bluuebunny/crossref_metadata_2025 huggingface dataset:
Breast Reconstruction and Nipple-Sparing Mastectomy
Authors: Pestana Ivo A. , Jones V. Morgan , Velazquez Christine
Published: January 2021

Background

Superior aesthetic outcomes can be achieved with mastectomy techniques that maximize breast envelope preservation and maintain the nipple-areolar complex. This is the impetus for the popularization of the nipple-sparing mastectomy (NSM). Nipple-sparing mastectomy is a challenging procedure due to potential ischemia of the mastectomy flap (which includes the nipple-areolar complex) and the risk of incomplete oncologic resection. We review our experience with NSM, identify technique modifications used over time, and evaluate reconstructive outcomes of NSM and its modifications.

Methods

A retrospective review of consecutive patients with NSM and breast reconstruction over an 8-year period was completed.

Results

Fifty-five patients underwent 95 NSMs. Indications included invasive and in situ cancer, atypical ductal hyperplasia, and risk reduction. In the first 4 years of experience, the most frequently used NSM incision was radial (lateral) whereas use of a variety of incision patterns was noted in the second 4 years. Overall NSM and breast reconstruction complication rate for the entire study period was 50.9% and included a full-thickness mastectomy skin flap necrosis/nipple necrosis rate of 8.4%. In situ cancer of the nipple was identified in 3.2% of the patients, and 1 patient had locoregional recurrence. Overall complication rate was lower in the second 4 years of experience with NSM and reconstruction. One third of the patients underwent intraoperative fluorescent angiography (FA) to assess mastectomy skin perfusion before reconstruction start. Of the patients who had FA due to perfusion concerns, more than 70% of studies demonstrated poor perfusion and 83.3% of these patients had reconstruction delayed based on these results. Immediate, implant-based reconstruction was performed most commonly. An average of 2.66 procedures were required to achieve reconstruction completion, and 92.4% of the patients who sought reconstruction achieved completion.

Conclusions

At our institution, NSM use is increasing, NSM incision pattern types used are expanding, and complication rates are decreasing. Immediate, implant-based reconstruction is most commonly used in combination with NSM at our institution. Fluorescent angiography is used to assess mastectomy skin perfusion and likely limits mastectomy complication effects on reconstruction. Despite the occurrence of complications, most patients will complete the breast reconstruction process.
Association Between Postoperative Complications and Long-term Survival After Non-cardiac Surgery Among Veterans
Authors: Portuondo Jorge I. , Itani Kamal M. F. , Massarweh Nader N.
Published: January 2021

Objective:

To evaluate the relationship between postoperative complications and long-term survival.

Summary and Background:

Postoperative complications remain a significant driver of healthcare costs and are associated with increased perioperative mortality, yet the extent to which they are associated with long-term survival is unclear.

Methods:

National cohort study of Veterans who underwent non-cardiac surgery using data from the Veterans Affairs Surgical Quality Improvement Program (2011–2016). Patients were classified as having undergone outpatient, low-risk inpatient, or high-risk inpatient surgery. Patients were categorized based on number and type of complications. The association between the number of complications (or the specific type of complication) and risk of death was evaluated using multivariable Cox regression with robust standard errors using a 90-day survival landmark.

Results:

Among 699,002 patients, complication rates were 3.0%, 6.1%, and 18.3% for outpatient, low-risk inpatient, and high-risk inpatient surgery, respectively. There was a dose-response relationship between an increasing number of complications and overall risk of death in all operative settings [outpatient surgery: no complications (ref); one—hazard ratio (HR) 1.30 (1.23 – 1.38); multiple—HR 1.61 (1.46 – 1.78); low-risk inpatient surgery: one—HR 1.34 (1.26 – 1.41); multiple—HR 1.69 (1.55 – 1.85); high-risk inpatient surgery: one—HR 1.14 (1.10 – 1.18); multiple—HR 1.42 (1.36 – 1.48)]. All complication types were associated with risk of death in at least 1 operative setting, and pulmonary complications, sepsis, and clostridium difficile colitis were associated with higher risk of death across all settings. Conclusions: Postoperative complications have an adverse impact on patients’ long-term survival beyond the immediate postoperative period. Although most research and quality improvement initiatives primarily focus on the perioperative impact of complications, these data suggest they also have important longer-term implications that merit further investigation.
Long-term Metabolic Morbidity and Steatohepatosis Following Standard Pancreatic Resections and Parenchyma-sparing, Local Extirpations for Benign Tumor
Authors: Beger Hans G. , Mayer Benjamin , Vasilescu Catalin , Poch Bertram
Published: January 2021

Objective:

To assess metabolic dysfunctions and steatohepatosis after standard and local pancreatic resections for benign and premalignant neoplasms.

Summary of Background Data:

Duodenopancreatectomy, hemipancreatectomy, and parenchyma-sparing, limited pancreatic resections are currently in use for nonmalignant tumors.

Methods:

Medline, Embase, and Cochrane libraries were searched for studies reporting measured data of metabolic functions following PD, pancreatic left resection (PLR), duodenum-sparing pancreatic head resection (DPPHR), pancreatic middle segment resection (PMSR), and tumor enucleation (TEN). Forty cohort studies comprising data of 2729 patients were eligible.

Results:

PD for benign tumor was associated in 46 of 327 patients (14.1%) with postoperative new onset of diabetes mellitus (pNODM) and in 109 of 243 patients (44.9%) with postoperative new onset of pancreatic exocrine insufficiency measured after a mean follow-up of 32 months. The meta-analysis displayed pNODM following PD in 32 of 204 patients (15.7%) and in 10 of 200 patients (5%) after DPPHR [P < 0.01; OR: 0.33; (95%-CI: 0.15–0.22)]. PEI was found in 77 of 174 patients following PD (44.3%) and in 7 of 104 patients (6.7%) following DPPHR (P < 0.01;OR: 0.15; 95%-CI: 0.07–0.32). pNODM following PLR was reported in 107 of 459 patients (23.3%) and following PMSR 23 of 412 patients (5.6%) (P < 0.01; OR: 0.20; 95%-CI: 0.12–0.32). Postoperative new onset of pancreatic exocrine insufficiency was found in 17% following PLR and in 8% following PMSR (P < 0.01). pNODM following PPPD and tumor enucleation was observed in 19.7% and 5.7% (P < 0.03) of patients, respectively. Following PD/PPPD, 145 of 608 patients (23.8%) developed a nonalcoholic fatty liver disease after a mean follow-up of 30.4 months. Steatohepatosis following DPPHR developed in 2 of 66 (3%) significantly lower than following PPPD (P < 0.01).

Conclusion:

Standard pancreatic resections for benign tumor carry a considerable high risk for a new onset of diabetes, pancreatic exocrine insufficiency and following PD for steatohepatosis. Parenchyma-sparing, local resections are associated with low grade metabolic dysfunctions.
Palliative and end-of-life care for the older adult with cancer
Authors: Huynh Lise , Moore Jennifer
Published: January 2021

Purpose of review

Despite established benefits of palliative care in the oncology population, it remains an underutilized resource particularly among older adults. The illness trajectory and needs of an older adult with cancer are unique. The purpose of this paper is to review the current literature on providing comprehensive palliative and end-of-life care for the older adult with cancer.

Recent findings

Though the difficulties of applying traditional palliative care principles in the older patients with cancer have been discussed, this review reveals a clear gap in the literature in discussing the provision of comprehensive palliative and end-of-life care in this population. Very few articles have been published in this domain with even fewer published within the past 18 months.

As such, this article reviews key aspects of palliative and geriatric medicine that need to be considered and integrated in order to provide comprehensive palliative care to the older adult with cancer. This includes a discussion of proper pain and symptoms assessment, performance status assessment, advance care planning, and end-of-life care while considering the nuances of geriatric syndromes.
Docosahexaenoic acid decreased inflammatory gene expression, but not 18-kDa translocator protein binding, in rat pup brain after controlled cortical impact
Authors: Schober Michelle Elena , Requena Daniela F. , Ohde Joshua W. , Maves Sydney , Pauly James R.
Published: January 2021

BACKGROUND

Traumatic brain injury is the leading cause of acquired neurologic disability in children. In our model of pediatric traumatic brain injury, controlled cortical impact (CCI) in rat pups, docosahexaenoic acid (DHA) improved lesion volume and cognitive testing as late as postinjury day (PID) 50. Docosahexaenoic acid decreased proinflammatory messenger RNA (mRNA) in microglia and macrophages at PIDs 3 and 7, but not 30. We hypothesized that DHA affected inflammatory markers differentially relative to impact proximity, early and persistently after CCI.

METHODS

To provide a temporal snapshot of regional neuroinflammation, we measured 18-kDa translocator protein (TSPO) binding using whole brain autoradiography at PIDs 3, 7, 30, and 50. Guided by TSPO results, we measured mRNA levels in contused cortex and underlying hippocampus for genes associated with proinflammatory and inflammation-resolving states at PIDs 2 and 3.

RESULTS

Controlled cortical impact increased TSPO binding at all time points, most markedly at PID 3 and in regions closest to impact, not blunted by DHA. Controlled cortical impact increased cortical and hippocampal mRNA proinflammatory markers, blunted by DHA at PID 2 in hippocampus.

CONCLUSION

Controlled cortical impact increased TSPO binding in the immature brain in a persistent manner more intensely with more severe injury, not altered by DHA. Controlled cortical impact increased PIDs 2 and 3 mRNA levels of proinflammatory and inflammation-resolving genes. Docosahexaenoic acid decreased proinflammatory markers associated with inflammasome activation at PID 2. We speculate that DHA’s salutary effects on long-term outcomes result from early effects on the inflammasome. Future studies will examine functional effects of DHA on microglia both early and late after CCI.
Neuroprotective potential of fisetin in an experimental model of spinal cord injury: via modulation of NF-κB/IκBα pathway
Authors: Cui Jing , Fan Jingshi , Li Huanxia , Zhang Jinku , Tong Jianzhou
Published: January 2021

Aim

To evaluate neuroprotective efficacy of fisetin against the experimental model of spinal cord injury (SCI).

Materials and methods

SCI was induced in male Sprague-Dawley rats by placing an aneurysm clip extradurally. Rats were treated either with vehicle or fisetin for 28 days after SCI.

Results

Treatment with fisetin significantly attenuated SCI-induced alternations in mechano-tactile and thermal allodynia, hyperalgesia and nerve conduction velocities. SCI-induced upregulated tumor necrosis factor-alpha, interleukins, inducible nitric oxide synthase, cyclooxygenase-II, Bcl-2-associated X protein and caspase-3 mRNA expressions in the spinal cord and these were markedly reduced by fisetin. Spinal nuclear factor kappa B and nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor-alpha protein levels were also significantly downregulated by fisetin. Hematoxylin and eosin staining of spinal cord suggested that fisetin significantly ameliorated histological aberrations such as neuronal degeneration, necrosis and inflammatory infiltration induced in it.

Conclusion

Fisetin exerts neuroprotection via modulation of nuclear factor kappa B/nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor-alpha pathway by inhibiting release of inflammatory mediators (inducible nitric oxide synthase and cyclooxygenase-II), proinflammatory cytokines (tumor necrosis factor-alpha and interleukins), apoptotic mediators (Bcl-2-associated X protein and caspase-3).
Malcolm L. H. Green. 16 April 1936—24 July 2020
Authors: Crabtree Robert H.
Published: January 2021

Malcolm Green was a remarkable man—even a short meeting was enough to make this clear. He had that rare charismatic ability to connect personally with those around him, whatever their rank or status. Generous of his time with his current coworkers, he also made sure to provide help, encouragement or advice to his alumni as the need arose during their subsequent careers. Inspired by his lead, an unusually large number of them have become widely known figures in chemistry in the UK and beyond. Malcolm laid out his view on his students on one occasion when a visitor to the lab commented on how quickly a large sum had been raised by his alumni for a lectureship in his name. ‘They must really love you’, he said, to which Malcolm replied with his simple philosophy: ‘If you love them, they will love you.’

Malcolm's infectious passion for science and his imaginative approach led him in many diverse directions during his career. Although his signature field was organometallic chemistry, he made later important contributions in nanomaterials and heterogeneous catalysis. Always interested in the reasons why Nature behaves as it does, he pioneered several new and imaginative methods for interpreting and understanding chemical bonding and reactivity, such as the covalent bond classification scheme or the rules for predicting the regiochemistry of nucleophilic attack on organometallics. He cared deeply about education and was the author of the first textbook devoted to the organometallic chemistry of the transition metals,
Organometallic compounds. Volume 2: the transition elements
, which originally appeared as early as 1968.
Development of Novel Measures for Alzheimer’s Disease Prevention Trials (NoMAD)
Authors: Bell Sophie A. , Cohen Hannah R. , Lee Seonjoo , Kim Hyun , Ciarleglio Adam , Andrews Howard , Rivera Andres M. , Igwe Kay , Brickman Adam M. , Devanand D.P. , Harvey Philip D. , Schneider Lon S. , Goldberg Terry E.
Published: January 2021

Introduction

Assessment of cognition and everyday function is essential in clinical trials for Alzheimer’s disease (AD). Two novel measures of cognition (No Practice Effects (NPE) cognitive battery and Miami Computerized Functional Assessment Scale (CFAS)) were designed to have robust psychometric properties and reduced practice and ceiling effects. This study aims to evaluate if the NPE and CFAS demonstrate stronger psychometric properties and reduced practice effects compared with established measures, including the Preclinical Alzheimer Cognitive Composite (PACC), Alzheimer’s Disease Assessment Scale-Cognitive Subscale (ADAS-Cog), and Functional Activities Questionnaire (FAQ).

Methods

This parallel group, four-site study will randomize 320 cognitively intact adults aged 60 to 85 years to novel or well-established measures of cognition and function. All participants will receive assessments at baseline (week 0), week 12, and week 52, as well as a brain MRI scan and Apolipoprotein E genetic test at study entry. Analyses will determine psychometric properties of the NPE and CFAS, compare the sensitivity of measures to AD risk markers, and identify cognitive domains within the NPE.

Discussion

Practice effects have been a major limitation of Alzheimer’s disease clinical trials that typically assess cognitive changes over serial assessments. Detection of functional impairment in cognitively normal individuals with biomarkers for Alzheimer’s disease requires instruments sensitive to very subtle functional changes. This study is intended to support the validation of two new composite measures, the NPE battery and the CFAS, which may advance clinical testing of interventions for individuals across the spectrum of early stage Alzheimer’s disease.

Trial Registration

NCT03900273
Metabolic markers distinguish COVID-19 from other intensive care patients and show potential to stratify for disease risk
Authors: Schmelter Franziska , Foeh Bandik , Mallagaray Alvaro , Rahmoeller Johann , Ehlers Marc , Lehrian Selina , Kopylow Vera von , Künsting Inga , Lixenfeld Anne Sophie , Martin Emily , Ragab Mohab , Borsche Max , Balck Alexander , Vollstedt Eva Juliane , Meyer-Saraei Roza , Kreutzmann Fabian , Eitel Ingo , Taube Stefan , Klein Christine , Katalinic Alexander , Rupp Jan , Jantzen Eckard , Graf Tobias , Sina Christian , Günther Ulrich L
Published: January 2021

Coronavirus disease 2019 (COVID-19) is a viral infection affecting multiple organ systems of great significance for metabolic processes. Thus. there is increasing interest in metabolic and lipoprotein signatures of the disease and early analyses have demonstrated metabolic pattern typical for atherosclerotic and hepatic damage in COVID-19 patients. However, it remains unclear whether these are specific for COVID-19 or a general marker of critical illness. To answer this question, we have analyzed 276 serum samples from 92 individuals using NMR metabolomics, including longitudinally collected samples from 5 COVID-19 and 11 cardiogenic shock intensive care patients, 18 SARS-CoV-2 antibody-positive individuals, and 58 healthy controls.

COVID-19 patients showed a distinct metabolic serum profile, including changes typical for severe dyslipidemia and a deeply altered metabolic status compared to healthy controls. Specifically, VLDL parameters, IDL particles, large-sized LDL particles, and the ApoB100/ApoA1 ratio were significantly increased, whereas HDL fractions were decreased. Moreover, a similarly perturbed profile was apparent, even when compared to other ICU patients suffering from cardiogenic shock, highlighting the impact of COVID-19 especially on lipid metabolism and energy status. COVID-19 patients were separated with an AUROC of 1.0 when compared to both healthy controls and cardiogenic shock patients. Anti-SARS-CoV-2 antibody-positive individuals without acute COVID-19 did not show a significantly perturbed metabolic profile compared to age- and sex-matched healthy controls, but SARS-CoV-2 antibody-titers correlated significantly with metabolic parameters, including levels of glycine, ApoA2, and small-sized LDL and HDL subfractions. Our data suggest that NMR metabolic profiles are suitable for COVID-19 patient stratification and post-treatment monitoring.
Large-scale genetic association and single cell accessible chromatin mapping defines cell type-specific mechanisms of type 1 diabetes risk
Authors: Chiou Joshua , Geusz Ryan J , Okino Mei-Lin , Han Jee Yun , Miller Michael , Benaglio Paola , Huang Serina , Korgaonkar Katha , Heller Sandra , Kleger Alexander , Preissl Sebastian , Gorkin David U , Sander Maike , Gaulton Kyle J
Published: January 2021

Translating genome-wide association studies (GWAS) of complex disease into mechanistic insight requires a comprehensive understanding of risk variant effects on disease-relevant cell types. To uncover cell type-specific mechanisms of type 1 diabetes (T1D) risk, we combined genetic association mapping and single cell epigenomics. We performed the largest to-date GWAS of T1D in 489,679 samples imputed into 59.2M variants, which identified 74 novel association signals including several large-effect rare variants. Fine-mapping of 141 total signals substantially improved resolution of causal variant credible sets, which primarily mapped to non-coding sequence. To annotate cell type-specific regulatory mechanisms of T1D risk variants, we mapped 448,142 candidatecis-regulatory elements (cCREs) in pancreas and peripheral blood mononuclear cell types using snATAC-seq of 131,554 nuclei. T1D risk variants were enriched in cCREs active in CD4+ T cells as well as several additional cell types including pancreatic exocrine acinar and ductal cells. High-probability T1D risk variants at multiple signals mapped to exocrine-specific cCREs including novel loci nearCEL, GP2andCFTR. At theCFTRlocus, the likely causal variant rs7795896 mapped in a ductal-specific distal cCRE which regulatedCFTRand the risk allele reduced transcription factor binding, enhancer activity andCFTRexpression in ductal cells. These findings support a role for the exocrine pancreas in T1D pathogenesis and highlight the power of combining large-scale GWAS and single cell epigenomics to provide insight into the cellular origins of complex disease.
A single-cell based precision medicine approach using glioblastoma patient-specific models
Authors: Park James H. , Feroze Abdullah H. , Emerson Samuel N. , Mihalas Anca B. , Keene C. Dirk , Cimino Patrick J. , de Lomana Adrian Lopez Garcia , Kannan Kavya , Wu Wei-Ju , Turkarslan Serdar , Baliga Nitin S. , Patel Anoop P.
Published: January 2021

Glioblastoma (GBM) is a heterogeneous tumor made up of cell states that evolve over time. Here, we modeled tumor evolutionary trajectories during standard-of-care treatment using multimodal single-cell analysis of a primary tumor sample, corresponding mouse xenografts subjected to standard of care therapy, and recurrent tumor at autopsy. We mined the multimodal data with single cell SYstems Genetics Network AnaLysis (scSYGNAL) to identify a network of 52 regulators that mediate treatment-induced shifts in xenograft tumor-cell states that were also reflected in recurrence. By integrating scSYGNAL-derived regulatory network information with transcription factor accessibility deviations derived from single-cell ATAC-seq data, we developed consensus networks that regulate subpopulations of primary and recurrent tumor cells. Finally, by matching targeted therapies to active regulatory networks underlying tumor evolutionary trajectories, we provide a framework for applying single-cell-based precision medicine approaches in a concurrent, neo-adjuvant, or recurrent setting.

Inference of mechanistic drivers of therapy-induced evolution of glioblastoma at single cell resolution using RNA-seq and ATAC-seq from patient samples and model systems undergoing standard-of-care treatment informs strategy for identification of tumor evolutionary trajectories and possible cell state-directed therapeutics.
RBCeq: An Integrated Bioinformatics Algorithm Designed to Improve Blood Type Compatibility Testing
Authors: Jadhao Sudhir , Davison Candice , Roulis Eileen V. , Schoeman Elizna M. , Divate Mayur , Shankar Arvind Jaya , Lee Simon , Pecheniuk Natalie M. , Irving David O , Hyland Catherine A. , Flower Robert L. , Nagaraj Shivashankar H.
Published: January 2021

While blood transfusion is an essential cornerstone of hematological care, patients that require repetitive transfusion remain at persistent risk of alloimmunization due to the diversity of human blood group polymorphisms. Next-generation sequencing (NGS) is an effective means of identifying genotypic and phenotypic variations among the blood groups, while the accurate interpretation of such NGS data is currently hampered by a lack of accessibility to bioinformatics support. To address this unmet need, we have developed the RBCeq (https://www.rbceq.org/) platform, which consists of a novel bioinformatics algorithm coupled with a user-friendly web server capable of comprehensively delineating different blood group variants from genomics data with advanced visualization of results. The software profiles genomic data for 36 blood group systems, including two transcription factors and can identify small genetic alterations, including small indels and copy number variants. The RBCeq algorithm was validated on 403 samples which include 58 complex serology cases from Australian Red Cross LifeBlood, 100 samples from The MedSeq Project (phs000958) and a further 245 from Indigenous Australian participants. The final blood typing data from RBCeq was 99.83% concordant for 403 samples (85 different antigens in 21 blood group systems) with that listed from the International Society for Blood Transfusion database.
Maternal infection promotes offspring tissue-specific immune fitness
Authors: Lim Ai Ing , McFadden Taryn , Link Verena M. , Han Seong-Ji , Karlsson Rose-Marie , Stacy Apollo , Farley Taylor K. , Harrison Oliver J. , Shih Han-Yu , Cameron Heather A. , Belkaid Yasmine
Published: January 2021

The mammalian immune system has evolved in the face of microbial exposure. How maternal infection experienced at distinct developmental stages shapes the offspring immune system remains poorly understood. Here we show that during pregnancy, maternally restricted infection can have permanent and tissue-specific impacts on offspring immunity. Mechanistically, maternal IL-6 produced in response to infection can specifically and directly impose epigenetic changes on fetal intestinal epithelial cells. Such imprinting is associated with long-lasting impacts on intestinal immune homeostasis, characterized by enhanced tonic immunity to the microbiota and heightened Th17 responses within the gut, but not at other barrier sites. Furthermore, the offspring from IL-6-exposed dams developed enhanced protective immunity to gastrointestinal infection. Together, this work demonstrates that maternal infection experienced during pregnancy can be coopted by the fetus to promote long-term tissue-specific fitness.

Summary sentence

Infection-induced maternal IL-6 impacts offspring epithelial cells, resulting in heightened immunity to the microbiota and pathogens.
A causal test of affect processing bias in response to affect regulation
Authors: Bush Keith A. , Kilts Clinton D.
Published: January 2021

In this study we merged methods from machine learning and human neuroimaging to causally test the role of self-induced affect processing states in biasing the affect processing of subsequent image stimuli. To test this causal relationship we developed a novel paradigm in which (n=40) healthy adult participants observed affective neural decodings of their real-time functional magnetic resonance image (rtfMRI) responses as feedback to guide explicit regulation of their brain (and corollary affect processing) state towards a positive valence goal state. By this method individual differences in affect regulation ability were controlled. Attaining this brain-affect goal state triggered the presentation of pseudo-randomly selected affectively congruent (positive valence) or incongruent (negative valence) image stimuli drawn from the International Affective Picture Set. Separately, subjects passively viewed randomly triggered positively and negatively valent image stimuli during fMRI acquisition. Multivariate neural decodings of the affect processing induced by these stimuli were modeled using the task trial type (state- versus randomly-triggered) as the fixed-effect of a general linear mixed-effects model. Random effects were modeled subject-wise. We found that self-induction of a positive valence brain state significantly positively biased valence processing of subsequent stimuli. As a manipulation check, we validated affect processing state induction achieved by the image stimuli using independent psychophysiological response measures of hedonic valence and autonomic arousal. We also validated the predictive fidelity of the trained neural decoding models using brain states induced by an out-of-sample set of image stimuli. Beyond its contribution to our understanding of the neural mechanisms that bias affect processing this work demonstrated the viability of novel experimental paradigms triggered by pre-defined cognitive states. This line of individual differences research potentially provides neuroimaging scientists with a valuable tool for causal exploration of the roles and identities of intrinsic cognitive processing mechanisms that shape our perceptual processing of sensory stimuli.
Characterisation of the R2R3 Myb subgroup 9 family of transcription factors in tomato
Authors: Davis Gwen. V. , Glover Beverley. J.
Published: January 2021

Tomato (Solanum lycopersicum)has many epidermal cell outgrowths including conical cells and multiple types of trichomes. These include the anther-specific trichome mesh which holds the anthers connate. The R2R3 Myb Subgroup 9 family of transcription factors is involved in development of epidermal cell outgrowths throughout the angiosperms. No previous study has examined all members of this transcription factor family in a single species. All 7R2R3 Myb Subgroup 9genes were isolated from tomato. They were ectopically expressed in tobacco to assess their ability to induce epidermal cell outgrowth. Endogenous expression patterns were examined by semi-quantitative RT-PCR at different stages of floral development relative to the development of anther trichomes. We report variation in the degree of epidermal cell outgrowth produced in transgenic tobacco for each ectopically expressed gene. Based on expression profile and ectopic activity,SlMIXTA-2is likely involved in the production of leaf trichomes whileSlMYB17-2is the best candidate for the regulation of the anther trichome mesh. Analysis of the phenotypes of transgenic plants ectopically expressing all 7 genes has revealed the different extent to which members of the same transcription factor subfamily can induce cellular outgrowth.

Highlight

Characterisation of all members of an important family of transcription factors within tomato showing that all are able to induce epidermal cell outgrowths to varying degrees.
Learning interpretable cellular and gene signature embeddings from single-cell transcriptomic data
Authors: Zhao Yifan , Cai Huiyu , Zhang Zuobai , Tang Jian , Li Yue
Published: January 2021

The advent of single-cell RNA sequencing (scRNA-seq) technologies has revolutionized transcriptomic studies. However, large-scale integrative analysis of scRNA-seq data remains a challenge largely due to unwanted batch effects and the limited transferabilty, interpretability, and scalability of the existing computational methods. We present single-cell Embedded Topic Model (scETM). Our key contribution is the utilization of a transferable neural-network-based encoder while having an interpretable linear decoder via a matrix tri-factorization. In particular, scETM simultaneously learns an encoder network to infer cell type mixture and a set of highly interpretable gene embeddings, topic embeddings, and batch effect linear intercepts from multiple scRNA-seq datasets. scETM is scalable to over 106cells and confers remarkable cross-tissue and cross-species zero-shot transfer-learning performance. Using gene set enrichment analysis, we find that scETM-learned topics are enriched in biologically meaningful and disease-related pathways. Lastly, scETM enables the incorporation of known gene sets into the gene embeddings, thereby directly learning the associations between pathways and topics via the topic embeddings.
CAR-NK Cells Effectively Target the D614 and G614 SARS-CoV-2-infected Cells
Authors: Ma Minh , Badeti Saiaditya , Chen Chih-Hsiung , Pinter Abraham , Jiang Qingkui , Shi Lanbo , Zhou Renping , Xu Huanbin , Li Qingsheng , Gause William , Liu Dongfang
Published: January 2021

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is highly contagious presenting a significant public health issue. Current therapies used to treat coronavirus disease 2019 (COVID-19) include monoclonal antibody cocktail, convalescent plasma, antivirals, immunomodulators, and anticoagulants, though the current therapeutic options remain limited and expensive. The vaccines from Pfizer and Moderna have recently been authorized for emergency use, which are invaluable for the prevention of SARS-CoV-2 infection. However, their long-term side effects are not yet to be documented, and populations with immunocompromised conditions (e.g., organ-transplantation and immunodeficient patients) may not be able to mount an effective immune response. In addition, there are concerns that wide-scale immunity to SARS-CoV-2 may introduce immune pressure that could select for escape mutants to the existing vaccines and monoclonal antibody therapies. Emerging evidence has shown that chimeric antigen receptor (CAR)- natural killer (NK) immunotherapy has potent antitumor response in hematologic cancers with minimal adverse effects in recent studies, however, the potentials of CAR-NK cells in preventing and treating severe cases of COVID-19 has not yet been fully exploited. Here, we improve upon a novel approach for the generation of CAR-NK cells for targeting SARS-CoV-2 and its D614G mutant. CAR-NK cells were generated using the scFv domain of S309 (henceforward, S309-CAR-NK), a SARS-CoV and SARS-CoV-2 neutralizing antibody that targets the highly conserved region of SARS-CoV-2 spike (S) glycoprotein, therefore would be more likely to recognize different variants of SARS-CoV-2 isolates. S309-CAR-NK cells can specifically bind to pseudotyped SARS-CoV-2 virus and its D614G mutant. Furthermore, S309-CAR-NK cells can specifically kill target cells expressing SARS-CoV-2 S proteinin vitroand show superior killing activity and cytokine production, compared to that of the recently published CR3022-CAR-NK cells. Thus, these results pave the way for generating ‘off-the-shelf’ S309-CAR-NK cells for treatment in high-risk individuals as well as provide an alternative strategy for patients unresponsive to current vaccines.
Evaluating Extraction Methods to Study Canine Urine Microbiota
Authors: Mrofchak R. , Madden C. , Evans M.V. , Hale V.L.
Published: January 2021

The urinary microbiota is the collection of microbes present in urine that play a role in host health. Studies of urine microbiota have traditionally relied upon culturing methods aimed at identifying pathogens. However, recent culture-free sequencing studies of the urine microbiota have determined that a diverse array of microbes are present in health and disease. To study these microbes and their potential role in diseases like bladder cancer or interstitial cystitis, consistent extraction and detection of microbial DNA from urine is critical. However, urine is a low biomass substrate, requiring sensitive methods to capture DNA and making the risk of contamination high. To address this challenge, we collected urine samples from ten healthy dogs and extracted DNA from each sample using five different commercially available extraction methods. Extraction methods were compared based on total and bacterial DNA concentrations and microbial community composition and diversity assessed through 16S rRNA gene sequencing. Significant differences in the urinary microbiota were observed by dog and sex but not extraction method. The Bacteremia kit yielded the highest total DNA concentrations (Kruskal-Wallis,p= 0.165, not significant) and the highest bacterial DNA concentrations (Kruskal-Wallis,p= 0.044). Bacteremia also extracted bacterial DNA from the greatest number of samples. Taken together, these results suggest that the Bacteremia kit is an effective option for studying the urine microbiota. This work lays the foundation to study the urine microbiome in a wide range of urogenital diseases in dogs and other species.

Highlights

Canine urine microbiota differed by sex and dog but not extraction method.

Qiagen Bacteremia kit yielded the highest bacterial DNA concentrations from urine.

The Bacteremia kit extracted bacterial DNA from the greatest number of samples.

Absolute abundance ofSphingomonasspecies increased in female dog urine.

Pasteurellaceaebacterium canine oral taxon 272 increased in male dog urine.
Serotonin modulates learning content-specific neuroplasticity of functional brain networks
Authors: Klöbl Manfred , Seiger René , Vanicek Thomas , Handschuh Patricia , Reed Murray Bruce , Spurny Benjamin , Ritter Vera , Godbersen Godber Mathis , Gryglewski Gregor , Kraus Christoph , Hahn Andreas , Lanzenberger Rupert
Published: January 2021

Learning-induced neuroplastic changes, further modulated by content and setting, are mirrored in brain functional connectivity (FC). In animal models, serotonergic agents were shown to facilitate neuroplasticity. This is especially prominent during emotional relearning, such as fear extinction, which may translate to clinical improvements in human patients. To investigate this assumption, 99 healthy subjects underwent six weeks of emotional or non-emotional learning and subsequent relearning. Resting-state functional magnetic resonance imaging was performed before and after the learning phases to investigate changes in FC. During relearning, subjects received either a daily dose of the selective serotonin reuptake inhibitor (SSRI) escitalopram or placebo. Escitalopram intake modulated FC changes in a network comprising Broca’s area, the medial prefrontal cortex, the right inferior temporal and left lingual gyrus. More specifically, escitalopram increased the bidirectional connectivity between medial prefrontal cortex and lingual gyrus for non-emotional and additionally the connectivity from medial prefrontal cortex to Broca’s area for emotional relearning. The context-dependence of these effects supports the assumption that SSRIs in clinical practice might improve neuroplasticity rather than psychiatric symptoms per se. Correlations with learning behavior further point towards a relationship with extinction processes in relearning. These results demonstrate that escitalopram intake during relearning results in content-dependent network adaptations and support the conclusion that enhanced neuroplasticity might be the major underlying mechanism also in humans. Beyond expanding the complexities of learning, these findings emphasize the influence of external factors on serotonin-facilitated neuroplasticity of the human brain.
The human cerebellum is essential for modulating perceptual sensitivity based on temporal expectations
Authors: Breska Assaf , Ivry Richard B.
Published: January 2021

A functional benefit of attention is to proactively enhance perceptual sensitivity in space and time. Although attentional orienting has traditionally been associated with cortico-thalamic networks, recent evidence has shown that individuals with cerebellar degeneration (CD) show a reduced reaction time benefit from cues that enable temporal anticipation. While this deficit may reflect impairment in anticipatory motor preparation, it could also arise from cerebellar contribution to attentional modulation in time of perceptual sensitivity. To examine this, we tested CD participants on a non-speeded, challenging perceptual discrimination task, asking if they benefit from temporal cues. Strikingly, the CD group showed no duration-specific perceptual sensitivity benefit when cued by repeated but aperiodic presentation of the target interval. In contrast, they performed similar to controls when cued by a rhythmic stream. This dissociation further specifies the functional domain of the cerebellum and establishes its role in the attentional adjustment of perceptual sensitivity in time.
Convergent evolution of resistance pathways during early stage breast cancer treatment with combination cell cycle (CDK) and endocrine inhibitors
Authors: Griffiths Jason I. , Chen Jinfeng , Cosgrove Patrick A. , O’Dea Anne , Sharma Priyanka , Ma Cynthia , Trivedi Meghna , Kalinsky Kevin , Wisinski Kari B. , O’Regan Ruth , Makhoul Issam , Spring Laura M. , Bardia Aditya , Adler Frederick R. , Cohen Adam L. , Chang Jeffrey T. , Khan Qamar J. , Bild Andrea H.
Published: January 2021

Combining cyclin-dependent kinase (CDK) inhibitors with endocrine therapy improves outcomes for metastatic estrogen receptor positive (ER+), HER2 negative, breast cancer patients. However, the value of this combination in potentially curable earlier stage patients is not clear. Using single cell transcriptomic profiling, we examined the evolutionary trajectories of early stage breast cancer tumors using serial tumor biopsies from a clinical trial of preoperative endocrine therapy (letrozole) alone or in combination with the cell cycle inhibitor ribociclib. Applying hierarchical regression and Gaussian process mathematical modelling, we classified each tumor by whether it shrinks or persists with therapy and determined cancer phenotypes related to evolution of resistance and cell cycle transcriptional rewiring. We found that all patients’ tumors undergo subclonal evolution during therapy, irrespective of the clinical response. However, tumors subjected to endocrine therapy alone showed reduced diversity over time, while those facing combination therapy exhibited increased diversity. Despite different subclonal diversity, single nuclei RNA sequencing uncovered common phenotypic changes in tumor cells that persist following treatment. In these tumors, cancer cells with accelerated loss of estrogen signaling have convergent up-regulation of the JNK pathway, while cells that maintain estrogen signaling during therapy show potentiation of CDK4/6 activation consistent with ERBB4 and ERK signaling up-regulation. These convergent phenotypes were associated with growing tumors resistant to combination therapy. Cell cycle reconstruction identified that these tumors can rebound during combination therapy treatment, indicating stronger selection and promotion of a proliferative state. These results indicate that combination therapy in early stage ER+ breast cancers with ER and CDK inhibition drives rapid evolution of resistance via a shift from estrogen signaling to alternative growth factor receptor mediated proliferation and JNK signaling activation, concordant with a bypass in the G1 checkpoint.
Polymorphism and structure formation in copper phthalocyanine thin films
Authors: Reisz Berthold , Belova Valentina , Duva Giuliano , Zeiser Clemens , Hodas Martin , Hagara Jakub , Šiffalovič Peter , Pithan Linus , Hosokai Takuya , Hinderhofer Alexander , Gerlach Alexander , Schreiber Frank
Published: January 2021

Many polymorphic crystal structures of copper phthalocyanine (CuPc) have been reported over the past few decades, but despite its manifold applicability, the structure of the frequently mentioned α polymorph remained unclear. The base-centered unit cell (space groupC2/c) suggested in 1966 was ruled out in 2003 and was replaced by a primitive triclinic unit cell (space groupP1). This study proves unequivocally that both α structures coexist in vacuum-deposited CuPc thin films on native silicon oxide by reciprocal space mapping using synchrotron radiation in grazing incidence. The unit-cell parameters and the space group were determined by kinematic scattering theory and provide possible molecular arrangements within the unit cell of theC2/cstructure by excluded-volume considerations.In situX-ray diffraction experiments andex situatomic force microscopy complement the experimental data further and provide insight into the formation of a smooth thin film by a temperature-driven downward diffusion of CuPc molecules during growth.
Using the life course paradigm to study financial well-being in late life
Authors: Prakitsuwan Pattharanitcha , Moschis George P. , Shannon Randall
Published: January 2021

Purpose

This study aims to show how the increasingly popular life course paradigm (LCP) can be employed as an alternative to the successful aging perspective (SAP) as an overarching conceptual research framework to study elderly consumers' financial well-being.

Design/methodology/approach

A questionnaire was administered to a convenience sample of 804 Thai consumers over the age of 45 selected via the snowball method.

Findings

Significant results were found for hypotheses derived from the LCP for older consumers' financial well-being, suggesting critical roles of early life experiences, developmental factors, adaptation mechanisms and contextual factors.

Originality/value

This paper shows how efforts to study consumers over the course of their lives can be improved by utilizing the principles and theoretical perspectives of the LCP and offers research directions for studying not only older consumer well-being but also numerous consumer behavior issues at any stage of life in an innovative way.
Exploring the roles of lead organisations in spreading sustainability standards throughout food supply chains in an emerging economy
Authors: Silva Minelle E. , Dias Gustavo Picanço , Gold Stefan
Published: January 2021

Purpose

This paper investigates how food supply chains (SCs) introduce sustainability standards (i.e. organic and/or Fair Trade labels). The authors combined the concepts of power and dependence with types of governance mechanisms to analyse for-profit and cooperative organisations. The authors explored nuances of how lead organisations are spreading sustainability standards.

Design/methodology/approach

Four cashew nut and honey SCs were investigated as case studies in Brazil, with data gathered through 15 interviews, secondary data and field visits. Data were examined through a content analysis process following a combined deductive and inductive approach.

Findings

Sustainability is spread driven by market pressure, mainly through the diffusion of technical information, either by lead organisations enablers or inter-organisational relations. The authors found that the type and structure of organisations impact the source of power (mediated or non-mediated) and level of mutual dependence between buyer and supplier. For instance, suppliers that hold a strategic position use direct governance mechanisms, which, in turn, lessens the power imbalance in regard to the lead organisation. The authors found in the analysis, a close relation between governance mechanisms and the spread of sustainability, which is ultimately based on strong SC relationships.

Practical implications

By recognising their role and the contingencies in spreading sustainability standards along the SC, managers of lead organisations can better design their relationships as well as create strategies to increase their supply chain sustainability (SCS) performance.

Originality/value

This paper contributes to the underexplored issue of how sustainability standards are spread throughout SCs in Latin America. Also, it shows how different types of SC rely on governance mechanisms that foster SCS.
Reinforcement learning for content's customization: a first step of experimentation in Skyscanner
Authors: Giachino Chiara , Bollani Luigi , Bonadonna Alessandro , Bertetti Marco
Published: January 2021

Purpose

The aim of the paper is to test and demonstrate the potential benefits in applying reinforcement learning instead of traditional methods to optimize the content of a company's mobile application to best help travellers finding their ideal flights. To this end, two approaches were considered and compared via simulation: standard randomized experiments or A/B testing and multi-armed bandits.

Design/methodology/approach

The simulation of the two approaches to optimize the content of its mobile application and, consequently, increase flights conversions is illustrated as applied by Skyscanner, using R software.

Findings

The first results are about the comparison between the two approaches – A/B testing and multi-armed bandits – to identify the best one to achieve better results for the company. The second one is to gain experiences and suggestion in the application of the two approaches useful for other industries/companies.

Research limitations/implications

The case study demonstrated, via simulation, the potential benefits to apply the reinforcement learning in a company. Finally, the multi-armed bandit was implemented in the company, but the period of the available data was limited, and due to its strategic relevance, the company cannot show all the findings.

Practical implications

The right algorithm can change according to the situation and industry but would bring great benefits to the company's ability to surface content that is more relevant to users and help improving the experience for travellers. The study shows how to manage complexity and data to achieve good results.

Originality/value

The paper describes the approach used by an European leading company operating in the travel sector in understanding how to adapt reinforcement learning to its strategic goals. It presents a real case study and the simulation of the application of A/B testing and multi-armed bandit in Skyscanner; moreover, it highlights practical suggestion useful to other companies.