VCP/p97-associated proteins are binders and debranching enzymes of K48-K63-branched ubiquitin chains.

Branched ubiquitin (Ub) chains constitute a sizable fraction of Ub polymers in human cells. Despite their abundance, our understanding of branched Ub function in cell signaling has been stunted by the absence of accessible methods and tools. Here we identify cellular branched-chain-specific binding proteins and devise approaches to probe K48-K63-branched Ub function.

Discovery and characterization of noncanonical E2-conjugating enzymes.

E2-conjugating enzymes (E2s) play a central role in the enzymatic cascade that leads to the attachment of ubiquitin to a substrate. This process, termed ubiquitylation, is required to maintain cellular homeostasis and affects almost all cellular process. By interacting with multiple E3 ligases, E2s dictate the ubiquitylation landscape within the cell.

Endocannabinoid regulation in the cervix during pregnancy: insights into molecular mechanisms of premature labor.

In Brief: The cervix plays a crucial role not only in the maintenance of pregnancy but also during delivery, when it undergoes extensive changes. This study highlights the involvement of the endocannabinoidome in cervical remodeling, emphasizing its relevance in the shift from a nonpregnant to pregnant state and its potential contribution to preterm delivery in inflammatory contexts.

Abstract: During pregnancy, the main role of the cervix is to isolate the fetus from outside pathogens and maintain the relatively closed system of uterine gestation.

Discovery and Preclinical Evaluation of a Novel Inhibitor of FABP5, ART26.12, Effective in Oxaliplatin-Induced Peripheral Neuropathy.

Oxaliplatin-induced peripheral neuropathy (OIPN) is a dose-limiting toxicity characterised by mechanical allodynia and thermal hyperalgesia, without any licensed medications. ART26.12 is a fatty acid-binding protein (FABP) 5 inhibitor with antinociceptive properties, characterised here for the prevention and treatment of OIPN.

"Work with us… to make it more accessible". What women with intellectual disabilities want from infant-feeding health resources: an exploratory study.

Background: More women with intellectual disabilities are becoming mothers but fewer are known to breastfeed compared with other women. Women with intellectual disabilities are entitled to accessible antenatal and infant feeding information, yet are rarely asked for their views on available resources. This article reports on the final stage of a UK project exploring how women with intellectual disabilities are supported to make infant feeding decisions.

Plasma endocannabinoids and cannabimimetic fatty acid derivatives are altered in cyclic vomiting syndrome: The effects of sham feeding.

Cyclic vomiting syndrome (CVS) is an underdiagnosed disorder of the gut-brain interaction. Our understanding of the pathophysiology of CVS is evolving. Here, we tested the hypotheses that: (1) the levels of endocannabinoids and related lipids are altered in CVS, and (2) cephalic-vagal stimulation drive changes in endolipid levels.

Effects of combined use of alcohol and delta-9-tetrahydrocannibinol on working memory in Long Evans rats.

The increase in social acceptance and legalization of cannabis over the last several years is likely to increase the prevalence of its co-use with alcohol. In spite of this, the potential for effects unique to co-use of these drugs, especially in moderate doses, has been studied relatively infrequently. We addressed this in the current study using a laboratory rat model of voluntary drug intake.

Effects of inhaled cannabis high in Δ9-THC or CBD on the aging brain: A translational MRI and behavioral study.

With the recent legalization of inhaled cannabis for medicinal and recreational use, the elderly represents one of the newest, rapidly growing cohorts of cannabis users. To understand the neurobiological effects of cannabis on the aging brain, 19-20 months old mice were divided into three groups exposed to vaporized cannabis containing ~10% Δ9-THC, ~10% CBD, or placebo for 30 min each day. Voxel based morphometry, diffusion weighted imaging, and resting state functional connectivity data were gathered after 28 days of exposure and following a two-week washout period.

Effects of combined use of alcohol and delta-9-tetrahydrocannibinol on working memory in Long Evans rats.

The increase in social acceptance and legalization of cannabis over the last several years is likely to increase the prevalence of its co-use with alcohol. In spite of this, the potential for effects unique to co-use of these drugs, especially in moderate doses, has been studied relatively infrequently. We addressed this in the current study using a laboratory rat model of voluntary drug intake.

Cannabinoids accumulate in mouse breast milk and differentially regulate lipid composition and lipid signaling molecules involved in infant development.

Maternal cannabis use during lactation may expose developing infants to cannabinoids (CBs) such as Δ-9-tetrahydrocannabinol (THC) and cannabidiol (CBD). CBs modulate lipid signaling molecules in the central nervous system in age- and cell-dependent ways, but their influence on the lipid composition of breast milk has yet to be established. This study investigates the effects of THC, CBD, or their combination on milk lipids by analyzing the stomach contents of CD1 mouse pups that have been nursed by dams injected with CBs on postnatal days (PND) 1 -10.

Measuring the Content of Endocannabinoid-Like Compounds in Biological Fluids: A Critical Overview of Sample Preparation Methodologies.

Different mass spectrometric techniques have been used over the past decade to quantify endocannabinoids (eCBs) and related lipids. Even with the level of molecular fingerprinting accuracy of an instrument like the most advanced triple quadrupole mass spectrometer, if one is not getting the most optimized sample to the detector in a way that this improved technology can be of use, then advancements can be stymied. Here, our focus is on review and discussion of sample preparation methodologies used to isolate the eCB anandamide and its close congeners N-acyl ethanolamines and structural congeners (i.

Supporting women with learning disabilities in infant feeding decisions: UK health care professionals' experiences.

Women with learning disabilities are less likely to breastfeed than other women. They may find it hard to understand or learn feeding techniques or know that they have infant feeding choices. This population may be supported during their pregnancies by a range of professionals with differing priorities and responsibilities towards both the mother and the baby.

Cannabinoid CB1 receptors regulate salivation.

Saliva serves multiple important functions within the body that we typically take for granted, such as helping prepare food for swallowing and defense against oral pathogens. Dry mouth is a primary symptom of Sjӧgren's syndrome and is a side effect of many drug treatments. Cannabis users frequently report dry mouth, but the basis for this is still unknown.

An Unfolding Tabletop Simulation Training Exercise on Disaster Planning for Nursing Students.

Background: Disaster planning is an essential component for nursing students to learn.

Problem: Clinical experiences of disasters are typically unavailable for nursing students. Increasing frequency of disaster events around the globe has made disaster planning knowledge and skills a critical component in nursing education and professional practice.

Analytical validity of DecisionDx-SCC, a gene expression profile test to identify risk of metastasis in cutaneous squamous cell carcinoma (SCC) patients.

Background: To improve identification of patients with cutaneous squamous cell carcinoma (SCC) at high risk for metastatic disease, the DecisionDx-SCC assay, a prognostic 40-gene expression profile (40-GEP) test, was developed and validated. The 40-GEP assay utilizes RT-PCR gene expression analysis on primary tumor biopsy tissue to evaluate the expression of 34 signature gene targets and 6 normalization genes. The test provides classifications of low risk (Class 1), moderate risk (Class 2A), and high risk (Class 2B) of metastasis within 3 years of diagnosis.

Supporting women with learning disabilities in infant feeding decisions: A scoping review.

Mothers with learning disabilities face many challenges during the perinatal period including preparing for and establishing infant feeding. Evidence shows that women with learning disabilities are less likely to breastfeed than other mothers. A scoping review was undertaken using Arksey and O'Malley's methodology to understand what is known about how women with learning disabilities can be supported to make infant feeding decisions, particularly in relation to the use of appropriate and accessible images.

Monoacylglycerol Lipase Inhibitor MJN110 Reduces Neuronal Hyperexcitability, Restores Dendritic Arborization Complexity, and Regulates Reward-Related Behavior in Presence of HIV-1 Tat.

While current therapeutic strategies for people living with human immunodeficiency virus type 1 (HIV-1) suppress virus replication peripherally, viral proteins such as transactivator of transcription (Tat) enter the central nervous system early upon infection and contribute to chronic inflammatory conditions even alongside antiretroviral treatment. As demand grows for supplemental strategies to combat virus-associated pathology presenting frequently as HIV-associated neurocognitive disorders (HAND), the present study aimed to characterize the potential utility of inhibiting monoacylglycerol lipase (MAGL) activity to increase inhibitory activity at cannabinoid receptor-type 1 receptors through upregulation of 2-arachidonoylglycerol (2-AG) and downregulation of its degradation into proinflammatory metabolite arachidonic acid (AA). The MAGL inhibitor MJN110 significantly reduced intracellular calcium and increased dendritic branching complexity in Tat-treated primary frontal cortex neuron cultures.

Modulatory Potential of Cannabidiol on the Opioid-Induced Inflammatory Response.

Opioids are effective analgesics; however, there are many negative consequences of chronic use. One important side effect of chronic opioid use is the continuous engagement of the immune response that can exacerbate chronic pain. The opioid, morphine, initiates a Toll-like receptor 4 (TLR4) signaling cascade that drives the activation of NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) inflammasome proteins, resulting in cytokine production and effectively creating a positive feedback loop for continuous TLR4 activation.

Potentially Inappropriate Medication Use in Older Adults with Alzheimer's Disease and Related Dementias Living in the Community: A Cross-Sectional Analysis.

Background: With the older adult population in the USA increasing, so is the population of those with Alzheimer's disease and related dementias (ADRD). Older adults are vulnerable to the effects of potentially inappropriate medications as established by the Beers Criteria; however, some medications continue to be prescribed against recommendations.

Objectives: Our objectives were to describe potentially inappropriate medication (PIM) use linked to cognitive impairment or decline (referred to as Cog-PIM) in older adults with and without ADRD and to investigate whether the odds of Cog-PIM report differ by ADRD status in ambulatory care (i.

Cannabidiol has a unique effect on global brain activity: a pharmacological, functional MRI study in awake mice.

Background: The phytocannabinoid cannabidiol (CBD) exhibits anxiolytic activity and has been promoted as a potential treatment for post-traumatic stress disorders. How does CBD interact with the brain to alter behavior? We hypothesized that CBD would produce a dose-dependent reduction in brain activity and functional coupling in neural circuitry associated with fear and defense.

Methods: During the scanning session awake mice were given vehicle or CBD (3, 10, or 30 mg/kg I.

Comparative host-coronavirus protein interaction networks reveal pan-viral disease mechanisms.

The COVID-19 pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a grave threat to public health and the global economy. SARS-CoV-2 is closely related to the more lethal but less transmissible coronaviruses SARS-CoV-1 and Middle East respiratory syndrome coronavirus (MERS-CoV). Here, we have carried out comparative viral-human protein-protein interaction and viral protein localization analyses for all three viruses.

Integrating the melanoma 31-gene expression profile test with surgical oncology practice within national guideline and staging recommendations.

Define changes in clinical management resulting from the use of the prognostic 31-gene expression profile (31-GEP) test for cutaneous melanoma in a surgical oncology practice. Management plans for 112 consecutively tested patients with stage I-III melanoma were evaluated for duration and number of clinical visits, blood work and imaging. 31-GEP high-risk (class 2; n = 46) patients received increased management compared with low-risk (class 1; n = 66) patients.

Validation of a 40-gene expression profile test to predict metastatic risk in localized high-risk cutaneous squamous cell carcinoma.

Background: Current staging systems for cutaneous squamous cell carcinoma (cSCC) have limited positive predictive value for identifying patients who will experience metastasis.

Objective: To develop and validate a gene expression profile (GEP) test for predicting risk for metastasis in localized, high-risk cSCC with the goal of improving risk-directed patient management.

Methods: Archival formalin-fixed paraffin-embedded primary cSCC tissue and clinicopathologic data (n = 586) were collected from 23 independent centers in a prospectively designed study.