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Article ; Online: Characterization of cell-cell communication in COVID-19 patients

Lin, Yingxin / Loo, Lipin / Tran, Andy / Moreno, Cesar / Hesselson, Daniel / Neely, Greg G / Yang, Jean Yee Hwa

bioRxiv

Abstract: COVID-19 patients display a wide range of disease severity, ranging from asymptomatic to critical symptoms with high mortality risk. Our ability to understand the interaction of SARS-CoV-2 infected cells within the lung, and of protective or ... ...

Abstract	COVID-19 patients display a wide range of disease severity, ranging from asymptomatic to critical symptoms with high mortality risk. Our ability to understand the interaction of SARS-CoV-2 infected cells within the lung, and of protective or dysfunctional immune responses to the virus, is critical to effectively treat these patients. Currently, our understanding of cell-cell interactions across different disease states, and how such interactions may drive pathogenic outcomes, is incomplete. Here, we developed a generalizable workflow for identifying cells that are differentially interacting across COVID-19 patients with distinct disease outcomes and use it to examine five public single-cell RNA-seq datasets with a total of 85 individual samples. By characterizing the cell-cell interaction patterns across epithelial and immune cells in lung tissues for patients with varying disease severity, we illustrate diverse communication patterns across individuals, and discover heterogeneous communication patterns among moderate and severe patients. We further illustrate patterns derived from cell-cell interactions are potential signatures for discriminating between moderate and severe patients.
Keywords	covid19
Language	English
Publishing date	2020-12-30
Publisher	Cold Spring Harbor Laboratory
Document type	Article ; Online
DOI	10.1101/2020.12.30.424641
Database	COVID19

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Article ; Online: TMPRSS2 activation of Omicron lineage Spike glycoproteins is regulated by TMPRSS2 cleavage of ACE2

bioRxiv

Abstract: Continued high levels spread of SARS-CoV-2 globally enabled accumulation of changes within the Spike glycoprotein, leading to resistance to neutralising antibodies and concomitant changes to entry requirements that increased viral transmission fitness. ... ...

Abstract	Continued high levels spread of SARS-CoV-2 globally enabled accumulation of changes within the Spike glycoprotein, leading to resistance to neutralising antibodies and concomitant changes to entry requirements that increased viral transmission fitness. Herein, we demonstrate a significant change in ACE2 and TMPRSS2 use by primary SARS-CoV-2 isolates that occurred upon arrival of Omicron lineages. Mechanistically we show this shift to be a function of two distinct ACE2 pools based on cleavage or non-cleavage of ACE2 by TMPRSS2 activity. In engineered cells overexpressing ACE2 and TMPRSS2, ACE2 was cleaved by TMPRSS2 and this led to either augmentation or progressive attenuation of pre-Omicron and Omicron lineages, respectfully. In contrast, TMPRSS2 resistant ACE2 restored infectivity across all Omicron lineages through enabling ACE2 binding that facilitated TMPRSS2 spike activation. Therefore, our data support the tropism shift of Omicron lineages to be a function of evolution towards the use of uncleaved pools of ACE2 with the latter consistent with its role as a chaperone for many tissue specific amino acid transport proteins.
Keywords	covid19
Language	English
Publishing date	2023-09-22
Publisher	Cold Spring Harbor Laboratory
Document type	Article ; Online
DOI	10.1101/2023.09.22.558930
Database	COVID19

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Article ; Online: TMPRSS2 activation of Omicron lineage Spike glycoproteins is regulated by TMPRSS2 cleavage of ACE2

bioRxiv

Abstract	Continued high levels spread of SARS-CoV-2 globally enabled accumulation of changes within the Spike glycoprotein, leading to resistance to neutralising antibodies and concomitant changes to entry requirements that increased viral transmission fitness. Herein, we demonstrate a significant change in ACE2 and TMPRSS2 use by primary SARS-CoV-2 isolates that occurred upon arrival of Omicron lineages. Mechanistically we show this shift to be a function of two distinct ACE2 pools based on cleavage or non-cleavage of ACE2 by TMPRSS2 activity. In engineered cells overexpressing ACE2 and TMPRSS2, ACE2 was cleaved by TMPRSS2 and this led to either augmentation or progressive attenuation of pre-Omicron and Omicron lineages, respectfully. In contrast, TMPRSS2 resistant ACE2 restored infectivity across all Omicron lineages through enabling ACE2 binding that facilitated TMPRSS2 spike activation. Therefore, our data support the tropism shift of Omicron lineages to be a function of evolution towards the use of uncleaved pools of ACE2 with the latter consistent with its role as a chaperone for many tissue specific amino acid transport proteins.
Keywords	covid19
Language	English
Publishing date	2023-09-22
Publisher	Cold Spring Harbor Laboratory
Document type	Article ; Online
DOI	10.1101/2023.09.22.558930
Database	COVID19

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Article ; Online: Enhanced Sleep Is an Evolutionarily Adaptive Response to Starvation Stress in Drosophila.

Slocumb, Melissa E / Regalado, Josue M / Yoshizawa, Masato / Neely, Greg G / Masek, Pavel / Gibbs, Allen G / Keene, Alex C

PloS one

2015 Volume 10, Issue 7, Page(s) e0131275

Abstract: Animals maximize fitness by modulating sleep and foraging strategies in response to changes in nutrient availability. Wild populations of the fruit fly, Drosophila melanogaster, display highly variable levels of starvation and desiccation resistance that ...

Abstract	Animals maximize fitness by modulating sleep and foraging strategies in response to changes in nutrient availability. Wild populations of the fruit fly, Drosophila melanogaster, display highly variable levels of starvation and desiccation resistance that differ in accordance with geographic location, nutrient availability, and evolutionary history. Further, flies potently modulate sleep in response to changes in food availability, and selection for starvation resistance enhances sleep, revealing strong genetic relationships between sleep and nutrient availability. To determine the genetic and evolutionary relationship between sleep and nutrient deprivation, we assessed sleep in flies selected for desiccation or starvation resistance. While starvation resistant flies have higher levels of triglycerides, desiccation resistant flies have enhanced glycogen stores, indicative of distinct physiological adaptations to food or water scarcity. Strikingly, selection for starvation resistance, but not desiccation resistance, leads to increased sleep, indicating that enhanced sleep is not a generalized consequence of higher energy stores. Thermotolerance is not altered in starvation or desiccation resistant flies, providing further evidence for context-specific adaptation to environmental stressors. F2 hybrid flies were generated by crossing starvation selected flies with desiccation selected flies, and the relationship between nutrient deprivation and sleep was examined. Hybrids exhibit a positive correlation between starvation resistance and sleep, while no interaction was detected between desiccation resistance and sleep, revealing that prolonged sleep provides an adaptive response to starvation stress. Therefore, these findings demonstrate context-specific evolution of enhanced sleep in response to chronic food deprivation, and provide a model for understanding the evolutionary relationship between sleep and nutrient availability.
MeSH term(s)	Adaptation, Physiological/physiology ; Animals ; Body Size ; Crosses, Genetic ; Desiccation ; Disease Resistance ; Drosophila melanogaster/chemistry ; Drosophila melanogaster/physiology ; Energy Metabolism ; Female ; Food Deprivation/physiology ; Glycogen/analysis ; Hot Temperature ; Insect Proteins/analysis ; Kaplan-Meier Estimate ; Male ; Motor Activity ; Phenotype ; Selection, Genetic ; Sleep/physiology ; Starvation/physiopathology ; Stress, Physiological/physiology ; Triglycerides/analysis
Chemical Substances	Insect Proteins ; Triglycerides ; Glycogen (9005-79-2)
Language	English
Publishing date	2015-07-06
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ISSN	1932-6203
ISSN (online)	1932-6203
DOI	10.1371/journal.pone.0131275
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article: Syncrip/hnRNP Q influences synaptic transmission and regulates BMP signaling at the Drosophila neuromuscular synapse.

Halstead, James M / Lin, Yong Qi / Durraine, Lita / Hamilton, Russell S / Ball, Graeme / Neely, Greg G / Bellen, Hugo J / Davis, Ilan

Biology open

2014 Volume 3, Issue 9, Page(s) 839–849

Abstract: Synaptic plasticity involves the modulation of synaptic connections in response to neuronal activity via multiple pathways. One mechanism modulates synaptic transmission by retrograde signals from the post-synapse that influence the probability of ... ...

Abstract	Synaptic plasticity involves the modulation of synaptic connections in response to neuronal activity via multiple pathways. One mechanism modulates synaptic transmission by retrograde signals from the post-synapse that influence the probability of vesicle release in the pre-synapse. Despite its importance, very few factors required for the expression of retrograde signals, and proper synaptic transmission, have been identified. Here, we identify the conserved RNA binding protein Syncrip as a new factor that modulates the efficiency of vesicle release from the motoneuron and is required for correct synapse structure. We show that syncrip is required genetically and its protein product is detected only in the muscle and not in the motoneuron itself. This unexpected non-autonomy is at least partly explained by the fact that Syncrip modulates retrograde BMP signals from the muscle back to the motoneuron. We show that Syncrip influences the levels of the Bone Morphogenic Protein ligand Glass Bottom Boat from the post-synapse and regulates the pre-synapse. Our results highlight the RNA-binding protein Syncrip as a novel regulator of synaptic output. Given its known role in regulating translation, we propose that Syncrip is important for maintaining a balance between the strength of presynaptic vesicle release and postsynaptic translation.
Language	English
Publishing date	2014-08-29
Publishing country	England
Document type	Journal Article
ZDB-ID	2632264-X
ISSN	2046-6390
ISSN	2046-6390
DOI	10.1242/bio.20149027
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Article ; Online: Workers' interpretation of self-assessment of exposure.

Pettersson-Strömbäck, Anita / Liljelind, Ingrid / Neely, Greg / Järvholm, Bengt

The Annals of occupational hygiene

2008 Volume 52, Issue 7, Page(s) 663–671

Abstract: Objectives: The aim was to investigate how workers interpret and act upon results from self-assessment of exposure (SAE).: Methods: Workers in four sawmills in Sweden were supplied with diffusive samplers for measurement of terpenes. Workers received ...

Abstract	Objectives: The aim was to investigate how workers interpret and act upon results from self-assessment of exposure (SAE). Methods: Workers in four sawmills in Sweden were supplied with diffusive samplers for measurement of terpenes. Workers received both oral and written instructions about terpenes, their medical effects and how to handle the samplers. Responsibility for sampling was left to the individual worker; written feedback about terpene levels was provided after each measurement. The number of measurements was registered. The workers and supervisors were interviewed about their attitudes, perceived control of their work environment, need for preventive actions and future surveillance of the workplace. Results: In total, 28 workers performed 100 terpene measurements. At one sawmill, there was a significant association between exposure levels and the number of measurements performed by each worker (rho = 0.79, P = 0.03). Contrary to instructions, supervisors played an important role in spontaneous organization of the measurements at each mill. Four measurements revealed terpene concentrations that exceeded the occupational exposure limits, and one preventive action was taken as a consequence of high levels. Seventy percent of the workers could not identify any reason for more measurements. Only 15% considered the measurements as their 'own' project, and the rest stated that they participated in order to satisfy the researchers. Conclusions: Previous studies have shown that workers can perform valid measurements, both select a day and technically perform measurements. This study indicates that this ability is not sufficient to ensure that measurements will be done or that implementing measurements will result in preventive actions. Workers need additional support to take preventive actions and use SAE for ongoing surveillance.
MeSH term(s)	Air Pollutants, Occupational/analysis ; Attitude to Health ; Environmental Monitoring/methods ; Health Behavior ; Humans ; Occupational Exposure/analysis ; Occupational Exposure/prevention & control ; Self Care/psychology ; Sweden ; Terpenes/toxicity ; Wood
Chemical Substances	Air Pollutants, Occupational ; Terpenes
Language	English
Publishing date	2008-10
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	390312-6
ISSN	1475-3162 ; 0003-4878
ISSN (online)	1475-3162
ISSN	0003-4878
DOI	10.1093/annhyg/men042
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Article ; Online: Corrigendum to "Insulin controls food intake and energy balance via NPY neurons" [Mol Metabol 6 (2017) 574-584].

Loh, Kim / Zhang, Lei / Brandon, Amanda / Wang, Qiaoping / Begg, Denovan / Qi, Yue / Fu, Melissa / Kulkarni, Rishikesh / Teo, Jonathan / Baldock, Paul / Bruning, Jens C / Cooney, Gregory / Neely, Greg G / Herzog, Herbert

Molecular metabolism

2017 Volume 6, Issue 11, Page(s) 1562

Language	English
Publishing date	2017-07-08
Publishing country	Germany
Document type	Journal Article ; Published Erratum
ISSN	2212-8778
ISSN (online)	2212-8778
DOI	10.1016/j.molmet.2017.06.017
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Article ; Online: Insulin controls food intake and energy balance via NPY neurons.

Loh, Kim / Zhang, Lei / Brandon, Amanda / Wang, Qiaoping / Begg, Denovan / Qi, Yue / Fu, Melissa / Kulkarni, Rishikesh / Teo, Jonathan / Baldock, Paul / Brüning, Jens C / Cooney, Gregory / Neely, Greg G / Herzog, Herbert

Molecular metabolism

2017 Volume 6, Issue 6, Page(s) 574–584

Abstract: Objectives: Insulin signaling in the brain has been implicated in the control of satiety, glucose homeostasis and energy balance. However, insulin signaling is dispensable in energy homeostasis controlling AgRP or POMC neurons and it is unclear which ... ...

Abstract	Objectives: Insulin signaling in the brain has been implicated in the control of satiety, glucose homeostasis and energy balance. However, insulin signaling is dispensable in energy homeostasis controlling AgRP or POMC neurons and it is unclear which other neurons regulate these effects. Here we describe an ancient insulin/NPY neuronal network that governs energy homeostasis across phyla. Methods: To address the role of insulin action specifically in NPY neurons, we generated a variety of models by selectively removing insulin signaling in NPY neurons in flies and mice and testing the consequences on energy homeostasis. Results: By specifically targeting the insulin receptor in both fly and mouse NPY expressing neurons, we found NPY-specific insulin signaling controls food intake and energy expenditure, and lack of insulin signaling in NPY neurons leads to increased energy stores and an obese phenotype. Additionally, the lack of insulin signaling in NPY neurons leads to a dysregulation of GH/IGF-1 axis and to altered insulin sensitivity. Conclusions: Taken together, these results suggest that insulin actions in NPY neurons is critical for maintaining energy balance and an impairment of this pathway may be causally linked to the development of metabolic diseases.
MeSH term(s)	Animals ; Brain/cytology ; Brain/metabolism ; Drosophila ; Eating ; Energy Metabolism ; Insulin/metabolism ; Male ; Mice ; Mice, Inbred C57BL ; Neurons/metabolism ; Neuropeptide Y/metabolism
Chemical Substances	Insulin ; Neuropeptide Y
Language	English
Publishing date	2017-04-12
Publishing country	Germany
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	2212-8778
ISSN (online)	2212-8778
DOI	10.1016/j.molmet.2017.03.013
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Article ; Online: Genome-wide gene-based analyses of weight loss interventions identify a potential role for NKX6.3 in metabolism.

Nature communications

2019 Volume 10, Issue 1, Page(s) 540

Abstract: Hundreds of genetic variants have been associated with Body Mass Index (BMI) through genome-wide association studies (GWAS) using observational cohorts. However, the genetic contribution to efficient weight loss in response to dietary intervention ... ...

Abstract	Hundreds of genetic variants have been associated with Body Mass Index (BMI) through genome-wide association studies (GWAS) using observational cohorts. However, the genetic contribution to efficient weight loss in response to dietary intervention remains unknown. We perform a GWAS in two large low-caloric diet intervention cohorts of obese participants. Two loci close to NKX6.3/MIR486 and RBSG4 are identified in the Canadian discovery cohort (n = 1166) and replicated in the DiOGenes cohort (n = 789). Modulation of HGTX (NKX6.3 ortholog) levels in Drosophila melanogaster leads to significantly altered triglyceride levels. Additional tissue-specific experiments demonstrate an action through the oenocytes, fly hepatocyte-like cells that regulate lipid metabolism. Our results identify genetic variants associated with the efficacy of weight loss in obese subjects and identify a role for NKX6.3 in lipid metabolism, and thereby possibly weight control.
MeSH term(s)	Adult ; Animals ; Bayes Theorem ; Cohort Studies ; Drosophila Proteins/genetics ; Drosophila melanogaster/metabolism ; Female ; Genome-Wide Association Study ; Homeodomain Proteins/genetics ; Homeodomain Proteins/metabolism ; Humans ; Male ; Middle Aged ; Polymorphism, Single Nucleotide/genetics ; Risk Factors ; Transcription Factors/genetics ; Transcription Factors/metabolism ; Triglycerides/metabolism ; Weight Loss/genetics
Chemical Substances	Drosophila Proteins ; HGTX protein, Drosophila ; Homeodomain Proteins ; Nkx6-3 protein, human ; Transcription Factors ; Triglycerides
Language	English
Publishing date	2019-02-01
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2553671-0
ISSN	2041-1723 ; 2041-1723
ISSN (online)	2041-1723
ISSN	2041-1723
DOI	10.1038/s41467-019-08492-8
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Article ; Online: The effect of different warming methods on sensory nerve conduction velocity in shipyard workers occupationally exposed to hand-arm vibration.

Cherniack, Martin / Brammer, Anthony J / Lundstrom, Ronnie / Morse, Tim F / Neely, Greg / Nilsson, Tohr / Peterson, Donald / Toppila, Esko / Warren, Nicholas / Diva, Ulysses / Croteau, Marc / Dussetschleger, Jeffrey

International archives of occupational and environmental health

2008 Volume 81, Issue 8, Page(s) 1045–1058

Abstract: Objectives: Segmental sensory nerve conduction velocity (SNCV) was measured from the wrists to the hands and digits in a population of 134 (126 men and 8 women) vibration-exposed shipyard workers following systemic warming using a bicycle ergometer. ... ...

Abstract	Objectives: Segmental sensory nerve conduction velocity (SNCV) was measured from the wrists to the hands and digits in a population of 134 (126 men and 8 women) vibration-exposed shipyard workers following systemic warming using a bicycle ergometer. Results were compared to earlier nerve conduction tests, identical in execution, except that the warming process was segmental and cutaneous. The study was designed to investigate whether SNCVs, which were selectively slow in the fingers after segmental cutaneous (skin surface) warming, would be affected differently by systemic warming. Methods: Wrist-palm, palm-proximal digit, and digital sensory nerve segments were assessed antidromically by stimulating at the wrist with recording electrodes placed distally. The same subjects were cutaneously warmed in 2001 to >or=31 degrees C and were systemically warmed 28 months later in 2004 by ramped sustained exercise to 100 W for 12 min. Skin temperatures were measured by traditional thermistry and by infrared thermal images taken over the hand and wrist surfaces. Results: When systemic warming was compared to segmental cutaneous warming, SNCVs were increased by 15.1% in the third digit and 20.4% in the fifth digit of the dominant hand. Respective increases in the non-dominant hand were 11.0% and 19.4%. A strong association between increased surface skin temperature and faster SNCV, which had been observed after segmental cutaneous warming, was largely eliminated for both digit and palmar anatomic segments after systemic warming. Significant differences in SNCV between vibration-exposed and non-exposed workers, which had been observed after segmental cutaneous warming, were eliminated after systemic warming. Systemic warming had only a small effect on the wrist-palm (transcarpal) segmental SNCVs. Conclusions: Reduced SNCV in the digits was observed in vibration-exposed and non-exposed workers. Substituting exercise-induced systemic warming for segmental cutaneous warming significantly increased SNCV in the digits and appeared to reduce differences in SNCV between vibration-exposed and non-exposed workers. These findings persisted despite a substantial time interval between tests, during which the subjects continued to work. There may be more general implications for diagnosing clinical conditions in industrial workers, such as the carpal tunnel syndrome and the hand-arm vibration syndrome.
MeSH term(s)	Adult ; Electrophysiology/methods ; Exercise/physiology ; Female ; Hand/innervation ; Hand/physiology ; Humans ; Male ; Middle Aged ; Neural Conduction/physiology ; Occupational Exposure/adverse effects ; Skin Temperature/physiology ; Vibration/adverse effects ; Wrist Joint/innervation ; Wrist Joint/physiology ; Young Adult
Language	English
Publishing date	2008-08
Publishing country	Germany
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	129038-1
ISSN	1432-1246 ; 0340-0131 ; 0367-9977
ISSN (online)	1432-1246
ISSN	0340-0131 ; 0367-9977
DOI	10.1007/s00420-007-0299-4
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