Site-specific drug release of monomethyl fumarate to treat oxidative stress disorders.

Treatment of diseases of oxidative stress through activation of the antioxidant nuclear factor E2-related factor 2 (NRF2) is limited by systemic side effects. We chemically functionalize the NRF2 activator monomethyl fumarate to require Baeyer-Villiger oxidation for release of the active drug at sites of oxidative stress. This prodrug reverses chronic pain in mice with reduced side effects and could be applied to other disorders of oxidative stress.

B cells drive neuropathic pain-related behaviors in mice through IgG-Fc gamma receptor signaling.

Neuroimmune interactions are essential for the development of neuropathic pain, yet the contributions of distinct immune cell populations have not been fully unraveled. Here, we demonstrate the critical role of B cells in promoting mechanical hypersensitivity (allodynia) after peripheral nerve injury in male and female mice. Depletion of B cells with a single injection of anti-CD20 monoclonal antibody at the time of injury prevented the development of allodynia.

18 kDa Translocator protein (TSPO) is upregulated in rat brain after peripheral nerve injury and downregulated by diroximel fumarate.

Neuroimmune signaling is a key process underlying neuropathic pain. Clinical studies have demonstrated that 18 kDa translocator protein (TSPO), a putative marker of neuroinflammation, is upregulated in discrete brain regions of patients with chronic pain. However, no preclinical studies have investigated TSPO dynamics in the brain in the context of neuropathic pain and in response to analgesic treatments.

Injectable, reversibly thermoresponsive captopril-laden hydrogel for the local treatment of sensory loss in diabetic neuropathy.

A major and irreversible complication of diabetes is diabetic peripheral neuropathy (DPN), which can lead to significant disability and decreased quality of life. Prior work demonstrates the peptide hormone Angiotensin II (Ang II) is released locally in neuropathy and drives inflammation and impaired endoneurial blood flow. Therefore, we proposed that by utilizing a local thermoresponsive hydrogel injection, we could deliver inhibitors of angiotensin-converting enzyme (ACE) to suppress Ang II production and reduce nerve dysfunction in DPN through local drug release.

Systemic and targeted activation of Nrf2 reverses doxorubicin-induced cognitive impairments and sensorimotor deficits in mice.

While cancer survivorship has increased due to advances in treatments, chemotherapy often carries long-lived neurotoxic side effects which reduce quality of life. Commonly affected domains include memory, executive function, attention, processing speed and sensorimotor function, colloquially known as chemotherapy-induced cognitive impairment (CICI) or "chemobrain". Oxidative stress and neuroimmune signaling in the brain have been mechanistically linked to the deleterious effects of chemotherapy on cognition and sensorimotor function.

Diroximel fumarate acts through Nrf2 to attenuate methylglyoxal-induced nociception in mice and decreases ISR activation in DRG neurons.

Diabetic neuropathic pain is associated with elevated plasma levels of methylglyoxal (MGO). MGO is a metabolite of glycolysis that causes mechanical hypersensitivity in mice by inducing the integrated stress response (ISR), which is characterized by phosphorylation of eukaryotic initiation factor 2α (p-eIF2α). Nuclear factor erythroid 2-related factor 2 (Nrf2) is a transcription factor that regulates the expression of antioxidant proteins that neutralize MGO.

Erratum: CXCL12-mediated monocyte transmigration into brain perivascular space leads to neuroinflammation and memory deficit in neuropathic pain: Erratum.

[This corrects the article DOI: 10.7150/thno.44364.

Voluntary wheel running prevents formation of membrane attack complexes and myelin degradation after peripheral nerve injury.

Regular aerobic activity is associated with a reduced risk of chronic pain in humans and rodents. Our previous studies in rodents have shown that prior voluntary wheel running can normalize redox signaling at the site of peripheral nerve injury, attenuating subsequent neuropathic pain. However, the full extent of neuroprotection offered by voluntary wheel running after peripheral nerve injury is unknown.

Grazing management for soil carbon in Australia: A review.

The livestock industry accounts for a considerable proportion of agricultural greenhouse gas emissions, and in response, the Australian red meat industry has committed to an aspirational target of net-zero emissions by 2030. Increasing soil carbon storage in grazing lands has been identified as one method to help achieve this, while also potentially improving production and provision of other ecosystem services. This review examined the effects of grazing management on soil carbon and factors that drive soil carbon sequestration in Australia.

Interleukin-1beta and inflammasome expression in spinal cord following chronic constriction injury in male and female rats.

Females represent a majority of chronic pain patients and show greater inflammatory immune responses in human chronic pain patient populations as well as in animal models of neuropathic pain. Recent discoveries in chronic pain research have revealed sex differences in inflammatory signaling, a key component of sensory pathology in chronic neuropathic pain, inviting more research into the nuances of these sex differences. Here we use the chronic constriction injury (CCI) model to explore similarities and differences in expression and production of Inflammatory cytokine IL-1beta in the lumbar spinal cord, as well as its role in chronic pain.

One immune system plays many parts: The dynamic role of the immune system in chronic pain and opioid pharmacology.

The transition from acute to chronic pain is an ongoing major problem for individuals, society and healthcare systems around the world. It is clear chronic pain is a complex multidimensional biological challenge plagued with difficulties in pain management, specifically opioid use. In recent years the role of the immune system in chronic pain and opioid pharmacology has come to the forefront.

Termite sensitivity to temperature affects global wood decay rates.

Deadwood is a large global carbon store with its store size partially determined by biotic decay. Microbial wood decay rates are known to respond to changing temperature and precipitation. Termites are also important decomposers in the tropics but are less well studied.

HDAC6 Inhibition Reverses Cisplatin-Induced Mechanical Hypersensitivity via Tonic Delta Opioid Receptor Signaling.

Peripheral neuropathic pain induced by the chemotherapeutic cisplatin can persist for months to years after treatment. Histone deacetylase 6 (HDAC6) inhibitors have therapeutic potential for cisplatin-induced neuropathic pain since they persistently reverse mechanical hypersensitivity and spontaneous pain in rodent models. Here, we investigated the mechanisms underlying reversal of mechanical hypersensitivity in male and female mice by a 2 week treatment with an HDAC6 inhibitor, administered 3 d after the last dose of cisplatin.

How Modelers Model: the Overlooked Social and Human Dimensions in Model Intercomparison Studies.

There is a growing realization that the complexity of model ensemble studies depends not only on the models used but also on the experience and approach used by modelers to calibrate and validate results, which remain a source of uncertainty. Here, we applied a multi-criteria decision-making method to investigate the rationale applied by modelers in a model ensemble study where 12 process-based different biogeochemical model types were compared across five successive calibration stages. The modelers shared a common level of agreement about the importance of the variables used to initialize their models for calibration.

Preconditioning by voluntary wheel running attenuates later neuropathic pain via nuclear factor E2-related factor 2 antioxidant signaling in rats.

Animal and human studies have shown that exercise prior to nerve injury prevents later chronic pain, but the mechanisms of such preconditioning remain elusive. Given that exercise acutely increases the formation of free radicals, triggering antioxidant compensation, we hypothesized that voluntary running preconditioning would attenuate neuropathic pain by supporting redox homeostasis after sciatic nerve injury in male and female rats. We show that 6 weeks of voluntary wheel running suppresses neuropathic pain development induced by chronic constriction injury across both sexes.

Genome-Wide Analysis of Cytochrome P450s of Species: Evolutionary Origin, Family Expansion and Putative Functions.

Cytochrome P450s are a group of monooxygenase enzymes involved in primary, secondary and xenobiotic metabolisms. They have a wide application in the agriculture sector where they could serve as a target for herbicides or fungicides, while they could function in the pharmaceutical industry as drugs or drugs structures or for bioconversions. species are among the most commonly encountered fungal genera, with most of them living as saprophytes in different habitats, while others are parasites of plants and animals.

Small molecule targeting NaV1.7 via inhibition of the CRMP2-Ubc9 interaction reduces pain in chronic constriction injury (CCI) rats.

The voltage-gated sodium channel isoform NaV1.7 is a critical player in the transmission of nociceptive information. This channel has been heavily implicated in human genetic pain disorders and is a validated pain target.

Important constraints on soil organic carbon formation efficiency in subtropical and tropical grasslands.

More than 10% of Australia's 49 M ha of grassland is considered degraded, prompting widespread interest in the management of these ecosystems to increase soil carbon (C) sequestration-with an emphasis on long-lived C storage. We know that management practices that increase plant biomass also increase C inputs to the soil, but we lack a quantitative understanding of the fate of soil C inputs into different soil organic carbon (SOC) fractions that have fundamentally different formation pathways and persistence in the soil. Our understanding of the factors that constrain SOC formation in these fractions is also limited, particularly within tropical climates.

Ammonia and nitrous oxide emission factors for excreta deposited by livestock and land-applied manure.

Manure application to land and deposition of urine and dung by grazing animals are major sources of ammonia (NH ) and nitrous oxide (N O) emissions. Using data on NH and N O emissions following land-applied manures and excreta deposited during grazing, emission factors (EFs) disaggregated by climate zone were developed, and the effects of mitigation strategies were evaluated. The NH data represent emissions from cattle and swine manures in temperate wet climates, and the N O data include cattle, sheep, and swine manure emissions in temperate wet/dry and tropical wet/dry climates.

Environmental and economic trade-offs of using composted or stockpiled manure as partial substitute for synthetic fertilizer.

Manure generated from livestock production could represent an important source of plant nutrients in substitution of synthetic fertilizer. To evaluate the sustainability of partially substituting synthetic fertilizer with soil organic amendments (OAs) in horticulture, an economic and greenhouse gas (GHG) budget was developed. The boundary for analysis included manure processing (stockpiling vs.

Autoimmune regulation of chronic pain.

Chronic pain is an unpleasant and debilitating condition that is often poorly managed by existing therapeutics. Reciprocal interactions between the nervous system and the immune system have been recognized as playing an essential role in the initiation and maintenance of pain. In this review, we discuss how neuroimmune signaling can contribute to peripheral and central sensitization and promote chronic pain through various autoimmune mechanisms.

Emerging Therapeutic Applications for Fumarates.

Fumarates are successfully used for the treatment of psoriasis and multiple sclerosis. Their antioxidative, immunomodulatory, and neuroprotective properties make fumarates attractive therapeutic candidates for other pathologies. The exact working mechanisms of fumarates are, however, not fully understood.

Can seasonal soil N mineralisation trends be leveraged to enhance pasture growth?

Background: Soil N mineralisation is the process by which organic N is converted into plant-available forms, while soil N immobilisation is the transformation of inorganic soil N into organic matter and microbial biomass, thereafter becoming bio-unavailable to plants. Mechanistic models can be used to explore the contribution of mineralised or immobilised N to pasture growth through simulation of plant, soil and environment interactions driven by management.

Purpose: Our objectives were (1) to compare the performance of three agro-ecosystems models (APSIM, DayCent and DairyMod) in simulating soil N, pasture biomass and soil water using the same experimental data in three diverse environments (2), to determine if tactical application of N fertiliser in different seasons could be used to leverage seasonal trends in N mineralisation to influence pasture growth and (3), to explore the sensitivity of N mineralisation to changes in N fertilisation, cutting frequency and irrigation rate.