Biology subjects

Gu, C.

Publications and source records attributed to Gu, C..

6 recordsLinked to original sources

bioRxiv2018

A rapid visuomotor response on the human upper limb is selectively influenced by implicit, but not explicit, motor learning

How do humans learn to adapt their motor actions to achieve task success? Recent behavioral and patient studies have challenged the classic notion that motor learning arises solely from the errors produced during a task, suggesting instead that explicit cognitive strategies can act in concert with the implicit, error\"based, motor learning component. Here, we show that the earliest wave of directionally-tuned neuromuscular activity that occurs within ~100 ms of peripheral visual stimulus onset is selectively influenced by the implicit component of motor learning. In contrast, the voluntary neuromuscular activity associated with reach initiation, which evolves ~100 to 200 ms later is influenced by both the implicit and explicit components of motor learning. The selective influence of the implicit, but not explicit, component of motor learning on the earliest cascade of neuromuscular activity supports the notion that these components of motor learning can differentially influence descending motor pathways.

neuroscience↗

bioRxiv2018

ATRAID, a genetic factor that regulates the clinical action of nitrogen-containing bisphosphonates on bone.

Nitrogen-containing bisphosphonates (N-BPs), such as alendronate, are the most widely prescribed medications for diseases involving bone, with nearly 200 million prescriptions written annually. Recently, widespread use of N-BPs has been challenged due to the risk of rare but traumatic side effects such as atypical femoral fracture (AFFs) and osteonecrosis of the jaw (ONJ). N-BPs bind to and inhibit farnesyl diphosphate synthase (FDPS), resulting in defects in protein prenylation. Yet it remains poorly understood what other cellular factors might allow N-BPs to exert their pharmacological effects. Here, we performed genome-wide studies in cells and patients to identify the poorly characterized gene, ATRAID. Loss of ATRAID function results in selective resistance to N-BP-mediated loss of cell viability and the prevention of alendronate-mediated inhibition of prenylation. ATRAID is required for alendronate inhibition of osteoclast function, and ATRAID-deficient mice have impaired therapeutic responses to alendronate in both postmenopausal and senile (old age) osteoporosis models. Lastly, we performed exome sequencing on patients taking N-BPs that suffered ONJ or an AFF. ATRAID is one of three genes that contain rare non-synonymous coding variants in patients with ONJ or AFF that is also differentially expressed in poor outcome groups of patients treated with N-BPs. We functionally validated this patient variation in ATRAID as conferring cellular hypersensitivity to N-BPs. Our work adds key insight into the mechanistic action of N-BPs and the processes that might underlie differential responsiveness to N-BPs in people. One Sentence SummaryATRAID is essential for responses to the commonly prescribed osteoporosis drugs nitrogen-containing bisphosphonates. OverlineBONE

genomics↗

bioRxiv2018

Single-Cell RNA-seq Reveals a Subpopulation of Cells Underlying β Cell Expansion in the Postnatal Islets

Pancreatic {beta} cells undergo significant expansion and maturation during human and rodent postnatal development. Here, we used single-cell RNA-seq to characterize gene expression patterns at various stages of mouse islet cell development and uncovered a population of cells that is most abundant during the early postnatal period. This cell population lacks expression of FLTP and expresses PDGF receptors. Each of these conditions have previously been associated with proliferative capacity in {beta} cells suggesting that we have identified the proliferative competent of {beta} cell mass expansion. The subpopulation co-express many endocrine lineage-specific genes and exhibits a downregulation of genes associated with mitochondrial oxidative phosphorylation and global protein synthesis. It has upregulated activity of genes in the Wnt, Hippo, PDGF, and Notch pathways and has a significantly higher proliferation potential than the more mature {beta} population. We show that activity of the Notch pathway is required in postnatal {beta} cell expansion where it serves to maintain an undifferentiated endocrine state in the polyhormonal cell population. Collectively, our study identifies a proliferative, progenitor-like cell subpopulation in the postnatal islet as the source of postnatal {beta} cell expansion.

developmental biology↗

bioRxiv2017

Evaluating a sepsis prediction machine learning algorithm using minimal electronic health record data in the emergency department and intensive care unit

IntroductionSepsis is a major health crisis in US hospitals, and several clinical identification systems have been designed to help care providers with early diagnosis of sepsis. However, many of these systems demonstrate low specificity or sensitivity, which limits their clinical utility. We evaluate the effects of a machine learning algodiagnostic (MLA) sepsis prediction and detection system using a before-and-after clinical study performed at Cabell Huntington Hospital (CHH) in Huntington, West Virginia. Prior to this study, CHH utilized the St. Johns Sepsis Agent (SJSA) as a rules-based sepsis detection system.\n\nMethodsThe Predictive algoRithm for EValuation and Intervention in SEpsis (PREVISE) study was carried out between July 1, 2017 and August 30, 2017. All patients over the age of 18 who were admitted to the emergency department or intensive care units at CHH were monitored during the study. We assessed pre-implementation baseline metrics during the month of July, 2017, when the SJSA was active. During implementation in the month of August, 2017, SJSA and the MLA concurrently monitored patients for sepsis risk. At the conclusion of the study period, the primary outcome of sepsis-related in-hospital mortality and secondary outcome of sepsis-related hospital length of stay were compared between the two groups.\n\nResultsSepsis-related in-hospital mortality decreased from 3.97% to 2.64%, a 33.5% relative decrease (P = 0.038), and sepsis-related length of stay decreased from 2.99 days in the pre-implementation phase to 2.48 days in the post-implementation phase, a 17.1% relative reduction (P < 0.001).\n\nConclusionReductions in patient mortality and length-of-stay were observed with use of a machine learning algorithm for early sepsis detection in the emergency department and intensive care units at Cabell Huntington Hospital, and may present a method for improving patient outcomes.\n\nTrial RegistrationClinicalTrials.gov, NCT03235193, retrospectively registered on July 27th 2017.

clinical trials↗

bioRxiv2017

Done in 100 ms: Path-dependent visuomotor transformation in the human upper limb

A core assumption underlying mental chronometry is that more complex tasks increase cortical processing, prolonging reaction times. Here we show that increases in task complexity alter the magnitude, rather than the latency, of the output for a circuit that rapidly transforms visual information into motor actions. We quantified visual stimulus-locked responses (SLRs), which are changes in upper limb muscle recruitment that evolve at a fixed latency [~]100 ms after novel visual stimulus onset. First, we studied the underlying reference frame of the SLR, by dissociating initial eye and hand position. Despite its quick latency, we found that the SLR was expressed in a hand-centric reference frame, suggesting that the circuit mediating the SLR integrated retinotopic visual information with body configuration. Next, we studied the influence of planned movement trajectory, requiring participants to prepare and generate curved or straight reaches in the presence of obstacles to attain the same visual stimulus. We found that SLR magnitude reflected the initial planned movement trajectory, regardless of the ensuing movement curvature. Based on these results, we suggest that the circuit mediating the SLR lies in parallel to other well-studied corticospinal pathways. Although the fixed latency of the SLR precludes extensive cortical processing, inputs conveying information relating to task complexity, such as body configuration and planned movement trajectory, can pre-set nodes within the circuit underlying to the SLR to modulate its magnitude.\n\nSIGNIFICANCE STATEMENTA core assumption underlying mental chronometry is that more complex tasks increase cortical processing, prolonging reaction times. Here, we showed that increases in task complexity altered the magnitude, rather than the latency, of a circuit that rapidly transforms visual information into motor actions. We focus on stimulus-locked responses (SLRs), which are changes in upper limb muscle recruitment that evolve at a fixed latency [~]100 ms after novel visual stimulus onset. We showed that despite is quick latency, the circuitry mediating the SLR transformed a retinotopic visual signal into a hand-centric motor command suitable to contribute to the initial movement trajectory. We suggest that this circuit lies in parallel to other well-studied corticospinal pathways.

neuroscience↗

bioRxiv2016

DNA Methylation Landscape Reflects the Spatial Organization of Chromatin in Different Cells

The relation between DNA methylation and chromatin structure is still largely unknown. By analyzing a large set of sequencing data, we observed a long-range power law correlation of DNA methylation with cell-class-specific scaling exponents in the range of thousands to millions of base pairs. We showed such cell-class-specific scaling exponents are caused by different patchiness of DNA methylation in different cells. By modeling the chromatin structure using Hi-C data and mapping the methylation level onto the modeled structure, we demonstrated the patchiness of DNA methylation is related to chromatin structure. The scaling exponents of the power law correlation is thus a display of the spatial organization of chromatin. Besides, the local correlation of DNA methylation is associated with nucleosome positioning and different between partially-methylated-domain and non-partially-methylated-domain, suggesting their different chromatin structures at several nucleosomes level. Our study provides a novel view of the spatial organization of chromatin structure from a perspective of DNA methylation, in which both long-range and local correlations of DNA methylation along the genome reflect the spatial organization of chromatin.

biophysics↗