julilili42/papers huggingface dataset:
Horizontal transfer of bacteriocin biosynthesis genes requires metabolic adaptation to improve compound production and cellular fitness
2022-07-30

Abstract Biosynthetic gene clusters (BGCs) encoding the production of bacteriocins are widespread amongst bacterial isolates and are important genetic determinants of competitive fitness within a given habitat. Staphylococci produce a tremendous diversity of compounds and the corresponding BGCs are frequently associated with mobile genetic elements, suggesting gain and loss of biosynthetic capacity. Pharmaceutical biology has shown that compound production in heterologous hosts is often challenging and many BGC recipients produce initially low compound amounts or show reduced growth rates. To assess whether transfer of BGCs between closely related S. aureus strains can be instantly effective or requires elaborate metabolic adaptation, we investigated the intra species transfer of a BGC encoding the ribosomally synthesized and post-translationally modified peptide (RiPP) micrococcin P1 (MP1). We found that acquisition of the BGC by S. aureus RN4220 enabled immediate MP1 production but also imposed a metabolic burden, which was relieved after prolonged cultivation by adaptive mutation. We used a multiomics approach to study this phenomenon and found adaptive evolution to select for strains with increased activity of the tricarboxylic acid cycle (TCA), which enhanced metabolic fitness and levels of compound production. Metabolome analysis revealed increases of central metabolites including citrate and α-ketoglutarate in the adapted strain, suggesting metabolic adaptation to overcome the BGC-associated growth defects. Our results indicate that BCG acquisition requires genetic and metabolic predispositions allowing the integration of bacteriocin production into the cellular metabolism. Inappropriate metabolic characteristics of recipients can entail physiological burdens, negatively impacting the competitive fitness of recipients within natural bacterial communities. Importance Human microbiomes are critically associated with human health and disease. Importantly, pathogenic bacteria can hide in human associated communities and can cause disease when the composition of the community becomes dysbalanced. Bacteriocin producing commensals are able to displace pathogens from microbial communities, suggesting that their targeted introduction in human microbiomes might prevent pathogen colonisation and infection. However, in view of future probiotic approaches, strains are needed that produce high levels of bioactive compounds and retain cellular fitness within mixed bacterial communities. Our work offers insights into the metabolic burdens associated with the production of the bacteriocin micrococcin P1 and highlights evolutionary strategies that increase cellular fitness in the context of production. Most likely metabolic adaptations are broadly relevant for bacteriocin producers and need to be considered for the future development of effective microbiome editing strategies.
Effective splicing restoration of a deep-intronic ABCA4 variant in cone photoreceptor precursor cells by CRISPR/SpCas9 approaches
2022-07-31

Stargardt disease is an autosomal recessively inherited retinal disorder commonly caused by pathogenic variants in the <i>ABCA4</i> gene encoding the ATP-binding cassette subfamily A member 4 (ABCA4) protein. Several deep-intronic variants in <i>ABCA4</i> have been classified as disease causing. By strengthening a cryptic splice site, deep-intronic variant c.5197-557G>T induces the inclusion of a 188-bp intronic sequence in the mature mRNA, resulting in a premature termination codon. Here, we report the design and evaluation of three CRISPR-Cas9 approaches implementing <i>Streptococcus pyogenes</i> Cas9 (single and dual guide RNA) or <i>Streptococcus pyogenes</i> Cas9 nickase (dual guide RNA) for their potential to correct c.5197-557G>T-induced aberrant splicing in minigene splicing assays and patient-derived cone photoreceptor precursor cells. The different strategies were able to rescue correct splicing by up to 83% and increase the overall correctly spliced transcripts by 1.8-fold, demonstrating the successful CRISPR-Cas9-mediated rescue in patient-derived photoreceptor precursor cells of an <i>ABCA4</i> splicing defect. The results provide initial evidence of possible permanent splicing correction for Stargardt disease, expanding the therapeutic toolbox to counteract deep-intronic pathogenic variants in <i>ABCA4</i>.
Time‐dependent prediction of mortality and cytomegalovirus reactivation after allogeneic hematopoietic cell transplantation using machine learning
2022-07-31

Abstract Allogeneic hematopoietic cell transplantation (HCT) effectively treats high‐risk hematologic diseases but can entail HCT‐specific complications, which may be minimized by appropriate patient management, supported by accurate, individual risk estimation. However, almost all HCT risk scores are limited to a single risk assessment before HCT without incorporation of additional data. We developed machine learning models that integrate both baseline patient data and time‐dependent laboratory measurements to individually predict mortality and cytomegalovirus (CMV) reactivation after HCT at multiple time points per patient. These gradient boosting machine models provide well‐calibrated, time‐dependent risk predictions and achieved areas under the receiver‐operating characteristic of 0.92 and 0.83 and areas under the precision–recall curve of 0.58 and 0.62 for prediction of mortality and CMV reactivation, respectively, in a 21‐day time window. Both models were successfully validated in a prospective, non‐interventional study and performed on par with expert hematologists in a pilot comparison.
Cluster-independent marker feature identification from single-cell omics data using SEMITONES
2022-07-31

Abstract Identification of cell identity markers is an essential step in single-cell omics data analysis. Current marker identification strategies typically rely on cluster assignments of cells. However, cluster assignment, particularly for developmental data, is nontrivial, potentially arbitrary, and commonly relies on prior knowledge. In response, we present SEMITONES, a principled method for cluster-free marker identification. We showcase and evaluate its application for marker gene and regulatory region identification from single-cell data of the human haematopoietic system. Additionally, we illustrate its application to spatial transcriptomics data and show how SEMITONES can be used for the annotation of cells given known marker genes. Using several simulated and curated data sets, we demonstrate that SEMITONES qualitatively and quantitatively outperforms existing methods for the retrieval of cell identity markers from single-cell omics data.
Multi‐surveyor capture‐mark‐recapture as a powerful tool for butterfly population monitoring in the pre‐imaginal stage
2022-07-31

Abstract For many elusive insect species, which are difficult to cover by standard monitoring schemes, innovative survey methods are needed to gain robust data on abundance and population trends. We suggest a monitoring of overwintering larvae for the endangered nymphalid butterfly Limenitis reducta . We tested different removal and capture‐mark‐recapture (CMR) approaches in a field study in the “Alb‐Donau” region, Germany. Classical removal and CMR studies require movement of the organisms under study, but in our approach, we replaced movement of the study organisms by random movement of multiple different surveyors. We tested the validity of the approach by comparing detection frequencies from our field data with simulated detections. Our results indicate that multi‐surveyor removal/CMR techniques are suitable for estimating abundance of overwintering L. reducta larvae. Depending on surveyor experience, the average detection probability ranged between 16% for novices and 35% for experts. The uncertainty of population estimates increased with a decrease in personnel expenditure. Estimated larval densities on a spruce clear‐cut varied between one and three individuals per 100 m 2 , probably related to habitat conditions. We suggest a CMR approach with three to four trained surveyors for the monitoring of L. reducta populations in the overwintering stage. Compared with previous sampling methods, our approach is a powerful tool with clear advantages: long survey period, estimates of the absolute population size accompanied by uncertainty measures, and estimates of overwinter mortality. The proposed method can be adapted and used for several different butterfly species, other insect taxa with specific immobile life stages, and some sessile organisms, for example, elusive plants, fungi, or corals.
Sulfate Land Application Enhances Biodegradation in a Petroleum Hydrocarbon Smear Zone
2022-07-31

Abstract Delivery of sulfate to petroleum hydrocarbons (PHCs) source zones and groundwater plumes is desirable to enhance biodegradation rates when treatment has become limited due to depletion of sulfate. Sulfate land application involves spreading sulfate salts on ground surface and allowing their dissolution and infiltration of sulfate into subsurface. The objectives of this pilot‐scale investigation were to capture the vertical transport of sulfate beneath an application area, confirm that sulfate reduction was occurring, and explore how the added sulfate affected biodegradation of benzene and toluene. Approximately 4000 kg of gypsum was spread over a 30 m × 30 m study area above a smear zone located approximately 2 m below‐ground surface. Precipitation was augmented by two irrigation events. Groundwater samples, collected over 1058 days from multilevel wells and a conventional long‐screened monitoring well, were analyzed for benzene, toluene, ethylbenzene, and xylenes (BTEX), sulfate, bromide, dissolved inorganic carbon (DIC) and methane. Compound‐specific isotope analyses (CSIA) for benzene and toluene, and isotope analyses of 13 C‐DIC and 34 S‐SO 4 2− were performed. Following application, an increase in sulfate concentration was noted in the smear zone. 34 S‐SO 4 2− enrichment and 13 C‐DIC depletion indicated that sulfate reduction and mineralization of PHCs were enhanced. CSIA results provided unequivocal evidence of anaerobic biodegradation of benzene and toluene. After 1058 days when sulfate was depleted, methane concentrations were about three times greater than baseline conditions suggesting syntrophic benefit of the delivered sulfate. Observations from this investigation support the viability of sulfate land application to enhance biodegradation rates in shallow PHC smear zones.
Integration of p16/HPV DNA Status with a 24-miRNA-Defined Molecular Phenotype Improves Clinically Relevant Stratification of Head and Neck Cancer Patients
2022-07-31

Human papillomavirus (HPV)-driven head and neck squamous cell carcinomas (HNSCC) generally have a more favourable prognosis. We hypothesized that HPV-associated HNSCC may be identified by an miRNA-signature according to their specific molecular pathogenesis, and be characterized by a unique transcriptome compared to HPV-negative HNSCC. We performed miRNA expression profiling of two p16/HPV DNA characterized HNSCC cohorts of patients treated by adjuvant radio(chemo)therapy (multicentre DKTK-ROG n = 128, single-centre LMU-KKG n = 101). A linear model predicting HPV status built in DKTK-ROG using lasso-regression was tested in LMU-KKG. LMU-KKG tumours (n = 30) were transcriptome profiled for differential gene expression and miRNA-integration. A 24-miRNA signature predicted HPV-status with 94.53% accuracy (AUC: 0.99) in DKTK-ROG, and 86.14% (AUC: 0.86) in LMU-KKG. The prognostic values of 24-miRNA- and p16/HPV DNA status were comparable. Combining p16/HPV DNA and 24-miRNA status allowed patient sub-stratification and identification of an HPV-associated patient subgroup with impaired overall survival. HPV-positive tumours showed downregulated MAPK, Estrogen, EGFR, TGFbeta, WNT signaling activity. miRNA-mRNA integration revealed HPV-specific signaling pathway regulation, including PD−L1 expression/PD−1 checkpoint pathway in cancer in HPV-associated HNSCC. Integration of clinically established p16/HPV DNA with 24-miRNA signature status improved clinically relevant risk stratification, which might be considered for future clinical decision-making with respect to treatment de-escalation in HPV-associated HNSCC.
Review of Particle Physics
2022-08-01

Abstract The Review summarizes much of particle physics and cosmology. Using data from previous editions, plus 2,143 new measurements from 709 papers, we list, evaluate, and average measured properties of gauge bosons and the recently discovered Higgs boson, leptons, quarks, mesons, and baryons. We summarize searches for hypothetical particles such as supersymmetric particles, heavy bosons, axions, dark photons, etc. Particle properties and search limits are listed in Summary Tables. We give numerous tables, figures, formulae, and reviews of topics such as Higgs Boson Physics, Supersymmetry, Grand Unified Theories, Neutrino Mixing, Dark Energy, Dark Matter, Cosmology, Particle Detectors, Colliders, Probability and Statistics. Among the 120 reviews are many that are new or heavily revised, including a new review on Machine Learning, and one on Spectroscopy of Light Meson Resonances. The Review is divided into two volumes. Volume 1 includes the Summary Tables and 97 review articles. Volume 2 consists of the Particle Listings and contains also 23 reviews that address specific aspects of the data presented in the Listings. The complete Review (both volumes) is published online on the website of the Particle Data Group (pdg.lbl.gov) and in a journal. Volume 1 is available in print as the PDG Book. A Particle Physics Booklet with the Summary Tables and essential tables, figures, and equations from selected review articles is available in print, as a web version optimized for use on phones, and as an Android app.
EANO - EURACAN - SNO Guidelines on circumscribed astrocytic gliomas, glioneuronal, and neuronal tumors
2022-08-01

Abstract In the new WHO 2021 Classification of CNS Tumors the chapter “Circumscribed astrocytic gliomas, glioneuronal and neuronal tumors” encompasses several different rare tumor entities, which occur more frequently in children, adolescents, and young adults. The Task Force has reviewed the evidence of diagnostic and therapeutic interventions, which is low particularly for adult patients, and draw recommendations accordingly. Tumor diagnosis, based on WHO 2021, is primarily performed using conventional histological techniques; however, a molecular workup is important for differential diagnosis, in particular, DNA methylation profiling for the definitive classification of histologically unresolved cases. Molecular factors are increasing of prognostic and predictive importance. MRI finding are non-specific, but for some tumors are characteristic and suggestive. Gross total resection, when feasible, is the most important treatment in terms of prolonging survival and achieving long-term seizure control. Conformal radiotherapy should be considered in grade 3 and incompletely resected grade 2 tumors. In recurrent tumors reoperation and radiotherapy, including stereotactic radiotherapy, can be useful. Targeted therapies may be used in selected patients: BRAF and MEK inhibitors in pilocytic astrocytomas, pleomorphic xanthoastrocytomas, and gangliogliomas when BRAF altered, and mTOR inhibitor everolimus in subependymal giant cells astrocytomas. Sequencing to identify molecular targets is advocated for diagnostic clarification and to direct potential targeted therapies.
Exploring cell and tissue mechanics with optical tweezers
2022-08-01

ABSTRACT Cellular and tissue biosystems emerge from the assembly of their constituent molecules and obtain a set of specific material properties. To measure these properties and understand how they influence cellular function is a central goal of mechanobiology. From a bottoms-up, physics or engineering point-of-view, such systems are a composition of basic mechanical elements. However, the sheer number and dynamic complexity of them, including active molecular machines and their emergent properties, makes it currently intractable to calculate how biosystems respond to forces. Because many diseases result from an aberrant mechanotransduction, it is thus essential to measure this response. Recent advances in the technology of optical tweezers have broadened their scope from single-molecule applications to measurements inside complex cellular environments, even within tissues and animals. Here, we summarize the basic optical trapping principles, implementations and calibration procedures that enable force measurements using optical tweezers directly inside cells of living animals, in combination with complementary techniques. We review their versatility to manipulate subcellular organelles and measure cellular frequency-dependent mechanics in the piconewton force range from microseconds to hours. As an outlook, we address future challenges to fully unlock the potential of optical tweezers for mechanobiology.
Ectomycorrhizal and non‐mycorrhizal rhizosphere fungi increase root‐derived C input to soil and modify enzyme activities: A 14C pulse labelling of Picea abies seedlings
2022-08-01

Abstract Consequences of interactions between ectomycorrhizal fungi (EcMF) and non‐mycorrhizal rhizosphere fungi (NMRF) for plant carbon (C) allocation belowground and nutrient cycling in soil remain unknown. To address this topic, we performed a mesocosm study with Norway spruce seedlings [ Picea abies (L.) H. Karst] inoculated with EcMF, NMRF, or a mixture of both (MIX). 14 CO 2 pulse labelling of spruce was applied to trace and visualize the 14 C incorporation into roots, rhizohyphosphere and hyphosphere. Activities and localization of enzymes involved in the C, nitrogen (N) and phosphorus (P) cycling were visualized using zymography. Spruce seedlings inoculated with EcMF and NMRF allocated more C to soils (EcMF: 10.7%; NMRF: 3.5% of total recovered C) compared to uninoculated control seedlings. The 14 C activity in the hyphosphere was highest for EcMF and lowest for NMRF. In the presence of both, NMRF and EcMF (MIX), the 14 C activity was 64% lower compared with EcMF inoculation alone. This suggests a suppressed C allocation via EcMF likely due to the competition between EcMF and NMRF for N and P. Furthermore, we observed 57% and 49% higher chitinase and leucine‐aminopeptidase activities in the rhizohyphosphere of EcMF compared to the uninoculated control, respectively. In contrast, β‐glucosidase activity (14.3 nmol cm −2 h −1 ) was highest in NMRF likely because NMRF consumed rhizodeposits efficiently. This was further supported by that enzyme stoichiometry in soil with EcMF shifted to a higher investment of nutrient acquisition enzymes (e.g., chitinase, leucine‐aminopeptidase, acid phosphatase) compared to NMRF inoculation, where investment in β‐glucosidase increased. In conclusion, the alleviation of EcMF from C limitation promotes higher activities of enzymes involved in the N and P cycle to cover the nutrient demand of EcMF and host seedlings. In contrast, C limitation of NMRF probably led to a shift in investment towards higher activities of enzymes involved in the C cycle.
S2k guideline: Rosacea
2022-08-01

Summary This updated and upgraded S2k guideline deals with the diagnosis and treatment of rosacea, which is a common, chronic inflammatory skin disease mostly affecting the face. Initially, rosacea is characterized by recurrent erythema, telangiectasia and flushing. Later, the inflammatory component predominates, with persistent erythema with follicular papules, papulopustules and pustules. The development of phyma, which usually occurs on the acral localizations, is the most severe manifestation. For the treatment of rosacea, the interdisciplinary guideline committee, with representatives of the German Dermatological Society (DDG), the Professional Association of German Dermatologists (BVDD), the German Opthalmological Society (DOG), the Society for Dermopharmacy (GD), the Swiss Society for Dermatology and Venereology (SGDV) and the German Rosacea Aid e. V., recommends the avoidance of trigger factors and topical applications of metronidazole, azelaic acid or ivermectin. For symptomatic treatment of persistent centrofacial erythema, the topical vasoconstrictors brimonidine or oxymetazoline can also be used. Systemic therapy is recommended for therapy‐resistant and severe forms of rosacea papulopustulosa. The drug of choice is low‐dose doxycycline. Alternatively, low‐dose isotretinoin can be recommended. Ocular rosacea should be treated with lid margin hygiene. For topical treatment, ciclosporin eye drops, azithromycin, ivermectin or metronidazole are suggested.
Recent Metal-Catalyzed Methods for Thioether Synthesis
2022-08-01

Abstract This review summarizes the more recent methods (since 2015) for the synthesis of thioethers using homogeneous metals as catalysts. The thioether moiety can be found in numerous compounds for pharmaceutical, agricultural, or material applications and it is therefore important to develop new, efficient methods for their synthesis. The recent efforts in this field focus on the use of non-precious metal catalysts, as well as on the development of new bond-forming processes. 1 Introduction 2 Cross-Couplings 3 C–H Activation 4 Hydrothiolation 5 Carbothiolation 6 Miscellaneous 7 Conclusion
Near-infrared Accretion Signatures from the Circumbinary Planetary-mass Companion Delorme 1 (AB)b*
2022-08-01

Abstract Accretion signatures from bound brown dwarf and protoplanetary companions provide evidence for ongoing planet formation, and accreting substellar objects have enabled new avenues to study the astrophysical mechanisms controlling the formation and accretion processes. Delorme 1 (AB)b, a ∼30–45 Myr circumbinary planetary-mass companion, was recently discovered to exhibit strong H α emission. This suggests ongoing accretion from a circumplanetary disk, somewhat surprising given canonical gas disk dispersal timescales of 5–10 Myr. Here, we present the first NIR detection of accretion from the companion in Pa β , Pa γ , and Br γ emission lines from SOAR/TripleSpec 4.1, confirming and further informing its accreting nature. The companion shows strong line emission, with L line ≈ 1–6 × 10 −8 L ⊙ across lines and epochs, while the binary host system shows no NIR hydrogen line emission ( L line &lt; 0.32–11 × 10 −7 L ⊙ ). Observed NIR hydrogen line ratios are more consistent with a planetary accretion shock than with local line excitation models commonly used to interpret stellar magnetospheric accretion. Using planetary accretion shock models, we derive mass accretion rate estimates of <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" overflow="scroll"> <mml:msub> <mml:mrow> <mml:mover accent="true"> <mml:mrow> <mml:mi>M</mml:mi> </mml:mrow> <mml:mrow> <mml:mo>̇</mml:mo> </mml:mrow> </mml:mover> </mml:mrow> <mml:mrow> <mml:mi>pla</mml:mi> </mml:mrow> </mml:msub> <mml:mo>∼</mml:mo> <mml:mn>3</mml:mn> </mml:math> –4 × 10 −8 M J yr −1 , somewhat higher than expected under the standard star formation paradigm. Delorme 1 (AB)b’s high accretion rate is perhaps more consistent with formation via disk fragmentation. Delorme 1 (AB)b is the first protoplanet candidate with clear (signal-to-noise ratio ∼5) NIR hydrogen line emission.