bluuebunny/crossref_metadata_2025_split huggingface dataset:
CRISPR/Cas9 disruption of UGT71L1 in poplar connects salicinoid and salicylic acid metabolism and alters growth and morphology
Authors: Gordon Harley , Fellenberg Christin , Lackus Nathalie D , Archinuk Finn , Sproule Amanda , Nakamura Yoko , K�llner Tobias G , Gershenzon Jonathan , Overy David P , Constabel C Peter 
Published: May 2022

Abstract
Salicinoids are salicyl alcohol-containing phenolic glycosides with strong antiherbivore effects found only in poplars and willows. Their biosynthesis is poorly understood, but recently a UDP-dependent glycosyltransferase, UGT71L1, was shown to be required for salicinoid biosynthesis in poplar tissue cultures. UGT71L1 specifically glycosylates salicyl benzoate, a proposed salicinoid intermediate. Here, we analyzed transgenic CRISPR/Cas9-generated UGT71L1 knockout plants. Metabolomic analyses revealed substantial reductions in the major salicinoids, confirming the central role of the enzyme in salicinoid biosynthesis. Correspondingly, UGT71L1 knockouts were preferred to wild-type by white-marked tussock moth (Orgyia leucostigma) larvae in bioassays. Greenhouse-grown knockout plants showed substantial growth alterations, with decreased internode length and smaller serrated leaves. Reinserting a functional UGT71L1 gene in a transgenic rescue experiment demonstrated that these effects were due only to the loss of UGT71L1. The knockouts contained elevated salicylate (SA) and jasmonate (JA) concentrations, and also had enhanced expression of SA- and JA-related genes. SA is predicted to be released by UGT71L1 disruption, if salicyl salicylate is a pathway intermediate and UGT71L1 substrate. This idea was supported by showing that salicyl salicylate can be glucosylated by recombinant UGT71L1, providing a potential link of salicinoid metabolism to SA and growth impacts. Connecting this pathway with growth could imply that salicinoids are under additional evolutionary constraints beyond selective pressure by herbivores.
Directing cyanobacterial photosynthesis in a cytochrome c oxidase mutant using a heterologous electron sink
Authors: Torrado Alejandro , Connabeer Hannah M , Röttig Annika , Pratt Nicola , Baylay Alison J , Terry Matthew J , Moore C Mark , Bibby Thomas S 
Published: May 2022

Abstract
Photosynthesis holds the promise of sustainable generation of useful products using light energy. Key to realizing this potential is the ability to rationally design photosynthesis to redirect energy and reductant derived from photons to desired products. Cytochrome P450s (P450s), which catalyze a broad array of reactions, have been engineered into a variety of photosynthetic organisms, where their activity has been shown to be photosynthesis-dependent, thus acting as heterologous sinks of electrons derived from photosynthesis. Furthermore, the addition of P450s can increase the photosynthetic capacity of the host organism. In this study, we developed this technology further using a P450 (CYP1A1) expressed in the cyanobacterium Synechococcus sp. PCC 7002. We show that rationally engineering photosynthesis by the removal of a competing electron sink, the respiratory terminal oxidase cytochrome c oxidase, increased the activity of CYP1A1. We provide evidence that this enhanced CYP1A1 activity was facilitated via an increase in the flux of electrons through Photosystem I. We also conducted a transcriptomic analysis on the designed strains to gain a more holistic understanding of how the cell responds to rational engineering. We describe a complex response including changes in expression of genes involved in photosynthesis and electron transfer linked to respiration. Specifically, the expression of CYP1A1 resulted in the reduction in expression of other natural electron dissipation pathways. This study emphasizes the potential for engineering photosynthetic organisms in biotechnology but also highlights the need to consider the broader impacts on cellular metabolism of any rationally induced changes.
The transcription factor MdMYB2 influences cold tolerance and anthocyanin accumulation by activating SUMO E3 ligase MdSIZ1 in apple
Authors: Jiang Han , Zhou Li-Jie , Gao Huai-Na , Wang Xiao-Fei , Li Zhi-Wen , Li Yuan-Yuan 
Published: May 2022

Abstract
Conjugation of the small ubiquitin-like modifier (SUMO) peptide to target proteins is an important post-translational modification. SAP AND MIZ1 DOMAIN-CONTAINING LIGASE1 (MdSIZ1) is an apple (Malus domestica Borkh). SUMO E3 ligase that mediates sumoylation of its targets during plant growth and development under adverse environmental conditions. However, it is unclear how MdSIZ1 senses the various environmental signals and whether sumoylation is regulated at the transcriptional level. In this study, we analyzed the MdSIZ1 promoter and found that it contained an MYB binding site (MBS) motif that was essential for the response of MdSIZ1 to low temperature (LT) and drought. Subsequently, we used yeast one-hybridization screening to demonstrate that a MYB transcription factor, MdMYB2, directly bound to the MBS motif in the MdSIZ1 promoter. Phenotypic characterization of MdMYB2 and MdSIZ1 suggested that the expression of both MdMYB2 and MdSIZ1 substantially improved cold tolerance in plants. MdMYB2 was induced by LT and further activated the expression of MdSIZ1, thereby promoting the sumoylation of MdMYB1, a key regulator of anthocyanin biosynthesis in apple. MdMYB2 promoted anthocyanin accumulation in apple fruits, apple calli, and Arabidopsis (Arabidopsis thaliana) in an MdSIZ1-dependent manner. In addition, the interaction of MdMYB2 and the MdSIZ1 promoter substantially improved plant tolerance to cold stress. Taken together, our findings reveal an important role for transcriptional regulation of sumoylation and provide insights into plant anthocyanin biosynthesis regulation mechanisms and stress response.
Panel sequencing links rare, likely damaging gene variants with distinct clinical phenotypes and outcomes in juvenile-onset SLE
Authors: Charras Amandine , Haldenby Sam , Smith Eve M D , Egbivwie Naomi , Olohan Lisa , Kenny John G , Schwarz Klaus , Roberts Carla , Al-Abadi Eslam , Armon Kate , Bailey Kathryn , Ciurtin Coziana , Gardner-Medwin Janet , Haslam Kirsty , Hawley Daniel P , Leahy Alice , Leone Valentina , McErlane Flora , Modgil Gita , Pilkington Clarissa , Ramanan Athimalaipet V , Rangaraj Satyapal , Riley Phil , Sridhar Arani , Beresford Michael W , Hedrich Christian M 
Published: May 2022

AbstractObjectivesJuvenile-onset systemic lupus erythematosus (jSLE) affects 15–20% of lupus patients. Clinical heterogeneity between racial groups, age groups and individual patients suggests variable pathophysiology. This study aimed to identify highly penetrant damaging mutations in genes associated with SLE/SLE-like disease in a large national cohort (UK JSLE Cohort Study) and compare demographic, clinical and laboratory features in patient sub-cohorts with ‘genetic’ SLE vs remaining SLE patients.MethodsBased on a sequencing panel designed in 2018, target enrichment and next-generation sequencing were performed in 348 patients to identify damaging gene variants. Findings were integrated with demographic, clinical and treatment related datasets.ResultsDamaging gene variants were identified in ∼3.5% of jSLE patients. When compared with the remaining cohort, ‘genetic’ SLE affected younger children and more Black African/Caribbean patients. ‘Genetic’ SLE patients exhibited less organ involvement and damage, and neuropsychiatric involvement developed over time. Less aggressive first line treatment was chosen in ‘genetic’ SLE patients, but more second and third line agents were used. ‘Genetic’ SLE associated with anti-dsDNA antibody positivity at diagnosis and reduced ANA, anti-LA and anti-Sm antibody positivity at last visit.ConclusionApproximately 3.5% of jSLE patients present damaging gene variants associated with younger age at onset, and distinct clinical features. As less commonly observed after treatment induction, in ‘genetic’ SLE, autoantibody positivity may be the result of tissue damage and explain reduced immune complex-mediated renal and haematological involvement. Routine sequencing could allow for patient stratification, risk assessment and target-directed treatment, thereby increasing efficacy and reducing toxicity.
Does Money Talk? Divestitures and Corporate Environmental and Social Policies
Authors: Gantchev Nickolay , Giannetti Mariassunta , Li Rachel 
Published: May 2022

Abstract
Can shareholders’ divestitures and threats of exit trigger improvements in firms’ environmental and social (E&S) policies? We show that E&S incidents are followed by some, but relatively small, divestitures. Nevertheless, following E&S incidents, firms with a one-standard-deviation higher E&S-conscious institutional ownership decrease their greenhouse gas emissions by 36.5% and improve their E&S scores by 7.2% more than other firms if their managers receive equity compensation. We do not observe any improvements associated with sales in E&S-conscious countries. Our results suggest that the threats of future exits and divestitures can improve E&S policies if shareholders are E&S-conscious and managers’ compensation is linked to the stock price.
Measuring “pain load” during general anesthesia
Authors: Green Stephen , Karunakaran Keerthana Deepti , Peng Ke , Berry Delany , Kussman Barry David , Micheli Lyle , Borsook David 
Published: May 2022

Abstract

Introduction
Functional near-infrared spectroscopy (fNIRS) allows for ongoing measures of brain functions during surgery. The ability to evaluate cumulative effects of painful/nociceptive events under general anesthesia remains a challenge. Through observing signal differences and setting boundaries for when observed events are known to produce pain/nociception, a program can trigger when the concentration of oxygenated hemoglobin goes beyond ±0.3 mM from 25 s after standardization.

Method
fNIRS signals were retrieved from patients undergoing knee surgery for anterior cruciate ligament repair under general anesthesia. Continuous fNIRS measures were measured from the primary somatosensory cortex (S1), which is known to be involved in evaluation of nociception, and the medial polar frontal cortex (mPFC), which are both involved in higher cortical functions (viz. cognition and emotion).

Results
A ±0.3 mM threshold for painful/nociceptive events was observed during surgical incisions at least twice, forming a basis for a potential near-real-time recording of pain/nociceptive events. Evidence through observed true positives in S1 and true negatives in mPFC are linked through statistically significant correlations and this threshold.

Conclusion
Our results show that standardizing and observing concentrations over 25 s using the ±0.3 mM threshold can be an arbiter of the continuous number of incisions performed on a patient, contributing to a potential intraoperative pain load index that correlates with post-operative levels of pain and potential pain chronification.
Dietary Folate Intake and Fecundability in Two Preconception Cohorts
Authors: Cueto Heidi T. , Jacobsen Bjarke H. , Laursen Anne Sofie Dam , Riis Anders H. , Hatch Elizabeth E. , Wise Lauren A. , Trolle Ellen , Sørensen Henrik Toft , Rothman Kenneth J. , Wesselink Amelia K. , Willis Sydney , Johannesen Benjamin R. , Mikkelsen Ellen M. 
Published: May 2022

(Abstracted from Hum Reprod 2022;37(4):828–837)
Folate is an antioxidant micronutrient present in many vegetables, fruits, whole grains, beans, and the liver. Its synthetic counterpart, folic acid, is used as a dietary supplement for fortification of wheat and other foods.
Impact of Homologous Recombination Status and Responses With Veliparib Combined With First-Line Chemotherapy in Ovarian Cancer in the Phase 3 VELIA/GOG-3005 Study
Authors: Swisher Elizabeth M. , Aghajanian Carol , O'Malley David M. , Fleming Gini F. , Kaufmann Scott H. , Levine Douglas A. , Birrer Michael J. , Moore Kathleen N. , Spirtos Nick M. , Shahin Mark S. , Reid Thomas J. , Friedlander Michael , Steffensen Karina Dahl , Okamoto Aikou , Sehgal Vasudha , Ansell Peter J. , Dinh Minh H. , Bookman Michael A. , Coleman Robert L. 
Published: May 2022

(Abstracted from Gynecol Oncol 2022;164:245–253)
Cancers with genetic homologous repair defects such as the breast cancer susceptibility genes BRCA1 and BRCA2 are particularly sensitive to poly (ADP-ribose) polymerase (PARP) inhibition. Identification of other homologous recombination deficiencies (HRD) beyond BRCA loss could expand utilization of PARP inhibitors (PARPi).
Expanding Homogeneous Culture of Human Primordial Germ Cell–Like Cells Maintaining Germline Features Without Serum or Feeder Layers
Authors: Kobayashi Mutsumi , Kobayashi Misato , Odajima Junko , Shioda Keiko , Hwang Young Sun , Sasaki Kotaro , Chatterjee Pranam , Kramme Christian , Kohman Richie E. , Church George M. , Loehr Amanda R. , Weiss Robert S. , Jüppner Harald , Gell Joanna J. , Lau Ching C. , Shioda Toshi 
Published: May 2022

(Abstracted from Stem Cell Rep 2022;17(3):507–521)
Primordial germ cells (PGCs) are embryonic precursors of gametes that are extensively studied in research settings. Human primordial PGC–like cells (hPGCLCs) are a surrogate model for embryonic PGCs that present difficulties in in vitro cell culture and expansion due to rapid loss of PGC-like identity and limited cell survival.
Perinatal Death by Bile Acid Levels in Intrahepatic Cholestasis of Pregnancy: A Systematic Review
Authors: Di Mascio Daniele , Quist-Nelson Johanna , Riegel Melissa , George Brandon , Saccone Gabriele , Brun Romana , Haslinger Christian , Herrera Christina , Kawakita Tetsuya , Lee Richard H. , Panici Pierluigi Benedetti , Berghella Vincenzo 
Published: May 2022

(Abstracted from J Matern Fetal Neonatal Med 2021;34(21):3614–3622)
Intrahepatic cholestasis of pregnancy (ICP) is characterized by elevated total bile acids (TBAs) and is the most common liver disease during pregnancy. The etiology and pathophysiology of ICP are not well understood, but genetics, ethnicity, hormones, nutrition, and the environment have been cited as risk factors.
Trends, Characteristics, and Outcomes of Placenta Accreta Spectrum: A National Study in the United States
Authors: Matsuzaki Shinya , Mandelbaum Rachel S. , Sangara Rauvynne N. , McCarthy Lauren E. , Vestal Nicole L. , Klar Maximilian , Matsushima Kazuhide , Amaya Rodolfo , Ouzounian Joseph G. , Matsuo Koji 
Published: May 2022

(Abstracted from Am J Obstet Gynecol 2021;225:534.e1–534.e38)
Placenta accreta spectrum (PAS) describes the phenomenon wherein the trophoblastic placental tissue morbidly attaches to the myometrium of the gravid uterus, preventing normal detachment and causing morbidity. Depending on the degree of invasion, PAS is categorized as accreta if attached to the myometrium without decidua, increta if invasion occurs into the myometrium, and percreta if invasion through the myometrium into surrounding organs occurs.
A Novel Innovation and Entrepreneurship (I&E) Training Program for Biomedical Research Trainees
Authors: Grailer Joseph G. , Alhallak Kinan , Antes Alison L. , Kinch Michael S. , Woods Letha , Toker Emre , Garbutt Jane M. 
Published: May 2022

Problem
Contemporary science emphasizes efficient translation of scientific discoveries into tangible, innovative products and services to improve human health. Therefore, researchers need skills in innovation and entrepreneurship (I&E) to select which problems to address and bring to market the most promising solutions. Training in this skillset is not currently available to most biomedical research trainees.

Approach
The Entrepreneurship for Biomedicine (E4B) training program was created to develop biomedical researchers’ I&E skills. The program comprises 2 semester-length courses: E4B1 teaches core skills; E4B2 focuses on advanced skills for those interested in pursuing funding for a new venture. In addition to traditional entrepreneurship training, E4B teaches ethics and personal skills such as resilience, communication, and team-building. Each course is delivered online and requires about 4 hours weekly. Program elements include short videos for didactic content; a team-based capstone project; mentorship from experienced entrepreneurs; and a live, virtual pitch presentation. The program is housed at Washington University School of Medicine in St. Louis and is open to pre- and postdoctoral biomedical research trainees and faculty nationwide.

Outcomes
In 2020, 77 trainees completed E4B1 and 13 went on to complete E4B2. Trainees in both courses were satisfied with learning content and mentorship and would recommend the program to a friend. Pre- and postanalyses demonstrated that trainees’ confidence in their knowledge about and ability to perform I&E tasks taught throughout the program increased. Since completion, 4 graduates have received external funding for an innovation and 3 have started a company.

Next Steps
E4B is well accepted, and this preliminary evaluation suggests the program is effective. It could serve to support medical school curricula, business competitions, and technology transfer efforts, which are opportunities for future exploration. A more robust evaluation is planned and recruitment will be expanded to increase participation from women and underrepresented populations.
Expanding Underrepresented in Medicine to Include Lesbian, Gay, Bisexual, Transgender, and Queer Individuals
Authors: Kelly Tim , Rodriguez Sarah B. 
Published: May 2022

In 2003, the Association of American Medical Colleges (AAMC) stopped using the term “underrepresented minority” and instead adopted “underrepresented in medicine.” This was not the first time the AAMC revised this definition. In this article, the authors call on the AAMC to revise and expand this definition to include another group that is underrepresented in medicine: lesbian, gay, bisexual, transgender, and queer (LGBTQ) individuals. It is difficult to know whether LGBTQ populations are underrepresented in medicine; however, the data that do exist suggest a significant lack of LGBTQ representation in medicine. It is unclear if this underrepresentation is due to a true numerical lack of LGBTQ physicians, to LGBTQ physicians not publicly self-identifying due to anti-LGBTQ sentiments and reactions, or to both.
The authors urge the AAMC to take 3 actions: to anonymously and sensitively poll physicians nationwide to obtain a better estimate of the current number of LGBTQ physicians, to formulate improved standards for an LGBTQ health curriculum for all medical trainees to consistently produce LGBTQ-competent physicians, and to once again expand its definition of underrepresented in medicine to include LGBTQ populations. Such a change to this definition would likely lead to concerted efforts to increase the number of LGBTQ physicians, which could then lead to increased visibility, inclusivity, and mentorship programs where LGBTQ trainees could thrive. With these 3 actions, the authors believe that the AAMC has the opportunity to forge a path forward that is not only beneficial to LGBTQ trainees but also to LGBTQ patients who currently face a myriad of health disparities due to the lack of LGBTQ-identifying and LGBTQ-competent physicians.
Learning the Language of Medical Device Innovation: A Longitudinal Interdisciplinary Elective for Medical Students
Authors: Maloney Lauren M. , Hakimi Mathew , Hays Thomas , Adachi Joseph , Chau Annie , Esper Brecken S. , Koulouris Vasilios , Kung Preston , Meier Karl R. , Schum Ryan S. , Sha Sha , Wong Ada , Wu Ariel , Yin Wei , Page Christopher R. 
Published: May 2022

Problem
Physicians are playing a growing role as clinician–innovators. Academic physicians are well positioned to contribute to the medical device innovation process, yet few medical school curricula provide students opportunities to learn the conceptual framework for clinical needs finding, needs screening, concept generation and iterative prototyping, and intellectual property management. This framework supports innovation and encourages the development of valuable interdisciplinary communication skills and collaborative learning strategies.

Approach
Our university offers a novel 3-year-long medical student Longitudinal Interdisciplinary Elective in Biodesign (MSLIEB) that teaches medical device innovation in 4 stages: (1) seminars and small-group work, (2) shared clinical experiences for needs finding, (3) concept generation and product development by serving as consultants for biomedical engineering capstone projects, and (4) reflection and mentorship. The MSLIEB objectives are to: create a longitudinal interdisciplinary peer mentorship relationship between undergraduate biomedical engineering students and medical students, and encourage codevelopment of professional identities in relation to medical device innovation.

Outcomes
The MSLIEB enrolled 5 entering cohorts from 2017 to 2021 with a total of 37 medical student participants. The first full entering cohort of 12 medical students produced 8 mentored biomedical engineering capstone projects, 7 of which were based on clinical needs statements derived from earlier in the elective. Medical student participants have coauthored poster and oral presentations; contributed to projects that won WolfieTank, a university-wide competition modeled after the television show Shark Tank; and participated in the filing of provisional patents. Students reflecting on the course reported a change in their attitude towards existing medical problems, felt better-equipped to collaboratively design solutions for clinical needs, and considered a potential career path in device design.

Next Steps
The MSLIEB will be scaled up by recruiting additional faculty, broadening clinical opportunities to include the outpatient setting, and increasing medical student access to rapid prototyping equipment.