The malate shuttle detoxifies ammonia in exhausted T cells by producing 2-ketoglutarate.

The malate shuttle is traditionally understood to maintain NAD+/NADH balance between the cytosol and mitochondria. Whether the malate shuttle has additional functions is unclear. Here we show that chronic viral infections induce CD8+ T cell expression of GOT1, a central enzyme in the malate shuttle. Got1 deficiency decreased the NAD+/NADH ratio and limited antiviral CD8+ T cell responses to chronic infection; however, increasing the NAD+/NADH ratio did not restore T cell responses. Got1 deficiency reduced the production of the ammonia scavenger 2-ketoglutarate (2-KG) from glutaminolysis and led to a toxic accumulation of ammonia in CD8+ T cells. Supplementation with 2-KG assimilated and detoxified ammonia in Got1-deficient T cells and restored antiviral responses. These data indicate that the major function of the malate shuttle in CD8+ T cells is not to maintain the NAD+/NADH balance but rather to detoxify ammonia and enable sustainable ammonia-neutral glutamine catabolism in CD8+ T cells during chronic infection.

MicroRNAs modulate SARS-CoV-2 infection of primary human hepatocytes by regulating the entry factors ACE2 and TMPRSS2.

BACKGROUND AND AIMS: Severe acute respiratory syndrome coronavirus (SARS-CoV-2) preferentially infects the respiratory tract; however, several studies have implicated a multi-organ involvement. Hepatic dysfunctions caused by SARS-CoV-2 infection have been increasingly recognized and described to correlate with disease severity. To elucidate molecular factors that could contribute towards hepatic infection, we concentrated on microRNAs (miRNAs), a class of small non-coding RNAs that modulate various cellular processes and which are reported to be differentially regulated during liver injury. We aimed to study the infection of primary human hepatocytes (PHH) with SARS-CoV-2 and to evaluate the potential of miRNAs for modulating viral infection. METHODS: We analysed liver autopsies from a coronavirus disease 19 (COVID-19)-positive cohort for the presence of viral RNA using Nanopore sequencing. PHH were used for the infection with SARS-CoV-2. The candidate miRNAs targeting angiotensin converting enzyme 2 (ACE2) and transmembrane serine protease 2 (TMPRSS2) were identified using in silico approaches. To discover the potential regulatory mechanism, transfection experiments, qRT-PCRs, western blots and luciferase reporter assays were performed. RESULTS: We could detect SARS-CoV-2 RNA in COVID-19-positive liver autopsies. We show that PHH express ACE2 and TMPRSS2 and can be readily infected with SARS-CoV-2, resulting in robust replication. Transfection of selected miRNA mimics reduced SARS-CoV-2 receptor expression and SARS-CoV-2 burden in PHH. In silico and biochemical analyses supported a potential direct binding of miR-141-3p to the SARS-CoV-2 genome. CONCLUSION: We confirm that PHH are susceptible to SARS-CoV-2 infection and demonstrate selected miRNAs targeting SARS-CoV-2 entry factors and/or the viral genome reduce viral loads. These data provide novel insights into hepatic susceptibility to SARS-CoV-2 and associated dysfunctions in COVID-19.

Ab Initio Prediction of Excited-State and Polaron Effects in Transient XUV Measurements of α-Fe2O3.

Transient X-ray and extreme ultraviolet (XUV) spectroscopies have become invaluable tools for studying photoexcited dynamics due to their sensitivity to carrier occupations and local chemical or structural changes. One of the most studied materials using transient XUV spectroscopy is α-Fe2O3 because of its rich photoexcited dynamics, including small polaron formation. The interpretation of carrier and polaron effects in α-Fe2O3 is currently carried out using a semi-empirical method that is not transferrable to most materials. Here, an ab initio, Bethe-Salpeter equation (BSE) approach is developed that can incorporate photoexcited-state effects into arbitrary material systems. The accuracy of this approach is proven by calculating the XUV absorption spectra for the ground, photoexcited, and polaron states of α-Fe2O3. Furthermore, the theoretical approach allows for the projection of the core-valence excitons and different components of the X-ray transition Hamiltonian onto the band structure, providing new insights into old measurements. From this information, a physical intuition about the origins and nature of the transient XUV spectra can be built. A route to extracting electron and hole energies is even shown possible for highly angular momentum split XUV peaks. This method is easily generalized to K, L, M, and N edges to provide a general approach for analyzing transient X-ray absorption or reflection data.

Validation of the CoGEF Method as a Predictive Tool for Polymer Mechanochemistry.

The development of force-responsive molecules called mechanophores is a central component of the field of polymer mechanochemistry. Mechanophores enable the design and fabrication of polymers for a variety of applications ranging from sensing to molecular release and self-healing materials. Nevertheless, an insufficient understanding of structure-activity relationships limits experimental development, and thus computation is necessary to guide the structural design of mechanophores. The constrained geometries simulate external force (CoGEF) method is a highly accessible and straightforward computational technique that simulates the effect of mechanical force on a molecule and enables the prediction of mechanochemical reactivity. Here, we use the CoGEF method to systematically evaluate every covalent mechanophore reported to date and compare the predicted mechanochemical reactivity to experimental results. Molecules that are mechanochemically inactive are also studied as negative controls. In general, mechanochemical reactions predicted with the CoGEF method at the common B3LYP/6-31G* level of density functional theory are in excellent agreement with reactivity determined experimentally. Moreover, bond rupture forces obtained from CoGEF calculations are compared to experimentally measured forces and demonstrated to be reliable indicators of mechanochemical activity. This investigation validates the CoGEF method as a powerful tool for predicting mechanochemical reactivity, enabling its widespread adoption to support the developing field of polymer mechanochemistry. Secondarily, this study provides a contemporary catalog of over 100 mechanophores developed to date.

Inflammatory bowel disease is associated with an increase in the incidence of multiple sclerosis: a retrospective cohort study of 24,934 patients.

BACKGROUND: Recent data suggest a potential pathophysiological link between inflammatory bowel disease (IBD) and multiple sclerosis (MS), two immune-mediated diseases both of which can have a significant impact on patients' quality of life. In the present manuscript, we investigate the association between IBD and MS in a German cohort of general practice patients. These results may have important implications for the screening and management of patients with IBD, as well as for further research into the pathophysiological mechanisms underlying both disorders. METHODS: 4,934 individuals with IBD (11,140 with Crohn's disease (CD) and 13,794 with ulcerative colitis (UC)) as well as 24,934 propensity score matched individuals without IBD were identified from the Disease Analyzer database (IQVIA). A subsequent diagnosis of MS was analyzed as a function of IBD using Cox regression models. RESULTS: After 10 years of follow-up, 0.9% and 0.7% of CD and UC patients but only 0.5% and 0.3% of matched non-IBD pairs were diagnosed with MS, respectively (pCD = 0.002 and pUC < 0.001). Both CD (HR: 2.09; 95% CI 1.28-3.39) and UC (HR: 2.35; 95% CI 1.47-3.78) were significantly associated with a subsequent MS diagnosis. Subgroup analysis revealed that the association between both CD and UC and MS was more pronounced among male patients. CONCLUSION: The results of our analysis suggest a notable association between IBD and a subsequent MS diagnosis. These findings warrant further pathophysiological investigation and may have clinical implications for the screening of IBD patients in the future.

Association between Helicobacter pylori and its eradication and the development of cancer.

BACKGROUND: Helicobacter pylori (H. pylori) is a gram-negative gastrointestinal pathogen that colonises the human stomach and is considered a major risk factor for gastric cancer and mucosa-associated lymphoid tissue lymphoma. Furthermore, H. pylori is a potential trigger of a wide spectrum of extragastric cancer entities, extraintestinal chronic inflammatory processes and autoimmune diseases. In the present study, we evaluated the association between H. pylori infection and its eradication with the development of subsequent gastrointestinal and non-gastrointestinal cancer. METHODS: We identified 25 317 individuals with and 25 317 matched individuals without a diagnosis of H. pylori from the Disease Analyzer database (IQVIA). A subsequent cancer diagnosis was analysed using Kaplan-Meier and conditional Cox-regression analysis as a function of H. pylori and its eradication. RESULTS: After 10 years of follow-up, 12.8% of the H. pylori cohort and 11.8% of the non-H. pylori cohort were diagnosed with cancer (p=0.002). Results were confirmed in regression analysis (HR: 1.11; 95% CI 1.04 to 1.18). Moreover, a non-eradicated H. pylori status (HR: 1.18; 95% CI 1.07 to 1.30) but not an eradicated H. pylori status (HR: 1.06; 95% CI 0.97 to 1.15) was associated with a subsequent diagnosis of cancer. In subgroup analyses, H. pylori eradication was negatively associated with bronchus and lung cancer (HR: 0.60; 95% CI 0.44 to 0.83). CONCLUSION: Our data from a large outpatient cohort in Germany reveal a distinct association between H. pylori infection and the subsequent development of cancer. These data might help to identify patients at risk and support eradication strategies in the future.

Prevalence of and factors associated with a treatment delay due to the COVID-19 pandemic in patients with gastrointestinal cancer in Europe.

BACKGROUND: Recent studies have raised the issue of delayed cancer care during the COVID-19 pandemic, but the extent of delays and cancellations in cancer treatment, screening and diagnosis varied widely by geographic region and study design, highlighting the need for further research. METHODS: We used the Oncology Dynamics (OD) database featuring data from a cross-sectional, partially retrospective survey to analyze treatment delays in 30,171 GI cancer patients from five European countries (Germany, France, UK, Spain, and Italy). Risk factors for treatment delays were identified using multivariable logistic regression models. RESULTS: Treatment delays were documented in 1342 (4.5%) of the study patients, with most patients having a delay of less than 3 months (3.2%). We observed decisive differences of treatment delay in relation to geographical, healthcare- and patient-related factors. Treatment delay was highest in France (6.7%) and Italy (6.5%) and lowest in Spain (1.9%, p < 0.001). 5.9% of patients treated at general hospitals but only 1.9% of those treated by office-based physicians experienced treatment delays (p < 0.001). Moreover, the difference between lines of therapy was highly significant and ranged from 7.2% for early-stage patients in primary therapy to 2.6% in advanced/metastatic cancer patients receiving 4th or later line therapy (p < 0.001). Finally, the proportion of cases with delayed treatments increased from 3.5% in asymptomatic patients (ECOG 0) to 9.9% in bedridden patients (ECOG IV, p < 0.001). Results were confirmed in multivariable logistic regression models. Our data highlight the problem of delayed treatment of tumor patients in the context of the COVID-19 pandemic. Identified risk factors for delayed treatment, such as poor general health or treatment in smaller hospitals, offer starting points for future concepts of "pandemic preparedness".

Measuring Photoexcited Electron and Hole Dynamics in ZnTe and Modeling Excited State Core-Valence Effects in Transient Extreme Ultraviolet Reflection Spectroscopy.

Transient extreme ultraviolet (XUV) spectroscopy is becoming a valuable tool for characterizing solar energy materials because it can separate photoexcited electron and hole dynamics with element specificity. Here, we use surface-sensitive femtosecond XUV reflection spectroscopy to separately measure photoexcited electron, hole, and band gap dynamics of ZnTe, a promising photocathode for CO2 reduction. We develop an ab initio theoretical framework based on density functional theory and the Bethe-Salpeter equation to robustly assign the complex transient XUV spectra to the material's electronic states. Applying this framework, we identify the relaxation pathways and quantify their time scales in photoexcited ZnTe, including subpicosecond hot electron and hole thermalization, surface carrier diffusion, ultrafast band gap renormalization, and evidence of acoustic phonon oscillations.

Biobanking in times of crisis - The COVID-19 Autopsy and Biosample Registry Baden-Wuerttemberg.

Biobanking plays a critical role in diagnostics, biomarker research and development of novel treatment approaches for various diseases. In urgent need of understanding, preventing and treating coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), the importance of biobanking including data sharing and management further increased. To provide high quality tissue biomaterials and data for research and public health, the COVID-19 Autopsy and Biosample Registry was established in the state of Baden-Wuerttemberg (BW) in Germany, combining expertise and technologies of the Institutes of Pathology of the five university hospitals in BW (Heidelberg, Tübingen, Ulm, Freiburg, Mannheim). The COVID-19 Autopsy and Biosample Registry BW comprises tissue samples from autopsies and associated data of deceased patients in the context of SARS-CoV-2 infection and/or vaccination against SARS-CoV-2. The aim is to collect autopsy biospecimens, associated clinical and diagnostic data in a timely manner, register them, make them accessible for research projects and thus to support especially tissue-related research addressing COVID-19. By now, the BW network holds multiple collaborations and supported numerous publications to increase the understanding of COVID-19 disease. The achievements of the BW network as a landmark biobanking model project represent a potential blueprint for future disease-related biobanking and registry effort.

[Wirksamkeit und Verträglichkeit eines homöopathischen Komplexmittels (Sinusitis Hevert SL) bei akuter, unkomplizierter Rhinosinusitis: Eine multizentrische, randomisierte, doppelblinde, placebokontrollierte Studie an erwachsenen Patienten].

Hintergrund: In der vorliegenden Studie wurden die Wirksamkeit und Verträglichkeit des homöopathischen Arzneimittels Sinusitis Hevert SL an Patienten mit akuter Rhinosinusitis untersucht. Methoden: In einer randomisierten, placebokontrollierten klinischen Studie wurden 314 Patienten mit bis zu 3 Tagen bestehenden Symptomen, leichtem bis moderatem Gesichtsschmerz und einem Major Rhinosinusitis Symptom Score (MRSS) ≥ 8 und ≤ 14 für 15 Tage (Tag 0 erster Arztbesuch plus 14 Tage Behandlung) eingeschlossen und mit Sinusitis Hevert SL oder Placebo behandelt. Den primären Endpunkt bildeten die Responderrate im MRSS (Reduktion ≥ 50%) bei der Abschlussvisite sowie die Rate der Remissionen (komplettes Abklingen aller 5 Hauptsymptome). Sekundäre Zielkriterien bildeten die Einschätzung der Wirksamkeit durch den Prüfer (auf einer 4-Punkte-Skala) und der Sino-Nasal Outcome Test 20 German Adapted Version (SNOT-20 GAV; Selbsterhebung durch die Patienten). Ergebnisse: 314 Patienten wurden in die Studie eingeschlossen. Davon wurden 308 mit der Studienmedikation behandelt: 153 mit Sinusitis Hevert SL und 155 mit Placebo. 265 Patienten schlossen die Studie vollständig und valide ab (Valid Completers). Die MRSSpat-Responderrate aller Patienten war für Sinusitis Hevert SL nicht signifikant besser (85,6% vs. 80,6%; p = 0,243), die Rate der Remissionen war mit 31,4% für Sinusitis Hevert SL und 37,4% für Placebo in beiden Gruppen nicht signifikant unterschiedlich (p = 0,2641). In der sekundären Completer-Analyse zeigte sich eine signifikante Differenz der Responderraten von 92,1% versus 83,5% zugunsten von Sinusitis Hevert SL (p = 0,032). Weiter war die Zeit bis zur Verbesserung der Rhinorrhoe signifikant kürzer (4,0 vs. 6,0 Tage; p = 0,040). Vor allem relevante nasale Symptome des SNOT-20 und die Lebensqualität verbesserten sich unter Behandlung mit Sinusitis Hevert SL signifikant deutlicher. Schlussfolgerungen: Es zeigte sich in dieser Studie bei akuter Rhinosinusitis und hoher Placebo-Ansprechrate keine Überlegenheit für Sinusitis Hevert SL in der Gesamtresponder- und Remissionsrate. Es fand sich ein Nutzen von Sinusitis Hevert SL in der Auswertung der Valid Completers für die Response sowie für spezifische Verbesserungen klinisch relevanter Symptome und die Abheilungsgeschwindigkeit der akuten Rhinosinusitis bei guter Verträglichkeit.