Kim Eunchul , Akimoto Seiji , Yokono Makio , Fujimura-Kamada Konomi , Ohnishi Norikazu , Ueno Yoshifumi , Minagawa Jun
Published: July 2022

Land plants and microalgae convert solar energy into electrochemical energy by using cooperative two photosystems (PSI and PSII). To maintain optimal photosynthetic rates under variable light conditions in nature, phosphorylation of light-harvesting complex for PSII (LHCII) balances the excitation energy distribution between the two photosystems. Here, we investigated the mechanism of this balancing in a green alga. We show that phospho-LHCIIs physically bind to both photosystems. The energy transfer from the LHCIIs to the PSII core complexes becomes less efficient, whereas the excitation level of PSI increases. The time-resolved fluorescence spectra showed an increase in delayed PSI fluorescence, which represents energetical spillover from PSII to PSI. In addition, the spillover is likely mediated by phospho-LHCIIs and PSI antennas. We hypothesize that the spillover explains the larger extent of phospho-LHCIIs dependent energy balancing in the green alga than land plants, which is important for the short-term photoadaptaion in the algal habitat.
Adaptive dynamic surface output feedback control for a class of quadrotor aircraft with actuator faults
Authors: Zhu Guoqiang , Li He , Zhang Huan , Wang Sen , Zhang Xiuyu
Published: July 2022

Purpose

The purpose of this study is to propose an adaptive fault-tolerant control approach based on output feedback for a class of quadrotor unmanned aerial vehicles system. In the event of a controlled actuator failure, a stable flying of the aircraft can be achieved by selecting an appropriate sliding mode surface.

Design/methodology/approach

Aiming at the actuator failure of quadrotor aircraft during flight in the controllable range, a dynamic surface sliding mode passive fault-tolerant controller based on output feedback is designed based on the strong robustness of sliding mode method. Due to the unknown nonlinearity dynamics and parameter uncertainties in the system, a nonlinear observer is used to estimate them online.

Findings

The stability of the suggested algorithm is established using appropriate Lyapunov functions, and the performance of the proposed control approach is demonstrated using hardware-in-the-loop simulation.

Originality/value

An error performance function is introduced into the controller to ensure the convergence speed and accuracy of errors are within the predetermined range. By using the norm estimation method, there is only one parameter that needs to be updated in each step of the control process, which considerably minimizes the calculation burden. Finally, the validity of the proposed control scheme is verified on the hardware-in-the-loop simulation, and the results show that the proposed control method has achieved the desired results.