Measuring psychotherapeutic processes in the context of psychedelic experiences: Validation of the General Change Mechanisms Questionnaire (GCMQ).

BACKGROUND: Therapeutic and salutogenic effects of psychedelic drugs have been attributed to psychotherapeutic or psychotherapy-like processes that can unfold during the acute psychedelic experience and beyond. Currently, there are no psychometric instruments available to comprehensively assess psychotherapeutic processes (as conceptualized by empirical psychotherapy research) in the context of psychedelic experiences. AIMS: We report the initial validation of the General Change Mechanisms Questionnaire (GCMQ), a self-report instrument designed to measure five empirically established general change mechanisms (GCMs) of psychotherapy-(1) resource activation, (2) therapeutic relationship, (3) problem actuation, (4) clarification, and (5) mastery-in the context of psychedelic experiences. METHODS: An online survey in a sample of 1153 English-speaking and 714 German-speaking psychedelic users was conducted to evaluate simultaneously developed English- and German-language versions of the GCMQ. RESULTS: The theory-based factor structure was confirmed. The five GCMQ scales showed good internal consistency. Evidence for convergent validity with external measures was obtained. Significant associations with different settings and with therapeutic, hedonic, and escapist use motives confirmed the hypothesized context dependence of GCM-related psychedelic experiences. Indicating potential therapeutic effects, the association between cumulative stressful life events and well-being was significantly moderated by resource activation, clarification, and mastery. Factor mixture modeling revealed five distinct profiles of GCM-related psychedelic experiences. CONCLUSION: Initial testing indicates that the GCMQ is a valid and reliable instrument that can be used in future clinical and nonclinical psychedelic research. The five identified profiles of GCM-related experiences may be relevant to clinical uses of psychedelics and psychedelic harm reduction.

DépistaFest: The evaluation of an inclusive, positive, and playful STBBI screening campaign's effectiveness.

OBJECTIVES: Young adults are disproportionately affected by sexually transmitted and blood-borne infections (STBBIs), and rates of STBBI screening in this population are persistently low. The present study examined the effectiveness of Club Sexu's social marketing campaign, DépistaFest, in increasing STBBI screening, screening intentions, and general STBBI and STBBI screening knowledge among young adults in Quebec, Canada. Grounded in the health belief model, the campaign provided practical and scientifically accurate information on STBBIs and screening using an inclusive, positive, and playful approach. METHODS: A sample of 686 participants (M = 28.0 years old) was recruited through Club Sexu's social media to complete an online survey assessing campaign exposure, recent STBBI screening, screening intentions, and general STBBI and screening knowledge. Logistic regressions and ANCOVAs were performed to examine group differences on outcome variables. RESULTS: Compared to nonexposed participants, those who were exposed to the campaign were 2.11 times more likely to report having been tested in the past 6 months, and 2.07 times more likely to report planning to get tested in the next 6 months. Exposed participants were also more likely to correctly answer general STBBI knowledge questions and reported higher levels of self-perceived STBBI screening knowledge than nonexposed participants. CONCLUSION: The findings support the effectiveness of an STBBI prevention campaign grounded in the health belief model. Future STBBI prevention campaigns aimed at young adults would benefit from destigmatizing STBBIs and normalizing STBBI screening using an inclusive, positive, and playful approach.

RéSUMé: OBJECTIFS: Les jeunes adultes sont disproportionnellement affectés par les infections transmissibles sexuellement et par le sang (ITSS), et les taux de dépistage des ITSS au sein de cette population demeurent faibles. La présente étude a examiné l'efficacité de DépistaFest, une campagne de marketing social créée par Club Sexu, pour augmenter le dépistage des ITSS, les intentions de dépistage et les connaissances générales sur les ITSS et le dépistage chez les jeunes adultes québécois. Fondée sur le modèle des croyances relatives à la santé, cette campagne a fourni des informations pratiques et des informations sur les ITSS et le dépistage basées sur les données probantes en employant une approche inclusive, positive et ludique. MéTHODOLOGIE: Un échantillon de 686 participants (M = 28,0 ans) a été recruté à travers les réseaux sociaux de Club Sexu pour remplir un questionnaire en ligne évaluant l'exposition à la campagne, le dépistage récent des ITSS, les intentions de dépistage et les connaissances générales sur les ITSS et le dépistage. Des régressions logistiques et des ANCOVAs ont été effectués pour examiner les différences entre les groupes à l'égard des variables dépendantes. RéSULTATS: Comparativement aux participant·e·s non exposé·e·s, ceux et celles qui ont été exposé·e·s à la campagne étaient 2,11 fois plus susceptibles d'indiquer avoir eu recours au dépistage au cours des six derniers mois, et 2,07 fois plus susceptibles de déclarer qu'ils et elles prévoyaient de se faire dépister au cours des six prochains mois. Les participant·e·s exposé·e·s étaient également plus susceptibles que les participant·e·s non exposé·e·s de répondre correctement aux questions de connaissances générales sur ITSS et rapportaient des niveaux plus élevés de connaissances auto-perçues en matière de dépistage des ITSS. CONCLUSION: Les résultats soutiennent l'efficacité d'une campagne de prévention des ITSS fondée sur le modèle de croyances en santé. Les futures campagnes de prévention des ITSS ciblant les jeunes adultes gagneraient à déstigmatiser les ITSS et à normaliser le dépistage des ITSS en employant une approche inclusive, positive et ludique.

Deep learning to estimate impaired glucose metabolism from Magnetic Resonance Imaging of the liver: An opportunistic population screening approach.

AIM: Diabetes is a global health challenge, and many individuals are undiagnosed and not aware of their increased risk of morbidity/mortality although dedicated tests are available, which indicates the need for novel population-wide screening approaches. Here, we developed a deep learning pipeline for opportunistic screening of impaired glucose metabolism using routine magnetic resonance imaging (MRI) of the liver and tested its prognostic value in a general population setting. METHODS: In this retrospective study a fully automatic deep learning pipeline was developed to quantify liver shape features on routine MR imaging using data from a prospective population study. Subsequently, the association between liver shape features and impaired glucose metabolism was investigated in individuals with prediabetes, type 2 diabetes and healthy controls without prior cardiovascular diseases. K-medoids clustering (3 clusters) with a dissimilarity matrix based on Euclidean distance and ordinal regression was used to assess the association between liver shape features and glycaemic status. RESULTS: The deep learning pipeline showed a high performance for liver shape analysis with a mean Dice score of 97.0±0.01. Out of 339 included individuals (mean age 56.3±9.1 years; males 58.1%), 79 (23.3%) and 46 (13.6%) were classified as having prediabetes and type 2 diabetes, respectively. Individuals in the high risk cluster using all liver shape features (n = 14) had a 2.4 fold increased risk of impaired glucose metabolism after adjustment for cardiometabolic risk factors (age, sex, BMI, total cholesterol, alcohol consumption, hypertension, smoking and hepatic steatosis; OR 2.44 [95% CI 1.12-5.38]; p = 0.03). Based on individual shape features, the strongest association was found between liver volume and impaired glucose metabolism after adjustment for the same risk factors (OR 1.97 [1.38-2.85]; p<0.001). CONCLUSIONS: Deep learning can estimate impaired glucose metabolism on routine liver MRI independent of cardiometabolic risk factors and hepatic steatosis.

Pressure- and time-dependent alveolar recruitment/derecruitment in a spatially resolved patient-specific computational model for injured human lungs.

We present a novel computational model for the dynamics of alveolar recruitment/derecruitment (RD), which reproduces the underlying characteristics typically observed in injured lungs. The basic idea is a pressure- and time-dependent variation of the stress-free reference volume in reduced dimensional viscoelastic elements representing the acinar tissue. We choose a variable reference volume triggered by critical opening and closing pressures in a time-dependent manner from a straightforward mechanical point of view. In the case of (partially and progressively) collapsing alveolar structures, the volume available for expansion during breathing reduces and vice versa, eventually enabling consideration of alveolar collapse and reopening in our model. We further introduce a method for patient-specific determination of the underlying critical parameters of the new alveolar RD dynamics when integrated into the tissue elements, referred to as terminal units, of a spatially resolved physics-based lung model that simulates the human respiratory system in an anatomically correct manner. Relevant patient-specific parameters of the terminal units are herein determined based on medical image data and the macromechanical behavior of the lung during artificial ventilation. We test the whole modeling approach for a real-life scenario by applying it to the clinical data of a mechanically ventilated patient. The generated lung model is capable of reproducing clinical measurements such as tidal volume and pleural pressure during various ventilation maneuvers. We conclude that this new model is an important step toward personalized treatment of ARDS patients by considering potentially harmful mechanisms-such as cyclic RD and overdistension-and might help in the development of relevant protective ventilation strategies to reduce ventilator-induced lung injury (VILI).

Treatment with psychedelics is psychotherapy: beyond reductionism.

Treatment of psychiatric disorders with psychedelic substances represents one of the most promising current treatment approaches in psychiatry. Since its inception in the 1950s, therapy with psychedelics has been conceptualised as psychedelic-assisted psychotherapy-ie, a form of psychotherapy that uses the profound biological effects of this class of substances as a catalyst for changing thinking, emotions, and behaviour. In this view, the psychotherapy component of the treatment is considered as being of the utmost importance for both the safety and efficacy of the therapy. This conceptualisation has been challenged by the idea that the latest clinical studies suggest that the potential therapeutic effects of psychedelics must be attributed solely to the substance itself, with no role for psychotherapy. Here, accompaniment by therapists is understood as mere psychological support, to maintain the safety of the substance administration. In this Personal View, we contrast these two views and argue that the characterisation of treatment with psychedelics as a biological intervention (with psychological support as a purely safety-related component) represents an outdated and reductionistic dualism that has dominated psychiatric treatment and research for far too long. This discussion has important implications for the study and the regulation of these compounds.

Spared nerve injury decreases motivation in long-access homecage-based operant tasks in mice.

ABSTRACT: Neuropathic pain causes both sensory and emotional maladaptation. Preclinical animal studies of neuropathic pain-induced negative affect could result in novel insights into the mechanisms of chronic pain. Modeling pain-induced negative affect, however, is variable across research groups and conditions. The same injury may or may not produce robust negative affective behavioral responses across different species, strains, and laboratories. Here, we sought to identify negative affective consequences of the spared nerve injury model on C57BL/6J male and female mice. We found no significant effect of spared nerve injury across a variety of approach-avoidance conflict, hedonic choice, and coping strategy assays. We hypothesized these inconsistencies may stem in part from the short test duration of these assays. To test this hypothesis, we used the homecage-based Feeding Experimentation Device version 3 to conduct 12-hour, overnight progressive ratio testing to determine whether mice with chronic spared nerve injury had decreased motivation to earn palatable food rewards. Our data demonstrate that despite equivalent task learning, spared nerve injury mice are less motivated to work for a sugar pellet than sham controls. Furthermore, when we normalized behavioral responses across all the behavioral assays we tested, we found that a combined normalized behavioral score is predictive of injury state and significantly correlates with mechanical thresholds. Together, these results suggest that homecage-based operant behaviors provide a useful platform for modeling nerve injury-induced negative affect and that valuable pain-related information can arise from agglomerative data analyses across behavioral assays-even when individual inferential statistics do not demonstrate significant mean differences.

Smaller herring larval size-at-stage in response to environmental changes is associated with ontogenic processes and stress response.

Global change puts coastal systems under pressure, affecting the ecology and physiology of marine organisms. In particular, fish larvae are sensitive to environmental conditions, and their fitness is an important determinant of fish stock recruitment and fluctuations. To assess the combined effects of warming, acidification and change in food quality, herring larvae were reared in a control scenario (11°C*pH 8.0) and a scenario predicted for 2100 (14°C*pH 7.6) crossed with two feeding treatments (enriched in phosphorus and docosahexaenoic acid or not). The experiment lasted from hatching to the beginning of the post-flexion stage (i.e. all fins present) corresponding to 47 days post-hatch (dph) at 14°C and 60 dph at 11°C. Length and stage development were monitored throughout the experiment and the expression of genes involved in growth, metabolic pathways and stress responses were analysed for stage 3 larvae (flexion of the notochord). Although the growth rate was unaffected by acidification and temperature changes, the development was accelerated in the 2100 scenario, where larvae reached the last developmental stage at a smaller size (-8%). We observed no mortality related to treatments and no effect of food quality on the development of herring larvae. However, gene expression analyses revealed that heat shock transcripts expression was higher in the warmer and more acidic treatment. Our findings suggest that the predicted warming and acidification environment are stressful for herring larvae, inducing a decrease in size-at-stage at a precise period of ontogeny. This could either negatively affect survival and recruitment via the extension of the predation window or positively increase the survival by reducing the larval stage duration.

Interleukin 17 signaling supports clinical benefit of dual CTLA-4 and PD-1 checkpoint inhibition in melanoma.

Recent studies suggest that BRAFV600-mutated melanomas in particular respond to dual anti-programmed cell death protein 1 (PD-1) and anti-cytotoxic T lymphocyte-associated protein 4 (CTLA-4) immune checkpoint inhibition (ICI). Here we identified an over-representation of interleukin (IL)-17-type 17 helper T (TH17) gene expression signatures (GES) in BRAFV600-mutated tumors. Moreover, high baseline IL-17 GES consistently predicted clinical responses in dual-ICI-treated patient cohorts but not in mono anti-CTLA-4 or anti-PD-1 ICI cohorts. High IL-17 GES corresponded to tumor infiltration with T cells and neutrophils. Accordingly, high neutrophil infiltration correlated with clinical response specifically to dual ICI, and tumor-associated neutrophils also showed strong IL-17-TH17 pathway activity and T cell activation capacity. Both the blockade of IL-17A and the depletion of neutrophils impaired dual-ICI response and decreased T cell activation. Finally, high IL-17A levels in the blood of patients with melanoma indicated a higher global TH17 cytokine profile preceding clinical response to dual ICI but not to anti-PD-1 monotherapy, suggesting a future role as a biomarker for patient stratification.

Impact of the COVID-19 pandemic on working conditions and mental well-being of mental health professionals in the Netherlands: a cross-sectional study.

OBJECTIVES: To examine the extent of the impact of the COVID-19 pandemic on the mental health and well-being of mental health professionals (MHPs) in the Netherlands and understand their needs during the COVID-19 pandemic. DESIGN AND SETTING: A cross-sectional, mixed-methods study was conducted with MHPs from the Netherlands from June 2020 to October 2020, consisting of an online survey and three online focus group discussions. PARTICIPANTS: Participants were MHPs from various occupational groups (psychologists, social workers, mental health nurses, developmental education workers, etc). PRIMARY AND SECONDARY OUTCOME MEASURES: The online survey included questions about work-related changes due to COVID-19 perceived resilience to stress, changes in lifestyle behaviours and mental health symptoms. The focus group discussions focused mostly on work experiences during the first wave of the COVID-19 pandemic. RESULTS: MHP's reported an increase in experience workload during the pandemic (mean score 8.04 based on a scale of 1-10) compared to before the pandemic (mean score of 7). During the first wave of the pandemic, 50% of respondents reported increased stress, 32% increased sleeping problems and 24% increased mental health problems. Adverse occupational (eg, increased workload OR 1.72, 95% CI 1.28-2.32), psychological (eg, life satisfaction OR 0.63, 95% CI 0.52-0.75), lifestyle (eg, increased sleep problems OR 2.80, 95% CI 2.07-3.80) and physical factors (decline in physical health OR 3.56, 95% CI 2.61-4.85) were associated with a decline in mental health. Participants expressed significant concern in the focus group discussions about the duration of the pandemic, the high workload, less work-life balance and lack of contact with colleagues. Suggestions to improve working conditions included ensuring clear communication about guidelines and facilitating worker contact and support via peer-to-peer coaching where experiences can be shared. CONCLUSIONS: The current study indicates that MHP experienced a decline in mental health status during the first wave of the COVID-19 pandemic, which should be taken into consideration by employers, policymakers and researchers.

The basolateral amygdala-anterior cingulate pathway contributes to depression-like behaviors and comorbidity with chronic pain behaviors in male mice.

While depression and chronic pain are frequently comorbid, underlying neuronal circuits and their psychopathological relevance remain poorly defined. Here we show in mice that hyperactivity of the neuronal pathway linking the basolateral amygdala to the anterior cingulate cortex is essential for chronic pain-induced depression. Moreover, activation of this pathway in naive male mice, in the absence of on-going pain, is sufficient to trigger depressive-like behaviors, as well as transcriptomic alterations that recapitulate core molecular features of depression in the human brain. These alterations notably impact gene modules related to myelination and the oligodendrocyte lineage. Among these, we show that Sema4a, which was significantly upregulated in both male mice and humans in the context of altered mood, is necessary for the emergence of emotional dysfunction. Overall, these results place the amygdalo-cingulate pathway at the core of pain and depression comorbidity, and unravel the role of Sema4a and impaired myelination in mood control.

Stem cell programming - prospects for perinatal medicine.

Recreating human cell and organ systems in vitro has tremendous potential for disease modeling, drug discovery and regenerative medicine. The aim of this short overview is to recapitulate the impressive progress that has been made in the fast-developing field of cell programming during the past years, to illuminate the advantages and limitations of the various cell programming technologies for addressing nervous system disorders and to gauge their impact for perinatal medicine.

Lowering the Symmetry of Cofacial Porphyrin Prisms for Selective Oxygen Reduction Electrocatalysis.

Cofacial porphyrin catalysts for the Oxygen Reduction Reaction (ORR) formed via coordination-driven self-assembly have so far been limited to designs with fourfold symmetry, where four molecular clips bridge two porphyrin sites. We have synthesized six PynPhm (Py = pyridyl, Ph = phenyl) metalloporphyrin prisms (Co2+, Zn2+) bridged by molecular clips containing two Rh3+ centers. Four of these structures are lower symmetry, with the Py3Ph and Py2Ph2 prisms containing three and two molecular clips, respectively. The Co2+ species were evaluated for their ORR activity. Cyclic and hydrodynamic voltammetry studies of heterogeneous catalyst inks in aqueous media revealed marked differences in selectivity from ∼5% (Py3Ph) to ∼37% (Py2Ph2) for the formation of H2O2. The single-crystal X-ray structure of the Zn2 Py2Ph2 prism shows an offset between the porphyrin faces. This structural feature may be responsible for the change in selectivity, consistent with previous studies of covalently tethered cofacial porphyrins that have shown that geometry is a critical determinant of two-electron/two-proton versus four-electron/four-proton pathways. Extraction of standard rate constants ks for the ORR revealed a cofacial enhancement of ∼2 orders of magnitude over mononuclear Co2+ tetrapyridyl porphyrin. Even though all the prisms described here use the same molecular clip, the resultant structures, and thus the reactivity for the ORR, differ significantly based on the number and orientation of pyridyl donor groups on the porphyrins, highlighting how coordination-driven self-assembly can be used to rapidly tune dinuclear catalysts.

The rigidity of self-assembled cofacial porphyrins influences selectivity and kinetics of oxygen reduction electrocatalysis.

We report the electrocatalytic Oxygen Reduction Reaction on a rigid Co(II) porphyrin prism scaffold bridged by Ag(I) ions. The reactivity of this scaffold differs significantly from previous prism catalysts in that its selectivity is similar to that of monomer (∼35% H2O) yet it displays sluggish kinetics, with an order of magnitude lower ks of ∼0.5 M-1 s-1. The deleterious cofacial effect is not simply due to metal-metal separation, which is similar to our most selective prism catalysts. Instead we conclude the structural rigidity is responsible for these differences.

"I've Learned to Convert My Sensations into Sounds": Understanding During-Sex Sexual Communication.

Research generally supports the idea that sexual communication is beneficial to partners in committed relationships. However, much existing sexual communication research has a verbal communication bias and has examined sexual communication in non-sexual contexts, neglecting a wide variability of other forms of communication that occur during sex. Thus, from a sexual scripts theoretical framework, the purpose of the present study was to: (1) explore how individuals communicate needs, desires, pleasure, and displeasure to their partners during sex; (2) investigate perceptions of during-sex sexual communication's purposes; and (3) document individuals' perceived barriers and facilitators to during-sex sexual communication. Data from 27 interviews conducted among individuals in committed different-gender relationships (15 women, 11 men, 1 queer person; 21-68 years old), were analyzed using thematic analysis. Participants reported communicating using a combination of verbal, vocal, and bodily forms of communication. Most participants indicated that communicating during sex increased sexual pleasure and emotional intimacy and was useful for clarifying doubts and reducing insecurities. Many individuals nonetheless reported avoiding verbal communication during sex to preserve the mood, protect a partner's feelings, and avoid experiencing negative emotions and a partner's judgment. Sexual communication was also described as a skill that is developed over time and through the development of sexual subjectivity. Implications for sexual script theory and future sexual communication research are discussed.

Hepatic interleukin-1 receptor type 1 signalling regulates insulin sensitivity in the early phases of nonalcoholic fatty liver disease.

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) is associated with hepatic as well as systemic insulin resistance even in the absence of type 2 diabetes. The extent and pathways through which hepatic inflammation modulates insulin sensitivity in NAFLD are only partially understood. We explored the contribution of hepatic interleukin (IL)-1 signalling in a novel conditional knockout mouse model and expand the knowledge on this signalling pathway with regard to its liver-specific functions. METHODS: A high-fat, high-carbohydrate diet (HFD) over 12 weeks was used in male hepatocyte-specific IL-1 receptor type 1 (IL-1R1) knockout mice (Il1r1Hep-/- ) and wild-type (WT) littermates. RESULTS: Both genotypes developed an obese phenotype and accompanying macrovesicular hepatic steatosis. In contrast to WT mice, microvesicular steatosis and ballooning injury was less pronounced in HFD-fed Il1r1Hep-/- mice, and alanine aminotransferase remained in the normal range. This was paralleled by the suppression of injurious and proinflammatory hepatic c-Jun N-terminal kinases and extracellular signal-regulated kinases signalling, stable peroxisome proliferator activated receptor gamma coactivator-1alpha and farnesoid X receptor-alpha expression and preservation of mitochondrial function. Strikingly, despite HFD-feeding Il1r1Hep-/- mice remained highly insulin sensitive as indicated by lower insulin levels, homeostatic model assessment for insulin resistance, higher glucose tolerance, more stable hepatic insulin signalling cascade, and less adipose tissue inflammation compared to the WT. CONCLUSIONS: The current data highlights that hepatocyte IL-1R1 contributes to hepatic and extrahepatic insulin resistance. Future liver-directed therapies in NAFLD could have effects on insulin sensitivity when improving hepatic inflammation and IL-1R1 signalling.

An LKB1-mitochondria axis controls TH17 effector function.

CD4+ T cell differentiation requires metabolic reprogramming to fulfil the bioenergetic demands of proliferation and effector function, and enforce specific transcriptional programmes1-3. Mitochondrial membrane dynamics sustains mitochondrial processes4, including respiration and tricarboxylic acid (TCA) cycle metabolism5, but whether mitochondrial membrane remodelling orchestrates CD4+ T cell differentiation remains unclear. Here we show that unlike other CD4+ T cell subsets, T helper 17 (TH17) cells have fused mitochondria with tight cristae. T cell-specific deletion of optic atrophy 1 (OPA1), which regulates inner mitochondrial membrane fusion and cristae morphology6, revealed that TH17 cells require OPA1 for its control of the TCA cycle, rather than respiration. OPA1 deletion amplifies glutamine oxidation, leading to impaired NADH/NAD+ balance and accumulation of TCA cycle metabolites and 2-hydroxyglutarate-a metabolite that influences the epigenetic landscape5,7. Our multi-omics approach revealed that the serine/threonine kinase liver-associated kinase B1 (LKB1) couples mitochondrial function to cytokine expression in TH17 cells by regulating TCA cycle metabolism and transcriptional remodelling. Mitochondrial membrane disruption activates LKB1, which restrains IL-17 expression. LKB1 deletion restores IL-17 expression in TH17 cells with disrupted mitochondrial membranes, rectifying aberrant TCA cycle glutamine flux, balancing NADH/NAD+ and preventing 2-hydroxyglutarate production from the promiscuous activity of the serine biosynthesis enzyme phosphoglycerate dehydrogenase (PHGDH). These findings identify OPA1 as a major determinant of TH17 cell function, and uncover LKB1 as a sensor linking mitochondrial cues to effector programmes in TH17 cells.

Interaction of replacing corn silage with soyhulls as a roughage source with or without 3% added wheat straw in the diet: impacts on intake, digestibility, and ruminal fermentation in steers fed high-concentrate diets.

Six ruminally cannulated steers [475.0 ± 49.6 kg initial body weight (BW)] were used in a 6 × 3 incomplete Latin square design (six treatments and three periods), to evaluate the impacts replacing of corn silage with pelleted soyhulls as roughage in high-concentrate finishing diets containing 30% modified distillers grains with solubles. Treatments were based on increasing dietary inclusion of soyhulls and consisted of: (1) Control (0), roughage supplied by dietary inclusion of 20% corn silage [dry matter (DM) basis]; (2) 50% replacement of corn silage with soyhulls (50); (3) 100% replacement of corn silage with soyhulls (100), and the same three treatments repeated with 3% added wheat straw (DM basis) replacing corn in the diet (0S, 50S, and 100S, respectively). Absolute dry matter intake (DMI; kg/d basis) tended to decrease both linearly and quadratically (P ≤ 0.09) and proportional DMI (% of BW) decreased linearly (P = 0.04) with increasing soyhull inclusion but was not affected by the addition of straw in the diet (P = 0.68). Total tract digestibility of organic matter and crude protein were not affected by soyhull inclusion or added straw (P ≥ 0.32). Ruminal pH did not differ (P = 0.65) with increasing soyhull inclusion but increased with the addition of straw (P < 0.01; 5.9 vs. 6.1 for no straw and straw, respectively). Molar proportions of acetate and butyrate decreased while propionate increased with increased soyhull inclusion (P ≤ 0.03; linearly and quadratically, respectively). Ruminal fluid kinetics were unaffected by either rate of replacement of corn silage with soyhulls or wheat straw inclusion (P ≥ 0.13). Decreases in DMI observed in this study would likely decrease finishing cattle performance and underscores the need for additional research before recommending this practice to cattle feeders.

SARS-CoV-2 Causes Lung Inflammation through Metabolic Reprogramming and RAGE.

Clinical studies indicate that patients infected with SARS-CoV-2 develop hyperinflammation, which correlates with increased mortality. The SARS-CoV-2/COVID-19-dependent inflammation is thought to occur via increased cytokine production and hyperactivity of RAGE in several cell types, a phenomenon observed for other disorders and diseases. Metabolic reprogramming has been shown to contribute to inflammation and is considered a hallmark of cancer, neurodegenerative diseases, and viral infections. Malfunctioning glycolysis, which normally aims to convert glucose into pyruvate, leads to the accumulation of advanced glycation end products (AGEs). Being aberrantly generated, AGEs then bind to their receptor, RAGE, and activate several pro-inflammatory genes, such as IL-1b and IL-6, thus, increasing hypoxia and inducing senescence. Using the lung epithelial cell (BEAS-2B) line, we demonstrated that SARS-CoV-2 proteins reprogram the cellular metabolism and increase pyruvate kinase muscle isoform 2 (PKM2). This deregulation promotes the accumulation of AGEs and senescence induction. We showed the ability of the PKM2 stabilizer, Tepp-46, to reverse the observed glycolysis changes/alterations and restore this essential metabolic process.