Neuron-like function of the nephron central command

SUMMARYInteroceptive neurons that sense and regulate our internal milieu have been identified in several organs except in the kidney cortex despite its major importance in maintaining body homeostasis. Here we report that the chief kidney cell type of the macula densa (MD) forms coordinated neural networks in each nephron that resemble peripheral ganglia. A combined in vivo single-cell 4D physiology (sc4DP) and scRNA sequencing approach identified the MD mechanisms of neuronal differentiation, heterogeneity (pacemaker MD cells), sensing of the local and systemic environment via multi-organ crosstalk, and regulation of organ functions by acting as the nephron central command. Consistent with their neuron-like nature, MD cells express the molecular fingerprint of neurodegeneration. Here we put forth the single-cell MD model and concept of local neural networks that control organ and body functions via interoception in normal physiological state and use an integrated mechanism of neurodegeneration in disease.

Substance Use Affects Type 1 Diabetes Pancreas Pathology: Implications for Future Studies

Access to human pancreas samples from organ donors has greatly advanced our understanding of type 1 diabetes pathogenesis; however, previous studies have shown that donors have a high rate of substance use, and its impact on pancreatic histopathology in this disease is not well described. One-hundred-thirty-one type 1 diabetes and 111 control organ donor pancreata from persons 12-89 years of age (mean 29.8 ± 15.5 years) within the Network for Pancreatic Organ donors with Diabetes (nPOD) were examined for insulin positivity, insulitis, amyloid staining, acute and chronic pancreatitis, and chronic exocrine changes (acinar atrophy, fibrosis, fatty infiltration, or periductal fibrosis); findings were compared by history of substance use. A secondary analysis compared exocrine pancreatic histopathologic findings in type 1 diabetes versus control organ donors regardless of substance use history. We observed a high but congruent rate of substance use in type 1 diabetes and control organ donors (66.4% and 64% respectively). Among donors with type 1 diabetes (but not controls), islet amyloid (OR 9.96 [1.22, 81.29]) and acute pancreatitis (OR 3.2 [1.06, 9.63]) were more common in alcohol users while chronic exocrine changes (OR 8.86 [1.13, 69.31]) were more common in cocaine users. Substance use impacted the pancreata of donors with type 1 diabetes more than controls. Overall, despite similar rates of substance use, acute pancreatitis (15.3% versus 4.5%, p=0.0061), chronic pancreatitis (29.8% versus 9.9%, p=0.0001), and chronic exocrine changes (73.3% versus 36.9%, p<0.0001) were more common in type 1 diabetes donors than controls. Alcohol and/or cocaine use in type 1 diabetes organ donors increases exocrine pancreas pathology and islet amyloid deposition but does not affect insulitis or insulin positivity. Exocrine pathology in type 1 diabetes donors is common, and further study of the pathophysiology of these changes is needed.

MOB: Pivotal Conserved Proteins in Cytokinesis, Cell Architecture and Tissue Homeostasis

The MOB family proteins are constituted by highly conserved eukaryote kinase signal adaptors that are often essential both for cell and organism survival. Historically, MOB family proteins have been described as kinase activators participating in Hippo and Mitotic Exit Network/ Septation Initiation Network (MEN/SIN) signaling pathways that have central roles in regulating cytokinesis, cell polarity, cell proliferation and cell fate to control organ growth and regeneration. In metazoans, MOB proteins act as central signal adaptors of the core kinase module MST1/2, LATS1/2, and NDR1/2 kinases that phosphorylate the YAP/TAZ transcriptional co-activators, effectors of the Hippo signaling pathway. More recently, MOBs have been shown to also have non-kinase partners and to be involved in cilia biology, indicating that its activity and regulation is more diverse than expected. In this review, we explore the possible ancestral role of MEN/SIN pathways on the built-in nature of a more complex and functionally expanded Hippo pathway, by focusing on the most conserved components of these pathways, the MOB proteins. We discuss the current knowledge of MOBs-regulated signaling, with emphasis on its evolutionary history and role in morphogenesis, cytokinesis, and cell polarity from unicellular to multicellular organisms.

Characterization of poplar growth-regulating factors and analysis of their function in leaf size control

Background Growth-regulating factors (GRFs) are plant-specific transcription factors that control organ size. Nineteen GRF genes were identified in the Populus trichocarpa genome and one was reported to control leaf size mainly by regulating cell expansion. In this study, we further characterize the roles of the other poplar GRFs in leaf size control in a similar manner. Results The 19 poplar GRF genes were clustered into six groups according to their phylogenetic relationship with Arabidopsis GRFs. Bioinformatic analysis, degradome, and transient transcription assays showed that 18 poplar GRFs were regulated by miR396, with GRF12b the only exception. The functions of PagGRF6b (Pag, Populus alba × P. glandulosa), PagGRF7a, PagGRF12a, and PagGRF12b, representing three different groups, were investigated. The results show that PagGRF6b may have no function on leaf size control, while PagGRF7a functions as a negative regulator of leaf size by regulating cell expansion. By contrast, PagGRF12a and PagGRF12b may function as positive regulators of leaf size control by regulating both cell proliferation and expansion, primarily cell proliferation. Conclusions The diversity of poplar GRFs in leaf size control may facilitate the specific, coordinated regulation of poplar leaf development through fine adjustment of cell proliferation and expansion.

Design of Pulse Oximeter Solution for Conscious Rodents

Neuromodulation can be used to control organ function through exogenous augmentation of neural activity via targeted delivery of an electrical stimulus. Recently, neuromodulation has been a topic of investigation to treat many illnesses and conditions including Parkinson’s disease, epilepsy, obesity, chronic pain, type 1 diabetes, and hypertension. During neuromodulatory treatments, it is important to measure both the physiological response of the target system as well as any off-target systems that may be engaged from the delivered stimulus. Stimulation of the vagus nerve, a common target of neuromodulatory therapies, causes a vasovagal response which results in decreased cardiac rate and arteriolar dilatation. It is possible to measure these physiological parameters in anesthetized rats, but it is a challenge in conscious, moving rats because of motion artifact introduced to the sensors. By creating a noninvasive, stabilized pulse oximeter that measures the blood oxygenation waveform, one can analyze the heart rate in awake behaving animals. This study reports the design of a heart rate monitor used to monitor effects of heart rate variability during neuromodulation experiments. Design of this device included testing different sensors, methods of attaching to the rodent, microcontrollers, and wireless communication modules.

Emerging roles for angiomotin in the nervous system

Angiomotins are a family of molecular scaffolding proteins that function to organize contact points (called tight junctions in vertebrates) between adjacent cells. Some angiomotin isoforms bind to the actin cytoskeleton and are part of signaling pathways that influence cell morphology and migration. Others cooperate with components of the Hippo signaling pathway and the associated networks to control organ growth. The 130-kDa isoform, AMOT-p130, has critical roles in neural stem cell differentiation, dendritic patterning, and synaptic maturation—attributes that are essential for normal brain development and are consistent with its association with autism. Here, we review and discuss the evidence that supports a role for AMOT-p130 in neuronal development in the central nervous system.

Characterization of poplar growth-regulating factors and analysis of their function in leaf size control

Background: Growth-regulating factors (GRFs) are plant-specific transcription factors that control organ size. Nineteen GRF genes were identified in the Populus trichocarpa genome and one was reported to control leaf size by regulating cell expansion. In this study, we further characterize the roles of the other poplar GRFs in leaf size control in a similar manner.Results: The 19 poplar GRF genes were clustered into six groups according to their phylogenetic relationship with Arabidopsis GRFs. Bioinformatic analysis, degradome, and transient transcription assays showed that 18 poplar GRFs were regulated by miR396, with GRF12b the only exception. The functions of PagGRF6b (Pag, Populus alba × P. glandulosa), PagGRF7a, PagGRF12a, and PagGRF12b, representing three different groups, were investigated. The results show that PagGRF6b may have no function on leaf size control, while PagGRF7a functions as a negative regulator of leaf size by regulating cell expansion. By contrast, PagGRF12a and PagGRF12b may function as positive regulators of leaf size control by regulating both cell proliferation and expansion, primarily cell proliferation.Conclusions: The diversity of poplar GRFs in leaf size control may facilitate the specific, coordinated regulation of poplar leaf development through fine adjustment of cell proliferation and expansion.

Characterization of poplar growth-regulating factors and analysis of their function in leaf size control

Background: Growth-regulating factors (GRFs) are plant-specific transcription factors that control organ size. Nineteen GRF genes were identified in the Populus trichocarpa genome and one was reported to control leaf size by regulating cell expansion. In this study, we further characterize the roles of the other poplar GRFs in leaf size control in a similar manner. Results: The 19 poplar GRF genes were clustered into six groups according to their phylogenetic relationship with Arabidopsis GRFs. Bioinformatic analysis, degradome, and transient transcription assays showed that 18 poplar GRFs were regulated by miR396, with GRF12b the only exception. The functions of PagGRF6b (Pag, Populus alba × P. glandulosa), PagGRF7a, PagGRF12a, and PagGRF12b, representing three different groups, were investigated. The results show that PagGRF6b may have no function on leaf size control, while PagGRF7a functions as a negative regulator of leaf size by regulating cell expansion. By contrast, PagGRF12a and PagGRF12b may function as positive regulators of leaf size control by regulating both cell proliferation and expansion, primarily cell proliferation. Conclusions: The diversity of poplar GRFs in leaf size control may facilitate the specific, coordinated regulation of poplar leaf development through fine adjustment of cell proliferation and expansion.

Characterization of poplar growth-regulating factors and analysis of their function in leaf size control

Background: Growth-regulating factors (GRFs) are plant-specific transcription factors that control organ size. Nineteen GRF genes were identified in the Populus trichocarpa genome and one was reported to control leaf size by regulating cell expansion. In this study, we further characterize the roles of the other poplar GRFs in leaf size control in a similar manner.Results: The 19 poplar GRF genes were clustered into six groups according to their phylogenetic relationship with Arabidopsis GRFs. Bioinformatic analysis, degradome, and transient transcription assays showed that 18 poplar GRFs were regulated by miR396, with GRF12b the only exception. The functions of PagGRF6b (Pag, Populus alba × P. glandulosa), PagGRF7a, PagGRF12a, and PagGRF12b, representing three different groups, were investigated. The results show that PagGRF6b may have no function on leaf size control, while PagGRF7a functions as a negative regulator of leaf size by regulating cell expansion. By contrast, PagGRF12a and PagGRF12b may function as positive regulators of leaf size control by regulating both cell proliferation and expansion, primarily cell proliferation.Conclusions: The diversity of poplar GRFs in leaf size control may facilitate the specific, coordinated regulation of poplar leaf development through fine adjustment of cell proliferation and expansion.