Perinatal Obesity Induces Hepatic Growth Restriction with Increased DNA Damage Response,Senescence, and Dysregulated Igf-1-Akt-Foxo1 Signaling in Male Offspring of Obese Mice

Maternal obesity predisposes for hepato-metabolic disorders early in life. However, the underlying mechanisms causing early onset dysfunction of the liver and metabolism remain elusive. Since obesity is associated with subacute chronic inflammation and accelerated aging, we test the hypothesis whether maternal obesity induces aging processes in the developing liver and determines thereby hepatic growth. To this end, maternal obesity was induced with high-fat diet (HFD) in C57BL/6N mice and male offspring were studied at the end of the lactation [postnatal day 21 (P21)]. Maternal obesity induced an obese body composition with metabolic inflammation and a marked hepatic growth restriction in the male offspring at P21. Proteomic and molecular analyses revealed three interrelated mechanisms that might account for the impaired hepatic growth pattern, indicating prematurely induced aging processes: (1) Increased DNA damage response (γH2AX), (2) significant upregulation of hepatocellular senescence markers (Cdnk1a, Cdkn2a); and (3) inhibition of hepatic insulin/insulin-like growth factor (IGF)-1-AKT-p38-FoxO1 signaling with an insufficient proliferative growth response. In conclusion, our murine data demonstrate that perinatal obesity induces an obese body composition in male offspring with hepatic growth restriction through a possible premature hepatic aging that is indicated by a pathologic sequence of inflammation, DNA damage, senescence, and signs of a possibly insufficient regenerative capacity.     

Long COVID: Association of Functional Autoantibodies against G-Protein-Coupled Receptors with an Impaired Retinal Microcirculation

Long COVID (LC) describes the clinical phenotype of symptoms after infection with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Diagnostic and therapeutic options are limited, as the pathomechanism of LC is elusive. As the number of acute SARS-CoV-2 infections was and is large, LC will be a challenge for the healthcare system. Previous studies revealed an impaired blood flow, the formation of microclots, and autoimmune mechanisms as potential factors in this complex interplay. Since functionally active autoantibodies against G-protein-coupled receptors (GPCR-AAbs) were observed in patients after SARS-CoV-2 infection, this study aimed to correlate the appearance of GPCR-AAbs with capillary microcirculation. The seropositivity of GPCR-AAbs was measured by an established cardiomyocyte bioassay in 42 patients with LC and 6 controls. Retinal microcirculation was measured by OCT–angiography and quantified as macula and peripapillary vessel density (VD) by the Erlangen-Angio Tool. A statistical analysis yielded impaired VD in patients with LC compared to the controls, which was accentuated in female persons. A significant decrease in macula and peripapillary VD for AAbs targeting adrenergic β2-receptor, MAS-receptor angiotensin-II-type-1 receptor, and adrenergic α1-receptor were observed. The present study might suggest that a seropositivity of GPCR-AAbs can be linked to an impaired retinal capillary microcirculation, potentially mirroring the systemic microcirculation with consecutive clinical symptoms.     

A Novel Neurofilament Light Chain ELISA Validated in Patients with Alzheimer’s Disease,Frontotemporal Dementia,and Subjective Cognitive Decline,and the Evaluation of Candidate Proteins for Immunoassay Calibration

Neurofilament light chain (Nf-L) is a well-known biomarker for axonal damage; however, the corresponding circulating Nf-L analyte in cerebrospinal fluid (CSF) is poorly characterized. We therefore isolated new monoclonal antibodies against synthetic peptides, and these monoclonals were characterized for their specificity on brain-specific intermediate filament proteins. Two highly specific antibodies, ADx206 and ADx209, were analytically validated for CSF applications according to well-established criteria. Interestingly, using three different sources of purified Nf-L proteins, a significant impact on interpolated concentrations was observed. With a lower limit of analytical sensitivity of 100 pg/mL using bovine Nf-L as the calibrator, we were able to quantify the Nf-L analyte in each sample, and these Nf-L concentrations were highly correlated to the Uman diagnostics assay (Spearman rho = 0.97, p < 0.001). In the clinical diagnostic groups, the new Nf-L ELISA could discriminate patients with Alzheimer’s disease (AD, n = 20) from those with frontotemporal lobe dementia (FTD, n = 20) and control samples with subjective cognitive decline (SCD, n = 20). Henceforth, this novel Nf-L ELISA with well-defined specificity and epitopes can be used to enhance our understanding of harmonizing the use of Nf-L as a clinically relevant marker for neurodegeneration in CSF.     

Low Doses of PFOA Promote Prostate and Breast Cancer Cells Growth through Different Pathways

Endocrine Disrupting Compounds (EDCs) are found in everyday products. Widely distributed throughout the environment, persistent organic pollutants (POPs) are a specific class of EDCs that can accumulate in adipose tissue. Many of them induce adverse effects on human health—such as obesity, fertility disorders and cancers—by perturbing hormone effects. We previously identified many compounds with EDC activity in the circulation of obese patients who underwent bariatric surgery. Herein, we analyzed the effects of four of them (aldrin, BDE28, PFOA and PCB153) on two cancer cell lines of hormone-sensitive organs (prostate and breast). Each cell line was exposed to serial dilutions of EDCs from 10⁻⁶ M to 10⁻¹² M; cytotoxicity and proliferation were monitored using the IncuCyte^® technology. We showed that none of these EDCs induce cytotoxicity and that PFOA and PCB153, only at very low doses (10⁻¹² M), increase the proliferation of DU145 (prostate cancer) and MCF7 (breast cancer) cells, while the same effects are observed with high concentrations (10⁻⁶ M) for aldrin or BDE28. Regarding the mechanistic aspects, PFOA uses two different signaling pathways between the two lines (the Akt/mTORC1 and PlexinD1 in MCF7 and DU145, respectively). Thus, our study demonstrates that even at picomolar (10⁻¹² M) concentrations PFOA and PCB153 increase the proliferation of prostate and breast cancer cell lines and can be considered possible carcinogens.     

Supporting Scientific Collaboration: Methods, Tools and Concepts

This paper discusses the interrelationship between e-Science and CSCW in terms of key substantive, methodological and conceptual innovations made in both fields. In so doing, we hope to draw out the existing relationship between CSCW and e-Science research, and to map out some key future challenges where the two areas of research may become more closely aligned. In considering what may be required to draw the two more closely together, the paper focuses primarily on investigations that have been undertaken in two dedicated initiatives into e-Science, along with the key issues emerging from these studies.     

Harmonizing agriculture and health sector actions to improve household nutrition: policy experiences from Afghanistan (2002–2007)

Coordination across sectors to address undernutrition with its varied underlying causes remains a challenge in developing countries. In Afghanistan, harmonization of health and agriculture policies and actions to reduce endemic undernutrition occurred during 2002-2007. This qualitative case study explores the forms of harmonization, enabling features and constraints in the policy process. We interviewed 57 stakeholders (39 central level, 18 provincial) involved in public nutrition or food security issues. Forms of harmonization included written policies, reseach, training and advocacy. Important features of the policy process included: policy entrepreneurs with operational and strategic capacity, consensus-building using a shared causal framework, working groups and strategic alliances. This case presents an interesting alternative to a national nutrition coordinating body, an approach that has met with mixed results, often due to the lack of authority, budget, and operational capacity of such a body to oversee ministries and enforce national nutrition objectives. Mid-level professionals mobilized into task forces achieved much with the support of national and international partners. This study highlights the importance of building capacity for sustaining change through local institutions.     

Complementary integrated circuits on plastic foil using inkjet printed n- and p-type organic semiconductors: Fabrication,characterization, and circuit analysis

Complementary thin-film transistor circuits composed of 6,13-bis(triisopropyl-silylethynyl) pentacene (TIPS–PEN) and a rylene carboxylic diimide derivative for p- and n-channel thin-film transistors (TFTs) were fabricated on flexible foils. The so-called staggered TFT configuration is used, meaning that the semiconductors layers are deposited last. The work-function of the injecting gold electrodes were modified using several self-assembled monolayers (SAMs). For optimized contacts the mobility of the n- and p-channel TFTs was 0.5 cm²/Vs and 0.2 cm²/Vs, respectively. Strongly degraded performance is obtained when the n-channel material was printed on contacts optimized for the p-channel TFT, and vice versa. This illustrates that for CMOS circuits we need careful work-function engineering to allow proper injection for both electrons and holes. We show for the first time that by using a bimolecular mixture for the SAM we can systematically vary the work function, and demonstrate how this affects the performance of discrete n-type and p-type transistors, as well as CMOS inverters and ring oscillators. Under optimal processing conditions we realized complementary 19-stage ring oscillators with 10 μs stage delay operating at 20 V.     

Flexible thin-film transistors using multistep UV nanoimprint lithography

A multistep imprinting process is presented for the fabrication of a bottom-contact, bottom-gate thin-film transistor (TFT) on poly(ethylene naphthalate) (PEN) foil by patterning all layers of the metal–insulator–metal stack by UV nanoimprint lithography (UV NIL). The flexible TFTs were fabricated on a planarization layer, patterned in a novel way by UV NIL, on a foil reversibly glued to a Si carrier. This planarization step enhances the dimensional stability and flatness of the foil and thus results in a thinner and more homogeneous residual layer. The fabricated TFTs have been electrically characterized as demonstrators of the here developed fully UV NIL-based patterning process on PEN foil, and compared to TFTs made on Si with the same process. TFTs with channel lengths from 5 μm down to 250 nm have been fabricated on Si and PEN foil, showing channel length-dependent charge carrier mobilities, μ, in the range of 0.06–0.92 cm² V⁻¹ s⁻¹ on Si and of 0.16–0.56 cm² V⁻¹ s⁻¹ on PEN foil.     

Horton and Wohl Revisited: Exploring Viewers' Experience of Parasocial Interaction

Linking back to D. Horton and R. Wohl (1956) , the present approach conceptualizes and empirically examines viewers' parasocial interaction experience with a TV performer. Causes and outcomes of parasocial interaction experience are examined. To this end, a new Experience of Parasocial Interaction (EPSI) scale is introduced. In a 2 (Bodily Addressing) × 2 (Verbal Addressing) between‐subjects experiment (N = 198) viewers reported a more intense parasocial experience if they were addressed by a TV performer on a bodily and verbal level. In addition, the more viewers perceived the performer to be attractive and the stronger their perspective‐taking ability, the more intense their parasocial experience. Stronger parasocial experience resulted in higher commitment to social norms and a greater enjoyment of the exposure situation.