What are canonical pathways

In modern ecosystems, the carbon stable isotope (δ13 C) ratios of consumers generally conform to the principle "you are what you eat, +1‰." However, this metric may not apply to microbial mat systems where diverse communities, using a variety of carbon substrates via multiple assimilation pathways, live in close physical association and phagocytosis is minimal or absent. To interpret the δ13 C record of the Proterozoic and early Paleozoic, when mat-based productivity likely was widespread, it is necessary to understand how a microbially driven producer-consumer structure affects the δ13 C compositions of biomass and preservable lipids...

PURPOSE OF REVIEW: Recent research has shown that older people with high blood pressure (BP), or hypertension, are more likely to have biomarkers of Alzheimer's disease (AD). Essential hypertension represents the most common cardiovascular disease worldwide and is thought to be responsible for about 13% of all deaths. People with essential hypertension who regularly take prescribed BP medications are half as likely to develop AD as those who do not take them. What then is the connection? RECENT FINDINGS: We know that high BP can damage small blood vessels in the brain, affecting those parts that are responsible for memory and thinking...

Streptococcus pneumoniae (Spn) is the primary agent of community-acquired pneumonia. Neutrophils are innate immune cells that are essential for bacterial clearance during pneumococcal pneumonia but can also do harm to host tissue. Neutrophil migration in pneumococcal pneumonia is therefore a major determinant of host disease outcomes. During Spn infection, detection of the bacterium leads to an increase in proinflammatory signals and subsequent expression of integrins and ligands on both the neutrophil as well as endothelial and epithelial cells...

A fundamental question in cell biology underlies how nutrients are regenerated to maintain and renew tissues. Physiologically, the canonical Wnt signaling is a vital pathway for cell growth, tissue remodeling, and organ formation; pathologically, Wnt signaling contributes to the development of myriad human diseases such as cancer. Despite being the focus of intense research, how Wnt intersects with the metabolic networks to promote tissue growth and remodeling has remained mysterious. Our understanding of metabolism has been revolutionized by technological advances in the fields of chemical biology, metabolomics, and live microscopy that have now made it possible to visualize and manipulate metabolism in living cells and tissues...

Methylthio-d-ribose-1-phosphate (MTR1P) isomerase (MtnA) functions in the methionine salvage pathway by converting the cyclic aldose MTR1P to its open-chain ketose isomer methylthio-d-ribulose 1-phosphate (MTRu1P). What is particularly challenging for this enzyme is that the substrate's phosphate ester prevents facile equilibration to an aldehyde, which in other aldose-ketose isomerases is known to activate the α-hydrogen for proton or hydride transfer between adjacent carbons. We speculated that MtnA could use covalent catalysis via a phosphorylated residue to permit isomerization by one of the canonical mechanisms, followed by phosphoryl transfer back to form the product...

Cardiovascular diseases are the leading cause of death in western societies and neutrophils were long thought to play a detrimental role in ischaemic heart disease. But recent data showed that neutrophils also play an important role in cardiac remodelling and can exhibit an anti-inflammatory N2-phenotype or a pro-inflammatory N1 phenotype. Previous experiments showed that short-term treatment with insulin-like growth factor (IGF1) preserves cardiac function after myocardial infarction (MI). This effect was mediated by myeloid cells...

Apoptosis is the most well-studied form of cell death, but there exist other cell death pathways that also have roles in normal physiology and disease. It is unclear what other forms of cell death remain to be discovered and how these pathways could inform our understanding of cell and molecular biology. Caspase-independent lethal 56 (CIL56) is a compound that kills cells via a novel cell death mechanism. We conducted a genome-wide CRISPR screen to identify novel regulators of this death pathway. From the screen, we identified trans-2-enoyl-CoA reductase (TECR) as a key regulator of CIL56-induced death...

Traditionally, functional representations in early visual areas are conceived as retinotopic maps preserving ego-centric spatial location information while ensuring that other stimulus features are uniformly represented for all locations in space. Recent results challenge this framework of relatively independent encoding of location and features in the early visual system, emphasizing location-dependent feature sensitivities that reflect specialization of cortical circuits for different locations in visual space...

We previously molecularly and clinically characterized Mazzanti syndrome, a RASopathy related to Noonan syndrome that is mostly caused by a single recurrent missense variant (c.4A > G, p.Ser2Gly) in SHOC2, which encodes a leucine-rich repeat-containing protein facilitating signal flow through the RAS-mitogen-associated protein kinase (MAPK) pathway. We also documented that the pathogenic p.Ser2Gly substitution causes upregulation of MAPK signaling and constitutive targeting of SHOC2 to the plasma membrane due to the introduction of an N-myristoylation recognition motif...

Although the conventional activities of p53 such as cell cycle arrest, senescence, and apoptosis are well accepted as the major checkpoints in stress responses, accumulating evidence implicates the importance of other tumor suppression mechanisms. Among these unconventional activities, an iron-dependent form of non-apoptotic cell death, termed ferroptosis, attracts great interest. Unlike apoptotic cell death, activation of p53 alone is not sufficient to induce ferroptosis directly; instead, through its metabolic targets, p53 is able to modulate the ferroptosis response in the presence of ferroptosis inducers such as GPX4 inhibitors or high levels of ROS...

Non-canonical Wnt signaling (encompassing Wnt/PCP and WntCa2+ ) has a dual identity in the literature. One stream of research investigates its role in antagonizing canonical Wnt/β-catenin signaling in cancer, typically through Ca2+ , while the other stream investigates its effect on polarity in development, typically through Vangl2. Rarely do these topics intersect or overlap. What has become clear is that Wnt5a can mobilize intracellular calcium stores to inhibit Wnt/β-catenin in cancer cells but there is no evidence that Vangl2 is involved in this process...

BACKGROUND AND PURPOSE: Aberrant activation of the Wnt pathway contributes to differentiation and maintenance of cancer stem cells underlying gliomagenesis. The aim of our research was to determine as to what degrees some Wnt markers are expressed in gliomas of different grades, lineages and molecular subtypes. METHODS: Nine grade II, 10 grade III and 72 grade IV surgically removed, formalin-fixed paraffin-embedded glioma specimens were included. Mutation status of IDH1 codon 132 was defined by immunohistochemistry and pyrosequencing in all tumors...

Hypoxia and inflammation are frequently co-incidental features of the tissue microenvironment in a wide range of inflammatory diseases. While the impact of hypoxia on inflammatory pathways in immune cells has been well characterized, less is known about how inflammatory stimuli such as cytokines impact upon the canonical hypoxia-inducible factor (HIF) pathway, the master regulator of the cellular response to hypoxia. In this review, we discuss what is known about the impact of two major pro-inflammatory cytokines, tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β), on the regulation of HIF-dependent signaling at sites of inflammation...

We know little about the control of positional information (PI) during axolotl limb regeneration, which ensures that the limb regenerates exactly what was amputated, and the work reported here investigates this phenomenon. Retinoic acid administration changes the PI in a proximal direction so that a complete limb can be regenerated from a hand. Rather than identifying all the genes altered by RA treatment of the limb, we have eliminated many off-target effects by using retinoic acid receptor selective agonists...

The adverse outcome pathway (AOP) framework provides a practical means for organizing scientific knowledge that can be used to infer cause-effect relationships between stressor events and toxicity outcomes in intact organisms. It has reached wide acceptance as a tool to aid chemical safety assessment and regulatory toxicology by supporting a systematic way of predicting adverse health outcomes based on accumulated mechanistic knowledge. A major challenge for broader application of the AOP concept in regulatory toxicology, however, has been developing robust AOPs to a level where they are peer reviewed and accepted...

Proximal spinal muscular atrophy (SMA) is an autosomal recessive neurodegenerative disorder characterized by motor neuron loss and subsequent atrophy of skeletal muscle. SMA is caused by deficiency of the essential survival motor neuron (SMN) protein, canonically responsible for the assembly of the spliceosomal small nuclear ribonucleoproteins (snRNPs). Therapeutics aimed at increasing SMN protein levels are efficacious in treating SMA. However, it remains unknown how deficiency of SMN results in motor neuron loss, resulting in many reported cellular functions of SMN and pathways affected in SMA...

Opioid abuse has become a major public health crisis that affects millions of individuals across the globe. This widespread abuse of prescription opioids and dramatic increase in the availability of illicit opioids have created what is known as the opioid epidemic. Pregnant women are a particularly vulnerable group since they are prescribed for opioids such as morphine, buprenorphine, and methadone, all of which have been shown to cross the placenta and potentially impact the developing fetus. Limited information exists regarding the effect of oxycodone (oxy) on synaptic alterations...

Aberrant inflammation, such as that associated with inflammatory bowel disease (IBD), is fueled by the inordinate activity of RelA/NF-κB factors. As such, the canonical NF-κB module mediates controlled nuclear activation of RelA dimers from the latent cytoplasmic complexes. What provokes pathological RelA activity in the colitogenic gut remains unclear. The noncanonical NF-κB pathway typically promotes immune organogenesis involving Nfkb2 gene products. Because NF-κB pathways are intertwined, we asked whether noncanonical signaling aggravated inflammatory RelA activity...

All perceptual and cognitive circuits in the human cerebral cortex are organized into layers. Specializations of a canonical laminar network of bottom-up, horizontal, and top-down pathways carry out multiple kinds of biological intelligence across different neocortical areas. This article describes what this canonical network is and notes that it can support processes as different as 3D vision and figure-ground perception; attentive category learning and decision-making; speech perception; and cognitive working memory (WM), planning, and prediction...

Tissue injury initiates a tissue repair program, characterized by acute inflammation and recruitment of immune cells, dominated by neutrophils. Neutrophils prevent infection in the injured tissue through multiple effector functions, including the production of reactive oxygen species, the release of granules, the phagocytosis of invaders, and the extrusion of neutrophil extracellular traps (NETs). However, these canonical protective mechanisms can also have detrimental effects both in the context of infection and in response to sterile injuries...