Miracle-dz/UniFAR-FTUs huggingface dataset:
Feasibility of Group Visits for Advance Care Planning Among Patients with Heart Failure and Their Caregivers

Background: Group visits have the potential to help patients identify their health care values and engage in the emotionally and cognitively challenging task of advance care planning (ACP) in a resource-efficient manner by providing a forum for social learning and social support. Objective: To evaluate the feasibility and acceptability of disease-specific group visits for patients with heart failure and their caregivers. Design: Feasibility trial of a 90-minute group visit held for 10 separate groups and led by a trained facilitator using the video-based PREPARE for Your Care ACP tool. Setting:/Subjects: Older adults with recent hospitalization for heart failure (n = 36; median age, 74 years) and their caregivers (n = 21). Measurements: Pre- and post-visit surveys and a postvisit telephone interview assessing perceived value and acceptability; structured nonparticipant observations to assess process and feasibility. Results: Mean scores from the postgroup visit evaluation showed that participants reported that they felt comfortable discussing ACP in a group (4.59), understood the information covered (4.70), and were able to identify and clarify their health care values (4.43). Interview and observation data demonstrated that participants were able to identify and clarify their preferences by listening and learning from a diverse range of perspectives in the group and that the disease-focused nature of the group visit created a supportive space for participants to share their experiences. Conclusions: Disease-focused ACP group visits were feasible to conduct and acceptable to participants, underscoring their value as an efficient intervention to engage patients and caregivers in the otherwise time- and resource-intensive task of ACP.
A New Detection Method Defining the Aerobic Threshold for Endurance Exercise and Training Prescription Based on Fractal Correlation Properties of Heart Rate Variability

The short-term scaling exponent alpha1 of detrended fluctuation analysis (DFA a1), a nonlinear index of heart rate variability (HRV) based on fractal correlation properties, has been shown to steadily change with increasing exercise intensity. To date, no study has specifically examined using the behavior of this index as a method for defining a low intensity exercise zone. The aim of this report is to compare both oxygen intake (VO2) and heart rate (HR) reached at the first ventilatory threshold (VT1), a well-established delimiter of low intensity exercise, to those derived from a predefined DFA a1 transitional value. Gas exchange and HRV data were obtained from 15 participants during an incremental treadmill run. Comparison of both VO2 and HR reached at VT1 defined by gas exchange (VT1 GAS) was made to those parameters derived from analysis of DFA a1 reaching a value of 0.75 (HRVT). Based on Bland Altman analysis, linear regression, intraclass correlation (ICC) and t testing, there was strong agreement between VT1 GAS and HRVT as measured by both HR and VO2. Mean VT1 GAS was reached at 39.8 ml/kg/min with a HR of 152 bpm compared to mean HRVT which was reached at 40.1 ml/kg/min with a HR of 154 bpm. Strong linear relationships were seen between test modalities, with Pearson’s r values of 0.99 (p < 0.001) and.97 (p < 0.001) for VO2 and HR comparisons, respectively. Intraclass correlation between VT1 GAS and HRVT was 0.99 for VO2 and 0.96 for HR. In addition, comparison of VT1 GAS and HRVT showed no differences by t testing, also supporting the method validity. In conclusion, it appears that reaching a DFA a1 value of 0.75 on an incremental treadmill test is closely associated with crossing the first ventilatory threshold. As training intensity below the first ventilatory threshold is felt to have great importance for endurance sport, utilization of DFA a1 activity may provide guidance for a valid low training zone.
Pros and Cons of Aspirin for the Primary Prevention of Cardiovascular Events: A Secondary Study of Trial Sequential Analysis

Background and Aims: Aspirin leads to substantial benefits for the secondary prevention of cardiovascular disease (CVD). We aimed to cast more light on aspirin’s role for the primary prevention of CVD. Methods: Databases were searched for clinical trials comparing aspirin vs. no aspirin use in this meta-analysis. Efficacy and safety profiles were rigorously investigated. Trial sequential analysis (TSA) was used to determine the robustness of the results. Results: Fourteen studies with 163,840 participants were eligible (mean follow-up 6.2 y). Aspirin intake was found to be associated with 9, 13, and 12% reductions in the risk of cardiovascular events (CV events) (relative risk [RR]: 0.91, 95% confidence intervals [CI]: 0.87–0.96; risk difference (RD): 0.29%; absolute risk percentage (AR%): 7.61%; number needed to treat (NNT): 345), myocardial infarction (RR: 0.87, 95% CI: 0.77–0.97; RD: 0.21%; AR%: 11.11%; NNT: 488) and ischemic stroke (RR: 0.88, 95% CI: 0.80–0.96; RD: 0.21%; AR%: 16.14%; NNT: 476), respectively; aspirin intake was also associated with 40%, 30%, and 57% increases in the risk of major bleeding (RR: 1.40, 95% CI: 1.29–1.53; RD: 0.47%; AR%: 27.85; NNT: 214), intracranial bleeding (RR: 1.30, 95% CI: 1.11–1.52; RD: 0.10%; AR%: 22.99%; NNT: 1,000) and major gastrointestinal bleeding (RR: 1.57, 95% CI: 1.38–1.78; RD: 0.32%; AR%: 36.70%; NNT: 315), respectively. Further, populations with low doses of aspirin intake (≤100 mg), populations <65 y old or populations with body mass index (BMI) ≧ 25 experienced more advantages; high-risk (10-y cardiovascular risk ≧10%) and full diabetic individuals reported hardly clinical benefits. Conclusion: Aspirin intake was associated with a reduced risk of CV events and an increased incidence of bleeding profiles in primary prevention. It is necessary to identify individual’s CVD risk using clear examinations or assessments before aspirin intake, and truly realize individualized prescription.
The H3K36me2 writer-reader dependency in H3K27M-DIPG

The H3K36me2 histone modification pathway is an acquired dependency in H3K27M mutant diffuse intrinsic pontine glioma (DIPG). Histone H3K27M is a driving mutation in diffuse intrinsic pontine glioma (DIPG), a deadly pediatric brain tumor. H3K27M reshapes the epigenome through a global inhibition of PRC2 catalytic activity and displacement of H3K27me2/3, promoting oncogenesis of DIPG. As a consequence, a histone modification H3K36me2, antagonistic to H3K27me2/3, is aberrantly elevated. Here, we investigate the role of H3K36me2 in H3K27M-DIPG by tackling its upstream catalyzing enzymes (writers) and downstream binding factors (readers). We determine that NSD1 and NSD2 are the key writers for H3K36me2. Loss of NSD1/2 in H3K27M-DIPG impedes cellular proliferation and tumorigenesis by disrupting tumor-promoting transcriptional programs. Further, we demonstrate that LEDGF and HDGF2 are the main readers mediating the protumorigenic effects downstream of NSD1/2-H3K36me2. Treatment with a chemically modified peptide mimicking endogenous H3K36me2 dislodges LEDGF/HDGF2 from chromatin and specifically inhibits the proliferation of H3K27M-DIPG. Our results indicate a functional pathway of NSD1/2-H3K36me2-LEDGF/HDGF2 as an acquired dependency in H3K27M-DIPG.
Mining underutilized whole-genome sequencing projects to improve 16S rRNA databases

Current approaches to interpreting 16S rDNA amplicon data are hampered by several factors. Among these are database inaccuracy or incompleteness, sequencing error, and biased DNA/RNA extraction. Existing 16S rRNA databases source the majority of sequences from deposited amplicon sequences, draft genomes, and complete genomes. Most of the draft genomes available are assembled from short reads. However, repeated ribosomal regions are notoriously difficult to assemble well from short reads, and as a consequence the short-read-assembled 16S rDNA region may be an amalgamation of different loci within the genome. This complicates high-resolution community analysis, as a draft genome’s 16S rDNA sequence may be a chimera of multiple loci; in such cases, the draft-derived sequences in a database may not represent a 16S rRNA sequence as it occurs in biology. We present Focus16, a pipeline for improving 16S rRNA databases by mining NCBI’s Sequence Read Archive for whole-genome sequencing runs that could be reassembled to yield additional 16S rRNA sequences. Using riboSeed (a genome assembly tool for correcting rDNA misassembly), Focus16 provides a way to augment 16S rRNA databases with high-quality re-assembled sequences. In this study, we augmented the widely-used SILVA 16S rRNA database with the novel sequences disclosed by Focus16 and re-processed amplicon sequences from several benchmarking datasets with DADA2. Using this augmented SILVA database increased the number of amplicon sequence variants that could be assigned taxonomic annotations. Further, fine-scale classification was improved by revealing ambiguities. We observed, for example, that amplicon sequence variants (ASVs) may be assigned to a specific genus where Focus16-correction would indicate that the ASV is represented in two or more genera. Thus, we demonstrate that improvements can be made to taxonomic classification by incorporating these carefully re-assembled 16S rRNA sequences, and we invite the community to expand our work to augment existing 16S rRNA reference databases such as SILVA, GreenGenes, and RDP.
NMDARs expressed in Granule Cells are involved in cerebellar plasticity and motor learning

a. Department of Neuroscience, Erasmus MC, Rotterdam, The Netherlands. b. Neuroscience Graduate Program, UCSF, San Francisco, CA 94158, USA; Department of Neurology, UCSF, San Francisco, CA 94158, USA; Kavli Institute for Fundamental Neuroscience, UCSF, San Francisco, CA 94158, USA; Weill Institute for Neurosciences, UCSF, San Francisco, CA 94158, USA. c. Current address: Department of Neurobiology, Harvard Medical School, Boston, MA, USA; Howard Hughes Medical Institute, Harvard Medical School, Boston, MA, USA. d. Cell Biology of the Synapse. Ecole Normale Supérieure, IBENS, Paris, F-75005, France. CNRS, UMR 8197, Paris, F-75005, France. INSERM, U 1024, Paris, F-75005, France. PSL, Paris, France. e. Ecole Normale Supérieure, IBENS, Paris, F-75005, France. CNRS, UMR 8197, Paris, F-75005, France. INSERM, U 1024, Paris, F-75005, France. PSL, Paris, France. f. Netherlands Institute for Neuroscience, Royal Dutch Academy of Arts &Sciences, Amsterdam, The Netherlands. g. Current address: Department of Physiology, University of California, San Francisco, San Francisco, CA, USA; Howard Hughes Medical Institute, University of California, San Francisco, San Francisco, CA, USA.
LuxT controls specific quorum-sensing-regulated behaviors in Vibrionaceae spp. via repression of qrr1, encoding a small regulatory RNA

Quorum sensing (QS) is a process of chemical communication bacteria use to transition between individual and collective behaviors. QS depends on the production, release, and synchronous response to signaling molecules called autoinducers (AIs). The marine bacterium Vibrio harveyi monitors AIs using a signal transduction pathway that relies on five small regulatory RNAs (called Qrr1-5) that post-transcriptionally control target genes. Curiously, the small RNAs function redundantly making it difficult to understand the necessity for five of them. Here, we identify LuxT as a transcriptional repressor of qrr1. LuxT does not regulate qrr2-5, demonstrating that qrr genes can be independently controlled to drive unique downstream QS gene expression patterns. LuxT reinforces its control over the same genes it regulates indirectly via repression of qrr1, through a second transcriptional control mechanism. Genes dually regulated by LuxT specify public goods including an aerolysin-type pore-forming toxin. Phylogenetic analyses reveal that LuxT is conserved among Vibrionaceae and sequence comparisons predict that LuxT represses qrr1 in additional species. The present findings reveal that redundant QS regulatory RNAs can carry out both shared and unique functions to endow bacteria with plasticity in their output behaviors. Author Summary Bacteria communicate and count their cell numbers using a process called quorum sensing (QS). In response to changes in cell density, QS bacteria alternate between acting as individuals and participating in collective behaviors. Vibrio harveyi is used as a model organism to understand QS-mediated communication. Five small RNAs lie at the heart of the V. harveyi QS system, and they regulate the target genes that underlie the QS response. The small RNAs function redundantly making it difficult to understand why V. harveyi requires five of them. Here, we discover a regulator, called LuxT, that exclusively represses the gene encoding one of the QS small RNAs. LuxT regulation of one QS small RNA enables unique control of a specific subset of QS target genes. LuxT is broadly conserved among Vibrionaceae. Our findings show how redundant regulatory components can possess both common and unique roles that provide bacteria with plasticity in their behaviors.
Extreme parallel evolution of flagellar motility facilitated by silent mutations

12 There is a growing need for accurate evolutionary forecasting, but we must first understand how 13 possible evolutionary paths can be constrained by silent genetic features. Here we show that 14 synonymous sequence variation determines extreme parallel evolution during the evolutionary rescue 15 of flagellar motility. An immotile variant of the soil microbe, Pseudomonas fluorescens, swiftly 16 recovers flagellum-dependent motility through parallel de novo mutation. This typically manifests 17 within 96 h under strong selection through repeatable mutation within the nitrogen pathway’s histidine 18 kinase gene, ntrB. We found that evolution was parallel to nucleotide resolution in over 95% of cases 19 in minimal medium (M9), with lineages repeatedly fixing an identical mutation (ntrB A289C). There 20 was no evidence that this substitution is context-specific, as repeatable de novo mutation was robust to 21 nutrient condition despite evidence for antagonistic pleiotropy. Competition assays against alternative 22 motile alleles revealed some evidence for selection enforcing repeated fixation of ntrB mutants, but 23 there was no evidence for clonal interference driving parallel evolution to nucleotide resolution. Instead, 24 the introduction of 6 synonymous substitutions surrounding the mutational hotspot reduced parallel 25 evolution from >95% to 0% at the site. In a reciprocal experiment, we introduced 6 synonymous 26 substitutions into a homologous strain that did not ancestrally evolve in parallel and observed that 27 parallel evolution at the site rose from 0% to 80%. We propose that these silent mutations facilitate 28 extremely localised heterogeneity in de novo mutation. Our results reveal that unique quirks in how 29 DNA is structured at specific loci can strongly bias evolutionary outcomes. 30
Coordination of phage genome degradation versus host genome protection by a bifunctional restriction-modification enzyme visualized by CryoEM

Restriction enzymes that combine DNA methylation and cleavage activities into a single polypeptide or protein assemblage and that modify just one DNA strand for host protection are capable of more efficient adaptation towards novel target sites. However, they must solve the problem of discrimination between newly replicated and unmodified host sites (needing methylation) and invasive foreign site (needing to lead to cleavage). One solution to this problem might be that the activity that occurs at any given site is dictated by the oligomeric state of the bound enzyme. Methylation requires just a single bound site and is relatively slow, while cleavage requires that multiple unmethylated target sites (often found in incoming, foreign DNA) be brought together into an enzyme-DNA complex to license rapid cleavage. To validate and visualize the basis for such a mechanism, we have determined the catalytic behavior of a bifunctional Type IIL restriction-modification (‘RM’) enzyme (DrdV) and determined its high-resolution structure at several different stages of assembly and coordination with multiple bound DNA targets using CryoEM. The structures demonstrate a mechanism of cleavage by which an initial dimer is formed between two DNA-bound enzyme molecules, positioning the single endonuclease domain from each enzyme against the other’s DNA and requiring further oligomerization through differing protein-protein contacts of additional DNA-bound enzyme molecules to enable cleavage. The analysis explains how endonuclease activity is licensed by the presence of multiple target-containing DNA duplexes and provides a clear view of the assembly through 3D space of a DNA-bound RM enzyme ‘synapse’ that leads to rapid cleavage of foreign DNA.
INPP5E regulates CD3ζ enrichment at the immune synapse by phosphoinositide distribution control

The immune synapse, a specialized interface formed between T lymphocytes and antigen-presenting cells (APCs) after antigen recognition, is essential for T cell activation and the adaptive immune response. It has been shown that this interface shares similarities with the primary cilium, a sensory organelle in eukaryotic cells, although roles of ciliary proteins on the immune synapse remain elusive. In this study, we find that inositol polyphosphate-5-phosphatase E (INPP5E), a cilium-enriched protein responsible for regulating phosphoinositide localization, accumulated at the immune synapse during antigen-specific conjugation or antibody capping, and formed a complex with CD3ζ, ZAP-70, and Lck. Silencing INPP5E in T-cells impaired polarized distribution of CD3ζ at the immune synapse, and correlated with a failure of PI(4,5)P2 clearance at the center of the synapse. Moreover, INPP5E silencing decreased proximal TCR signaling, including phosphorylation of CD3ζ and ZAP-70, and finally, attenuated IL-2 secretion. Our results suggest that INPP5E is a new player in phosphoinositide manipulation at the synapse, controlling the TCR signaling cascade.
Genetic composition of queen conch (Lobatus gigas) population on Pedro Bank, Jamaica and its use in fisheries management

The queen conch fishery in Jamaica is sustained by Pedro Bank, which is the main harvesting site located approximately 80 km south-west from Kingston. Due to its relative size, Pedro Bank has been subdivided into zones for management purposes by the Fisheries Division and the Veterinary Services Division. Understanding whether these sub-divisions reflect different sub-populations is critical for managing exploitation levels because fisheries management must demonstrate that harvesting does not endanger the future viability of the population as queen conch are on Appendix II of the Convention in Trade in Endangered Species of Wild Fauna and Flora (CITES). This determination is essential for the continued export to international markets such as the European Union. Two hundred and eight samples were collected across the entire Pedro Bank and were genetically characterized using nine polymorphic microsatellite loci. Population structure analysis for Lobatus gigas from Pedro Bank yielded low but significant values (FST = 0.009: p = 0.006) and suggested a high magnitude of gene flow indicative of a fit and viable population throughout the bank. Analysis of molecular variance (AMOVA) indicated a 100% variation within individual samples with little variation (0.9%) between populations. In contrast pairwise genetic comparisons identified significant differences between populations located to the south eastern and eastern region of the bank to those in the central and western locations. Bayesian clustering analysis also indicated the likelihood of two population sub-divisions (K=2) on Pedro Bank. The results provided evidence of a weak but significant population structure which has crucial implications for the fishing industry as it suggests the use of ecosystem based management (EBM) in setting quotas to promote sustainable harvesting of L. gigas within each monitoring zone on Pedro Bank.
Kinetic characterization of the interaction of NO with the S2 and S3-states of the oxygen-evolving complex of Photosystem II

The reactivity of the S3 and S2 states towards NO and NH2OH was studied and compared using the period-4 oscillations in the F0-value induced by a train of single turnover Xenon flashes spaced 100 ms apart to monitor the reaction kinetics. The flash frequency also determined the time resolution of the assay, i.e. 100 ms. The S2 and S3-states were created by one and two single turnover pre-flashes, respectively. The NO-concentration-dependence of the S3-decay indicated that at low NO-concentrations an S2-state was formed as an intermediate, whereas at higher concentrations a seemingly monophasic decay to the S1-state was observed. The sigmoidal concentration dependence indicated that a fast interaction of the S3-state with (at least) two NO-molecules is necessary for the fast S3 to S1 decay (τ ~0.4 s at 1.2 mM NO). The pH-dependence of the S3-decay suggests that a protonation-reaction (pK ~6.9) is involved in the S3 to S1 decay. At intermediate NO-concentrations the protonation is only partially rate limiting, since the pH effect is more pronounced at high compared to intermediate NO-concentrations. A comparison of the reactivity of NO and hydroxylamine suggests that hydroxylamine reacts more efficiently with the S1 and S2 states, whereas NO reacts more efficiently with the S3-state. Based on our present knowledge of the oxygen evolving complex a possible reaction mechanism is proposed for the interaction between NO and the S3 state.
Neuromolecular and behavioral effects of ethanol deprivation in Drosophila

Alcohol use disorder (AUD) is characterized by loss of control in limiting alcohol intake. This may involve intermittent periods of abstinence followed by alcohol seeking and, consequently, relapse. However, little is understood of the molecular mechanisms underlying the impact of alcohol deprivation on behavior. Using a new Drosophila melanogaster repeated intermittent alcohol exposure model, we sought to identify how ethanol deprivation alters spontaneous behavior, determine the associated neural structures, and reveal correlated changes in brain gene expression. We found that repeated intermittent ethanol-odor exposures followed by ethanol-deprivation dynamically induces behaviors associated with a negative affect state. Although behavioral states broadly mapped to many brain regions, persistent changes in social behaviors mapped to the mushroom body and surrounding neuropil. This occurred concurrently with changes in expression of genes associated with sensory responses, neural plasticity, and immunity. Like social behaviors, immune response genes were upregulated following three-day repeated intermittent ethanol-odor exposures and persisted with one or two days of ethanol-deprivation, suggesting an enduring change in molecular function. Our study provides a framework for identifying how ethanol deprivation alters behavior with correlated underlying circuit and molecular changes.