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Background: MG132, a proteasome inhibitor, is widely used to inhibit nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) activity by proteasome-mediated degradation of IκB. It has been marketed as a specific, reversible, cell-permeable and low-cost inhibitor. However, adverse effects of the compound have been reported in the literature. We recently discovered and characterised a point mutation in the acute phase protein serum amyloid A (SAA) in chickens, by overexpressing the protein in chicken hepatocellular carcinoma (LMH) cells. This serine to arginine exchange at amino acid position 90 (SAA.R90S) leads to intra- and extracellular accumulation of SAA, which is surprisingly counteracted by MG132 treatment, independent of SAA's intrinsic promoter., Methods and Results: To test, whether low proteasomal degradation of SAA.R90S is responsible for the observed intra- and extracellular SAA accumulation, we intended to inhibit the proteasome in SAA wild type (SAA.WT) overexpressing cells with MG132. However, we observed an unexpected drastic decrease in SAA protein expression at the transcript level. NF-κB gene expression was unchanged by MG132 at the measured time point., Conclusions: The observed results demonstrate that MG132 inhibits SAA expression at the transcript level, independent of its endogenous promoter. Further, the data might indicate that NF-κB is not involved in the observed MG132-induced inhibition of SAA expression. We, consequently, question in this brief report whether MG132 should truly be categorised as a specific ubiquitin proteasome inhibitor and recommend the usage of alternative compounds., (© 2024. The Author(s).)

Epilepsy is a complex genetic disorder that affects about 2% of the global population. Although the frequency and severity of epileptic seizures can be reduced by a range of pharmacological interventions, there are no disease-modifying treatments for epilepsy. The development of new and more effective drugs is hindered by a lack of suitable animal models. Available rodent models may not recapitulate all key aspects of the disease. Spontaneous epileptic convulsions were observed in few Göttingen Minipigs (GMPs), which may provide a valuable alternative animal model for the characterisation of epilepsy-type diseases and for testing new treatments. We have characterised affected GMPs at the genome level and have taken advantage of primary fibroblast cultures to validate the functional impact of fixed genetic variants on the transcriptome level. We found numerous genes connected to calcium metabolism that have not been associated with epilepsy before, such as ADORA2B, CAMK1D, ITPKB, MCOLN2, MYLK, NFATC3, PDGFD, and PHKB. Our results have identified two transcription factor genes, EGR3 and HOXB6, as potential key regulators of CACNA1H, which was previously linked to epilepsy-type disorders in humans. Our findings provide the first set of conclusive results to support the use of affected subsets of GMPs as an alternative and more reliable model system to study human epilepsy. Further neurological and pharmacological validation of the suitability of GMPs as an epilepsy model is therefore warranted., (© 2024. The Author(s).)

Chicken amyloid arthropathy is a debilitating disease with a major impact on animal welfare. Since the disease is triggered by bacterial infection, preventative treatment also contributes to the widespread overuse of antibiotics. Bacterial infection initiates an acute phase response including increased serum amyloid A (SAA) production by the liver. SAA accumulates at sites of infection and in particular in large joints of affected birds. Interestingly, white egg-laying chickens (WL) are resistant to the disease whilst brown egg-laying chickens (BL) are most affected. Disease susceptibility has an immunological basis but the possible contribution of underlying genetic risk factors is not understood. Using a whole genome sequencing approach, we discovered a novel variant in the SAA gene in WL, which is predicted to result in an arginine to serine substitution at position 90 (SAA.R90S). Surprisingly, when overexpressed in chicken hepatocellular carcinoma cells, SAA.R90S was expressed at a higher rate and secreted to a greater degree than the wild-type SAA protein. Moreover, RNASeq analysis showed that the R90S mutant exerted a differential effect on the expression of core transcription factors linked to cell fate determination and cell differentiation. Comparative analysis of gene expression in murine CD4 T-cells stimulated with IL-6/SAA, suggests that SAA.R90S might block an induced cell fate change toward pro-inflammatory T helper 17 cells, which are required for immunological protection against pathogenic bacteria during an acute phase response. Our results provide first mechanistic insights into the genetic resistance of WL to amyloid arthropathy and could be applied to commercial layer breeding programs to improve animal welfare and reduce the negative effects of the overuse of antibiotics., (© 2022 The Authors. The FASEB Journal published by Wiley Periodicals LLC on behalf of Federation of American Societies for Experimental Biology.)

Primary care clinics are a common treatment venue for a broad range of mental health conditions, including anxiety and depressive disorders, which are experienced by up to a fifth of primary care patients. Integrated primary care is a treatment model in which behavioral health providers are integrated into primary care clinics to treat mental health disorders and help improve the psychosocial functioning of patients. The Unified Protocol for Transdiagnostic Treatment of Emotional Disorders' (UP) focus on functional outcomes is consistent with the goals of integrated primary care. However, its 12-18 session length is not feasible for implementation in primary care. A 5-session group adaptation was developed for primary care. This pilot project examines changes in veterans' ( n = 48) self-reported anxiety, depression, and psychosocial adjustment following completion of the 5-week group adaptation. Participants were enrolled in a Veterans' Health Administration (VHA) primary care clinic and were diagnosed with mild to moderate mood and stressor disorders. Treatment completers experienced improvements on all outcome measures with significant increases in the proportion of participants scoring in the subclinical range upon treatment completion (anxiety [50.0%]: t = 6.67, df = 45, p = .000; Cohen's d = .86; depression [62.5%]: t = 5.60, df = 45, p = .000; Cohen's d = .55; psychosocial functioning [35.4%]: t = 4.89, df = 36, p = .000; Cohen's d = .66). This pilot project demonstrates that a 5-session group adaptation of the UP may be a promising transdiagnostic treatment appropriate for the primary care setting. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

As a pioneer of training in the field of psychology, the Veterans Affairs (VA) HealthCare System serves as a leader in the training in and provision of Telemental Health (TMH) services in the United States. To meet goals toward continued expansion of these services, the VA TMH training program includes both web-based didactic courses and a skills competency test at a basic level with supervision and consultation in TMH for more advanced training and is available to staff psychologists and psychologist trainees. Despite these efforts, barriers for training in and implementation of TMH occur at the provider, system, and patient level. At the national level, the VA is actively working to resolve these barriers and we share site-specific examples implemented by the VA Puget Sound Health Care System promoting access through TMH team to further address barriers to training and implementation., (© 2019 Wiley Periodicals, Inc.)