Heterologous Expression of Epoxomicin in Escherichia coli.

Epoxomicin is an epoxyketone proteasome inhibitor with synthetic derivatives approved or under investigation for treatment of multiple myeloma. To leverage the advantages of Escherichia coli as a rapidly growing and readily engineered host for the production of epoxomicin and analogues, we expressed codon-optimized versions of the epoxomicin biosynthetic genes, epxD, epxE, and epxF. Epoxomicin was detected, but the major product was a ketone resulting from α,ß-keto acid precursor decarboxylation. Epoxomicin yield was improved by altering the copy numbers of each gene and creating a fusion of epxE and epxF. Our optimized system offers promise for efficient engineering and biosynthesis of improved epoxomicin analogues.

Bird song comparison using deep learning trained from avian perceptual judgments.

Our understanding of bird song, a model system for animal communication and the neurobiology of learning, depends critically on making reliable, validated comparisons between the complex multidimensional syllables that are used in songs. However, most assessments of song similarity are based on human inspection of spectrograms, or computational methods developed from human intuitions. Using a novel automated operant conditioning system, we collected a large corpus of zebra finches' (Taeniopygia guttata) decisions about song syllable similarity. We use this dataset to compare and externally validate similarity algorithms in widely-used publicly available software (Raven, Sound Analysis Pro, Luscinia). Although these methods all perform better than chance, they do not closely emulate the avian assessments. We then introduce a novel deep learning method that can produce perceptual similarity judgements trained on such avian decisions. We find that this new method outperforms the established methods in accuracy and more closely approaches the avian assessments. Inconsistent (hence ambiguous) decisions are a common occurrence in animal behavioural data; we show that a modification of the deep learning training that accommodates these leads to the strongest performance. We argue this approach is the best way to validate methods to compare song similarity, that our dataset can be used to validate novel methods, and that the general approach can easily be extended to other species.

Acvr1b loss increases formation of pancreatic precancerous lesions from acinar and ductal cells of origin.

BACKGROUND & AIMS: Pancreatic ductal adenocarcinoma (PDAC) can develop from precursor lesions, including pancreatic intraepithelial neoplasia (PanIN) and intraductal papillary mucinous neoplasm (IPMN). Previous studies indicated that loss of Acvr1b accelerates the Kras-mediated development of papillary IPMN in the mouse pancreas, however, the cell type predominantly affected by these genetic changes remains unclear. METHODS: We investigated the contribution of cellular origin by inducing IPMN associated mutations- KRASG12D expression and Acvr1b loss - specifically in acinar (Ptf1aCreER;KrasLSL-G12D;Acvr1bfl/fl mice) or ductal (Sox9CreER;KrasLSL-G12D;Acvr1bfl/fl mice) cells in mice. We then performed MRI imaging and a thorough histopathological analysis of their pancreatic tissues. RESULTS: The loss of Acvr1b increased the development of PanIN and IPMN-like lesions when either acinar and ductal cells expressed a Kras mutation. MRI, immunohistochemistry and histology revealed large IPMN-like lesions in these mice that exhibited features of flat, gastric epithelium. In addition, cyst formation in both mouse models was accompanied by chronic pancreatitis. Experimental acute pancreatitis accelerated the development of large mucinous cysts and PanIN when acinar, but not ductal, cells expressed mutant Kras and lost Acvr1b. CONCLUSION: These findings indicate that loss of Acvr1b in the presence of the Kras oncogene promotes the development of large and small precancerous lesions from both ductal and acinar cells. However, the IPMN-like phenotype was not equivalent to that observed when these mutations were made in all pancreatic cells during development. Our study underscores the significance of the cellular context in the initiation and progression of precursor lesions from exocrine cells.

Age Differences in Prosociality Across the Adult Lifespan: A Meta-Analysis.

Lifespan developmental theories and research suggest a positive effect of adult age on prosociality. However, this effect lacks consistency, with many studies excluding the period of midlife. This study summarized cross-sectional studies on adult age and prosociality, combining 120 (independent) samples (n = 103,829) in a lifespan meta-analysis approach. Linear and quadratic age effects on prosociality were analyzed, as well as comparisons between younger, middle-aged, and older adults. Prosociality was assessed via behavioral measures and self-reports. In both these domains, results indicated small linear age effects and higher prosociality in older compared to younger adults, supporting the hypothesis of increased prosociality in older age. Additionally, leveraging open data sets (64/120 independent samples), predominantly unpublished, we found some evidence for potential quadratic age effects on behavioral prosociality: Middle-aged adults exhibited higher behavioral and self-reported prosociality than younger adults, but no differences between middle-aged and older adults were observed. This meta-analysis offers new perspectives on age trajectories of prosociality, suggesting midlife as a potentially important phase of pronounced prosociality.

An evaluation form to aid dairy producers to systematically assess cows prior to culling.

Objective: The objective of this prospective observational research project was to have dairy producers use and assess the utility of a cull cow evaluation form. Animals: Cull dairy cows. Procedure: Veterinarians were recruited to enrol a purposively selected group of dairy producers into a project to evaluate a cull cow evaluation form. Producers were provided with evaluation forms and asked to complete a form for every cow they culled from their herd from January to June 2017, inclusive. Results: A total of 44 producers used the form to record information on 323 cows prior to transport. Conclusion and clinical relevance: Despite the completion of 323 forms, only ~1/3 were completed fully, with compliance highest for body condition score, lameness, and temperature recordings (> 90% of forms). A cull cow evaluation form may improve the thoroughness and consistency of dairy producer assessment of cull dairy cows for fitness for transport.

Un formulaire d'évaluation pour aider les producteurs laitiers à évaluer systématiquement les vaches avant la réforme. Objectif: L'objectif de ce projet de recherche observationnelle prospective était d'amener les producteurs laitiers à utiliser et à évaluer l'utilité d'un formulaire d'évaluation des vaches de réforme. Animaux: Vaches laitières réformées. Procédure: Des vétérinaires ont été recrutés pour inscrire un groupe de producteurs laitiers sélectionnés à dessein dans un projet visant à évaluer un formulaire d'évaluation des vaches réformées. Les producteurs ont reçu des formulaires d'évaluation et ont été invités à remplir un formulaire pour chaque vache qu'ils ont éliminée de leur troupeau de janvier à juin 2017 inclusivement. Résultats: Au total, 44 producteurs ont utilisé le formulaire pour enregistrer des informations sur 323 vaches avant le transport. Conclusion et pertinence clinique: Malgré la complétion de 323 formulaires, seulement environ 1/3 ont été entièrement remplis, avec une conformité plus élevée pour le score d'état corporel, les boiteries et les enregistrements de température (> 90 % des formulaires). Un formulaire d'évaluation des vaches laitières réformées peut améliorer la rigueur et la cohérence de l'évaluation par le producteur laitier des vaches laitières réformées quant à leur aptitude au transport.(Traduit par Dr Serge Messier).

The Association Between the Development of Cam Morphology During Skeletal Growth in High-Impact Athletes and the Presence of Cartilage Loss and Labral Damage in Adulthood: A Prospective Cohort Study With a 12-Year Follow-up.

BACKGROUND: Cam morphology develops during skeletal growth, but its influence on cartilage and the labrum in high-impact athletes later in life is unknown. PURPOSE: To (1) explore the association between the presence and duration of cam morphology during adolescence and the cartilage and labral status 7 to 12 years later and (2) report the prevalence of cartilage loss and labral damage in a population of young male athletes (<32 years old) who played professional soccer during skeletal growth. STUDY DESIGN: Cohort study (Prognosis); Level of evidence, 2. METHODS: A total of 89 healthy male academy soccer players from the Dutch soccer club Feyenoord (aged 12-19 years) were included at baseline. At baseline and 2.5- and 5-year follow-ups, standardized supine anteroposterior pelvis and frog-leg lateral radiographs of each hip were obtained. At 12-year follow-up, magnetic resonance imaging of both hips was performed. Cam morphology was defined by a validated alpha angle ≥60° on radiographs at baseline or 2.5- or 5-year follow-up when the growth plates were closed. Hips with the presence of cam morphology at baseline or at 2.5-year follow-up were classified as having a "longer duration" of cam morphology. Hips with cam morphology only present since 5-year follow-up were classified as having a "shorter duration" of cam morphology. At 12-year follow-up, cartilage loss and labral abnormalities were assessed semiquantitatively. Associations were estimated using logistic regression, adjusted for age and body mass index. RESULTS: Overall, 35 patients (70 hips) with a mean age of 28.0 ± 2.0 years and mean body mass index of 24.1 ± 1.8 participated at 12-year follow-up. Cam morphology was present in 56 of 70 hips (80%). The prevalence of cartilage loss was 52% in hips with cam morphology and 21% in hips without cam morphology (adjusted odds ratio, 4.52 [95% CI, 1.16-17.61]; P = .03). A labral abnormality was present in 77% of hips with cam morphology and in 64% of hips without cam morphology (adjusted odds ratio, 1.99 [95% CI, 0.59-6.73]; P = .27). The duration of cam morphology did not influence these associations. CONCLUSION: The development of cam morphology during skeletal growth was associated with future magnetic resonance imaging findings consistent with cartilage loss in young adults but not with labral abnormalities.

The relationship between momentary experiential avoidance and anxiety symptoms.

BACKGROUND: Experiential avoidance (EA) may serve as a risk factor for a wide range of anxiety-related psychopathology. Anxiety is thought to trigger the use of EA, while also serving as a consequence of EA efforts. Previous ecological momentary assessment (EMA) studies found that EA was associated with greater anxiety in nonclinical undergraduates and patients with social anxiety disorder. METHODS: The present study examined the in-the-moment, bidirectional relationship between EA, perceived stress, and two facets of anxiety (autonomic arousal and worry/misery) in a sample of treatment-seeking patients broadly diagnosed with an anxiety-related disorder (N = 46). Participants completed a baseline assessment followed by an EMA assessment period (assessments three times daily for seven days). We hypothesized that there would be a bidirectional relationship between EA and anxiety/stress. RESULTS: Results largely supported a unidirectional relationship such that greater EA at one time point predicted higher stress at a later time point controlling for previous stress levels and linear time. Trend-level associations between EA and anxiety symptoms are discussed. CONCLUSIONS: The current study provides important insight into the relationship between EA and anxiety symptoms in a clinical sample of participants with anxiety-related disorders.

Rare Causes of Gastrointestinal Hemorrhage: A Case Series of Adult Duodenal and Jejunal Gastric Heterotopia.

Gastric heterotopia (GH) is a rare cause of gastrointestinal bleeding. GH of the small bowel is rare, and the duodenum is more commonly involved than the jejunum. Here, we present five cases of GH involving the duodenum and jejunum, with presentations including gastrointestinal bleeding, symptomatic anemia, and no symptoms. A 63-year-old man presented with melenic stools but could not identify an obvious bleeding source during endoscopy. He was ultimately diagnosed with jejunal GH. A 70-year-old woman with melena and severe anemia had a duodenal bulb mass detected during endoscopy, which was histopathologically diagnosed as GH. A 54-year-old woman experienced nausea, vomiting, and dysphagia. Endoscopy revealed esophagitis and a duodenal GH without malignancy. A 69-year-old woman incidentally had duodenal GH during evaluation for a lung mass, which was later diagnosed as an aggressive neuroendocrine tumor. The fifth patient was an 83-year-old woman who was admitted for profound significant anemia. Upper endoscopy showed a round, 0.3 cm ulcer in the duodenum and a duodenal polyp with a tiny ulcer, and her histopathology was consistent with GH. The exact mechanism of the action of GH remains unknown. Its clinical presentation is variable, gastrointestinal bleeding is rare, and diagnosis is based on histopathology only. Our case series emphasizes the need to include GH in the differential diagnosis of patients presenting with gastrointestinal bleeding, with or without other associated symptoms.

Characterization of the Antibody Response to SARS-CoV-2 Infection in COVID-19 Transplant versus Nontransplant Recipients by Ig-MS.

Solid organ transplant recipients with immunosuppressant regimens to prevent rejection are less able to mount effective immune responses to pathogenic infection. Here, we apply a recently reported mass spectrometry-based serological approach known as Ig-MS to characterize immune responses against infection with SARS-CoV-2 in cohorts of transplant recipients and immunocompetent controls, both at a single early time point following COVID-19 diagnosis as well as over the course of one-month postdiagnosis. We found that the antibody repertoires generated by transplant recipients against SARS-CoV-2 do not differ significantly compared to immunocompetent individuals with regard to repertoire titer, clonality, or glycan composition. Importantly, our study is the first to characterize the evolution of antibody glycan profiles in transplant recipients with COVID-19 disease, presenting evidence that the evolution of glycan composition in these immunocompromised individuals is similar to that in immunocompetent people.

From tree to plot: investigating stem CO2 efflux and its drivers along a logging gradient in Sabah, Malaysian Borneo.

Stem respiration constitutes a substantial proportion of autotrophic respiration in forested ecosystems, but its drivers across different spatial scales and land-use gradients remain poorly understood. This study quantifies and examines the impact of logging disturbance on stem CO2 efflux (EA) in Malaysian Borneo. EA was quantified at tree- and stand-level in nine 1-ha plots over a logging gradient from heavily logged to old-growth using the static chamber method. Tree-level results showed higher EA per unit stem area in logged vs old-growth plots (37.0 ± 1.1 vs 26.92 ± 1.14 g C m-2 month-1). However, at stand-level, there was no difference in EA between logged and old-growth plots (6.7 ± 1.1 vs 6.0 ± 0.7 Mg C ha-1 yr-1) due to greater stem surface area in old-growth plots. Allocation to growth respiration and carbon use efficiency was significantly higher in logged plots. Variation in EA at both tree- and stand-level was driven by tree size, growth and differences in investment strategies between the forest types. These results reflect different resource allocation strategies and priorities, with a priority for growth in response to increased light availability in logged plots, while old-growth plots prioritise maintenance and cell structure.

Opioid use disorder risk alleles in self-reported assigned African American/Afro-Caribbean and European biogeographical genetic ancestry groups and in males and females.

The influence of genetic variants related to opioid use disorder (OUD) was evaluated using multiple logistic regression analysis in self-reported assigned African American/Afro-Caribbean and European biogeographical ancestry groups (BGAGs) and by sex. From a sample size of 1301 adult patients (>18 years of age) seen in emergency departments of three medical centers in Ohio, six variants were found to be associated with OUD. Two of the variants, rs2740574 (CYP3A4) and rs324029 (DRD3), were included in the analysis having met criteria of at least five subjects for each BGAG, variant carrier status, and OUD status combinations. Variant carriers in the African/Afro-Caribbean BGAG had slightly lower predicted probabilities of OUD. Variant carriers in the European BGAG had slightly higher predicted probabilities of OUD. Relative to sex, all the six variants met evaluation criteria (five subjects for all sex, variant, and OUD status combinations). No statistically significant interactions were found between a given variant, BGAGs and sex. Findings suggest variant testing relative to OUD risk can be applied across BGAGs and sex, however, studies in larger populations are needed.

How Does Successful Aging Apply To Black Women?: A Latent Class Analysis.

BACKGROUND AND OBJECTIVES: Although prior research has identified racial/ethnic and gender differences in successful aging (SA), heterogeneity within groups has been little examined. We consequently explore the variety of aging experiences among older Black women. RESEARCH DESIGN AND METHODS: We used the 2010/2012 U.S. Health and Retirement Study, limiting analyses to Black women who completed the Psychosocial Leave-Behind Questionnaire (N = 1,186). We conducted latent class analysis (LCA) using indicators of physical health, psychological well-being, social support/strain, and social engagement. RESULTS: Six SA latent classes were identified and labeled according to their distinctive characteristics: infirm, isolated, taxed, independent, vivacious, and robust. The infirm class had uniformly poor health, while the isolated class was in poor physical health but also lacked social relations. Although both had average physical health and psychological well-being, the taxed class experienced high levels of social support and social strain compared to the high support (and unpartnered) independent class. The vivacious and robust classes exhibited high physical health and psychological well-being, high social support/low social strain, and high social engagement, but vivacious women (23% of respondents) were unpartnered and robust women (16% of respondents) were partnered. The robust class had the highest physical and psychological well-being, and best social relations across all classes. DISCUSSION AND IMPLICATIONS: Using nationally representative data, we reveal significant heterogeneity in Black women's aging experiences. Although many face difficult aging experiences, 39% of older Black women fit the SA framework well. Future work should recognize that Black women's aging experiences are not homogenous.

Treatment of ventral neurenteric cyst at the cervicothoracic junction with the anterior approach in a pediatric patient: illustrative case.

BACKGROUND: Neurenteric cysts are rare congenital lesions from heterotopic endodermal tissue, often presenting with radiculopathy or myelopathy in young adults. Gross-total resection is curative; however, the surgical approach remains widely debated for cervicothoracic cases. While the posterior approach is common, the anterior approach has had success in adults. The authors present the first pediatric case of anterior corpectomy with gross-total resection of a cervicothoracic neurenteric cyst alongside an extensive literature review. OBSERVATIONS: A 10-year-old male, who had undergone a previous cyst resection via a posterior approach at an outside institution, presented with back pain, paraplegia, and urinary incontinence. Magnetic resonance imaging of the spine revealed a ventral hyperintense cyst at C7-T1 consistent with a neurenteric cyst. An anterior approach involving C7 and T1 corpectomies was performed, including intradural exploration leading to complete cyst resection. This was followed by the placement of an expandable cage and anterior and posterior fixation with arthrodesis for stabilization. The patient's symptoms completely resolved after surgery, and there has been no recurrence. LESSONS: The anterior approach is a viable option for cervicothoracic neurenteric cyst resection in the pediatric population and can aid in gross-total resection by providing better lesion visualization. More studies are needed on long-term outcomes of the anterior approach in pediatric populations. https://thejns.org/doi/10.3171/CASE24120.

High expression of oleoyl-ACP hydrolase underpins life-threatening respiratory viral diseases.

Respiratory infections cause significant morbidity and mortality, yet it is unclear why some individuals succumb to severe disease. In patients hospitalized with avian A(H7N9) influenza, we investigated early drivers underpinning fatal disease. Transcriptomics strongly linked oleoyl-acyl-carrier-protein (ACP) hydrolase (OLAH), an enzyme mediating fatty acid production, with fatal A(H7N9) early after hospital admission, persisting until death. Recovered patients had low OLAH expression throughout hospitalization. High OLAH levels were also detected in patients hospitalized with life-threatening seasonal influenza, COVID-19, respiratory syncytial virus (RSV), and multisystem inflammatory syndrome in children (MIS-C) but not during mild disease. In olah-/- mice, lethal influenza infection led to survival and mild disease as well as reduced lung viral loads, tissue damage, infection-driven pulmonary cell infiltration, and inflammation. This was underpinned by differential lipid droplet dynamics as well as reduced viral replication and virus-induced inflammation in macrophages. Supplementation of oleic acid, the main product of OLAH, increased influenza replication in macrophages and their inflammatory potential. Our findings define how the expression of OLAH drives life-threatening viral disease.

Standing-up against moral violations: The predicting role of attribution, kinship, and severity.

Witnesses of moral violations stand up for their moral principles, despite facing substantial costs for intervening. Notwithstanding its importance, little is known whether responsibility attributions and the relation between the victim and a witness (i.e., kinship) have different effects on the intention to intervene in situations of different severity (e.g., moral courage situations). We predict an interaction between the situation's severity and the victims' responsibility for their plight. In less-severe situations, witnesses would be less willing to help when they perceive the victim to be responsible for their plight. However, those who are not seen as responsible would receive more help. For more-severe situations, responsibility is predicted to have no effect. Opposite effects are predicted for the relationship between the helper and the victim. We further predict that perceived costs for helping mediates witnesses' willingness to intervene. Two studies showed that people are more willing to help individuals who are perceived as being innocent, but only in less-severe situations. In more-severe situations, people's willingness to intervene increases, regardless of responsibility attributions. We did not observe effects for kinship. Moreover, we provide partial evidence that witnesses of more-severe situations indeed accept higher costs for intervention.

Neck apposition is a key factor for aneurysm occlusion after Woven EndoBridge device embolization.

BACKGROUND: Sealing of the aneurysm neck with a Woven EndoBridge (WEB) device is recommended for disrupting the blood flow inside the aneurysm. This study investigates the relationship between WEB neck apposition and aneurysm occlusion rates. METHODS: Aneurysms treated with a WEB from March 2017 to May 2022 at a single center were included. WEB neck apposition (poor/good) and WEB protrusion (yes/no) were evaluated on post-detachment high resolution cone beam CT images. Angiographic occlusion was assessed with the Bicêtre Occlusion Scale score (BOSS). Univariate and multivariable analysis tested the association between neck apposition and occlusion rates. RESULTS: The study included 159 aneurysms in 141 patients (mean age 55.8±11.2 years; 64.2% women). Good neck apposition and protrusion were noted in 123 (77.4%) and 30 (18.9%) cases, respectively. Inter-rater agreements were good for neck apposition (κ=0.75) and protrusion (κ=0.78). Complete and adequate occlusion was achieved in 104 (65%) and 130 (82%) cases, respectively (median follow-up 18 months). Good neck apposition was a strong independent predictor for both adequate (adjusted OR (aOR)=5.9, 95% CI 2.4 to 14.9; P<0.001) and complete occlusion (aOR=7.1, 95% CI 3.0 to 18.1; P<0.001). Protrusion was more frequent in the adequate occlusion group versus the aneurysm recurrence group without reaching statistical significance (P=0.06), but was associated with more thromboembolic complications (9/30 (30%) vs 12/129 (9%); P<0.01). WEB shape modification was significantly greater in poor apposition cases (P=0.03). CONCLUSIONS: Achieving good neck apposition of the WEB strongly predicts aneurysm occlusion during follow-up. WEB protrusion should be minimized due to the increase in thromboembolic risk with limited impact on aneurysm occlusion.

Functional plasticity of HCO3- uptake and CO2 fixation in Cupriavidus necator H16.

Despite its prominence, the ability to engineer Cupriavidus necator H16 for inorganic carbon uptake and fixation is underexplored. We tested the roles of endogenous and heterologous genes on C. necator inorganic carbon metabolism. Deletion of ß-carbonic anhydrase can had the most deleterious effect on C. necator autotrophic growth. Replacement of this native uptake system with several classes of dissolved inorganic carbon (DIC) transporters from Cyanobacteria and chemolithoautotrophic bacteria recovered autotrophic growth and supported higher cell densities compared to wild-type (WT) C. necator in batch culture. Strains expressing Halothiobacillus neopolitanus DAB2 (hnDAB2) and diverse rubisco homologs grew in CO2 similarly to the wild-type strain. Our experiments suggest that the primary role of carbonic anhydrase during autotrophic growth is to support anaplerotic metabolism, and an array of DIC transporters can complement this function. This work demonstrates flexibility in HCO3- uptake and CO2 fixation in C. necator, providing new pathways for CO2-based biomanufacturing.

Converging deep learning and human-observed tumor-adipocyte interaction as a biomarker in colorectal cancer.

BACKGROUND: Tumor-Adipose-Feature (TAF) as well as SARIFA (Stroma AReactive Invasion Front Areas) are two histologic features/biomarkers linking tumor-associated adipocytes to poor outcomes in colorectal cancer (CRC) patients. Whereas TAF was identified by deep learning (DL) algorithms, SARIFA was established as a human-observed histopathologic biomarker. METHODS: To study the overlap between TAF and SARIFA, we performed a systematic pathological review of TAF based on all published image tiles. Additionally, we analyzed the presence/absence of TAF in SARIFA-negative CRC cases to elucidate the biologic and prognostic role of a direct tumor-adipocyte contact. TCGA-CRC gene expression data is investigated to assess the association of FABP4 (fatty-acid binding protein 4) and CD36 (fatty-acid translocase) with both TAF and CRC prognosis. RESULTS: By investigating the TAF/SARIFA overlap, we show that many TAF patches correspond to the recently described SARIFA-phenomenon. Even though there is a pronounced morphological and biological overlap, there are differences in the concepts. The presence of TAF in SARIFA-negative CRCs is not associated with poor outcomes in this cohort, potentially highlighting the importance of a direct tumor-adipocyte interaction. Upregulation of FABP4 and CD36 gene expression seem both linked to a poor prognosis in CRC. CONCLUSIONS: By proving the substantial overlap between human-observed SARIFA and DL-based TAF as morphologic biomarkers, we demonstrate that linking DL-based image features to independently developed histopathologic biomarkers is a promising tool in the identification of clinically and biologically meaningful biomarkers. Adipocyte-tumor-cell interactions seem to be crucial in CRC, which should be considered as biomarkers for further investigations.

Different methods exist in assessing samples removed from cancer patients during surgery. We linked two independently established tissue-based methods for determining the outcome of colorectal cancer patients together: tumor adipose feature (TAF) and Stroma AReactive Invasion Front Areas (SARIFA). SARIFA as biological feature was observed solely by humans and TAF was identified by the help of a computer algorithm. We examined TAF in many cancer slides and looked at whether they showed similarities to SARIFA. TAF often matched SARIFA, but not always. Interestingly, these methods could be used to predict outcomes for patients and are associated with specific gene expression involved in tumor and fat cell interaction. Our study shows that combining computer algorithms with human expertize in evaluating tissue samples can identify meaningful features in patient samples, which may help to predict the best treatment options.

Association between Inhibitory-Excitatory Balance and Brain Activity Response during Cognitive Flexibility in Young and Older Individuals.

Cognitive flexibility represents the capacity to switch among different mental schemes, providing an adaptive advantage to a changing environment. The neural underpinnings of this executive function have been deeply studied in humans through fMRI, showing that the left inferior frontal cortex (IFC) and the left inferior parietal lobe (IPL) are crucial. Here, we investigated the inhibitory-excitatory balance in these regions by means of γ-aminobutyric acid (GABA+) and glutamate + glutamine (Glx), measured with magnetic resonance spectroscopy (MRS), during a cognitive flexibility task and its relationship with performance level and the local task-induced blood-oxygen level dependent (BOLD) response in 40 young (18-35 y.o.; 26 female) and 40 older (18-35 y.o.; 21 female) human adults. As the IFC and the IPL are richly connected regions, we also examined whole-brain effects associated with their local metabolic activity. Results did not show absolute metabolic modulations associated with flexibility performance, but performance level was related to the direction of metabolic modulation in the IPL with opposite patterns in young and older individuals. The individual inhibitory-excitatory balance modulation showed an inverse relationship with the local BOLD response in the IPL. Finally, the modulation of inhibitory-excitatory balance in IPL was related to whole-brain effects only in older individuals. These findings show disparities in the metabolic mechanisms underlying cognitive flexibility in young and older adults and their association with performance level and BOLD response. Such metabolic differences are likely to play a role in executive functioning during aging and specifically in cognitive flexibility.Significance Statement Cognitive flexibility provides an advantage in adapting to changing environments. We investigated the inhibitory-excitatory balance (GABA+/Glx) modulation in the frontal and parietal cortices during cognitive flexibility in young and older individuals through MRS. An increase in the excitatory tone during cognitive performance related to a better execution in younger adults. Interestingly, it was an increase in the inhibitory tone that was associated to a better performance in older adults. Furthermore, we revealed that an increased inhibitory tone in older adults related to a decreased oxygen consumption in remote brain areas (BOLD-fMRI). This may suggest that GABA modulation facilitates the segregation of neural networks, maximizing brain efficiency and cognitive performance. These findings underscore age-related disparities in the neurometabolic mechanisms underlying cognitive flexibility.