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Induction of cardiac contractility, although desirable for restoring heart function, often has long-term detrimental effects. From studies on RKIP, an upstream regulator of β-adrenergic receptor signaling, Schmid et al . show that cardiac contractility in mice can be increased in a well-tolerated manner through the balanced activation of the β1 and β2 subtypes of the adrenergic receptor. In heart failure therapy, it is generally assumed that attempts to produce a long-term increase in cardiac contractile force are almost always accompanied by structural and functional damage. Here we show that modest overexpression of the Raf kinase inhibitor protein (RKIP), encoded by Pebp1 in mice, produces a well-tolerated, persistent increase in cardiac contractility that is mediated by the β 1 -adrenoceptor (β 1 AR). This result is unexpected, as β 1 AR activation, a major driver of cardiac contractility, usually has long-term adverse effects. RKIP overexpression achieves this tolerance via simultaneous activation of the β 2 AR subtype. Analogously, RKIP deficiency exaggerates pressure overload–induced cardiac failure. We find that RKIP expression is upregulated in mouse and human heart failure, indicative of an adaptive role for RKIP. Pebp1 gene transfer in a mouse model of heart failure has beneficial effects, suggesting a new therapeutic strategy for heart failure therapy.

Nat. Med. 21, 1298–1306 (2015); published online 19 October 2015; corrected after print 29 October 2015 In the version of this article initially published, there are typographical errors in the labels to Fig. 3e–h: 'WT + AAV9-eGFP' and 'WT + AAV9-RKIPWT' are incorrect, and should be 'RKIP− + AAV9-eGFP' and 'RKIP− + AAV9-RKIPWT', respectively.

In heart failure therapy, it is generally assumed that attempts to produce a long-term increase in cardiac contractile force are almost always accompanied by structural and functional damage. Here we show that modest overexpression of the Raf kinase inhibitor protein (RKIP), encoded by Pebp1 in mice, produces a well-tolerated, persistent increase in cardiac contractility that is mediated by the [beta][sub.1]-adrenoceptor ([beta][sub.1]AR). This result is unexpected, as [beta][sub.1]AR activation, a major driver of cardiac contractility, usually has long-term adverse effects. RKIP overexpression achieves this tolerance via simultaneous activation of the [beta][sub.2]AR subtype. Analogously, RKIP deficiency exaggerates pressure overload-induced cardiac failure. We find that RKIP expression is upregulated in mouse and human heart failure, indicative of an adaptive role for RKIP. Pebp1 gene transfer in a mouse model of heart failure has beneficial effects, suggesting a new therapeutic strategy for heart failure therapy.

Background This study examines the longitudinal effects of COVID-19 pandemic regulations on health-related quality of life (HrQoL), glycaemic control and lifestyle characteristics and describes the epidemiology of COVID-19 in children with type 1 diabetes (T1D). Methods This monocentric, prospective study included, from May to November 2020, pediatric outpatients up to 18 years with T1D. During the first 16 weeks, COVID-19–associated symptoms were assessed weekly, while HrQoL, COVID-19 affectedness and appraisal, screen time, and physical activity were assessed monthly. Body-mass-index standard deviation scores (BMI-SDS), HbA1c, and glycaemic monitoring data were collected at clinical visits three monthly. All parameters were reassessed at final visit after 10 months and assigned to the pandemic restriction phases. Estimates of correlation (est) were tested by a linear mixed-effects model. Results 55 children with T1D were included, with a median age of 11 years and 56.4% male. HrQoL remained normal and stable throughout the pandemic, but showed significant associations with physical activity (est 3.63, p  < 0.01), screen time (est − 1.66, p  < 0.01) and financial situation (est − 9.15, p  < 0.05). During the pandemic, BMI-SDS increased ( p  < 0.01), but mean HbA1c remained at about 7.5% and glucose time in range improved ( p  < 0.01). During the lockdown phases, screen time tended to be highest ( p  < 0.1), while physical activity was lowest ( p  < 0.01). At baseline, one of 55 patients (1.8%) was COVID-19 seropositive from infection. At the study’s end 20.5% were positive from infection, and 4.9% from vaccination. Conclusions In children with T1D, HrQoL and metabolic control remained stable under pandemic regulations, but BMI-SDS and physical activity worsened. Continuation of outpatient care and opening of schools may have contributed to a healthy lifestyle and resilience. Trial registration Not applicable.

Colorectal cancer (CRC) represents the third leading cause of cancer‐related deaths. Integrating cellular and molecular data from individual patients has become valuable for diagnosis, prognosis, and treatment selection. Here, we present a comparative mRNA‐seq analysis of tissue samples from 32 CRC patients, pairing tumors with adjacent healthy tissues. Differential expression gene (DEG) analysis revealed dysregulated metabolic programs. We focused on the impact of overexpressed SLC7A11 (xCT) and SLC3A2, which compose the cystine/glutamate transporter (Xc‐) system. To assess the oncogenic potential of the Xc‐ system, we analyzed gene perturbations from CRISPR screens across various cell types and used functional assays in five primary patient‐derived organoid models. We identified a previously uncharacterized cell surface protein signature predicting chemotherapy resistance and highlighted the causality and potential of pharmacological blockage of ferroptosis as a promising avenue for cancer therapy. Redox homeostasis, ion/amino acid transporters, and regulators of neuronal survival and differentiation were pathways associated with these co‐dependent genes in patient specimens. This study highlights several potential clinical targets for CRC therapy and promotes the use of patient‐derived organoids oids to functionally validate in silico predictions.

Introduction The OCRA Tabletop MRI System is a compact, low-field (0.24T) magnetic resonance platform originally developed as an educational device to teach MR physics using chemical test tube–sized samples. Given its capabilities, we explored its diagnostic potential by performing relaxometric analysis on freshly resected human tissue specimens. Methods Matched pairs of histologically confirmed tumor and non-tumor samples were analyzed with the OCRA MRI system to determine T1 and T2 relaxation times via NMR spectroscopy. In parallel, mRNA expression levels of ZEB1, a key transcription factor involved in WNT signaling, stem cell maintenance and tumor–stroma interactions were quantified for each sample. Results The measured T1 and T2 relaxation times showed distinct profiles between tumor and non-tumor tissues. These biophysical properties were correlated with ZEB1 mRNA expression, revealing preliminary associations between tissue relaxation behavior and molecular signatures relevant to tumor microenvironment dynamics. Conclusion Although this pilot study does not yet confirm clinical diagnostic utility, it offers initial biophysical insights into tumor–associated tissue alterations and provides a foundation for future validation studies in larger patient cohorts.

The Random Positioning Machine (RPM) is used in the field of gravitational biology and space medicine. Rotational bioreactors such as the RPM create dynamic suspension cultures, providing shear stress, a crucial factor in circulatory homeostasis, but also in efficient mixing of nutrients and gases. This creates more physiologically relevant growth conditions than standard culture conditions translating the results to both microgravity and physiological systems on Earth. Immortalized monocyte-like THP-1 cells and primary blood-derived monocytes (PBMC) were cultured on the RPM for up to 7 days and evaluated for cell morphology, plasticity and functionality. For proliferating THP-1 cells, two different cell culture phases became obvious during random positioning: RPM early-phase (1–3 days) cells showed an increased responsiveness to lipopolysaccharide (LPS), plasticity for macrophage differentiation and phagocytic activity. RPM late-phase (4–7 days) cells demonstrated an impaired responsiveness to LPS, plasticity for macrophage differentiation and no phagocytic activity, emphasizing possible inhibitory effects of long-term random positioning on monocyte maturation and functionality. Interestingly, RPM cell culture had no significant effect on the phenotype of non-proliferating PBMCs, possibly related to their quiescence in G 0 phase. These insights provide valuable information about the behavior and susceptibility of human monocytic cells under changing mechanical influences, which is important not only for gravitational research, but also for a better understanding of disease mechanisms.

Pathological sections hold rich diagnostic information, yet their prognostic potential is underutilized. This study leverages deep learning to predict outcomes, advancing precision oncology of pathological sections with focus on pancreatic cancer. We analyzed H&E-stained whole section images of 125 cases from public databases as well as 28 real-world patients with pancreatic cancer and precancerous lesions. After image preprocessing, we identified and selected representative patches for subsequent analysis. We develop a modified visual transformer (ViT) model with spatial attention and fine-tuned on ImageNet2012, which was subsequently used to predict the survival times of the corresponding patients and to calculate risk scores. The modified ViT model demonstrated strong predictive accuracy for patient prognosis, with C-indices of 0.79 and 0.82 for Overall Survival (OS) and Disease Free Survival (DFS) in the test set and 0.62 in the validation set. Risk scores correlated well with patient survival, showing clustering between 0.17 and 0.95, aligning with a median survival of 24 months. Higher risk scores were associated with worse clinical prognosis, including shorter survival times and increased tumor recurrence risk, validated across all datasets. The model’s AUCs for OS and DFS prediction reached 0.847/0.849 in the training set and 0.813/0.834 in the test set, confirming its high accuracy and potential for clinical application in risk stratification and prognosis prediction. ViT network can discover the prognostic value of pancreatic cancer pathology sections via interpretable risk scores, providing a new insight for prognosis evaluation as well as opens new technology building on existing clinical diagnostics.

The sensitivity of pigs to deoxynivalenol (DON) might be increased by systemic inflammation (SI), which also has consequences for hepatic integrity. Liver lesions and a dys-regulated gene network might hamper hepatic handling and elimination of DON whereby the way of initiation of hepatic inflammation might play an additional role. First and second-pass exposure of the liver with LPS for triggering a SI was achieved by LPS infusion via pre- or post-hepatic venous route, respectively. Each infusion group was pre-conditioned either with a control diet (0.12 mg DON/kg diet) or with a DON-contaminated diet (4.59 mg DON/kg diet) for 4 wk. Liver transcriptome was evaluated at 195 min after starting infusions. DON exposure alone failed to modulate the mRNA expression significantly. However, pre- and post-hepatic LPS challenges prompted transcriptional responses in immune and metabolic levels. The mRNAs for B-cell lymphoma 2-like protein 11 as a key factor in apoptosis and IFN-γ released by T cells were clearly up-regulated in DON-fed group infused with LPS post-hepatically. On the other hand, mRNAs for nucleotide binding oligomerization domain containing 2, IFN-α and eukaryotic translation initiation factor 2α kinase 3 as ribosomal stress sensors were exclusively up-regulated in control pigs with pre-hepatic LPS infusion. These diverse effects were traced back to differences in TLR4 signalling.