Control of inducible gene expression links cohesin to hematopoietic progenitor self-renewal and differentiation.

Cohesin is important for 3D genome organization. Nevertheless, even the complete removal of cohesin has surprisingly little impact on steady-state gene transcription and enhancer activity. Here we show that cohesin is required for the core transcriptional response of primary macrophages to microbial signals, and for inducible enhancer activity that underpins inflammatory gene expression. Consistent with a role for inflammatory signals in promoting myeloid differentiation of hematopoietic stem and progenitor cells (HPSCs), cohesin mutations in HSPCs led to reduced inflammatory gene expression and increased resistance to differentiation-inducing inflammatory stimuli. These findings uncover an unexpected dependence of inducible gene expression on cohesin, link cohesin with myeloid differentiation, and may help explain the prevalence of cohesin mutations in human acute myeloid leukemia.

Towards responsible research assessment: How to reward research quality.

Researchers would be more willing to prioritize research quality over quantity if the incentive structure of the academic system aligned with this goal. The winner of a 2023 Einstein Foundation Award for Promoting Quality in Research explains how they rose to this challenge.

Revealing the Origin of Fast Delayed Fluorescence in a Donor Functionalized Bisterpyridine.

A new carbazole-substituted bisterpyridine with pronounced delayed fluorescence is presented. While the molecular donor-acceptor-donor design suggests the origin of this to be thermally activated delayed fluorescence (TADF), results from various photophysical characterizations, OLED characteristics, temperature-dependent NMR spectroscopy, and DFT calculations all point against the involvement of triplet states. The molecule exhibits blue emission at about 440 nm with two or more fast decay channels in the lower nanosecond range in both solution and thin films. The delayed emission is proposed to be caused by rotational vibrational modes. We suggest that these results are generally applicable, especially for more complex molecules, and should be considered as alternative or competitive emissive relaxation pathways in the field of organic light emitting materials.

Photostability of Phenoxazine Derivatives.

Phenoxazine is a commonly used molecular building block, for example in optoelectronic applications and pharmaceuticals. However, it is highly susceptible to rapid photodegradation, especially in halogenated solvents. In the present study, we identify the degradation products in both halogenated and non-halogenated solvents by UV/Vis absorption, NMR spectroscopy and mass spectrometry. We also propose a substitution strategy aimed at effectively suppressing the high photoreactivity. Kinetic studies show that the quantum yield of photodegradation Ï• differs by a factor of more than 1000 between trisubstituted derivatives and N-substituted phenoxazine.

Dihedral Angles and Photoluminescence Quantum Yields: An NMR Analysis.

The synthesis of two different series of donor-acceptor (D-A) molecules is reported, consisting of a series of four structurally related donors and two different acceptors. The subtle differences in the electron density of these D-A-D and D-A compounds are clearly reflected in the different chemical shifts of certain donor protons in the 1H NMR spectra. These shifts show a cosine squared correlation of the dihedral angle between the donor units and the neighbouring phenyl unit of the acceptor. This correlation is also related to optical properties such as the photoluminescence quantum yield, which shows a similar trend due to the different degree of charge transfer during excitation and relaxation processes. In this way, it is possible to directly correlate a molecular structural parameter with a material property on a purely experimental basis, which should be applicable to many donor-acceptor systems.

Guide catheter extension use are associated with higher procedural success in chronic total occlusion percutaneous coronary interventions.

BACKGROUND: Guide catheter extensions (GCEs) increase support and facilitate equipment delivery, but aggressive instrumentation may be associated with a higher risk of complications. AIM: Our aim was to assess the impact of GCEs on procedural success and complications in patients submitted to chronic total occlusion (CTO) percutaneous coronary intervention (PCI). METHODS: We analyzed data from the multicenter LATAM CTO Registry. Procedural success was defined as <30% residual stenosis and TIMI 3 distal flow. Major adverse cardiac and cerebrovascular events (MACCE) was defined as the composite of all-cause death, myocardial infarction, target vessel revascularization, and stroke. Propensity score matching (PSM) was used to compare outcomes with and without GCE use. RESULTS: From August 2010 to August 2021, 3049 patients were included. GCEs were used in 438 patients (14.5%). In unadjusted analysis, patients in the GCE group were older and had more comorbidities. The median J-CTO score and its components were higher in the GCE group. After PSM, procedural success was higher with GCE use (87.7% vs. 80.5%, p = 0.007). The incidence of coronary perforation (odds ratio [OR]: 1.46, 95% confidence interval [CI]: 0.78-2.71, p = 0.230), bleeding (OR: 1.99, 95% CI: 0.41-2.41, p = 0.986), in-hospital death (OR: 1.39, 95% CI: 0.54-3.62, p = 0.495) and MACCE (OR: 1.07, 95% CI: 0.52-2.19, p = 0.850) were similar in both groups. CONCLUSION: In a contemporary, multicenter cohort of patients undergoing CTO PCI, GCEs were used in older patients, with more comorbidities and complex anatomy. After PSM, GCE use was associated with higher procedural success, and similar incidence of adverse outcomes.

Demonstration of a 'leapfrog' randomized controlled trial as a method to accelerate the development and optimization of psychological interventions.

BACKGROUND: The scale of the global mental health burden indicates the inadequacy not only of current treatment options, but also the pace of the standard treatment development process. The 'leapfrog' trial design is a newly-developed simple Bayesian adaptive trial design with potential to accelerate treatment development. A first leapfrog trial was conducted to provide a demonstration and test feasibility, applying the method to a low-intensity internet-delivered intervention targeting anhedonia. METHODS: At the start of this online, single-blind leapfrog trial, participants self-reporting depression were randomized to an initial control arm comprising four weeks of weekly questionnaires, or one of two versions of a four-week cognitive training intervention, imagery cognitive bias modification (imagery CBM). Intervention arms were compared to control on an ongoing basis via sequential Bayesian analyses, based on a primary outcome of anhedonia at post-intervention. Results were used to eliminate and replace arms, or to promote them to become the control condition based on pre-specified Bayes factor and sample size thresholds. Two further intervention arms (variants of imagery CBM) were added into the trial as it progressed. RESULTS: N = 188 participants were randomized across the five trial arms. The leapfrog methodology was successfully implemented to identify a 'winning' version of the imagery CBM, i.e. the version most successful in reducing anhedonia, following sequential elimination of the other arms. CONCLUSIONS: The study demonstrates feasibility of the leapfrog design and provides a foundation for its adoption as a method to accelerate treatment development in mental health. Registration: clinicaltrials.gov, NCT04791137.

Replicability, Robustness, and Reproducibility in Psychological Science.

Replication-an important, uncommon, and misunderstood practice-is gaining appreciation in psychology. Achieving replicability is important for making research progress. If findings are not replicable, then prediction and theory development are stifled. If findings are replicable, then interrogation of their meaning and validity can advance knowledge. Assessing replicability can be productive for generating and testing hypotheses by actively confronting current understandings to identify weaknesses and spur innovation. For psychology, the 2010s might be characterized as a decade of active confrontation. Systematic and multi-site replication projects assessed current understandings and observed surprising failures to replicate many published findings. Replication efforts highlighted sociocultural challenges such as disincentives to conduct replications and a tendency to frame replication as a personal attack rather than a healthy scientific practice, and they raised awareness that replication contributes to self-correction. Nevertheless, innovation in doing and understanding replication and its cousins, reproducibility and robustness, has positioned psychology to improve research practices and accelerate progress.

Nearest-neighbour transition-state analysis for nucleic acid kinetics.

We used stopped-flow to monitor hypochromicity for 43 oligonucleotide duplexes to study nucleic acid kinetics and extract transition-state parameters for association and dissociation. Reactions were performed in 1.0 M NaCl (for literature comparisons) and 2.2 mM MgCl2 (PCR conditions). Dissociation kinetics depended on sequence, increased exponentially with temperature, and transition-state parameters inversely correlated to thermodynamic parameters (r = -0.99). Association had no consistent enthalpic component, varied little with temperature or sequence, and poorly correlated to thermodynamic parameters (r = 0.28). Average association rates decreased 78% in MgCl2 compared to NaCl while dissociation was relatively insensitive to ionic conditions. A nearest-neighbour kinetic model for dissociation predicted rate constants within 3-fold of literature values (n = 11). However, a nearest-neighbour model for association appeared overparameterized and inadequate for predictions. Kinetic predictions were used to simulate published high-speed (<1 min) melting analysis and extreme (<2 min) PCR experiments. Melting simulations predicted apparent melting temperatures increase on average 2.4°C when temperature ramp rates increased from 0.1 to 32°C/s, compared to 2.8°C reported in the literature. PCR simulations revealed that denaturation kinetics are dependent on the thermocycling profile. Simulations overestimated annealing efficiencies at shorter annealing times and suggested that polymerase interactions contribute to primer-template complex stability at extension temperatures.

Bioprospecting for Rhizobacteria with the Ability to Enhance Drought Tolerance in Lessertia frutescens.

Lessertia frutescens is a multipurpose medicinal plant indigenous to South Africa that is used for the management of cancer, stomach ulcers, wounds, etc. The use and demand for the raw materials from this plant have been increasing steadily over the years, putting strain on the dwindling wild populations. Although cultivation may provide relief to the strained supply, the persistent drought climate poses a threat to the plant's growth and productivity. This study explored three plant-growth-promoting rhizobacteria isolates, TUTLFNC33, TUTLFNC37 and TUTLFWC74, obtained from the root nodules of Lessertia frutescens as potential bioinoculants that can improve yield, biological activities and the production of secondary metabolites in the host plant. Isolate TUTLFNC37 was identified as the most promising isolate for inoculation of Lessertia frutescens under drought conditions as it induced drought tolerance through enhanced root proliferation, osmolyte proline accumulation and stomatal closure. Superior biomass yield, phenolics, triterpenes and antioxidant activity were evident in the extracts of Lessertia frutescens inoculated with TUTLFNC37 and under different levels of drought. Furthermore, the metabolomics of the plant extracts demonstrated the ability of the isolate to withstand drastic changes in the composition of unique metabolites, sutherlandiosides A-D and sutherlandins A-D. Molecular families which were never reported in the plant (peptides and glycerolipids) were detected and annotated in the molecular networks. Although drought had deleterious effects on Lessertia frutescens, isolate TUTLFNC37 alleviated the impact of the stress. Isolate TUTLFNC37 is therefore the most promising, environmentally friendly alternative to harmful chemicals such as nitrate-based fertilizers. The isolate should be studied to establish its field performance, cross infectivity with other medicinal plants and competition with inherent soil microbes.

Population structure of blaKPC-harbouring IncN plasmids at a New York City medical centre and evidence for multi-species horizontal transmission.

BACKGROUND: Carbapenem-resistant Enterobacterales (CRE) are highly concerning MDR pathogens. Horizontal transfer of broad-host-range IncN plasmids may contribute to the dissemination of the Klebsiella pneumoniae carbapenemase (KPC), spreading carbapenem resistance among unrelated bacteria. However, the population structure and genetic diversity of IncN plasmids has not been fully elucidated. OBJECTIVES: We reconstructed blaKPC-harbouring IncN plasmid genomes to characterize shared gene content, structural variability, and putative horizontal transfer within and across patients and diverse bacterial clones. METHODS: We performed short- and long-read sequencing and hybrid assembly on 45 CRE isolates with blaKPC-harbouring IncN plasmids. Eight serial isolates from two patients were included to assess intra-patient plasmid dynamics. Comparative genomic analysis was performed to assess structural and sequence similarity across plasmids. Within IncN sublineages defined by plasmid MLST and kmer-based clustering, phylogenetic analysis was used to identify closely related plasmids. RESULTS: Comparative analysis of IncN plasmid genomes revealed substantial heterogeneity including large rearrangements in serial patient plasmids and differences in structure and content across plasmid clusters. Within plasmid sublineages, core genome content and resistance gene regions were largely conserved. Closely related plasmids (≤1 SNP) were found in highly diverse isolates, including ten pST6 plasmids found in eight bacterial clones from three different species. CONCLUSIONS: Genomic analysis of blaKPC-harbouring IncN plasmids revealed the presence of several distinct sublineages as well as substantial host diversity within plasmid clusters suggestive of frequent mobilization. This study reveals complex plasmid dynamics within a single plasmid family, highlighting the challenge of tracking plasmid-mediated transmission of blaKPC in clinical settings.

Mouse screen reveals multiple new genes underlying mouse and human hearing loss.

Adult-onset hearing loss is very common, but we know little about the underlying molecular pathogenesis impeding the development of therapies. We took a genetic approach to identify new molecules involved in hearing loss by screening a large cohort of newly generated mouse mutants using a sensitive electrophysiological test, the auditory brainstem response (ABR). We review here the findings from this screen. Thirty-eight unexpected genes associated with raised thresholds were detected from our unbiased sample of 1,211 genes tested, suggesting extreme genetic heterogeneity. A wide range of auditory pathophysiologies was found, and some mutant lines showed normal development followed by deterioration of responses, revealing new molecular pathways involved in progressive hearing loss. Several of the genes were associated with the range of hearing thresholds in the human population and one, SPNS2, was involved in childhood deafness. The new pathways required for maintenance of hearing discovered by this screen present new therapeutic opportunities.

Proximal and distal honor fit and subjective well-being in the Mediterranean region.

OBJECTIVE: People's psychological tendencies are attuned to their sociocultural context and culture-specific ways of being, feeling, and thinking are believed to assist individuals in successfully navigating their environment. Supporting this idea, a stronger "fit" with one's cultural environment has often been linked to positive psychological outcomes. The current research expands the cultural, conceptual, and methodological space of cultural fit research by exploring the link between well-being and honor, a central driver of social behavior in the Mediterranean region. METHOD: Drawing on a multi-national sample from eight countries circum-Mediterranean (N = 2257), we examined the relationship between cultural fit in honor and well-being at the distal level (fit with one's perceived society) using response surface analysis (RSA) and at the proximal level (fit with one's university gender group) using profile analysis. RESULTS: We found positive links between fit and well-being in both distal (for some, but not all, honor facets) and proximal fit analyses (across all honor facets). Furthermore, most fit effects in the RSA were complemented with positive level effects of the predictors, with higher average honor levels predicting higher well-being. CONCLUSIONS: Our findings highlight the interplay between individual and environmental factors in honor as well as the important role honor plays in well-being in the Mediterranean region.

Efficiency in sequential testing: Comparing the sequential probability ratio test and the sequential Bayes factor test.

In a sequential hypothesis test, the analyst checks at multiple steps during data collection whether sufficient evidence has accrued to make a decision about the tested hypotheses. As soon as sufficient information has been obtained, data collection is terminated. Here, we compare two sequential hypothesis testing procedures that have recently been proposed for use in psychological research: Sequential Probability Ratio Test (SPRT; Psychological Methods, 25(2), 206-226, 2020) and the Sequential Bayes Factor Test (SBFT; Psychological Methods, 22(2), 322-339, 2017). We show that although the two methods have different philosophical roots, they share many similarities and can even be mathematically regarded as two instances of an overarching hypothesis testing framework. We demonstrate that the two methods use the same mechanisms for evidence monitoring and error control, and that differences in efficiency between the methods depend on the exact specification of the statistical models involved, as well as on the population truth. Our simulations indicate that when deciding on a sequential design within a unified sequential testing framework, researchers need to balance the needs of test efficiency, robustness against model misspecification, and appropriate uncertainty quantification. We provide guidance for navigating these design decisions based on individual preferences and simulation-based design analyses.

Measuring motivational relationship processes in experience sampling: A reliability model for moments, days, and persons nested in couples.

The investigation of within-person process models, often done in experience sampling designs, requires a reliable assessment of within-person change. In this paper, we focus on dyadic intensive longitudinal designs where both partners of a couple are assessed multiple times each day across several days. We introduce a statistical model for variance decomposition based on generalizability theory (extending P. E. Shrout & S. P. Lane, 2012), which can estimate the relative proportion of variability on four hierarchical levels: moments within a day, days, persons, and couples. Based on these variance estimates, four reliability coefficients are derived: between-couples, between-persons, within-persons/between-days, and within-persons/between-moments. We apply the model to two dyadic intensive experience sampling studies (n1 = 130 persons, 5 surveys each day for 14 days, ≥ 7508 unique surveys; n2 = 508 persons, 5 surveys each day for 28 days, ≥ 47764 unique surveys). Five different scales in the domain of motivational processes and relationship quality were assessed with 2 to 5 items: State relationship satisfaction, communal motivation, and agentic motivation; the latter consists of two subscales, namely power and independence motivation. Largest variance components were on the level of persons, moments, couples, and days, where within-day variance was generally larger than between-day variance. Reliabilities ranged from .32 to .76 (couple level), .93 to .98 (person level), .61 to .88 (day level), and .28 to .72 (moment level). Scale intercorrelations reveal differential structures between and within persons, which has consequences for theory building and statistical modeling.

Static Scanning Tunneling Microscopy Images Reveal the Mechanism of Supramolecular Polymerization of an Oligopyridine on Graphite.

Supramolecular polymerization of a donor-acceptor bisterpyridine (BTP) equipped with an electron-rich carbazole unit is observed by scanning tunneling microscopy (STM) at the highly oriented pyrolytic graphite (HOPG)|solution interface. It is shown that two-dimensional crystals of supramolecular (co)polymers are formed by chain growth polymerization, which in turn can be described by copolymerization statistics. From concentration-dependent measurements, derived copolymerization parameters and DFT calculations, a mechanism for self-assembly is developed that suggests a kinetically driven polymerization process in combination with thermodynamically controlled crystallization.

Carbapenemase-producing Enterobacterales causing secondary infections during the COVID-19 crisis at a New York City hospital.

BACKGROUND: Patients with COVID-19 may be at increased risk for secondary bacterial infections with MDR pathogens, including carbapenemase-producing Enterobacterales (CPE). OBJECTIVES: We sought to rapidly investigate the clinical characteristics, population structure and mechanisms of resistance of CPE causing secondary infections in patients with COVID-19. METHODS: We retrospectively identified CPE clinical isolates collected from patients testing positive for SARS-CoV-2 between March and April 2020 at our medical centre in New York City. Available isolates underwent nanopore sequencing for rapid genotyping, antibiotic resistance gene detection and phylogenetic analysis. RESULTS: We identified 31 CPE isolates from 13 patients, including 27 Klebsiella pneumoniae and 4 Enterobacter cloacae complex isolates. Most patients (11/13) had a positive respiratory culture and 7/13 developed bacteraemia; treatment failure was common. Twenty isolates were available for WGS. Most K. pneumoniae (16/17) belonged to ST258 and encoded KPC (15 KPC-2; 1 KPC-3); one ST70 isolate encoded KPC-2. E. cloacae isolates belonged to ST270 and encoded NDM-1. Nanopore sequencing enabled identification of at least four distinct ST258 lineages in COVID-19 patients, which were validated by Illumina sequencing data. CONCLUSIONS: While CPE prevalence has declined substantially in New York City in recent years, increased detection in patients with COVID-19 may signal a re-emergence of these highly resistant pathogens in the wake of the global pandemic. Increased surveillance and antimicrobial stewardship efforts, as well as identification of optimal treatment approaches for CPE, will be needed to mitigate their future impact.

Aggregation of Halloysite Nanotubes in the Presence of Multivalent Ions and Ionic Liquids.

Colloidal stability was investigated in two types of particle systems, namely, with bare (h-HNT) and polyimidazolium-functionalized (h-HNT-IP-2) alkali-treated halloysite nanotubes in solutions of metal salts and ionic liquids (ILs). The valence of the metal ions and the number of carbon atoms in the hydrocarbon chain of the IL cations (1-methylimidazolium (MIM+), 1-ethyl-3-methylimidazolium (EMIM+), 1-butyl-3-methylimidazolium (BMIM+), and 1-hexyl-3-methylimidazolium (HMIM+)) were altered in the measurements. For the bare h-HNT with a negative surface charge, multivalent counterions destabilized the dispersions at low values of critical coagulation concentration (CCC) in line with the Schulze-Hardy rule. In the presence of ILs, significant adsorption of HMIM+ took place on the h-HNT surface, leading to charge neutralization and overcharging at appropriate concentrations. A weaker affinity was observed for MIM+, EMIM+, and BMIM+, while they adsorbed on the particles to different extents. The order HMIM+ < BMIM+ < EMIM+ < MIM+ was obtained for the CCCs of h-HNT, indicating that HMIM+ was the most effective in the destabilization of the colloids. For h-HNT-IP-2 with a positive surface charge, no specific interaction was observed between the salt and the IL constituent cations and the particles, i.e., the determined charge and aggregation parameters were the same within experimental error, irrespective of the type of co-ions. These results clearly indicate the relevance of ion adsorption in the colloidal stability of the nanotubes and thus provide useful information for further design of processable h-HNT dispersions.

Studies of Phylogeny, Symbiotic Functioning and Ecological Traits of Indigenous Microsymbionts Nodulating Bambara Groundnut (Vigna subterranea L. Verdc) in Eswatini.

Rhizobial microsymbionts of grain legumes are ubiquitous in soils and exhibit a wide range of diversity with respect to colony morphology, genetic variability, biochemical characteristics, and phylogenetic relationships. This study assessed the phylogenetic positions of rhizobial microsymbionts of Bambara groundnut from Eswatini exhibiting variations in morpho-physiology, adaptive characteristics, and N2-fixing efficiency. The isolates' ERIC-PCR profiles revealed the presence of high genetic variation among them. These test isolates also exhibited differences in pH tolerance and IAA production. Multilocus sequence analysis based on the 16S rRNA, atpD, glnII, gyrB, and recA gene sequences of representative test isolates closely aligned them to the type strains of Bradyrhizobium arachidis, B. manausense, B. guangdongense, B. elkanii, and B. pachyrhizi. However, some isolates showed a high divergence from the known reference type strains, indicating that they may represent species yet to be properly characterized and described. Functional characterization in the glasshouse revealed that most of the isolates from the contrasting Agro-ecologies of Eswatini were efficient in N2 fixation, and therefore elicited greater stomatal conductance and photosynthetic rates in the homologous Bambara groundnut. Of the 75 isolates tested, 51% were more effective than the commercial Bradyrhizobium sp. strain CB756, with relative symbiotic effectiveness ranging from 138 to 308%. The findings of this study indicated that the analysis of housekeeping genes and functional traits of Bambara-nodulating microsymbionts can provide a clear view for understanding and predicting rhizobial community structure across environmental gradients.

Female ejaculation: An update on anatomy, history, and controversies.

Female ejaculation is a contentious topic. From a review of the literature, history indicates that it is not a modern concept; some females were aware of it in times past without understanding the role of the fluid or composition of the ejaculate. Over time, scholars experimented, mainly with anatomical studies, in an attempt to identify the source of the ejaculate and explore its physiological and anatomical benefits for the female sexual experience. Despite these studies, views about female ejaculation remain controversial and inconsistent, with no clear conclusion as to its function. This review discusses the history of studies of female ejaculation and presents various hypotheses from an anatomical and physiological perspective. After reviewing 44 publications from 1889 to 2019, it became apparent that clinical and anatomical studies conducted during recent decades provide substantial evidence in support of the female ejaculatory phenomenon. Anatomical studies have shown that the ejaculate originates in the paraurethral (Skene's) glands, but its composition has been debated. Female ejaculate differs from urine in its creatinine and urea concentrations. The fluid also contains prostate specific antigen (PSA) and could have antibacterial properties that serve to protect the urethra. While the specific function of female ejaculation remains a topic of debate, there is sufficient evidence to support the existence of the phenomenon.