Miracle-dz/UniFAR-FTUs huggingface dataset:
3D bioprinting of E. coli MG1655 biofilms on human lung epithelial cells for building complex in vitro infection models

Biofilm-associated infections are causing over half a million deaths each year, raising the requirement for innovative therapeutic approaches. For developing novel therapeutics against bacterial biofilm infections, complex in vitro models that allow to study drug effects on both pathogens and host cells as well as their interaction under controlled, physiologically relevant conditions appear as highly desirable. Nonetheless, building such models is quite challenging because (1) rapid bacterial growth and release of virulence factors may lead to premature host cell death and (2) maintaining the biofilm status under suitable co-culture requires a highly controlled environment. To approach that problem, we chose 3D bioprinting. However, printing living bacterial biofilms in defined shapes on human cell models, requires bioinks with very specific properties. Hence, this work aims to develop a 3D bioprinting biofilm method to build robust in vitro infection models. Based on rheology, printability and bacterial growth, a bioink containing 3% gelatin and 1% alginate in Luria-Bertani-medium was found optimal for Escherichia coli MG1655 biofilms. Biofilm properties were maintained after printing, as shown visually via microscopy techniques as well as in antibiotic susceptibility assays. Metabolic profile analysis of bioprinted biofilms showed high similarity to native biofilms. After printing on human bronchial epithelial cells (Calu-3), the shape of printed biofilms was maintained even after dissolution of non-crosslinked bioink, while no cytotoxicity was observed over 24 h. Therefore, the approach presented here may provide a platform for building complex in vitro infection models comprising bacterial biofilms and human host cells.
Long‐term opioid treatment and endocrine measures in chronic non‐cancer pain patients

The prevalence of chronic non‐cancer pain (CNCP) has increased dramatically the past decades, which combined with indiscriminate use of prescribed opioids has become a public health problem. Endocrine dysfunction may be a complication of long‐term opioid treatment (L‐TOT), but the evidence is limited. This study aimed at investigating the associations between L‐TOT and endocrine measures in CNCP patients.
Bornes de risque pour les forêts purement uniformément aléatoires

Introduites par Leo Breiman en 2001, les forets aleatoires sont une methode statistique tres performante. D'un point de vue theorique, leur analyse est difficile, du fait de la complexite de l'algorithme. Pour expliquer ces performances, des versions de forets aleatoires simplifiees (et donc plus faciles a analyser) ont ete introduites : les forets purement aleatoires. Dans cet article, nous introduisons une autre version simplifiee, que nous appelons forets purement uniformement aleatoires. Dans un contexte de regression avec une seule variable explicative, nous montrons que les arbres aleatoires ainsi que les forets aleatoires atteignent la vitesse de convergence minimax. Et plus important, nous prouvons que les forets aleatoires ameliorent les performances des arbres aleatoires, en reduisant la variance des estimateurs associes d'un facteur trois quarts.
Biomarkers to predict disease progression and therapeutic response in isolated methylmalonic acidemia

Methylmalonic Acidemia (MMA) is a heterogenous group of inborn errors of metabolism caused by a defect in the methylmalonyl‐CoA mutase (MMUT) enzyme or the synthesis and transport of its cofactor, 5′‐deoxy‐adenosylcobalamin. It is characterized by life‐threatening episodes of ketoacidosis, chronic kidney disease, and other multiorgan complications. Liver transplantation can improve patient stability and survival and thus provides clinical and biochemical benchmarks for the development of hepatocyte‐targeted genomic therapies. Data are presented from a US natural history protocol that evaluated subjects with different types of MMA including mut‐type (N = 91), cblB‐type (15), and cblA‐type MMA (17), as well as from an Italian cohort of mut‐type (N = 19) and cblB‐type MMA (N = 2) subjects, including data before and after organ transplantation in both cohorts. Canonical metabolic markers, such as serum methylmalonic acid and propionylcarnitine, are variable and affected by dietary intake and renal function. We have therefore explored the use of the 1‐13C‐propionate oxidation breath test (POBT) to measure metabolic capacity and the changes in circulating proteins to assess mitochondrial dysfunction (fibroblast growth factor 21 [FGF21] and growth differentiation factor 15 [GDF15]) and kidney injury (lipocalin‐2 [LCN2]). Biomarker concentrations are higher in patients with the severe mut0‐type and cblB‐type MMA, correlate with a decreased POBT, and show a significant response postliver transplant. Additional circulating and imaging markers to assess disease burden are necessary to monitor disease progression. A combination of biomarkers reflecting disease severity and multisystem involvement will be needed to help stratify patients for clinical trials and assess the efficacy of new therapies for MMA.
Chronic 3,4-Methylenedioxymethamphetamine (MDMA) Use Is Related to Glutamate and GABA Concentrations in the Striatum But Not the Anterior Cingulate Cortex

Abstract Background 3,4-Methylenedioxymethamphetamine (MDMA) is a widely used recreational substance inducing acute release of serotonin. Previous studies in chronic MDMA users demonstrated selective adaptations in the serotonin system, which were assumed to be associated with cognitive deficits. However, serotonin functions are strongly entangled with glutamate as well as γ-aminobutyric acid (GABA) neurotransmission, and studies in MDMA-exposed rats show long-term adaptations in glutamatergic and GABAergic signaling. Methods We used proton magnetic resonance spectroscopy (MRS) to measure the glutamate-glutamine complex (GLX) and GABA concentrations in the left striatum and medial anterior cingulate cortex (ACC) of 44 chronic but recently abstinent MDMA users and 42 MDMA-naïve healthy controls. While the Mescher-Garwood point-resolved-spectroscopy sequence (MEGA-PRESS) is best suited to quantify GABA, recent studies reported poor agreement between conventional short–echo-time PRESS and MEGA-PRESS for GLX measures. Here, we applied both sequences to assess their agreement and potential confounders underlying the diverging results. Results Chronic MDMA users showed elevated GLX levels in the striatum but not the ACC. Regarding GABA, we found no group difference in either region, although a negative association with MDMA use frequency was observed in the striatum. Overall, GLX measures from MEGA-PRESS, with its longer echo time, appeared to be less confounded by macromolecule signal than the short–echo-time PRESS and thus provided more robust results. Conclusion Our findings suggest that MDMA use affects not only serotonin but also striatal GLX and GABA concentrations. These insights may offer new mechanistic explanations for cognitive deficits (e.g., impaired impulse control) observed in MDMA users.
Autoantigen‐selected B cells are bystanders in spontaneous T cell‐driven experimental autoimmune hepatitis

Autoreactive B cells are considered pathogenic drivers in many autoimmune diseases; however, it is not clear whether autoimmune B cells are invariably pathogenic or whether they can also arise as bystanders of T cell‐driven autoimmune pathology. Here, we studied the B cell response in an autoantigen‐ and CD4+ T cell‐driven model of autoimmune hepatitis (AIH), the Alb‐iGP_Smarta mouse in which expression of a viral model antigen (GP) in hepatocytes and its recognition by GP‐specific CD4+ T cells causes spontaneous AIH‐like disease. T cell‐driven AIH in Alb‐iGP_Smarta mice was marked by autoantibodies and hepatic infiltration of plasma cells and B cells, particularly of isotype‐switched memory B cells, indicating antigen‐driven selection and activation. Immunosequencing of B cell receptor repertoires confirmed B cell expansion selectively in the liver, which was most likely driven by the hepatic GP model antigen, as indicated by branched networks of connected sequences and elevated levels of IgG antibodies to GP. However, intrahepatic B cells did not produce increased levels of cytokines and their depletion with anti‐CD20 antibody did not alter the CD4+ T cell response in Alb‐iGP_Smarta mice. Moreover, B cell depletion did not prevent spontaneous liver inflammation and AIH‐like disease in Alb‐iGP_Smarta mice. In conclusion, selection and isotype‐switch of liver‐infiltrating B cells was dependent on the presence of CD4+ T cells recognizing liver antigen. However, recognition of hepatic antigen by CD4+ T cells and CD4+ T cell‐mediated hepatitis was not dependent on B cells. Thus, autoreactive B cells can be bystanders and need not be drivers of liver inflammation in AIH.
Investigating genotype‐to‐phenotype correlation in CHARGE syndrome by deep phenotyping and multiparametric clustering

CHARGE syndrome, due to CHD7 pathogenic variations, is an autosomal dominant disorder characterized by a large spectrum of severity. Despite the great number of variations reported, no clear genotype‐to‐phenotype correlation has been reported. Unsupervised machine learning and clustering was undertaken using a retrospective cohort of 42 patients, after deep radiologic and clinical phenotyping, to establish genotype–phenotype correlation for CHD7‐related CHARGE syndrome. It resulted in three clusters showing phenotypes of different severities. While no clear genotype–phenotype correlation appeared within the first two clusters, a single patient was outlying the cohort data (cluster 3) with the most atypical phenotype and the most distal frameshift variant in the gene. We added two other patients with similar distal pathogenic variants and observed a tendency toward mild and/or atypical phenotypes. We hypothesized that this finding could potentially be related to escaping nonsense mediated RNA decay, but found no evidence of such decay in vivo for any of the CHD7 pathogenic variation tested. This indicates that this milder phenotype may rather result from the production of a protein retaining all functional domains.
Airflow obstruction and chronic obstructive pulmonary disease are common in pulmonary tuberculosis even without sequelae findings on chest X-ray

Abstract Purpose Pulmonary tuberculosis (TB) is a well-known risk factor for airflow obstruction and chronic obstructive pulmonary disease (COPD). The prognosis of TB without sequelae on chest X-ray (CXR) remains uncertain. Methods We used the 2008–2009 Korea National Health and Nutrition Examination Survey (KNHANES) data and 2007–2012 KNHANES-matched Health Insurance Review and Assessment Service cohort data. Airflow obstruction was assessed using a pulmonary function test. COPD was defined using diagnostic codes and the use of COPD medication for 3-year. We classified subjects into three groups based on TB history and sequelae on CXR. Results In 4911 subjects, the CXR(–) (no TB sequelae on CXR) post-TB group (n = 134) showed similar characteristics and normal lung function compared to that of the control group (n = 4,405), while the CXR(+) (TB sequelae on CXR) post-TB group (n = 372) showed different characteristics and reduced lung function. The prevalence of airflow obstruction was 9.3%, 13.4%, and 26.6% in control, CXR(-) post-TB, and CXR(+) post-TB groups, respectively. COPD was more common in the post-TB with CXR(+) (6.5%) or without CXR (–) (4.5%) groups, than in the control group (1.8%). Compared to the CXR(–) post-TB group, the control group showed a lower risk for airflow obstruction (OR, 0.774; p = .008). The CXR(+) post-TB group showed a higher risk for airflow obstruction (OR, 1.456; p = .011). The Control group also showed a lower risk for the development of COPD than the CXR(-) post-TB group (OR, 0.496; p = .011). Conclusions We need to educate TB patients that airway obstruction and COPD can easily develop, even if TB sequelae are not observed on CXR.
Predicting second breast cancer among women with primary breast cancer using machine learning algorithms, a population‐based observational study

Breast cancer survivors often experience recurrence or a second primary cancer. We developed an automated approach to predict the occurrence of any second breast cancer (SBC) using patient‐level data and explored the generalizability of the models with an external validation data source. Breast cancer patients from the cancer registry of Zurich, Zug, Schaffhausen, Schwyz (N = 3213; training dataset) and the cancer registry of Ticino (N = 1073; external validation dataset), diagnosed between 2010 and 2018, were used for model training and validation, respectively. Machine learning (ML) methods, namely a feed‐forward neural network (ANN), logistic regression, and extreme gradient boosting (XGB) were employed for classification. The best‐performing model was selected based on the receiver operating characteristic (ROC) curve. Key characteristics contributing to a high SBC risk were identified. SBC was diagnosed in 6% of all cases. The most important features for SBC prediction were age at incidence, year of birth, stage, and extent of the pathological primary tumor. The ANN model had the highest area under the ROC curve with 0.78 (95% confidence interval [CI] 0.750.82) in the training data and 0.70 (95% CI 0.61‐0.79) in the external validation data. Investigating the generalizability of different ML algorithms, we found that the ANN generalized better than the other models on the external validation data. This research is a first step towards the development of an automated tool that could assist clinicians in the identification of women at high risk of developing an SBC and potentially preventing it.
Encouraging minority trust and compliance with police in a procedural justice experiment: How identity and situational context matter

Poor police–minority relations have spurred calls for police reform worldwide. In response, scholars have suggested procedural justice as a way police might improve this relationship. This study explores how situational and person-specific factors condition how minorities interpret procedural justice in vicarious police encounters. The study adopts a randomized experiment with 504 Muslims. In the experiment, an officer’s and Muslim suspect’s behavior were both varied between groups in a police encounter. Participants’ strength of identification with police was also measured. As expected, Muslim participants trusted the officer and complied more when the officer was depicted as procedurally just compared to procedurally unjust. However, this effect was moderated by the suspect’s behavior; the procedural justice effect on trust was weaker when the Muslim suspect was depicted as disrespectful toward police. Identification with police also moderated the procedural justice effect on trust and compliance; the procedural justice effect was stronger for Muslims who identified more strongly with police. Finally, identification further moderated the Officer x Suspect Behavior interaction effect; the interaction was accentuated for those who identified more strongly with police. These findings suggest that procedural justice does promote minorities’ trust in police and compliance, but situational and person-specific factors condition this.
THE PALISADE LAYER OF THE POXVIRUS CORE IS COMPOSED OF FLEXIBLE A10-TRIMERS

Although vaccinia virus (VACV) is the best studied poxvirus, the structure of the mature virus (MV) remains poorly understood. Its asymmetric shape, size and compactness poses a major challenge for electron microscopy (EM) analysis, including cryoEM. Sub-viral particles, in particular membrane-free viral cores, may overcome these limitations. We compare cores obtained by detergent-stripping MVs with cores in the cellular cytoplasm, early in infection. By combining cryo-electron tomography (cryoET), subtomogram averaging (STA) and AlphaFold2 (AF2), abundant core-structures are analyzed, focusing on the prominent palisade layer on the core surface. On detergent-stripped cores, the palisade is composed of densely packed trimers of the major core protein A10. On the core surface they display a random order and their classification indicate structural flexibility. On cytoplasmic cores A10 is organized in a similar manner, indicating that the structures obtained in vitro are physiologically relevant. CryoET and STA also uncover unexpected details of the layers beneath the palisade both on in vitro and in situ cores, that are compared to AF2 structure predictions of known VACV core-associated proteins. Altogether, our data identify for the first time the structure and molecular composition of the palisade units. The results are discussed in the context of the VACV replicative cycle, the assembly and disassembly of the infectious MV.
Holographic Correspondence and Exploring New Regimes of AdS/CFT Duality

We aim to have a comprehensive understanding of holographic correspondence and to demonstrate how the holographic correspondence (or renormalization) can be applied. Thus this thesis is divided into two parts. The first part is devoted to the former purpose (chapters 1 to 4 including appendix A,B, and C), and the second part is dedicated for the latter purpose (chapter 5 to 7). In Part I, the structure of the AdS/CFT correspondence is analyzed, and the properties of the AdS spacetime is studied in the context of the AdS/CFT correspondence; Here, we investigate the isometry group, the conformal structure, and generation of asymptotic solution near the conformal boundary. This solution yields significant convenience for the process of holographic renormalization. Moreover the properties of the Minkowski spacetime are compared to those of the AdS spacetime. To develop a greater understanding of the Lifshitz/quantum critical theory correspondence, the quantum phase transition is studied. Furthermore The holographic renormalization is briefly reviewed. In part II, the holographic renormalization associated with the Mann-Marolf (MM) counterterm is investigated for the asymptotically Minkowski spacetime in (n+3) dimensions. As a boundary condition, the cylindrical coordinate is considered. The solution of the MM-counterterm is obtained by solving the given algebraic equation, and from the counterterm solution, the boundary stress tensor is calculated. It is proven that the formula for conserved quantities via the boundary stress tensor holds. Next, we investigate deformations of Lifshitz holography with the Gauss-Bonnet term in (n+1) dimensional spacetime. To admit the non-trivial solution of the sub-leading orders, a value of the dynamical critical exponent, z, is restricted by z = n − 1 − 2(n − 2)α̃, where α̃ is the (redefined) Gauss-Bonnet coupling constant. Such solution of sub-leading orders correspond to the marginally relevant modes for the massive vector field and are generated by U+039B ∼ 0, at the asymptotic region. A generic black hole solution, which is characterized by the horizon flux of the vector field and α̃, is considered in the bulk. We explore its thermodynamic properties, which depend on temperature, by varying n and α̃. As a result, the contribution of the marginally relevant mode is found in a function of Λz T , and the relation between the free energy density and the energy density is numerically recovered when the marginally relevant mode is turned off ( Λ = 0), is obtained.
National Health Portal: What Wishes and Needs do Family Physicians have?

The Federal Ministry of Health (BMG) recently established a national health portal in Germany to provide evidence-based health information in an accessible manner. One of the aims of the portal is to provide support to doctors in patient education and consultation. Family physicians (FPs) deal with a wide range of symptoms, diseases, and patients, and could especially benefit from the new portal. A research project was initiated in collaboration with the health innovation hub (hih) of the German Federal Ministry of Health to determine FPs’ positions, needs and requirements with regard to a national health portal. A total of 3,585 FPs in the federal states of Hesse, Rhineland-Palatinate, Saarland, and Baden-Württemberg were surveyed by online questionnaire between March and July 2021; the study was based on two preliminary studies. Due to the exploratory approach, only a descriptive analysis was carried out. Over half at 55% saw the establishment of a national health portal as positive while 52% saw great potential for support in everyday practice. Respondents especially saw relief in giving medical advice (67%), optimization of doctor-patient communications (59%), stabilization of anxious patients (41%) and improved awareness in dealing with the health system (40%) as benefits. The system should also help towards longer-term stabilization in care settings (39%). The respondents especially found prevention focus (91%) and symptom-oriented presentation (63%) important. Some saw a possibility of gathering information for their patients (44%) and exchanging information with their specialist colleagues (45%) using the platform. FPs see clear opportunities in improved patient education and consultation using a national health portal. The portal should be designed to provide comprehensible information compliant with guidelines and conveyed in a symptom-oriented manner while also supporting the doctor-patient relationship and helping patients navigate through the healthcare system.
ECOLOGICAL INTENSIFICATION DECREASED YIELD-SCALED N 2 O EMISSIONS IN A SOYBEAN-BARLEY-MAIZE SEQUENCE

Agricultural challenge today is to maximize crop production reducing negative environmental impacts by efficiently use of resources and inputs. Objectives: i) to evaluate N 2 O emissions during a soybean-barley-maize rotation and their respective interperiods -chemical fallows (ChF) and cover crops (CC)-, and ii) to understand the relationships between N 2 O flow rates with soil mineral N content (Nmin), water-filled porous space (WFPS), and soil temperature (ST). N 2 O emissions were evaluated weekly under two management systems, ecological intensification (EI) and farmer current practices (FP). EI included higher N rates than FP, split N application, a cover crop (CC) after barley, among other management practices. Simultaneously to N 2 O emissions, Nmin, WFPS and ST were determined. The N 2 O fluxes were highest during crop periods (9-43, 6-61 and 4-104 μg N 2 O-N m -2 h -1 , for soybean, barley and maize, respectively), intermediate during barley-maize interperiod (2-47 and 3-35 μg N 2 O-N m -2 h -1 , for CC and ChF, respectively) and lowest during ChF of maize-soybean and soybean-barley interperiods (1-26 and 5-22 μg N 2 O-N m -2 h -1 , respectively). Regression tree provided threshold splits for the effect of soil variables on emission rates: 7.4 mg N kg -1 for Nmin; 10.35 or 8.7°C for ST, depending on Nmin and WPFS values; 39.6 and 55.4 % for WPFS, both with high N. There were no significant differences in accumulated N 2 O emissions between management systems for the complete sequence (3050 and 3380 g N 2 O-N ha -1 , for EI and FP, respectively). Yield-based N 2 O emissions for the complete sequence were lower for EI than for FP. EI decreased yield-scaled N 2 O emissions by 29% for soybean (p<0.05) and barley (ns) and by 30% for maize (p<0.05) compared with FP. In conclusion for the complete sequence, the EI system did not increase N 2 O emissions per unit area and reduced emissions per unit yield despite utilizing higher N rates and including a CC.