julilili42/papers huggingface dataset:
Mimicking tumor cell heterogeneity of colorectal cancer in a patient-derived organoid-fibroblast model
2022-03-08

Abstract Patient-derived organoid (PDO) cancer models are generated from epithelial tumor cells. Although they reflect the molecular tumor characteristics, they lack the complexity of the tumor microenvironment, which is a key driver of tumorigenesis and therapy response. Here, we present a colorectal cancer (CRC) organoid model that incorporates epithelial cells and stromal fibroblasts from the same patient. Molecular characterization of primary cancer associated fibroblasts (CAFs) and matched normal fibroblasts (NF) revealed proteomic, secretome and gene expression differences in pathways associated with tumor related fibroblast function. Further, CAFs retained higher motility compared to NFs in vitro . Importantly, both CAFs and NFs supported cancer cell proliferation in 3D co-cultures, without the addition of classical niche factors. PDOs grown together with fibroblasts displayed a larger cellular heterogeneity of tumor cells compared to mono-cultures, and closely resembled the in vivo tumor morphology. This was also confirmed by the calculation of cellular proportions of epithelial cell subtypes in organoid mono-versus co-cultures, which were inferred through bioinformatics deconvolution of bulk RNA sequencing data using published single cell RNA sequencing datasets from CRC tissues. Additionally, we observed a mutual crosstalk between tumor cells and fibroblasts in the co-cultures. This was manifested by majorly deregulated pathways such as cell-cell communication and extracellular matrix remodeling in the organoids. For the fibroblasts, we observed enhanced expression of tumor induced marker genes and cytokines characteristic for myo- and immunogenic fibroblasts. This model will be vital as a physiological personalized tumor model to study disease mechanisms and therapy response in CRC. One Sentence Summary Patient matched fibroblasts support tumor organoid growth in 3D co-culture and maintain intratumoral cellular heterogeneity and histo-morphology.
Genome-wide meta-analysis for Alzheimer’s disease cerebrospinal fluid biomarkers
2022-03-09

Abstract Amyloid-beta 42 (Aβ42) and phosphorylated tau (pTau) levels in cerebrospinal fluid (CSF) reflect core features of the pathogenesis of Alzheimer’s disease (AD) more directly than clinical diagnosis. Initiated by the European Alzheimer &amp; Dementia Biobank (EADB), the largest collaborative effort on genetics underlying CSF biomarkers was established, including 31 cohorts with a total of 13,116 individuals (discovery n = 8,074; replication n = 5,042 individuals). Besides the APOE locus, novel associations with two other well-established AD risk loci were observed; CR1 was shown a locus for amyloid beta 42 (Aβ42) and BIN1 for phosphorylated Tau (pTau). GMNC and C16orf95 were further identified as loci for pTau, of which the latter is novel. Clustering methods exploring the influence of all known AD risk loci on the CSF protein levels, revealed 4 biological categories (amyloid, astrocyte, processing &amp; migration, and migration &amp; motility) suggesting multiple Aβ42 and pTau related biological pathways involved in the etiology of AD. In functional follow-up analyses, GMNC and C16orf95 both associated with lateral ventricular volume, implying an overlap in genetic etiology for tau levels and brain ventricular volume.
Evaluation of Local Rod and Cone Function in Stargardt Disease
2022-03-09

The functional analysis of the macular region in STGD1 disease indicates reduced central cone function, corresponding to photoreceptor degeneration. In contrast, the rod function in the central area was not affected. Nevertheless, some alteration of the time dynamics in the rod system was observed indicating a complex effect of cone degeneration on the functional performance of the rod system. Our results should be considered when interpreting safety and efficacy in interventional trials of STGD1.
The multi-factor modulated biogenesis of the mitochondrial multi-span protein Om14
2022-03-09

The mitochondrial outer membrane (MOM) harbors proteins that traverse the membrane via several helical segments and are called multi-span proteins. To obtain new insights into the biogenesis of these proteins, we utilized yeast mitochondria and the multi-span protein Om14. Testing different truncation variants, we show that while only the full-length protein contains all the information that assures perfect targeting specificity, shorter variants are targeted to mitochondria with compromised fidelity. Employing a specific insertion assay and various deletion strains, we show that proteins exposed to the cytosol do not contribute significantly to the biogenesis process. We further demonstrate that Mim1 and Porin support optimal membrane integration of Om14 but none of them are absolutely required. Unfolding of newly synthesized Om14, its optimal hydrophobicity, and higher fluidity of the membrane enhanced the import capacity of Om14. Collectively, these findings suggest that MOM multi-span proteins follow different biogenesis pathways in which proteinaceous elements and membrane behavior contribute to a variable extent to the combined efficiency.
Lipoproteins Cause Bone Resorption in a Mouse Model of Staphylococcus aureus Septic Arthritis
2022-03-09

Septic arthritis, most often caused by Staphylococcus aureus , is a rapidly progressive and destructive joint disease with substantial mortality and morbidity. Staphylococcus aureus lipoproteins (Lpps) are known to induce arthritis and bone destruction. Here, we aimed to investigate the bone resorptive effect of S. aureus Lpps in a murine arthritis model by intra-articular injection of purified S. aureus Lpps, synthetic lipopeptides, and live S. aureus strains. Analyses of the bone mineral density (BMD) of the distal femur bone were performed. Intra-articular injection of both live S. aureus and purified S. aureus Lpps were shown to significantly decrease total- and trabecular BMD. Liquid chromatography–mass spectrometry analyses revealed that the Lpps expressed by S. aureus SA113 strain contain both diacyl and triacyl lipid moieties. Interestingly, synthetic diacylated lipopeptide, Pam 2 CSK 4 , was more potent in inducing bone resorption than synthetic triacylated lipopeptide, Pam 3 CSK 4 . Modified lipoproteins lacking the lipid moiety were deprived of their bone resorptive abilities. Monocyte depletion by clodronate liposomes fully abrogated the bone resorptive capacity of S. aureus lipoproteins. Our data suggest that S. aureus Lpps induce bone resorption in locally-induced murine arthritis, an effect mediated by their lipid-moiety through monocytes/macrophages.
High Plasticity of the Amicetin Biosynthetic Pathway in Streptomyces sp. SHP 22-7 Led to the Discovery of Streptcytosine P and Cytosaminomycins F and G and Facilitated the Production of 12F-Plicacetin
2022-03-09

A chemical reinvestigation of the Indonesian strain <i>Streptomyces</i> sp. SHP 22-7 led to the isolation of three new pyrimidine nucleosides, along with six known analogues and zincphyrin. The structures of the new compounds (<b>6</b>, <b>7</b>, <b>10</b>) were elucidated by employing spectroscopic techniques (NMR, MS, CD, and IR) as well as enantioselective analyses of methyl branched side chain configurations. Application of the precursor-directed feeding approach led to the production and partial isolation of nine further pyrimidine analogues. The new compounds <b>6</b>, <b>7</b>, and <b>11</b> and three of the known compounds (<b>2</b>-<b>4</b>) were found to possess antimycobacterial and cytotoxic properties.
A thermodynamic chemical reaction network drove autocatalytic prebiotic peptides formation
2022-03-09

The chemical reaction networks (CRNs), which led to the transition on early Earth from geochemistry to biochemistry remain unknown. We show that the simplest substances—bicarbonate, sulfite/sulfate, and ammonium—were converted to peptides in one geological setting from Sammox (sulfite/sulfate reduction coupled to anaerobic ammonium oxidation)-driven CRNs under mild hydrothermal conditions. Peptides comprise 15 proteinogenic amino acids, endowed Sammox-driven CRNs with autocatalysis. The peptides exhibit both forward and reverse catalysis, with the opposite catalytic impact in sulfite- and sulfate-fueled Sammox-driven CRNs, respectively, at both a variable temperature range and a fixed temperature, resulting in seesaw-like catalytic properties. The variation of substrates concentration and temperature, can influence the redox property of the system, may disrupt the redox homeostasis of Sammox-driven CRNs, therefore, the catalytic orientation of peptides changed due to the stimulation, to maintain system redox homeostasis. The seesaw-like catalytic characteristics of peptides is critical to achieving the sustainability and evolution of Sammox-driven CRNs by preferentially destroy non-functional peptides and preserve peptides with high substrate specificities and/or novel functions. Moreover, the peptides generated from sulfite-fueled Sammox-driven CRNs could catalyze both sulfite-fueled Sammox, and Anammox (nitrite reduction coupling with anaerobic ammonium oxidation) reactions. We propose that Sammox-driven CRNs were critical in the creation of life and that Sammox and Anammox are primordial energy conservation traits.
Off-Label Treatment for Severe Craniomaxillofacial Fractures in Low-Income Countries—A Novel Operation Method with the External Face Fixator
2022-03-09

Introduction: Craniomaxillofacial fractures (CMF) are common in low-income countries (LIC). Due to limited resources, treatment of these fractures usually consists of interdental wiring or immobilization with a Barton bandage to maintain the reduction by permanent occlusion. These non-surgical treatment methods often lead to unsatisfactory results, such as a disturbed dental occlusion and lockjaw. The aim of this study is to present an off-label treatment option for CMF by applying a hand fixator as external face fixator (EFF) and to demonstrate the surgical method in detail. Materials and Methods: The feasibility and postoperative outcomes of this new off-label operation technique were evaluated by analyzing patients with CMF (n = 13) treated at an NGO hospital in Sierra Leone between 2015 and 2019. Results: The application of the EFF was feasible. The biggest advantage compared to the conventional non-operative methods was, that a dynamic occlusion was still possible during the 6 weeks healing period. Hence, patients could eat and drink almost normally and perform dental hygiene with the EFF in place. We did not discover pintrack infections or other complications. Three patients developed an oronasal fistula due to traumatic a palatal bone loss of about 7–8 mm which was treated by a palatal mucoperiosteal flap 15–20 days after the first operation. Discussion and Conclusions: In LIC, where plate osteosynthesis for CMF cannot be performed due to limited resources the application of an EFF is a promising alternative for a better outcome and an improved quality of life for the patients.
Exploring Need Fulfillment in Varsity Intercollegiate Student-Athletes’ Dual Roles: A Mixed-Methods, Person-Oriented Investigation
2022-03-09

Individuals competing in varsity intercollegiate sport are tasked with managing the dual roles of athletes and students. The purpose of current study was to simultaneously explore student-athletes’ perceived satisfaction of autonomy, competence and relatedness in sport and academics. A mixed-methods, person-oriented design was utilized. Quantitative data was collected with a sample of N = 238 student-athletes from various varsity intercollegiate sports. For sport, four clusters were revealed: ‘Low Need Satisfaction,’ ‘Moderately Low Need Satisfaction,’ ‘Moderate Relatedness,’ and ‘High Need Satisfaction.’ For academics, four clusters were revealed: ‘Low Need Satisfaction,’ ‘Moderate Relatedness,’ ‘Moderate Autonomy and Competence,’ and ‘High Need Satisfaction.’ Reflexive thematic analysis of semi-structured interviews with a sub-sample of n = 12 student-athletes representing all clusters revealed four themes: (a) global factors sensitized student-athletes to the experience of basic psychological needs, (b) contextual factors determined fluctuations in student-athletes’ need fulfillment, (c) student-athletes perceived interaction effects in the satisfaction of the three basic psychological needs within the same domain, and (d) student-athletes’ sport participation had a cross-contextual influence on their need fulfillment in academics. Findings provide an understanding of student-athletes’ perceived basic psychological needs across the achievement domains of academics and sport.
Vocal recognition of distance calls in a group-living basal bird: the greylag goose, Anser anser
2022-03-09

Vocal communication in group-living animals represents a major challenge when multiple individuals call simultaneously and generate a complex soundscape. Decoding relevant information from a vocal signal and its emitter can determine the survival of the receiver. In hierarchical social groups, information on sex, size and age can provide relevant context for vocal signals. Ultimately, individual vocal recognition is a keystone in vocal communication systems, especially in the context of sociality. Greylag geese (Aves: Anseriformes) are a basal, gregarious and highly social species, and adults produce a distance call when approaching or leaving the flock. In this study we (1) quantified the acoustic properties of distance calls to test whether they can provide information on the sex, size and age of the emitter, (2) evaluated whether distance calls have individual properties, from the sender's perspective, (3) tested whether receivers discriminate distance calls depending on the emitter's identity and (4) explored whether an individual's response strength towards its partner's distance call is associated with fitness-related traits (i.e. pair bond duration and average number of offspring per year). We recorded distance calls of individually marked geese, quantified the variation in call acoustic properties and carried out a playback experiment in the wild. Distance calls encoded information about the sex of the goose, but not its age or size. From the emitter's perspective, we found some support for individuality in distance calls. From the receiver's perspective, geese were capable of recognizing distance calls from different individuals. Finally, the response strength towards playback of the partner's call was positively correlated with pair bond duration. Vocal recognition has been proposed to be tightly related to social structure, the evolution of sociality and vocal learning. Here, we uncovered vocal recognition of individual affiliative calls in a social bird from the most basal avian group studied so far.
The effect of slow-wave sleep and rapid eye-movement sleep interventions on glycaemic control: a systematic review and meta-analysis of randomised controlled trials
2022-03-09

Poor glycaemic control is found in diabetes, one of the most common, serious, non-communicable diseases worldwide. Trials suggest a relationship between glycaemic control and measures of sleep including duration and quality of sleep. Currently, the relationship between specific sleep stages (including slow-wave sleep (SWS), a sleep stage mainly found early in the night and linked to restorative functioning) and glycaemic control remains unclear. This systematic review aimed to synthesise the evidence of the effectiveness of specific sleep stage manipulation on measures of glycaemic control (insulin resistance, fasting and post-prandial glucose and insulin). Public databases (eg psychINFO, MEDLINE, Academic Search Complete, psychARTICLES, OpenDissertations, Scopus and Cochrane library) were searched for randomised controlled trials. Trials were included if they involved direct manipulation of SWS and/or rapid eye-movement sleep to explore the impact on measures of glycaemic control (insulin resistance, fasting and post-prandial glucose and insulin). Eight trials met the eligibility criteria, with four providing data for inclusion in one of the three meta-analyses. Insulin resistance was significantly higher in the SWS disruption when compared to the normal sleep condition, (p = 0.02). No significant differences were found for measures of fasting or post-prandial glucose or insulin. Risk of bias was considered low for performance bias, detection bias and incomplete outcome data, with unclear selection bias. This is an emerging area of research and this review provides preliminary findings and recommendations for future research around optimising sleep stage disruption (to further explore mechanisms) and sleep stage enhancement techniques (to explore potential interventions).
Synthesis, Antiplasmodial, and Antileukemia Activity of Dihydroartemisinin–HDAC Inhibitor Hybrids as Multitarget Drugs
2022-03-09

Artemisinin-based combination therapies (ACTs) are the gold standard for the treatment of malaria, but the efficacy is threatened by the development of parasite resistance. Histone deacetylase inhibitors (HDACis) are an emerging new class of potential antiplasmodial drugs. In this work, we present the design, synthesis, and biological evaluation of a mini library of dihydroartemisinin–HDACi hybrid molecules. The screening of the hybrid molecules for their activity against selected human HDAC isoforms, asexual blood stage P. falciparum parasites, and a panel of leukemia cell lines delivered important structure–activity relationships. All synthesized compounds demonstrated potent activity against the 3D7 and Dd2 line of P. falciparum with IC50 values in the single-digit nanomolar range. Furthermore, the hybrid (α)-7c displayed improved activity against artemisinin-resistant parasites compared to dihydroartemisinin. The screening of the compounds against five cell lines from different leukemia entities revealed that all hydroxamate-based hybrids (7a–e) and the ortho-aminoanilide 8 exceeded the antiproliferative activity of dihydroartemisinin in four out of five cell lines. Taken together, this series of hybrid molecules represents an excellent starting point toward the development of antimalarial and antileukemia drug leads.
Toward Improved Bioremediation Strategies: Response of BAM-Degradation Activity to Concentration and Flow Changes in an Inoculated Bench-Scale Sediment Tank
2022-03-09

Compound-specific isotope analysis (CSIA) can reveal mass-transfer limitations during biodegradation of organic pollutants by enabling the detection of masked isotope fractionation. Here, we applied CSIA to monitor the adaptive response of bacterial degradation in inoculated sediment to low contaminant concentrations over time. We characterized <i>Aminobacter</i> sp. MSH1 activity in a flow-through sediment tank in response to a transient supply of elevated 2,6-dichlorobenzamide (BAM) concentrations as a priming strategy and took advantage of an inadvertent intermittence to investigate the effect of short-term flow fluctuations. Priming and flow fluctuations yielded improved biodegradation performance and increased biodegradation capacity, as evaluated from bacterial activity and residual concentration time series. However, changes in isotope ratios in space and over time evidenced that mass transfer became increasingly limiting for degradation of BAM at low concentrations under such stimulated conditions, and that activity decreased further due to bacterial adaptation at low BAM (μg/L) levels. Isotope ratios, in conjunction with residual substrate concentrations, therefore helped identifying underlying limitations of biodegradation in such a stimulated system, offering important insight for future optimization of remediation schemes.
A doctor, an astrologer, a heretic, an alchemist and a sorcerer, and a tame demon who taught him everything: traces of the mythologization and rehabilitation of the figure of a doctor in Collin de Plancy’s <i>Infernal Dictionary</i>
2022-03-09

This article is devoted to biographies of doctors contained in the Infernal Dictionary of Collin de Plancy, and narrative topoi formed around the figure of a doctor in the historical past. One of the stable attributes that place biographies of doctors in the context of the history of the Church is the statement of tense and conflict-rich interaction, which, however, cannot be assessed unambiguously as a confrontation. Another dimension of the texts under consideration is their transformation under the influence of the compiler’s conversion and the “сhristianization” of the Infernal Dictionary in the 1840s. The peculiarity of the approach of this study is the view of the figure of a doctor as a narrative construct, considered from the point of view of its internal logic, and not in relation to historical authenticity or unreliability. The aim of the study is to localize further stable combinations of narrative elements and attributes correlated with the figure of a doctor, and to formulate possible topics and disciplinary frameworks for further research of the problem, which is currently not described in Russian-language science. The material on which this article is written is also presented to the Russian-speaking scientific community for the first time, there are also practically no publications devoted to it in the Western tradition. The method used in the study is a qualitative analysis of the text following the example of field ethnographic studies with elements of quantitative methods.
Perspectives of measuring gravitational effects of laser light and particle beams
2022-03-09

We study possibilities of creation and detection of oscillating gravitational fields from high energy laser beams in an optical cavity and from the ultra-relativistic proton bunches circulating in the beam of the Large Hadron Collider (LHC) at CERN. These sources allow for signal frequencies much higher and far narrower in bandwidth than what most celestial sources produce. In addition, by modulating the beams, one can adjust the source frequency over a very broad range, from Hz to GHz. The gravitational field of these sources and responses of three different detectors are analyzed: a Weber-bar-type mechanical rod, a detector based on superfluid helium-4 coupled parametrically to a superconducting microwave cavity, and a monolithic pendulum. We find that with the planned high-luminosity upgrade of the LHC and an improved design of a recently experimentally demonstrated monolithic pendulum, a signal to noise ratio substantially larger than 1 should be achievable. This opens new perspectives of studying general relativistic effects and possibly quantum-gravitational effects with ultra-relativistic, well-controlled terrestrial sources.
Optimal estimation of time-dependent gravitational fields with quantum optomechanical systems
2022-03-09

We study the fundamental sensitivity that can be achieved with an ideal optomechanical system in the nonlinear regime for measurements of time-dependent gravitational fields. The optomechanical system consists of a cavity mode and a mechanical oscillator coupled to it via (non-linear) radiation pressure coupling. Using recently developed methods to solve the dynamics of a nonlinear optomechanical system with a time-dependent Hamiltonian, we compute the quantum Fisher information for linear displacements of the mechanical element due to gravity. We demonstrate that the sensitivity can be further enhanced by injecting squeezed states of the cavity field or by modulating the light–matter coupling of the optomechanical system. We specifically apply our results to the measurement of gravitational fields from small oscillating masses, where we show that, in principle, the gravitational field of an oscillating nanogram mass can be detected based on experimental parameters that will likely be accessible in the near-term future. Finally, we identify the experimental parameter regime necessary for gravitational wave detection with a quantum optomechanical sensor.