julilili42/papers huggingface dataset:
Visualization of BOK pores independent of BAX and BAK reveals a similar mechanism with differing regulation
2022-10-26

Abstract BOK is a poorly understood member of the BCL-2 family of proteins that has been proposed to function as a pro-apoptotic, BAX-like effector. However, the molecular mechanism and structural properties of BOK pores remain enigmatic. Here, we show that the thermal stability and pore activity of BOK depends on the presence of its C-terminus as well as on the mitochondrial lipid cardiolipin. We directly visualized BOK pores in liposomes by electron microscopy, which appeared similar to those induced by BAX, in line with comparable oligomerization properties quantified by single molecule imaging. In addition, super-resolution STED imaging revealed that BOK organized into dots and ring-shaped assemblies in apoptotic mitochondria, also reminiscent of those found for BAX and BAK. Yet, unlike BAX and BAK, the apoptotic activity of BOK was limited by partial mitochondrial localization and was independent of and unaffected by other BCL-2 proteins. These results suggest that, while BOK activity is kept in check by subcellular localization instead of interaction with BCL-2 family members, the resulting pores are structurally similar to those of BAX and BAK.
Green Chemistry for Biomimetic Materials: Synthesis and Electrospinning of High-Molecular-Weight Polycarbonate-Based Nonisocyanate Polyurethanes
2022-10-26

Conventional synthesis routes for thermoplastic polyurethanes (TPUs) still require the use of isocyanates and tin-based catalysts, which pose considerable safety and environmental hazards. To reduce both the ecological footprint and human health dangers for nonwoven TPU scaffolds, it is key to establish a green synthesis route, which eliminates the use of these toxic compounds and results in biocompatible TPUs with facile processability. In this study, we developed high-molecular-weight nonisocyanate polyurethanes (NIPUs) through transurethanization of 1,6-hexanedicarbamate with polycarbonate diols (PCDLs). Various molecular weights of PCDL were employed to maximize the molecular weight of NIPUs and consequently facilitate their electrospinnability. The synthesized NIPUs were characterized by nuclear magnetic resonance, Fourier-transform infrared spectroscopy, gel permeation chromatography, and differential scanning calorimetry. The highest achieved molecular weight (<i>M</i> <sub>w</sub>) was 58,600 g/mol. The NIPUs were consecutively electrospun into fibrous scaffolds with fiber diameters in the submicron range, as shown by scanning electron microscopy (SEM). To assess the suitability of electrospun NIPU mats as a possible biomimetic load-bearing pericardial substitute in cardiac tissue engineering, their cytotoxicity was investigated in vitro using primary human fibroblasts and a human epithelial cell line. The bare NIPU mats did not need further biofunctionalization to enhance cell adhesion, as it was not outperformed by collagen-functionalized NIPU mats and hence showed that the NIPU mats possess a great potential for use in biomimetic scaffolds.
Screening of a Halogen-Enriched Fragment Library Leads to Unconventional Binding Modes
2022-10-26

We conceived the Halogen-Enriched Fragment Library (HEFLib) to investigate the potential of halogen bonds in the early stages of drug discovery. As the number of competitive interactions increases with ligand size, we reasoned that a binding mode relying on halogen bonding is more likely for fragments than highly decorated molecules. Thus, fragments could feature unexplored binding modes. We screened the HEFLib against the human kinase DYRK1a and verified micromolar binding fragments via isothermal titration calorimetry (ITC). The crystal structure of one fragment revealed a noncanonical binding mode, despite the fragment's classical hinge binding motif. In addition, the fragment occupies a secondary binding site. Both binding modes feature a halogen bond, which we evaluated by <i>ab initio</i> calculations. Structure-affinity relationship (SAR) from a set of analogues improves the affinity, provides a promising fragment-growth vector, and highlights the benefits and applicability of halogen bonds in early lead development.
The Effect of 3 Methods (Buzzy, ShotBlocker, and DistrACTION Cards) Used While Taking Blood Samples From Children with Pain and Anxiety
2022-10-26

Objectives The aim of this study was to compare the effectiveness of 3 methods (Buzzy, ShotBlocker, and DistrACTION Cards) in reducing pain and anxiety while taking venous blood samples in children. Methods The study population consisted of children aged 9 to 12 years admitted to the Child Health and Diseases Department in a Faculty of Medicine in Turkey. The sample of the study consisted of 242 children (Buzzy = 60, ShotBlocker = 61, DistrACTION Cards = 60, control = 61) who met the patient selection criteria and agreed to participate in the study. The data were obtained using an Information Form, the State-Trait Anxiety Inventory for Children, visual analog scale, and the Faces Pain Scale–Revised. Design This article is an experimental randomized controlled study. Results During venous blood collection, the scores of visual analog scale were significantly lower in ShotBlocker, Buzzy, and DistrACTION Cards groups than the control group. It was also observed that the control group experienced more anxiety than the other groups. Conclusions Methods such as Buzzy, ShotBlocker, and DistrACTION Cards can be used to reduce the anxiety and pain of children during painful procedures such as blood collection and vascular access. Among these methods, “Buzzy” and “DistrACTION Cards” can be preferred as it is equally effective, and then ShotBlocker can be preferred.
The Acute Cytokine Response to 30-Minute Exercise Bouts Before and After 8-Week Endurance Training in Individuals With Obesity
2022-10-26

Abstract Context One acute bout of exercise leads to a rapid increase in the systemic cytokine concentration. Regular exercise might alter the cytokine response, in particular in beforehand untrained and obese individuals. Objective Using a proximity extension assay, we studied the effects of acute exercise as well as endurance training on a panel of 92 cytokines related to inflammation. Methods A total of 22 individuals (30 ± 9 years; peak oxygen uptake [VO2peak] 25.2 ± 4.2 mL/[kg × min]; body mass index [BMI] 31.7 ± 4.4) participated in an 8-week endurance exercise intervention. Blood samples were collected before and immediately after 30 minutes’ ergometer exercise at 80% VO2peak. Results Before and after the training intervention, 40 and 37 cytokines, respectively, were acutely increased more than 1.2-fold (Benjamini-Hochberg [BH]-adjusted P &amp;lt; .05). The exercise intervention did not change the acute increase in cytokines nor the resting cytokine levels, whereas fitness was improved and adiposity reduced. The increase in fitness led to a slight increase in power output when exercising at the same heart rate, which might explain the comparable increase in cytokines before and after the intervention. The largest acute increase was found for OSM, TGFA, CXCL1 and 5, and TNFSF14 (≥ 1.9-fold, BH-adjusted P &amp;lt; .001). The transcript levels of these proteins in whole blood were also elevated, particularly in the trained state. Only the acute increase in IL6 (1.3-fold) was related to the increase in lactate, confirming the lactate-driven secretion of IL6. Conclusion Our comprehensive proteomics approach detected several underexplored serum exerkines with up to now less understood function in the adaptation to exercise.
Antibiotic Acyldepsipeptides Stimulate the Streptomyces Clp-ATPase/ClpP Complex for Accelerated Proteolysis
2022-10-26

Clp proteases are antibiotic and anticancer drug targets. Composed of the proteolytic core ClpP and a regulatory Clp-ATPase, the protease machinery is important for protein homeostasis and regulatory proteolysis.
The effects of diverse fidelity scenarios on stress in medical students when taking patients' medical histories: A longitudinal study
2022-10-26

Abstract Taking patients' medical history correctly is the basis of diagnosis and therapy. Medical students as a vulnerable group may perceive patient–physician interactions as stressful. This study examines stress among medical students in different degrees of fidelity when taking a patient's medical history. In this longitudinal study, students' stress levels were assessed during scenarios with different degrees of fidelity (role‐play, simulated patient encounters and real patient encounters) using standardised questionnaires (State‐Trait Anxiety Inventory and a distress scale) and the physiological measurement of heart rate variability. The stress level of participating medical students ( N = 128) was expected to significantly increase during scenarios of increasing fidelity ( M roleplay = 2.08 ± 0.92; SPEs: M simulatedpatient = 2.68 ± 1.08; RPEs: M realpatient = 3.35 ± 1.08; p &lt; 0.001). Whereas physiological stress was significantly higher with real patients ( N = 106), psychological stress was not affected by the fidelity of the scenarios ( N = 85). Medical students experienced stress when taking patients' medical history. Medical students might be unaware of their perceived stress based on the results. Thus, they should know how to cope with stress in such situations.
Neuromagnetic representation of melodic contour processing in human auditory cortex
2022-10-26

The pattern of ups and downs in a sequence with varying pitch can be heard as a melodic contour. Contrary to single pitch, the neural representation of melodic contour information in the auditory cortex is rarely investigated, and it is not clear whether the processing entails a hemispheric asymmetry. The present magnetoencephalography study assessed the neuromagnetic responses of N = 18 normal-hearing adults to four-note sequences with fixed vs. varying pitch that were presented either monaurally or diotically; data were analyzed using minimum-norm reconstructions. The first note of the sequences elicited prominent transient activity in posterior auditory regions (Planum temporale), especially contralateral to the ear of entry. In contrast, the response to the subsequent notes originated from more anterior areas (Planum polare) and was larger for melodic contours than for fixed pitch sequences, independent from the ear of entry and without hemispheric asymmetry. Together, the results point to a gradient in the early cortical processing of melodic contours, both in spatial and functional terms, where posterior auditory activity reflects the onset of a pitch sequence and anterior activity reflects its subsequent notes, including the difference between sequences with fixed pitch and melodic contours.
Post-LGM environments and foragers on the move: New data from the lower Altmühl Valley (Franconian Jura, SE Germany)
2022-10-26

After the Last Glacial Maximum, the Swabian and Franconian Jura (in SW and SE Germany, respectively) were repopulated by Magdalenian hunter-gatherers within the same communication network. However, while the Magdalenian settlement of the Swabian Jura dates to 17-14 ka cal BP, permanent Magdalenian occupations in the Franconian Jura date to 15-14 ka cal BP. In comparison with its western counterpart, the Franconian Jura was mostly excavated in the early days of archaeological research. Does this different chronology reflect the different history of research? Why did Magdalenian foragers establish permanent occupation in the Franconian Jura nearly 2 millennia after settling in Swabia, despite the fact these regions are only 150 km apart? To address these questions, we reinvestigated two sites in the Altmühl Valley with micromorphology and luminescence dating, namely Felsenhäusl-Kellerhöhle and Klausennische. Our data show that both sites have intact Pleistocene deposits. Among these, we identified sediments dating between 17 and 15 ka that show only rare lithic artifacts and microfeatures indicative of cold and arid conditions. Our work and published data suggest that the steady settlement of Magdalenian foragers in the Altmühl Valley starting 15 ka cal BP coincides with the end of this harsh period and the onset of cool and wetter environments. Data from the Swabian Jura demonstrated that in the Lone Valley, similar environments and Magdalenian occupations commenced earlier, starting 17 ka cal BP. Therefore, we propose that regional environments acted as a barrier against the dispersal of foragers in the Franconian Jura and determined its later Magdalenian occupation. Our research highlighted that different environments, taphonomic processes, and site uses probably coexisted across the German Jura. Therefore, it remains fundamental to expand the multisite data set proposed in this article to further test hypotheses about human/environment interaction in this region.
Technical report on best practices for hybrid and long readde novoassembly of bacterial genomes utilizing Illumina and Oxford Nanopore Technologies reads
2022-10-26

Abstract The emergence of commercial long read sequencing technologies in the 2010s and the concomitant development of new bioinformatics tools bears the potential of de novo genome assemblies of unprecedented contiguity and quality. However, until today these novel technologies suffer from high rates of sequencing errors. These may be overcome by using long and short reads in combination, in so called hybrid approaches, or by increasing the through-put and thereby the coverage of sequencing runs. In particular the latter will thereby increase the cost of the assembly inevitably. Herein, to-date long read and hybrid assemblers were tested on real whole genome sequencing Illumina and Oxford Nanopore Technologies read data sets and sub samples of these in order to elaborate a best practice for de novo assembly. The findings suggest that although long reads alone can be used to reconstruct complete and contiguous genomes, in particular the single-nucleotide and indel error rate remains high compared to hybrid approaches and that this can impact downstream applications such as variation discovery and gene prediction negatively.
On the binary codes of length 552 which admit the simple group Co3 as a transitive permutation group
2022-10-26

In this this paper all binary codes of length 552 which admit the sporadic simple group Co3 as an imprimitive transitive permutation group are determined. Our aim is to understand the results also by using theoretical arguments and to discuss the combinatorial properties of the codes as well as their relation to some special properties of the Leech lattice group Co3. For all codes (with two exceptions) we obtain the weight enumerators and in many interesting cases the classification of codewords under the action of the group of code automorphisms Co3. The exceptional codes are both self-dual and have minimum weight 12.
Pupillotonia after endolaser retinopexy during vitrectomy for retinal detachment: a prospective cohort study comparing circumferential and focal retinopexy
2022-10-26

Purpose To determine differences in postoperative pupil diameter in eyes that undergo pars plana vitrectomy (PPV) for rhegmatogenous retinal detachment (RRD) with endolaser retinopexy (ELR), comparing 360° vs focal ELR. Methods Patients with uncomplicated RRD who underwent PPV were prospectively analysed regarding the postoperative pupil diameter difference (PDD) between the affected eye and the partner eye. Group 1 underwent 360° ELR and group 2 received focal ELR. Postoperative vision and complications, including redetachment rate, macular oedema and epiretinal membrane formation, were also compared. Results A total of 72 patients, 42 in group 1 and 30 in group 2, were analysed. PDD, as observed at 6 weeks, was significantly greater than the preoperative values in both groups 1 and 2. It increased by a mean of 1±1.11 mm in group 1 and by 0.5±0.78 in group 2. This initial increase in PDD receded over time, but remained statistically significant in both groups, even at 6 months. The top 20% of patients with the largest PDD change comprised 13 out of 15 eyes from group 1, which was a statistically significant overrepresentation (p=0.0435). Conclusions Moderate pupillotonia was induced post-ELR in vitrectomy and correlated to the extent of ELR. The pupillotonia effect of ELR was significantly less marked in pseudophakic eyes.
Guidelines for mouse and human DC generation
2022-10-27

Abstract This article is part of the Dendritic Cell Guidelines article series, which provides a collection of state‐of‐the‐art protocols for the preparation, phenotype analysis by flow cytometry, generation, fluorescence microscopy, and functional characterization of mouse and human dendritic cells (DC) from lymphoid organs and various non‐lymphoid tissues. This article provides protocols with top ticks and pitfalls for preparation and successful generation of mouse and human DC from different cellular sources, such as murine BM and HoxB8 cells, as well as human CD34 + cells from cord blood, BM, and peripheral blood or peripheral blood monocytes. We describe murine cDC1, cDC2, and pDC generation with Flt3L and the generation of BM‐derived DC with GM‐CSF. Protocols for human DC generation focus on CD34 + cell culture on OP9 cell layers for cDC1, cDC2, cDC3, and pDC subset generation and DC generation from peripheral blood monocytes (MoDC). Additional protocols include enrichment of murine DC subsets, CRISPR/Cas9 editing, and clinical grade human DC generation. While all protocols were written by experienced scientists who routinely use them in their work, this article was also peer‐reviewed by leading experts and approved by all co‐authors, making it an essential resource for basic and clinical DC immunologists.
Safety and Survival Outcomes of177Lu-Prostate-Specific Membrane Antigen Therapy in Patients with Metastatic Castration-Resistant Prostate Cancer with Prior223Ra treatment: The RALU Study
2022-10-27

The radium lutetium (RALU) study evaluated the feasibility of sequential α- and β-emitter use in patients with bone-predominant metastatic castration-resistant prostate cancer. <b>Methods:</b> This preplanned interim retrospective analysis investigated safety and survival outcomes with <sup>177</sup>Lu-PSMA in patients treated with prior <sup>223</sup>Ra. <b>Results:</b> Forty-nine patients were evaluated. Patients received a median of 6 <sup>223</sup>Ra injections; 59% of patients received at least 4 <sup>177</sup>Lu-PSMA cycles. Most (69%) patients received at least 4 life-prolonging therapies before <sup>177</sup>Lu-PSMA. Common Terminology Criteria for Adverse Events grade 3-4 treatment-emergent adverse events during <sup>177</sup>Lu-PSMA therapy and a 30-d follow-up period included anemia (18%) and thrombocytopenia (2%). Median overall survival was 12.6 mo (95% CI, 8.8-16.1 mo) and 31.4 mo (95% CI, 25.7-37.6 mo) from starting <sup>177</sup>Lu-PSMA or <sup>223</sup>Ra, respectively. <b>Conclusion:</b> <sup>177</sup>Lu-PSMA treatment was well tolerated in patients who had received prior <sup>223</sup>Ra. <sup>223</sup>Ra use before <sup>177</sup>Lu-PSMA is feasible and can be considered for future assessment of the optimal treatment sequence.
Stabilized recombinant SARS-CoV-2 spike antigen enhances vaccine immunogenicity and protective capacity
2022-10-27

The SARS-CoV-2 spike (S) glycoprotein is synthesized as a large precursor protein and must be activated by proteolytic cleavage into S1 and S2. A recombinant modified vaccinia virus Ankara (MVA) expressing native, full-length S protein (MVA-SARS-2-S) is currently under investigation as a candidate vaccine in phase I clinical studies. Initial results from immunogenicity monitoring revealed induction of S-specific antibodies binding to S2, but low-level antibody responses to the S1 domain. Follow-up investigations of native S antigen synthesis in MVA-SARS-2-S-infected cells revealed limited levels of S1 protein on the cell surface. In contrast, we found superior S1 cell surface presentation upon infection with a recombinant MVA expressing a stabilized version of SARS-CoV-2 S protein with an inactivated S1/S2 cleavage site and K986P and V987P mutations (MVA-SARS-2-ST). When comparing immunogenicity of MVA vector vaccines, mice vaccinated with MVA-SARS-2-ST mounted substantial levels of broadly reactive anti-S antibodies that effectively neutralized different SARS-CoV-2 variants. Importantly, intramuscular MVA-SARS-2-ST immunization of hamsters and mice resulted in potent immune responses upon challenge infection and protected from disease and severe lung pathology. Our results suggest that MVA-SARS-2-ST represents an improved clinical candidate vaccine and that the presence of plasma membrane-bound S1 is highly beneficial to induce protective antibody levels.
Case report: Immunovirotherapy as a novel add-on treatment in a patient with thoracic NUT carcinoma
2022-10-27

NUT carcinoma (NC) is a rare and extremely aggressive form of cancer, usually presenting with intrathoracic or neck manifestations in adolescents and young adults. With no established standard therapy regimen and a median overall survival of only 6.5 months, there is a huge need for innovative treatment options. As NC is genetically driven by a single aberrant fusion oncoprotein, it is generally characterized by a low tumor mutational burden, thus making it immunologically cold and insusceptible to conventional immunotherapy. Recently, we have demonstrated that oncolytic viruses (OVs) are able to specifically infect and lyse NC cells, thereby turning an immunologically cold tumor microenvironment into a hot one. Here, we report an intensive multimodal treatment approach employing for the first time an OV (talimogene laherparepvec (T-VEC); IMLYGIC ® ) together with the immune checkpoint inhibitor pembrolizumab as an add-on to a basic NC therapy (cytostatic chemotherapy, radiation therapy, epigenetic therapy) in a patient suffering from a large thoracic NC tumor which exhibits an aberrant, unique BRD3:NUTM1 fusion. This case demonstrates for the first time the feasibility of this innovative add-on immunovirotherapy regimen with a profound, repetitive and durable replication of T-VEC that is instrumental in achieving tumor stabilization and improvement in the patient ́s quality of life. Further, a previously unknown BRD3:NUTM1 fusion gene was discovered that lacks the extraterminal domain of BRD3 .