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Article ; Online: High-resolution secretory timeline from vesicle formation at the Golgi to fusion at the plasma membrane in <i>S. cerevisiae</i>.

Gingras, Robert M / Sulpizio, Abigail M / Park, Joelle / Bretscher, Anthony

2022 Volume 11

Abstract: ... exocyst complex, including Sec3, is assembled on to the vesicle. Before fusion, vesicles tether for 5 s ... protein Sec1, which appears for just 2 s prior to fusion. Perturbation experiments reveal an ordered and ...

Abstract	Most of the components in the yeast secretory pathway have been studied, yet a high-resolution temporal timeline of their participation is lacking. Here, we define the order of acquisition, lifetime, and release of critical components involved in late secretion from the Golgi to the plasma membrane. Of particular interest is the timing of the many reported effectors of the secretory vesicle Rab protein Sec4, including the myosin-V Myo2, the exocyst complex, the lgl homolog Sro7, and the small yeast-specific protein Mso1. At the trans-Golgi network (TGN) Sec4's GEF, Sec2, is recruited to Ypt31-positive compartments, quickly followed by Sec4 and Myo2 and vesicle formation. While transported to the bud tip, the entire exocyst complex, including Sec3, is assembled on to the vesicle. Before fusion, vesicles tether for 5 s, during which the vesicle retains the exocyst complex and stimulates lateral recruitment of Rho3 on the plasma membrane. Sec2 and Myo2 are rapidly lost, followed by recruitment of cytosolic Sro7, and finally the SM protein Sec1, which appears for just 2 s prior to fusion. Perturbation experiments reveal an ordered and robust series of events during tethering that provide insights into the function of Sec4 and effector exchange.
MeSH term(s)	Adaptor Proteins, Signal Transducing/metabolism ; Cell Membrane/metabolism ; Guanine Nucleotide Exchange Factors/metabolism ; rab GTP-Binding Proteins/metabolism ; rho GTP-Binding Proteins/metabolism ; Saccharomyces cerevisiae/genetics ; Saccharomyces cerevisiae/metabolism ; Saccharomyces cerevisiae Proteins/genetics ; Saccharomyces cerevisiae Proteins/metabolism ; Secretory Pathway ; Secretory Vesicles/metabolism ; Golgi Apparatus/metabolism
Chemical Substances	Adaptor Proteins, Signal Transducing ; Guanine Nucleotide Exchange Factors ; rab GTP-Binding Proteins (EC 3.6.5.2) ; rho GTP-Binding Proteins (EC 3.6.5.2) ; RHO3 protein, S cerevisiae (EC 3.6.5.2) ; Saccharomyces cerevisiae Proteins ; SEC2 protein, S cerevisiae ; SRO7 protein, S cerevisiae ; YPT31 protein, S cerevisiae (EC 3.6.1-)
Language	English
Publishing date	2022-11-04
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2687154-3
ISSN	2050-084X ; 2050-084X
ISSN (online)	2050-084X
ISSN	2050-084X
DOI	10.7554/eLife.78750
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Article ; Online: High-resolution secretory timeline from vesicle formation at the Golgi to fusion at the plasma membrane in S. cerevisiae

Robert M Gingras / Abigail M Sulpizio / Joelle Park / Anthony Bretscher

eLife, Vol

2022 Volume 11

Abstract: ... Mso1. At the trans-Golgi network (TGN) Sec4’s GEF, Sec2, is recruited to Ypt31-positive compartments ... exocyst complex, including Sec3, is assembled on to the vesicle. Before fusion, vesicles tether for 5 s ... protein Sec1, which appears for just 2 s prior to fusion. Perturbation experiments reveal an ordered and ...

Abstract	Most of the components in the yeast secretory pathway have been studied, yet a high-resolution temporal timeline of their participation is lacking. Here, we define the order of acquisition, lifetime, and release of critical components involved in late secretion from the Golgi to the plasma membrane. Of particular interest is the timing of the many reported effectors of the secretory vesicle Rab protein Sec4, including the myosin-V Myo2, the exocyst complex, the lgl homolog Sro7, and the small yeast-specific protein Mso1. At the trans-Golgi network (TGN) Sec4’s GEF, Sec2, is recruited to Ypt31-positive compartments, quickly followed by Sec4 and Myo2 and vesicle formation. While transported to the bud tip, the entire exocyst complex, including Sec3, is assembled on to the vesicle. Before fusion, vesicles tether for 5 s, during which the vesicle retains the exocyst complex and stimulates lateral recruitment of Rho3 on the plasma membrane. Sec2 and Myo2 are rapidly lost, followed by recruitment of cytosolic Sro7, and finally the SM protein Sec1, which appears for just 2 s prior to fusion. Perturbation experiments reveal an ordered and robust series of events during tethering that provide insights into the function of Sec4 and effector exchange.
Keywords	exocytosis ; membrane transport ; Sec1-Munc18 ; exocyst ; myosin-V ; Medicine ; R ; Science ; Q ; Biology (General) ; QH301-705.5
Subject code	571
Language	English
Publishing date	2022-11-01T00:00:00Z
Publisher	eLife Sciences Publications Ltd
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Association of Neighborhood Resources and Race and Ethnicity With Readmissions for Diabetic Ketoacidosis at US Children's Hospitals.

Bergmann, Kelly R / Nickel, Amanda / Hall, Matt / Cutler, Gretchen / Abuzzahab, M Jennifer / Bretscher, Brianna / Lammers, Shea / Watson, Dave / Hester, Gabrielle Z

JAMA network open

2022 Volume 5, Issue 5, Page(s) e2210456

Abstract: Importance: The Child Opportunity Index 2.0 (COI) assesses neighborhood resources and conditions that influence health. It is unclear whether the COI scores are associated with health outcomes by race and ethnicity among children with type 1 diabetes ( ... ...

Abstract	Importance: The Child Opportunity Index 2.0 (COI) assesses neighborhood resources and conditions that influence health. It is unclear whether the COI scores are associated with health outcomes by race and ethnicity among children with type 1 diabetes (T1D). Objective: To determine whether COI categories are associated with diabetes-related outcomes by race and ethnicity, including readmissions for diabetic ketoacidosis (DKA) and co-occurring acute kidney injury (AKI) or cerebral edema (CE). Design, setting, and participants: This cross-sectional study included children discharged with a primary diagnosis of T1D with DKA between January 1, 2009, and December 31, 2018. Merged data were obtained from the Pediatric Health Information System and COI. Participants included children and adolescents younger than 21 years with an encounter for DKA. Data were analyzed from April 29, 2021, to January 5, 2022. Exposures: Neighborhood opportunity, measured with the COI as an ordered, categorical score (where a higher score indicates more opportunity), and race and ethnicity. Main outcomes and measures: The primary outcome was readmission for DKA within 30 and 365 days from an index visit. Secondary outcomes included the proportion of encounters with AKI or CE. Mixed-effects logistic regression was used to generate probabilities of readmission, AKI, and CE for each quintile of COI category by race and ethnicity. Results: A total of 72 726 patient encounters were identified, including 38 924 (53.5%) for girls; the median patient age was 13 (IQR, 9-15) years. In terms of race and ethnicity, 600 (0.8%) of the encounters occurred in Asian patients, 9969 (13.7%) occurred in Hispanic patients, 16 876 (23.2%) occurred in non-Hispanic Black (hereinafter Black) patients, 40 129 (55.2%) occurred in non-Hispanic White (hereinafter White) patients, and 5152 (7.1%) occurred in patients of other race or ethnicity. The probability of readmission within 365 days was significantly higher among Black children with a very low COI category compared with Hispanic children (risk difference, 7.8 [95% CI, 6.0-9.6] percentage points) and White children (risk difference, 7.5 [95% CI, 5.9-9.1] percentage points) at the same COI category. Similar differences were seen for children with very high COI scores and across racial groups. The COI category was not associated with AKI or CE. However, race and ethnicity constituted a significant factor associated with AKI across all COI categories. The probability of AKI was 6.8% among Black children compared with 4.2% among Hispanic children (risk difference, 2.5 [95% CI, 1.7-3.3] percentage points) and 4.8% among White children (risk difference, 2.0 [95% CI, 1.3-2.6] percentage points). Conclusions and relevance: These results suggest that Black children with T1D experience disparities in health outcomes compared with other racial and ethnic groups with similar COI categories. Measures to prevent readmissions for DKA should include interventions that target racial disparities and community factors.
MeSH term(s)	Acute Kidney Injury/complications ; Adolescent ; Child ; Cross-Sectional Studies ; Diabetes Mellitus, Type 1/complications ; Diabetic Ketoacidosis/complications ; Diabetic Ketoacidosis/epidemiology ; Diabetic Ketoacidosis/therapy ; Ethnicity ; Female ; Hospitals, Pediatric ; Humans ; Male ; Patient Readmission
Language	English
Publishing date	2022-05-02
Publishing country	United States
Document type	Journal Article
ISSN	2574-3805
ISSN (online)	2574-3805
DOI	10.1001/jamanetworkopen.2022.10456
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Article ; Online: A life-history allele of large effect shortens developmental time in a wild insect population.

Cheng, Shixiong / Jacobs, Chris G C / Mogollón Pérez, Elisa A / Chen, Daipeng / van de Sanden, Joep T / Bretscher, Kevin M / Verweij, Femke / Bosman, Jelle S / Hackmann, Amke / Merks, Roeland M H / van den Heuvel, Joost / van der Zee, Maurijn

Nature ecology & evolution

2023 Volume 8, Issue 1, Page(s) 70–82

Abstract: Developmental time is a key life-history trait with large effects on Darwinian fitness. In many insects, developmental time is currently under strong selection to minimize ecological mismatches in seasonal timing induced by climate change. The genetic ... ...

Abstract	Developmental time is a key life-history trait with large effects on Darwinian fitness. In many insects, developmental time is currently under strong selection to minimize ecological mismatches in seasonal timing induced by climate change. The genetic basis of responses to such selection, however, is poorly understood. To address this problem, we set up a long-term evolve-and-resequence experiment in the beetle Tribolium castaneum and selected replicate, outbred populations for fast or slow embryonic development. The response to this selection was substantial and embryonic developmental timing of the selection lines started to diverge during dorsal closure. Pooled whole-genome resequencing, gene expression analysis and an RNAi screen pinpoint a 222 bp deletion containing binding sites for Broad and Tramtrack upstream of the ecdysone degrading enzyme Cyp18a1 as a main target of selection. Using CRISPR/Cas9 to reconstruct this allele in the homogenous genetic background of a laboratory strain, we unravel how this single deletion advances the embryonic ecdysone peak inducing dorsal closure and show that this allele accelerates larval development but causes a trade-off with fecundity. Our study uncovers a life-history allele of large effect and reveals the evolvability of developmental time in a natural insect population.
MeSH term(s)	Animals ; Ecdysone ; Alleles ; Coleoptera ; Insecta ; Tribolium/genetics
Chemical Substances	Ecdysone (3604-87-3)
Language	English
Publishing date	2023-11-13
Publishing country	England
Document type	Journal Article
ISSN	2397-334X
ISSN (online)	2397-334X
DOI	10.1038/s41559-023-02246-y
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Article ; Online: The impact of COVID-19 on disease epidemiology, family dynamics, and social justice in Minnesota: All that you cannot see.

Schleiss, Mark R / Blazar, Bruce / Chapman, Emily P / Cutler, Gretchen J / Cutts, Diana B / Eder, Milton Mickey / Li, Shengxu / Mason, Susan M / Bretscher, Brianna M / Neglia, Joseph P / Scal, Peter B / Winter, Stuart S

Journal of clinical and translational science

2022 Volume 6, Issue 1, Page(s) e85

Abstract: Objective: The COVID-19 pandemic presented a challenge to established seed grant funding mechanisms aimed at fostering collaboration in child health research between investigators at the University of Minnesota (UMN) and Children's Hospitals and Clinics ...

Abstract	Objective: The COVID-19 pandemic presented a challenge to established seed grant funding mechanisms aimed at fostering collaboration in child health research between investigators at the University of Minnesota (UMN) and Children's Hospitals and Clinics of Minnesota (Children's MN). We created a "rapid response," small grant program to catalyze collaborations in child health COVID-19 research. In this paper, we describe the projects funded by this mechanism and metrics of their success. Methods: Using seed funds from the UMN Clinical and Translational Science Institute, the UMN Medical School Department of Pediatrics, and the Children's Minnesota Research Institute, a rapid response request for applications (RFAs) was issued based on the stipulations that the proposal had to: 1) consist of a clear, synergistic partnership between co-PIs from the academic and community settings; and 2) that the proposal addressed an area of knowledge deficit relevant to child health engendered by the COVID-19 pandemic. Results: Grant applications submitted in response to this RFA segregated into three categories: family fragility and disruption exacerbated by COVID-19; knowledge gaps about COVID-19 disease in children; and optimizing pediatric care in the setting of COVID-19 pandemic restrictions. A series of virtual workshops presented research results to the pediatric community. Several manuscripts and extramural funding awards underscored the success of the program. Conclusions: A "rapid response" seed funding mechanism enabled nascent academic-community research partnerships during the COVID-19 pandemic. In the context of the rapidly evolving landscape of COVID-19, flexible seed grant programs can be useful in addressing unmet needs in pediatric health.
Language	English
Publishing date	2022-06-27
Publishing country	England
Document type	Journal Article
ISSN	2059-8661
ISSN (online)	2059-8661
DOI	10.1017/cts.2022.422
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Article ; Online: Differential sensitivity of inflammatory macrophages and alternatively activated macrophages to ferroptosis.

Piattini, Federica / Matsushita, Mai / Muri, Jonathan / Bretscher, Peter / Feng, Xiaogang / Freigang, Stefan / Dalli, Jesmond / Schneider, Christoph / Kopf, Manfred

European journal of immunology

2021 Volume 51, Issue 10, Page(s) 2417–2429

Abstract: Acumulation of oxidized membrane lipids ultimately results in ferroptotic cell death, which can be prevented by the selenoenzyme glutathione peroxidase 4 (Gpx4). In vivo conditions promoting ferroptosis and susceptible cell types are still poorly defined. ...

Abstract	Acumulation of oxidized membrane lipids ultimately results in ferroptotic cell death, which can be prevented by the selenoenzyme glutathione peroxidase 4 (Gpx4). In vivo conditions promoting ferroptosis and susceptible cell types are still poorly defined. In this study, we analyzed the conditional deletion of Gpx4 in mice specifically in the myeloid cell lineages. Surprisingly, development and maintenance of LysM
MeSH term(s)	Animals ; Biomarkers ; Cell Survival/genetics ; Cell Survival/immunology ; Disease Models, Animal ; Disease Susceptibility ; Ferroptosis/genetics ; Ferroptosis/immunology ; Inflammation/etiology ; Inflammation/metabolism ; Inflammation/pathology ; Lipid Peroxidation ; Macrophage Activation/immunology ; Macrophages/immunology ; Macrophages/metabolism ; Mice ; Mice, Transgenic ; Organ Specificity/immunology ; Phospholipid Hydroperoxide Glutathione Peroxidase/genetics ; Phospholipid Hydroperoxide Glutathione Peroxidase/metabolism
Chemical Substances	Biomarkers ; Phospholipid Hydroperoxide Glutathione Peroxidase (EC 1.11.1.12) ; glutathione peroxidase 4, mouse (EC 1.11.1.9)
Language	English
Publishing date	2021-07-29
Publishing country	Germany
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	120108-6
ISSN	1521-4141 ; 0014-2980
ISSN (online)	1521-4141
ISSN	0014-2980
DOI	10.1002/eji.202049114
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Zs.A 489: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (1.OG) ab Jg. 2022: Lesesaal (EG)
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Article: THE CHEMICAL NATURE OF THE S-RNA-POLYPEPTIDE COMPLEX.

BRETSCHER, M S

Journal of molecular biology

2003 Volume 7, Page(s) 446–449

MeSH term(s)	Carbon Isotopes ; Chemical Phenomena ; Chemistry ; Escherichia coli ; Lysine ; Nucleosides ; Peptides ; Phenylalanine ; Puromycin ; RNA ; RNA, Bacterial ; Research ; Tritium
Chemical Substances	Carbon Isotopes ; Nucleosides ; Peptides ; RNA, Bacterial ; Tritium (10028-17-8) ; Phenylalanine (47E5O17Y3R) ; Puromycin (4A6ZS6Q2CL) ; RNA (63231-63-0) ; Lysine (K3Z4F929H6)
Language	English
Publishing date	2003-08-22
Publishing country	England
Document type	Journal Article
ZDB-ID	80229-3
ISSN	1089-8638 ; 0022-2836
ISSN (online)	1089-8638
ISSN	0022-2836
DOI	10.1016/s0022-2836(63)80037-6
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Article ; Online: Effect of micronutrient supplementation in addition to nutritional therapy on clinical outcomes of medical inpatients: results of an updated systematic review and meta-analysis.

Kaegi-Braun, Nina / Germann, Sara / Faessli, Montserrat / Kilchoer, Fiona / Dragusha, Saranda / Tribolet, Pascal / Gomes, Filomena / Bretscher, Céline / Deutz, Nicolaas E / Stanga, Zeno / Mueller, Beat / Schuetz, Philipp

European journal of clinical nutrition

2022 Volume 76, Issue 7, Page(s) 964–972

Abstract: Background: There is increasing evidence from randomized controlled trials showing that different types of nutritional support interventions improve clinical outcomes in malnourished medical inpatients. Whether trials using micronutrient supplementation ...

Abstract	Background: There is increasing evidence from randomized controlled trials showing that different types of nutritional support interventions improve clinical outcomes in malnourished medical inpatients. Whether trials using micronutrient supplementation in addition to nutritional therapy are superior to trials without micronutrient supplementation remains unclear. Methods: This is a secondary analysis of a systematic search and meta-analysis. We searched Cochrane Library, MEDLINE, and EMBASE electronic database from inception to December 15, 2020, for randomized controlled trials comparing the nutritional support interventions vs. usual care on all-cause mortality (primary endpoint) of medical inpatients with nutritional risk. We stratified trials based on whether or not micronutrient supplementation was used as part of the nutritional strategy. Results: We included 23 randomized controlled trials (5 trials with and 18 trials without micronutrient supplementation) with a total of 6745 patients. Overall, mortality was significantly lower in patients receiving nutritional support compared to control group patients with an odds ratio of 0.74 (95% CI 0.59-0.94, p = 0.01). There was no difference between trials with and without micronutrient supplementation on mortality (odds ratio 0.70 (95% CI 0.46-1.08) vs. 0.77 (95% CI 0.57-1.04), I Conclusions: While nutritional support reduces mortality and improves other clinical outcomes, we did not find evidence that trials using micronutrient supplementation in addition to nutritional therapy were superior to trials with no supplementation. The role of micronutrient supplementation in addition to nutritional support needs further research.
MeSH term(s)	Humans ; Inpatients ; Length of Stay ; Malnutrition/complications ; Nutrition Therapy/methods ; Nutritional Support
Language	English
Publishing date	2022-01-20
Publishing country	England
Document type	Journal Article ; Meta-Analysis ; Systematic Review ; Research Support, Non-U.S. Gov't
ZDB-ID	639358-5
ISSN	1476-5640 ; 0954-3007
ISSN (online)	1476-5640
ISSN	0954-3007
DOI	10.1038/s41430-021-01061-7
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Article ; Online: Replication of Overall Survival, Progression-Free Survival, and Overall Response in Chemotherapy Arms of Non-Small Cell Lung Cancer Trials Using Real-World Data.

Ton, Thanh G N / Pal, Navdeep / Trinh, Huong / Mahrus, Sami / Bretscher, Michael T / Machado, Robson J M / Sadetsky, Natalia / Chaudhary, Nayan / Lu, Michael W / Riely, Gregory J

Clinical cancer research : an official journal of the American Association for Cancer Research

2022 Volume 28, Issue 13, Page(s) 2844–2853

Abstract: Purpose: The utility of real-world data (RWD) for use as external controls in drug development is informed by studies that replicate trial control arms for different endpoints. The purpose of this study was to replicate control arms from four non-small ... ...

Abstract	Purpose: The utility of real-world data (RWD) for use as external controls in drug development is informed by studies that replicate trial control arms for different endpoints. The purpose of this study was to replicate control arms from four non-small cell lung cancer (NSCLC) randomized controlled trials (RCT) to analyze overall survival (OS), progression-free survival (PFS), and overall response rate (ORR) using RWD. Patients and methods: This study used RWD from a nationwide de-identified database and a clinico-genomic database to replicate OS, PFS, and ORR endpoints in the chemotherapy control arms of four first-line NSCLC RCTs evaluating atezolizumab [IMpower150-wild-type (WT), IMpower130-WT, IMpower131, and IMpower132]. Additional objectives were to develop a definition of real-world PFS (rwPFS) and to evaluate the real-world response rate (rwRR) endpoint. Results: Baseline demographic and clinical characteristics were balanced after application of propensity score weighting methods. For rwPFS and OS, RWD external controls were generally similar to their RCT control counterparts. Across all four trials, the hazard ratio (HR) point estimates comparing trial controls with external controls were closer to 1.0 for the PFS endpoint than for the OS endpoint. An exploratory assessment of rwRR in RWD revealed a slight but nonsignificant overestimation of RCT ORR, which was unconfounded by baseline characteristics. Conclusions: RWD can be used to reasonably replicate the OS and PFS of chemotherapy control arms of first-line NSCLC RCTs. Additional studies can provide greater insight into the utility of RWD in drug development.
MeSH term(s)	Carcinoma, Non-Small-Cell Lung/drug therapy ; Humans ; Lung Neoplasms/drug therapy ; Progression-Free Survival ; Proportional Hazards Models ; Randomized Controlled Trials as Topic
Language	English
Publishing date	2022-05-05
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1225457-5
ISSN	1557-3265 ; 1078-0432
ISSN (online)	1557-3265
ISSN	1078-0432
DOI	10.1158/1078-0432.CCR-22-0471
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Article ; Online: Ultrafast Tracking of Exciton and Charge Carrier Transport in Optoelectronic Materials on the Nanometer Scale.

Schnedermann, Christoph / Sung, Jooyoung / Pandya, Raj / Verma, Sachin Dev / Chen, Richard Y S / Gauriot, Nicolas / Bretscher, Hope M / Kukura, Philipp / Rao, Akshay

The journal of physical chemistry letters

2019 Volume 10, Issue 21, Page(s) 6727–6733

Abstract: We present a novel optical transient absorption and reflection microscope based on a diffraction-limited pump pulse in combination with a wide-field probe pulse, for the spatiotemporal investigation of ultrafast population transport in thin films. The ... ...

Abstract	We present a novel optical transient absorption and reflection microscope based on a diffraction-limited pump pulse in combination with a wide-field probe pulse, for the spatiotemporal investigation of ultrafast population transport in thin films. The microscope achieves a temporal resolution down to 12 fs and simultaneously provides sub-10 nm spatial accuracy. We demonstrate the capabilities of the microscope by revealing an ultrafast excited-state exciton population transport of up to 32 nm in a thin film of pentacene and by tracking the carrier motion in p-doped silicon. The use of few-cycle optical excitation pulses enables impulsive stimulated Raman microspectroscopy, which is used for in situ verification of the chemical identity in the 100-2000 cm
Language	English
Publishing date	2019-10-17
Publishing country	United States
Document type	Journal Article
ISSN	1948-7185
ISSN (online)	1948-7185
DOI	10.1021/acs.jpclett.9b02437
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