julilili42/papers huggingface dataset:
Medical Clerkship in a State Registration and Reception Center for Forced Migrants in Germany: Students’ Experiences, Teachable Moments, and Psychological Burden
2019-05-15

Aspects of global health are becoming increasingly relevant for doctors of future generations. However, medical curricula rarely include courses which focus on global health or forced migration. Furthermore, it remains unclear whether students are at risk to develop psychological strain, after being confronted with highly burdened or even traumatized asylum seekers. This is a prospective study using a mixed-methods approach. We included n = 22 medical students performing a medical clerkship in a state registration and reception center for refugees. By applying (1) qualitative interviews, (2) reflective diaries, and (3) psychometric questionnaires, we examined the students’ experiences, teachable moments, and potential psychological burdens. In the interviews, the students emphasized the importance of cultural sensitivity during their clerkship. However, they also reported cognitive changes concerning their views of themselves and the world in general; this could indicate vicarious traumatization. The reflective diaries displayed high learning achievements. According to the psychometric questionnaires, the assignment in the reception center had not caused any significant psychological strain for the students. By completing their medical clerkship in a reception center, students were able to improve their medical, organizational, and interactional knowledge and skills. Furthermore, they reported that they had broadened their personal and cultural horizons.
Single-cell genomics identifies cell type–specific molecular changes in autism
2019-05-16

Brain cell transcriptomes in autism Autism manifests in many ways. Despite that diversity, the disorder seems to affect specific cellular pathways, including those observed in the neocortex of patients' brains. Velmeshev et al. analyzed the transcriptomes of single brain cells, including neurons and glia, from patients with autism. Single-nucleus RNA sequencing analysis suggested that affected pathways regulate synapse function as well as neural outgrowth and migration. Furthermore, in patient samples, specific sets of genes enriched in upper-layer projection neurons and microglia correlated with clinical severity. Science , this issue p. 685
MEK inhibitors activate Wnt signalling and induce stem cell plasticity in colorectal cancer
2019-05-16

Abstract In colorectal cancer (CRC), aberrant Wnt signalling is essential for tumorigenesis and maintenance of cancer stem cells. However, how other oncogenic pathways converge on Wnt signalling to modulate stem cell homeostasis in CRC currently remains poorly understood. Using large-scale compound screens in CRC, we identify MEK1/2 inhibitors as potent activators of Wnt/β-catenin signalling. Targeting MEK increases Wnt activity in different CRC cell lines and murine intestine in vivo. Truncating mutations of APC generated by CRISPR/Cas9 strongly synergize with MEK inhibitors in enhancing Wnt responses in isogenic CRC models. Mechanistically, we demonstrate that MEK inhibition induces a rapid downregulation of AXIN1. Using patient-derived CRC organoids, we show that MEK inhibition leads to increased Wnt activity, elevated LGR5 levels and enrichment of gene signatures associated with stemness and cancer relapse. Our study demonstrates that clinically used MEK inhibitors inadvertently induce stem cell plasticity, revealing an unknown side effect of RAS pathway inhibition.
Therapy-Induced MHC I Ligands Shape Neo-Antitumor CD8 T Cell Responses during Oncolytic Virus-Based Cancer Immunotherapy
2019-05-16

Oncolytic viruses (OVs), known for their cancer-killing characteristics, also overturn tumor-associated defects in antigen presentation through the MHC class I pathway and induce protective neo-antitumor CD8 T cell responses. Nonetheless, whether OVs shape the tumor MHC-I ligandome remains unknown. Here, we investigated if an OV induces the presentation of novel MHC I-bound tumor antigens (termed tumor MHC-I ligands). Using comparative mass spectrometry (MS)-based MHC-I ligandomics, we determined differential tumor MHC-I ligand expression following treatment with oncolytic reovirus in a murine ovarian cancer model. In vitro, we found that reovirus changes the tumor ligandome of cancer cells. Concurrent multiplexed quantitative proteomics revealed that the reovirus-induced changes in tumor MHC-I ligand presentation were mostly independent of their source proteins. In an in vivo model, tumor MHC-I ligands induced by reovirus were detectable not only in tumor tissues but also the spleens (a source of antigen-presenting cells) of tumor-bearing mice. Most importantly, therapy-induced MHC-I ligands stimulated antigen-specific IFNγ responses in antitumor CD8 T cells from mice treated with reovirus. These data show that therapy-induced MHC-I ligands may shape underlying neo-antitumor CD8 T cell responses. As such, they should be considered in strategies promoting the efficacy of OV-based cancer immunotherapies.
Metabolomic Characteristics of Fatty Pancreas
2019-05-16

Abstract Objective Pancreatic steatosis is associated with impaired beta cell function in patients with prediabetes. The pathomechanisms underlying this association still remain to be elucidated. Recent data show that adipocytes are situated within the pancreatic parenchyma and therefore give raise to hypothesize that pancreatic fat together with known and unknown metabolites such as hepatokines affect insulin secretion. Applying a targeted metabolomic approach we investigated possible circulating markers of pancreatic fat in order to better understand its role in the pathophysiology of impaired beta cell function. Methods We included 361 Caucasians, at increased risk of type 2 diabetes, from the Tübingen Family Study. All participants underwent a frequently sampled oral glucose tolerance test to assess insulin secretion and a magnetic resonance imaging to quantify pancreatic fat content, total body fat and visceral fat. Among the 152 subjects with prediabetes (IFG and/or IGT), two groups each with 20 individuals, having the lowest and highest pancreatic fat content were selected. The groups were matched for sex, age, BMI, total fat content, visceral fat content, liver fat content and insulin sensitivity. Metabolites were analyzed using the AbsoluteIDQ® p400 HR Kit by Biocrates. Results Pancreatic fat content of all 152 subjects with prediabetes was negatively associated with insulin secretion represented by AUCC-peptide 0–120/AUCGlucose 0–120 (p=0.04; β=− 3.24). Furthermore, pancreatic fat content was positively associated with BMI, total body and visceral fat (all p&lt;0.005). Levels of aminoacids, biogenic amines and monosaccharides were similar between the groups with high/low pancreatic fat content (p&gt;0.90). Also, levels of polar lipids such as lysophosphatidylcholines, phosphatidylcholines, sphingomyelins and ceramides did not differ significantly between the groups (p&gt;0.90). Investigating the levels of neutral lipids such as aclycarnitines, diglycerides, triglycerides and cholesteryl esters also revealed no differences between the groups (p&gt;0.90). Conclusion The amount of pancreatic fat is not associated with the metabolomic pattern in individuals with prediabetes. This might be due to the relatively low pancreatic fat content compared to the total amount of fat stored in other depots. The impact of pancreatic steatosis on insulin secretion might be mediated by paracrine effects which cannot be detected in the circulation.
Physical Activity and Exercise Outcomes in Huntington Disease (PACE-HD): Protocol for a 12-Month Trial Within Cohort Evaluation of a Physical Activity Intervention in People With Huntington Disease
2019-05-16

Abstract Background Exercise is emerging as an important aspect in the management of disease-related symptoms and functional decline in people with Huntington disease (HD). Long-term evaluation of physical activity and exercise participation in HD has yet to be undertaken. Objective The objective is to investigate the feasibility of a nested randomized controlled trial (RCT) alongside a longitudinal observational study of physical activity and exercise outcomes in people with HD. Design This will be a 12-month longitudinal observational study (n = 120) with a nested evaluation of a physical activity intervention (n = 30) compared with usual activity (n = 30) using a “trial within a cohort” design. Setting The study will take place in HD specialist clinics in Germany, Spain, and the United States, with intervention delivery in community settings. Participants The participants will have early-mid–stage HD and be participating in the Enroll-HD study. Intervention This will be a 12-month physical activity behavioral change intervention, delivered by physical therapists in 18 sessions, targeting uptake of aerobic exercise and increased physical activity. Measurements All participants (n = 120) will complete Enroll-HD assessments (motor, cognitive, behavioral, and quality of life) at baseline and at 12 months. Additional Physical ACtivity and Exercise Outcomes in Huntington Disease (PACE-HD) assessments include fitness (predicted maximal oxygen uptake [V o2max]), self-reported and quantitative measures of physical activity, disease-specific symptoms, and walking endurance. RCT participants (n = 60) will complete an additional battery of quantitative motor assessments and a 6-month interim assessment. Enroll-HD data will be linked to PACE-HD physical activity and fitness data. Limitations The limitations include that the embedded RCT is open, and assessors at RCT sites are not blinded to participant allocation. Conclusion PACE-HD will enable determination of the feasibility of long-term physical activity interventions in people with HD. The novel “trial within a cohort” design and incorporation of data linkage have potential to reduce participant burden. This design could be applied to other neurological diseases and movement disorders where recruitment and retention are challenging.
A gifted SNARC? Directional spatial-numerical associations in gifted children with high level math skills do not differ from controls
2019-05-16

The SNARC (Spatial-Numerical Association of Response Codes) effect (i.e., a tendency to associate small / large magnitude numbers with the left / right hand side), is prevalent across the whole lifespan. Because the ability to relate numbers to space has been viewed as a cornerstone in the development of mathematical skills, the relationship between the SNARC effect and math skill has been frequently examined. The results remain largely inconsistent. Studies testing groups of people with very low or very high skill levels in math sometimes found relationships between SNARC and math skill. So far, however, studies testing such extreme math skill level groups were mostly investigating the SNARC effect in individuals revealing math difficulties. Groups with above average math skills remain understudied, especially in regard to children. Here, we investigate the SNARC effect in gifted children, as compared to normally developing children (overall n = 165). Frequentist and Bayesian analysis suggested that the groups did not differ from each other in the SNARC effect. These results are the first to provide evidence for the SNARC effect in a relatively large sample of gifted (and mathematically highly skilled) children. In sum, our study provides another piece of evidence for no direct link between the SNARC effect and mathematical ability in childhood.
Imbalanced mitochondrial function provokes heterotaxy via aberrant ciliogenesis
2019-05-16

About 1% of all newborns are affected by congenital heart disease (CHD). Recent findings identify aberrantly functioning cilia as a possible source for CHD. Faulty cilia also prevent the development of proper left-right asymmetry and cause heterotaxy, the incorrect placement of visceral organs. Intriguingly, signaling cascades such as mTor that influence mitochondrial biogenesis also affect ciliogenesis, and can cause heterotaxy-like phenotypes in zebrafish. Here, we identify levels of mitochondrial function as a determinant for ciliogenesis and a cause for heterotaxy. We detected reduced mitochondrial DNA content in biopsies of heterotaxy patients. Manipulation of mitochondrial function revealed a reciprocal influence on ciliogenesis and affected cilia-dependent processes in zebrafish, human fibroblasts and Tetrahymena thermophila. Exome analysis of heterotaxy patients revealed an increased burden of rare damaging variants in mitochondria-associated genes as compared to 1000 Genome controls. Knockdown of such candidate genes caused cilia elongation and ciliopathy-like phenotypes in zebrafish, which could not be rescued by RNA encoding damaging rare variants identified in heterotaxy patients. Our findings suggest that ciliogenesis is coupled to the abundance and function of mitochondria. Our data further reveal disturbed mitochondrial function as an underlying cause for heterotaxy-linked CHD and provide a mechanism for unexplained phenotypes of mitochondrial disease.
Neutrophil-to-Lymphocyte Ratio in Rectal Cancer—Novel Biomarker of Tumor Immunogenicity During Radiotherapy or Confounding Variable?
2019-05-17

The aim of this study was to investigate the predictive value of blood-derived makers of local and systemic inflammatory responses on early and long-term oncological outcomes. A retrospective analysis of patients with locally advanced rectal cancer treated with preoperative long-course 5-fluorouracil-based radiochemotherapy was performed. Differential blood counts before neoadjuvant treatment were extracted from the patients’ electronic charts. Optimal cut-off values for neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and lymphocyte-to-monocyte ratio (LMR) were determined. Potential clinical and hematological prognostic factors for disease-free survival (DFS) were studied using uni- and multivariate analysis. A total of 220 patients were included in the analysis. Median follow-up was 67 months. Five-year DFS and overall survival (OS) were 70% and 85%, respectively. NLR with a cut-off value of 4.06 was identified as optimal to predict DFS events. In multivariate analysis, only tumor volume (HR 0.33, 95% CI (0.14–0.83), p = 0.017) and NLR (HR 0.3, 95% CI (0.11–0.81), p = 0.017) remained significant predictors of DFS. Patients with a good histological response (Dworak 3 and 4) to radiotherapy also had a lower NLR than patients with less pronounced tumor regression (3.0 vs. 4.2, p = 0.015). A strong correlation between primary tumor volume and NLR was seen (Pearson’s r = 0.64, p &lt; 0.001). Moreover, patients with T4 tumors had a significantly higher NLR than patients with T1–T3 tumors (6.6 vs. 3.3, p &lt; 0.001). An elevated pretherapeutic NLR was associated with higher T stage, inferior DFS, and poor pathological response to neoadjuvant radiochemotherapy. A strong correlation between NLR and primary tumor volume was seen. This association is important for the interpretation of study results and for the design of translational studies which are warranted.
The Multi-Purpose Airborne Sensor Carrier MASC-3 for Wind and Turbulence Measurements in the Atmospheric Boundary Layer
2019-05-17

For atmospheric boundary-layer (ABL) studies, unmanned aircraft systems (UAS) can provide new information in addition to traditional in-situ measurements, or by ground- or satellite-based remote sensing techniques. The ability of fixed-wing UAS to transect the ABL in short time supplement ground-based measurements and the ability to extent the data horizontally and vertically allows manifold investigations. Thus, the measurements can provide many new possibilities for investigating the ABL. This study presents the new mark of the Multi-Purpose Airborne Sensor Carrier (MASC-3) for wind and turbulence measurements and describes the subsystems designed to improve the wind measurement, to gain endurance and to allow operations under an enlarged range of environmental conditions. The airframe, the capabilities of the autopilot Pixhawk 2.1, the sensor system and the data acquisition software, as well as the post-processing software, provide the basis for flight experiments and are described in detail. Two flights in a stable boundary-layer and a close comparison to a measurement tower and a Sodar system depict the accuracy of the wind speed and direction measurements, as well as the turbulence measurements. Mean values, variances, covariance, turbulent kinetic energy and the integral length scale agree well with measurements from a meteorological measurement tower. MASC-3 performs valuable measurements of stable boundary layers with high temporal resolution and supplements the measurements of meteorological towers and sodar systems.
Impact of a Wastewater Treatment Plant Upgrade on Amphipods and Other Macroinvertebrates: Individual and Community Responses
2019-05-17

In the present study, we investigated the efficiency of additional wastewater treatment based on powdered activated carbon and its benefit for the ecosystem of a connected river system in the catchment area of Lake Constance, Southern Germany. We focused on the overall health status of gammarids and the integrity of the macrozoobenthic community. Samples were taken up- and down-stream of a wastewater treatment plant (WWTP), as well as before and after its upgrading. The investigations showed that both sex ratio and fecundity of gammarids, as well as the macrozoobenthic community were affected by the effluent prior to the WWTP upgrade. After the upgrade, gammarids from the downstream site did not differ any longer from those collected upstream of the WWTP with respect to the investigated health parameters. Furthermore, the overall number of taxa and, particularly, the number of sensitive taxa within the macrozoobenthic community downstream of the WWTP increased considerably. Therefore, we conclude that the additional treatment with powdered activated carbon was highly efficient to improve invertebrate health and community integrity.
Renal Fibrosis, Immune Cell Infiltration and Changes of TRPC Channel Expression after Unilateral Ureteral Obstruction in Trpc6-/- Mice
2019-05-17

BACKGROUND/AIMS: The transient receptor potential cation channel subfamily C member 6 (TRPC6) is a Ca2+-permeable nonselective cation channel and has received recent attention because of its capability to promote chronic kidney disease (CKD). The aims of this study were (i) to examine whether deletion of TRPC6 impacts on renal fibrosis and inflammatory cell infiltration in an early CKD model of unilateral ureter obstruction (UUO) in mice; and (ii) whether TRPC6-deficiency as well as UUO affect the regulation of TRPC expression in murine kidneys. METHODS: Wild-type (WT), Trpc6-knockout (Trpc6-/-) and New Zealand obese (NZO) mice underwent sham operation or unilateral ureteral obstruction (UUO). The kidneys were harvested 7 days after surgery. We examined renal fibrosis and inflammatory cell infiltration by histological and immunohistochemical staining. The mRNA expression of TRPC members and markers of fibrosis and inflammation in kidney were assessed by using real-time quantitative reverse transcription PCR. RESULTS: Histological and immunohistochemical analyses revealed less inflammatory cell infiltration (F4/80 and CD3) in UUO kidneys of Trpc6-/- mice compared to UUO kidneys of WT mice as well as less fibrosis. Genomic deletion of TRPC6 also affected the expression of pro-fibrotic genes in UUO Trpc6-/- kidneys compared to UUO WT kidneys while the expression of pro-inflammatory genes did not differ. UUO caused marked up-regulation of Trpc6 and down-regulation of Trpc1 mRNA in kidneys of WT and NZO mice. Trpc3 mRNA expression was significantly elevated in kidneys of Trpc6-/- mice underwent UUO while the levels did not change in kidneys of neither WT nor in NZO mice underwent UUO. CONCLUSION: TRPC6 contributes to renal fibrosis and immune cell infiltration in the UUO mouse model. Therefore, inhibition of TRPC6 emerges as a promising novel therapeutic strategy for treatment of chronic kidney failure in chronic obstructive nephropathy. However, confounding genomic and non-genomic effects of other TRPC channels should be taken into consideration to fully comprehend the renoprotective potential of targeting TRPC6 therapeutically under chronic kidney damaging conditions.
A critical comparison between the semisitting and the supine positioning in vestibular schwannoma surgery: subgroup analysis of a randomized, multicenter trial
2019-05-17

OBJECTIVE Patient positioning in vestibular schwannoma (VS) surgery is a matter of ongoing discussion. Factors to consider include preservation of cranial nerve functions, extent of tumor resection, and complications. The objective of this study was to determine the optimal patient positioning in VS surgery. METHODS A subgroup analysis of a randomized, multicenter trial that investigated the efficacy of prophylactic nimodipine in VS surgery was performed to investigate the impact of positioning (semisitting or supine) on extent of resection, functional outcomes, and complications. The data of 97 patients were collected prospectively. All procedures were performed via a retrosigmoid approach. The semisitting position was chosen in 56 patients, whereas 41 patients were treated while supine. RESULTS Complete resection was obtained at a higher percentage in the semisitting as compared to the supine position (93% vs 73%, p = 0.002). Logistic regression analysis revealed significantly better facial nerve function in the early postoperative course in the semisitting group (p = 0.004), particularly concerning severe facial nerve paresis (House-Brackmann grade IV or worse; p = 0.002). One year after surgery, facial nerve function recovered. However, there was still a tendency for better facial nerve function in the semisitting group (p = 0.091). There were no significant differences between groups regarding hearing preservation rates. Venous air embolism with the necessity to terminate surgery occurred in 2 patients in the semisitting position (3.6%). Supplementary analysis with a 2-tailed permutation randomization with 10,000 permutations of treatment choice and a propensity score matching showed either a tendency or significant results for better facial nerve outcomes in the early postoperative course and extent of resection in the semisitting group. CONCLUSIONS Although the results of the various statistical analyses are not uniform, the data indicate better results concerning both a higher rate of complete removal (according to the intraoperative impression of the surgeon) and facial nerve function after a semisitting as compared to the supine position. These advantages may justify the potential higher risk for severe complications of the semisitting position in VS surgery. The choice of positioning has to consider all individual patient parameters and risks carefully.