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IMPORTANCE: Rapid and accurate diagnosis of autoimmune encephalitis encourages prompt initiation of immunotherapy toward improved patient outcomes. However, clinical features alone may not sufficiently narrow the differential diagnosis, and awaiting autoantibody results can delay immunotherapy. OBJECTIVE: To identify simple magnetic resonance imaging (MRI) characteristics that accurately distinguish 2 common forms of autoimmune encephalitis, LGI1- and CASPR2-antibody encephalitis (LGI1/CASPR2-Ab-E), from 2 major differential diagnoses, viral encephalitis (VE) and Creutzfeldt-Jakob disease (CJD). DESIGN, SETTING, AND PARTICIPANTS: This cross-sectional study involved a retrospective, blinded analysis of the first available brain MRIs (taken 2000-2022) from 192 patients at Oxford University Hospitals in the UK and Mayo Clinic in the US. These patients had LGI1/CASPR2-Ab-E, VE, or CJD as evaluated by 2 neuroradiologists (discovery cohort; n = 87); findings were validated in an independent cohort by 3 neurologists (n = 105). Groups were statistically compared with contingency tables. Data were analyzed in 2023. MAIN OUTCOMES AND MEASURES: MRI findings including T2 or fluid-attenuated inversion recovery (FLAIR) hyperintensities, swelling or volume loss, presence of gadolinium contrast enhancement, and diffusion-weighted imaging changes. Correlations with clinical features. RESULTS: Among 192 participants with MRIs reviewed, 71 were female (37%) and 121 were male (63%); the median age was 66 years (range, 19-92 years). By comparison with VE and CJD, in LGI1/CASPR2-Ab-E, T2 and/or FLAIR hyperintensities were less likely to extend outside the temporal lobe (3/42 patients [7%] vs 17/18 patients [94%] with VE; P < .001, and 3/4 patients [75%] with CJD; P = .005), less frequently exhibited swelling (12/55 [22%] with LGI1/CASPR2-Ab-E vs 13/22 [59%] with VE; P = .003), and showed no diffusion restriction (0 patients vs 16/22 [73%] with VE and 8/10 [80%] with CJD; both P < .001) and rare contrast enhancement (1/20 [5%] vs 7/17 [41%] with VE; P = .01). These findings were validated in an independent cohort and generated an area under the curve of 0.97, sensitivity of 90%, and specificity of 95% among cases with T2/FLAIR hyperintensity in the hippocampus and/or amygdala. CONCLUSIONS AND RELEVANCE: In this study, T2 and/or FLAIR hyperintensities confined to the temporal lobes, without diffusion restriction or contrast enhancement, robustly distinguished LGI1/CASPR2-Ab-E from key differential diagnoses. These observations should assist clinical decision-making toward expediting immunotherapy. Their generalizability to other forms of autoimmune encephalitis and VE should be examined in future studies.

Purpose: Type I gastric neuroendocrine neoplasms (g-NENs) have a low risk of metastasis and a generally favourable prognosis. Patients with small type I g-NENs (≤10 mm) frequently require no treatment, whereas those with larger polyps usually undergo resection. We evaluated the safety and outcomes of endoscopic surveillance after no initial treatment in selected patients with type I g-NENs. Methods: Retrospective analysis of type I g-NEN patients across two European Neuroendocrine Tumour Society Centers of Excellence 2003–2019. Results: Following initial assessment, 87 of 115 patients with type I g-NEN (75 with polyps ≤10 mm) received no initial treatment and underwent endoscopic surveillance. 79/87 (91%) demonstrated no clinically meaningful change in tumour size or grade over a median 62 month follow up. Only two patients developed NEN progression that required a change in management and two other patients developed gastric adenocarcinoma/high grade dysplasia; all four initially had ≥11 mm g-NENs. Conclusions: Patients with ≤10 mm type I g-NENs were unlikely to develop clinically significant tumour progression and in most cases, resection was not needed. The endoscopic surveillance interval could therefore potentially be safely increased to every 2–3 years in such patients. However, lifelong surveillance is still advocated due to the additional risk of developing gastric adenocarcinoma.

Nonalcoholic steatohepatitis (NASH) is a severe liver disorder characterized by triglyceride accumulation, severe inflammation, and fibrosis. With the recent increase in prevalence, NASH is now the leading cause of liver transplant, with no approved therapeutics available. Although the exact molecular mechanism of NASH progression is not well understood, a widely held hypothesis is that fat accumulation is the primary driver of the disease. Therefore, diacylglycerol O-acyltransferase 2 (DGAT2), a key enzyme in triglyceride synthesis, has been explored as a NASH target. RNAi-based therapeutics is revolutionizing the treatment of liver diseases, with recent chemical advances supporting long-term gene silencing with single subcutaneous administration. Here, we identified a hyper-functional, fully chemically stabilized GalNAc-conjugated small interfering RNA (siRNA) targeting DGAT2 (Dgat2-1473) that, upon injection, elicits up to 3 months of DGAT2 silencing (>80%–90%, p < 0.0001) in wild-type and NSG-PiZ “humanized” mice. Using an obesity-driven mouse model of NASH (ob/ob-GAN), Dgat2-1473 administration prevents and reverses triglyceride accumulation (>85%, p < 0.0001) without increased accumulation of diglycerides, resulting in significant improvement of the fatty liver phenotype. However, surprisingly, the reduction in liver fat did not translate into a similar impact on inflammation and fibrosis. Thus, while Dgat2-1473 is a practical, long-lasting silencing agent for potential therapeutic attenuation of liver steatosis, combinatorial targeting of a second pathway may be necessary for therapeutic efficacy against NASH.

BackgroundThere is increasing evidence for the use of exercise in cancer patients and data supporting enhanced tumour volume reduction following chemotherapy in animal models. To date, there is no reported histopathological evidence of a similar oncological benefit in oesophageal cancer.MethodsA prospective non-randomised trial compared a structured prehabilitation exercise intervention during neoadjuvant chemotherapy and surgery versus conventional best-practice for oesophageal cancer patients. Biochemical and body composition analyses were performed at multiple time points. Outcome measures included radiological and pathological markers of disease regression. Logistic regression calculated ORs with 95% CI for the likelihood of pathological response adjusting for chemotherapy regimen and chemotherapy delivery.ResultsComparison of the Intervention (n=21) and Control (n=19) groups indicated the Intervention group had higher rates of tumour regression (Mandard TRG 1–3 Intervention n=15/20 (75%) vs Control n=7/19 (36.8%) p=0.025) including adjusted analyses (OR 6.57; 95% CI 1.52 to 28.30). Combined tumour and node downstaging (Intervention n=9 (42.9%) vs Control n=3 (15.8%) p=0.089) and Fat Free Mass index were also improved (Intervention 17.8 vs 18.7 kg/m2; Control 16.3 vs 14.7 kg/m2, p=0.026). Differences in markers of immunity (CD-3 and CD-8) and inflammation (IL-6, VEGF, INF-y, TNFa, MCP-1 and EGF) were observed.ConclusionThe results suggest improved tumour regression and downstaging in the exercise intervention group and should prompt larger studies on this topic.Trial registration numberNCT03626610.

Molecular switch proteins whose cycling between states is controlled by opposing regulators1,2are central to biological signal transduction. As switch proteins function within highly connected interaction networks3, the fundamental question arises of how functional specificity is achieved when different processes share common regulators. Here we show that functional specificity of the small GTPase switch protein Gsp1 in Saccharomyces cerevisiae(the homologue of the human protein RAN)4is linked to differential sensitivity of biological processes to different kinetics of the Gsp1 (RAN) switch cycle. We make 55 targeted point mutations to individual protein interaction interfaces of Gsp1 (RAN) and show through quantitative genetic5and physical interaction mapping that Gsp1 (RAN) interface perturbations have widespread cellular consequences. Contrary to expectation, the cellular effects of the interface mutations group by their biophysical effects on kinetic parameters of the GTPase switch cycle and not by the targeted interfaces. Instead, we show that interface mutations allosterically tune the GTPase cycle kinetics. These results suggest a model in which protein partner binding, or post-translational modifications at distal sites, could act as allosteric regulators of GTPase switching. Similar mechanisms may underlie regulation by other GTPases, and other biological switches. Furthermore, our integrative platform to determine the quantitative consequences of molecular perturbations may help to explain the effects of disease mutations that target central molecular switches.

The author reflects on the lessons he learned during his tenure with the U.S. Air Force (USAF) Air Combat Command (ACC). Topics discussed include the need to choose one's career path wisely, the way discipline and previous experience with temporary failure may serve as a guide in making hard decisions, and the selection of elite teams with the right skills and mindsets.

Impulse control behaviours (ICBs) are a range of behaviours linked by their reward-based, repetitive natures. They can be precipitated in Parkinson’s disease (PD) by dopamine replacement therapy, often with detrimental consequences for patients and caregivers. While now a well-recognised non-motor feature of treated PD, much remains unknown about the influence of risk factors, pathophysiological mechanisms, vulnerability factors for specific types of behaviour and the optimal management strategies. Imaging studies have identified structural and functional changes in striatal and prefrontal brain regions, among others. Gene association studies indicate a role for genetic predisposition to PD-ICB. Clinical observational studies have identified potential modifiable and non-modifiable risk factors. Psychological studies shed light on the neurocognitive domains implicated in PD-ICBs and identify psychosocial determinants that may perpetuate the cycle of impulsive and harm-avoidance behaviours. Based on these results, a range of pharmacological and non-pharmacological management strategies have been trialled in PD-ICBs with varying success. The purpose of this review is to update clinicians on the evidence around the pathophysiology of PD-ICB. We aim to translate our findings into an interpretable biopsychosocial model that can be applied to the clinical assessment and management of individual cases of PD-ICB.

Lignocellulosic biomass is an abundant renewable resource that can be upgraded to chemical and fuel products through a range of thermal conversion processes. Fast pyrolysis is a promising technology that uses high temperatures and fast heating rates to convert lignocellulose into bio-oils in high yields in the absence of oxygen. Hemicellulose is one of the three major components of lignocellulosic biomass and is a highly branched heteropolymer structure made of pentose, hexose sugars, and sugar acids. In this study, β-d-xylopyranose is proposed as a model structural motif for the essential chemical structure of hemicellulose. The gas-phase pyrolytic reactivity of β-d-xylopyranose is thoroughly investigated using computational strategies rooted in quantum chemistry. In particular, its thermal degradation potential energy surfaces are computed employing Minnesota global hybrid functional M06-2X in conjunction with the 6-311++G(d,p) Pople basis set. Electronic energies are further refined by performing DLPNO-CCSD(T)-F12 single-point calculations on top of M06-2X geometries using the cc-pVTZ-F12 basis set. Conformational analysis for minima and transition states is performed with state-of-the-art semiempirical quantum chemical methods coupled with metadynamics simulations. Key thermodynamic quantities (free energies, barrier heights, enthalpies of formation, and heat capacities) are computed. Rate coefficients for the initial steps of thermal decomposition are computed by means of reaction rate theory. For the first time, a detailed elementary reaction kinetic model for β-d-xylopyranose is developed by utilizing the thermodynamic and kinetic information acquired from the aforementioned calculations. This model specifically targets the initial stages of β-d-xylopyranose pyrolysis in the high-pressure limit, aiming to gain a deeper understanding of its reaction kinetics. This approach establishes a systematic strategy for exploring reactive pathways, evaluating competing parallel reactions, and selectively accepting or discarding pathways based on the analysis. The findings suggest that acyclic d-xylose plays a significant role as an intermediary in the production of key pyrolytic compounds during the pyrolysis of xylose. These compounds include furfural, anhydro-d-xylopyranose, glycolaldehyde, and dihydrofuran-3(2H)-one.

AbstractIn this response, while agreeing with Balibar’s substantive positive position, I take issue with the way he situates it. Specifically, he casts it as a via negativain relation to all previously existing thought. I suggest that it would be more accurate to say he is positioning the notion of the transindividual as a via mediabetween two alleged extremes, individualism and organicism. I argue that the idea that there is an opposite and equal error to individualism is mistaken, and that in actuality Balibar’s concept of the transindividual is not a radical departure from a long history of anti-individualism.

Interferon regulatory factor 3 (IRF3) and type I interferons (IFNs) protect against infections and cancer, but excessive IRF3 activation and type I IFN production cause autoinflammatory conditions such as Aicardi–Goutières syndrome and STING-associated vasculopathy of infancy (SAVI). Myocardial infarction (MI) elicits inflammation, but the dominant molecular drivers of MI-associated inflammation remain unclear. Here we show that ischemic cell death and uptake of cell debris by macrophages in the heart fuel a fatal response to MI by activating IRF3 and type I IFN production. In mice, single-cell RNA-seq analysis of 4,215 leukocytes isolated from infarcted and non-infarcted hearts showed that MI provokes activation of an IRF3–interferon axis in a distinct population of interferon-inducible cells (IFNICs) that were classified as cardiac macrophages. Mice genetically deficient in cyclic GMP-AMP synthase (cGAS), its adaptor STING, IRF3, or the type I IFN receptor IFNAR exhibited impaired interferon-stimulated gene (ISG) expression and, in the case of mice deficient in IRF3 or IFNAR, improved survival after MI as compared to controls. Interruption of IRF3-dependent signaling resulted in decreased cardiac expression of inflammatory cytokines and chemokines and decreased inflammatory cell infiltration of the heart, as well as in attenuated ventricular dilation and improved cardiac function. Similarly, treatment of mice with an IFNAR-neutralizing antibody after MI ablated the interferon response and improved left ventricular dysfunction and survival. These results identify IRF3 and the type I IFN response as a potential therapeutic target for post-MI cardioprotection.

Disruption of adipocyte de novolipogenesis (DNL) by deletion of fatty acid synthase (FASN) in mice induces browning in inguinal white adipose tissue (iWAT). However, adipocyte FASN knockout (KO) increases acetyl-coenzyme A (CoA) and malonyl-CoA in addition to depletion of palmitate. We explore which of these metabolite changes triggers adipose browning by generating eight adipose-selective KO mouse models with loss of ATP-citrate lyase (ACLY), acetyl-CoA carboxylase 1 (ACC1), ACC2, malonyl-CoA decarboxylase (MCD) or FASN, or dual KOs ACLY/FASN, ACC1/FASN, and ACC2/FASN. Preventing elevation of acetyl-CoA and malonyl-CoA by depletion of adipocyte ACLY or ACC1 in combination with FASN KO does not block the browning of iWAT. Conversely, elevating malonyl-CoA levels in MCD KO mice does not induce browning. Strikingly, adipose ACC1 KO induces a strong iWAT thermogenic response similar to FASN KO while also blocking malonyl-CoA and palmitate synthesis. Thus, ACC1 and FASN are strong suppressors of adipocyte thermogenesis through promoting lipid synthesis rather than modulating the DNL intermediates acetyl-CoA or malonyl-CoA.

The self-propagation of misfolded conformations of tau underlies neurodegenerative diseases, including Alzheimer's. There is considerable interest in discovering the minimal sequence and active conformational nucleus that defines this self-propagating event. The microtubule-binding region, spanning residues 244–372, reproduces much of the aggregation behaviour of tau in cells and animal models. Further dissection of the amyloid-forming region to a hexapeptide from the third microtubule-binding repeat resulted in a peptide that rapidly forms fibrils in vitro. We show that this peptide lacks the ability to seed aggregation of tau244–372in cells. However, as the hexapeptide is gradually extended to 31 residues, the peptides aggregate more slowly and gain potent activity to induce aggregation of tau244–372in cells. X-ray fibre diffraction, hydrogen–deuterium exchange and solid-state NMR studies map the beta-forming region to a 25-residue sequence. Thus, the nucleus for self-propagating aggregation of tau244–372in cells is packaged in a remarkably small peptide.

ABSTRACTThis article deals with the relationship between the thought of Michel Foucault and that of Axel Honneth, arguing in favour of the former against the latter. I begin by considering Honneth’s early engagement in The Critique of Powerwith Foucault’s thought. I rebut Honneth’s criticisms of Foucault here as a misreading, one which prevents Honneth from coming to grips with Foucault’s position and hence the challenge that it poses to Honneth’s project. I then move on to offer a Foucauldian critique of Honneth’s own position, arguing for a Foucauldian alternative to Critical Theory.

The article discusses the benefits of exercise for the prevention of cancer. Topics covered include the findings of a study that regular physical activity can help increase life expectancy after diagnosis of cancer, the role of epinephrine released during exercise in circulating natural killer cells, the association between epigenetics and exercise and the positive effects of exercise on colorectal, breast, lung and prostate cancer.

Building Information Modelling (BIM) refers to a new collaborative way of working, which places a digital model at the epicentre of the construction process to inform decisions during the entire lifecycle of a project. In the UK, BIM Level 2 is now a mandatory requirement for all centrally-procured government projects. This is not the case in Ireland but there is evidence that clients are driving this transition via the inclusion of Employer Information Requirements in design-phase tender documentation. This move towards BIM Level 2 poses a number of challenges as it marks a significant shift from the way a project has been traditionally procured, designed, constructed and operated. In this challenge lies an opportunity for the higher education sector to respond by developing appropriate learning opportunities, both for students and industry stakeholders. This paper will chart how a close collaboration between the Galway-Mayo Institute of Technology (GMIT) and the RPS Group facilitated the development of a flexible higher education programme in BIM.

Abstract:In this paper, I critically assess Gilles Deleuze’s ‘societies of control’ thesis in relation to the work of Michel Foucault that provides its ostensible inspiration. I argue, contra Deleuzian readings of Foucault that contemporary society continues to be a form of the disciplinary-biopolitical society identified by Foucault as having emerged in the late eighteenth century. My argument for this is dual. On the one hand, I point to claims of Deleuze’s that have not been borne out by subsequent developments, particularly the claim that disciplinary institutions are breaking down: while some institutions have declined, others (particularly the prison) have massively expanded. On the other hand, I argue that characteristics specifically assigned to societies of control by Deleuze were already part of disciplinary power as conceived by Foucault, noting that Foucault indeed uses the word ‘control’ as a synonym for discipline. I conclude that, due to his relative economism, Deleuze has misidentified real changes associated with the transition from Fordism to post-Fordism as comprising something much more dramatically new at a political level than they really are. That is, post-Fordism represents at most a modification of disciplinary power, rather than a new technology of power in a Foucauldian sense.

The article informs about 75 years of the Great Air Force consider the safety mindset will sustain with Airmen who maintain expensive aircraft, while requiring time-consuming and expensive training. Topics include three-fold vision for safety based on the premises of elite team researchers like Amy Edmondson; and Airmen are indispensable teammates in the Joint Force encounter on social media.