Patients' Identification, Management and Prevention of Adverse Drug Reactions: A Cross-Sectional Survey of Patients with Severe Adverse Drug Reactions.

Background: Few studies have been conducted on how patients identify, manage, and prevent severe adverse drug reactions (ADRs). This study aimed to explore the reasoning that patients use to identify symptoms of severe ADRs and the methods they employ to manage and prevent them. Methods: A cross-sectional survey using structured telephone interviews was administered to patients with a self-assessed severe ADR and to patients with serious skin ADRs from a hospital medical record database (in-patient and out-patient) from 1 September 2016 to 1 September 2019. Patients identified via the medical records were asked to assess their ADR for severity, and only patients that rated their ADR as severe were followed up with a telephone interview. Structured telephone interviews were conducted with respondents by a research pharmacist and audio-recorded. Results: A total of 722 patients with a severe ADR were identified, with 300 completing the interview (41.6%). The most frequently cited reasons for classifying ADRs as severe was worsening ADR symptoms (58.3%), severe ADR symptoms (44.4%), and ADR symptoms interfering with their life (36.4%). Only severe ADR symptoms were significantly different between the questionnaire and the medical records database groups (p = 0.007). The most frequent method of ADR management was discontinuation of drug by physicians (88.3%). About 79.0% of patients stated that they increased their carefulness when using other drugs after experiencing ADRs. The main method patients used to prevent ADRs was informing healthcare professionals (HCPs) about their drug allergy history (65.7%). Conclusions: Worsening ADR symptoms were often used to identify severe ADRs. However, HCPs were mainly responsible for the management and prevention of severe ADRs. Increasing awareness of ADRs by HCPs, and providing additional drug information, may improve patient safety.

Resource use differences of two coexisting chironomid species at localized scales.

Competing species may show positive correlations in abundance through time and space if they rely on a shared resource. Such positive correlations might obscure resource partitioning that facilitates competitor coexistence. Here, we examine the potential for resource partitioning between two ecologically similar midge species (Diptera: Chironomidae) in Lake Mývatn, Iceland. Tanytarsus gracilentus and Chironomus islandicus show large, roughly synchronized population fluctuations, implying potential reliance on a shared fluctuating resource and thereby posing the question of how these species coexist at high larval abundances. We first considered spatial partitioning of larvae. Abundances of both species were positively correlated in space; thus, spatial partitioning across different sites in the lake did not appear to be strong. We then inferred differences in dietary resources with stable carbon isotopes. T. gracilentus larvae had significantly higher δ13C values than C. islandicus, suggesting interspecific differences in resource use. Differences in resource selectivity, tube-building behavior, and feeding styles may facilitate resource partitioning between these species. Relative to surface sediments, T. gracilentus had higher δ13C values, suggesting that they selectively graze on 13C-enriched resources such as productive algae from the surface of their tubes. In contrast, C. islandicus had lower δ13C values than surface sediments, suggesting reliance on 13C-depleted resources that may include detrital organic matter and associated microbes that larvae selectively consume from the sediment surface or within their burrow walls. Overall, our study illustrates that coexisting and ecologically similar species may show positive correlations in space and time while using different resources at fine spatial scales.

New Probe of the High-z Baryon Acoustic Oscillation Scale: BAO Tomography with CMB×LIM-Nulling Convergence.

Standard rulers such as the baryon acoustic oscillation (BAO) scale serve as workhorses for precision tests of cosmology, enabling distance measurements that probe the geometry and expansion history of our Universe. Aside from BAO measurements from the cosmic microwave background (CMB), most standard ruler techniques operate at relatively low redshifts and depend on biased tracers of the matter density field. In a companion paper [H. Fronenberg, A. S. Maniyar, A. R. Pullen, and A. C. Liu, companion paper, Phys. Rev. D 109, 123518 (2024).PRVDAQ2470-001010.1103/PhysRevD.109.123518], we explored the scientific reach of nulling estimators, where CMB lensing convergence maps are cross-correlated with linear combinations of similar maps from line intensity mapping to precisely null out the low-redshift contributions to CMB lensing. We showed that nulling estimators can be used to constrain the high redshift matter power spectrum and that this spectrum exhibits discernible BAO features. Here we propose using these features as a standard ruler at high redshifts that does not rely on biased tracers. Forecasting such a measurement at z∼5, we find that next-generation instruments will be able to constrain the BAO scale to 7.2% precision, while our futuristic observing scenario can constrain the BAO scale to 4% precision. This constitutes a fundamentally new kind of BAO measurement during early epochs in our cosmic history.

Minimal Clinically Important Difference (MCID) for the Short Musculoskeletal Function Assessment (SMFA) in Severe Lower Extremity Trauma: Pooled Data from 7 Multicenter, Prospective Clinical Trials.

BACKGROUND: The Short Musculoskeletal Function Assessment (SMFA) is a well validated, widely used patient-reported outcome (PRO) measure for orthopaedic patients. Despite its widespread use and acceptance, this measure does not have an agreed upon minimal clinically important difference (MCID). The purpose of the present study was to create distributional MCIDs with use of a large cohort of research participants with severe lower extremity fractures. METHODS: Three distributional approaches were used to calculate MCIDs for the Dysfunction and Bother Indices of the SMFA as well as all its domains: (1) half of the standard deviation (one-half SD), (2) twice the standard error of measurement (2SEM), and (3) minimal detectable change (MDC). In addition to evaluating by patient characteristics and the timing of assessment, we reviewed these calculations across several injury groups likely to affect functional outcomes. RESULTS: A total of 4,298 SMFA assessments were collected from 3,185 patients who had undergone surgical treatment of traumatic injuries of the lower extremity at 60 Level-I trauma centers across 7 multicenter, prospective clinical studies. Depending on the statistical approach used, the MCID associated with the overall sample ranged from 7.7 to 10.7 for the SMFA Dysfunction Index and from 11.0 to 16.8 for the SMFA Bother Index. For the Dysfunction Index, the variability across the scores was small (<5%) within the sex and age subgroups but was modest (12% to 18%) across subgroups related to assessment timing. CONCLUSIONS: A defensible MCID can be found between 7 and 11 points for the Dysfunction Index and between 11 and 17 points for the Bother Index. The precise choice of MCID may depend on the preferred statistical approach and the population under study. While differences exist between MCID values based on the calculation method, values were consistent across the categories of the various subgroups presented. LEVEL OF EVIDENCE: Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence.

Evidence for direct CO2-mediated alterations in cerebral oxidative metabolism in humans.

AIM: How the cerebral metabolic rates of oxygen and glucose utilization (CMRO2 and CMRGlc, respectively) are affected by alterations in arterial PCO2 (PaCO2) is equivocal and therefore was the primary question of this study. METHODS: This retrospective analysis involved pooled data from four separate studies, involving 41 healthy adults (35 males/6 females). Participants completed stepwise steady-state alterations in PaCO2 ranging between 30 and 60 mmHg. The CMRO2 and CMRGlc were assessed via the Fick approach (CBF × arterial-internal jugular venous difference of oxygen or glucose content, respectively) utilizing duplex ultrasound of the internal carotid artery and vertebral artery to calculate cerebral blood flow (CBF). RESULTS: The CMRO2 was altered by 0.5 mL × min-1 (95% CI: -0.6 to -0.3) per mmHg change in PaCO2 (p < 0.001) which corresponded to a 9.8% (95% CI: -13.2 to -6.5) change in CMRO2 with a 9 mmHg change in PaCO2 (inclusive of hypo- and hypercapnia). The CMRGlc was reduced by 7.7% (95% CI: -15.4 to -0.08, p = 0.045; i.e., reduction in net glucose uptake) and the oxidative glucose index (ratio of oxygen to glucose uptake) was reduced by 5.6% (95% CI: -11.2 to 0.06, p = 0.049) with a + 9 mmHg increase in PaCO2. CONCLUSION: Collectively, the CMRO2 is altered by approximately 1% per mmHg change in PaCO2. Further, glucose is incompletely oxidized during hypercapnia, indicating reductions in CMRO2 are either met by compensatory increases in nonoxidative glucose metabolism or explained by a reduction in total energy production.

Real-world genetic testing outcomes of pan-cancer testing for mismatch repair deficiency.

BACKGROUND: In 2017, the Food and Drug Administration approved pembrolizumab for treatment of any mismatch repair-deficient (dMMR) tumor making MMR immunohistochemistry (IHC) testing beneficial for all tumor types. For the first time, MMR IHC was not performed exclusively to screen for Lynch syndrome (LS). METHODS: In this study, all MMR IHC reports issued between 2017 and 2021 at an academic hospital were reviewed and completion of genetic testing was determined through chart review. Colorectal cancers (CRCs), endometrial cancers (ECs), and noncancerous lesions were excluded. RESULTS: Between 2017 and 2021, MMR IHC was completed in 1939 patients with a malignancy other than CRC or EC. Absent or weak staining for at least one MMR protein was detected in 115 (5.9%) patients and 59 (51%) of those completed germline genetic testing. Overall, the identification rate of LS in this cohort was 0.72%, which is similar to the rate in our previously reported CRC and EC universal screening cohort. A diagnosis of LS was most commonly made in patients with dMMR brain (18.75%) and small intestinal cancers (10.20%). Five additional patients were found to carry a pathogenic variant in a non-LS gene. CONCLUSIONS: Pan-cancer MMR testing for pembrolizumab consideration can identify LS cases at a rate similar to universal CRC and EC screening programs. A persistent challenge is subsequent uptake of genetic testing. MMR testing should be prioritized in brain and small intestinal tumors, and multigene panel testing is recommended in patients with dMMR, as unexpected pathogenic variants in non-LS genes were found as frequently as LS gene variants.

High Healthcare Costs in Childhood Inflammatory Bowel Disease: Development of a Prediction Model Using Linked Clinical and Health Administrative Data.

BACKGROUND: The incidence of pediatric-onset inflammatory bowel disease (IBD) and the costs of caring for individuals with IBD are both increasing. We calculated the direct healthcare costs of pediatric IBD in the first year after diagnosis and developed a model to predict children who would have high costs (top 25th percentile). METHODS: Using data from the Canadian Children IBD Network inception cohort (≤16 years of age, diagnosed between 2013 and 2019) deterministically linked to health administrative data from Ontario, Canada, we estimated direct healthcare and medication costs accrued between 31 and 365 days after diagnosis. Candidate predictors included age at diagnosis, sex, rural/urban residence location, distance to pediatric center, neighborhood income quintile, IBD type, initial therapy, disease activity, diagnostic delay, health services utilization or surgery around diagnosis, regular primary care provider, and receipt of mental health care. Logistic regression with stepwise elimination was used for model building; 5-fold nested cross-validation optimized and improved model accuracy while limiting overfitting. RESULTS: The mean cost among 487 children with IBD was CA$15 168 ± 15 305. Initial treatment (anti-tumor necrosis factor therapy, aminosalicylates, or systemic steroids), having a mental health care encounter, undergoing surgery, emergency department visit at diagnosis, sex, and age were predictors of increased costs, while having a regular primary care provider was a predictor of decreased costs. The C-statistic for our model was 0.71. CONCLUSIONS: The cost of caring for children with IBD in the first year after diagnosis is immense and can be predicted based on characteristics at diagnosis. Efforts that mitigate rising costs without compromising quality of care are needed.

Cost of caring for children with IBD is high­CA$15 168 between 31 and 365 days from diagnosis in 487 Canadian children. Predictors of high costs included anti-tumor necrosis factor therapy and mental health care, with lower costs in those with a primary-care provider.

Delayed administration of interleukin-4 coacervate alleviates the neurotoxic phenotype of astrocytes and promotes functional recovery after a contusion spinal cord injury.

OBJECTIVE: Macrophages and astrocytes play a crucial role in the aftermath of a traumatic spinal cord injury (SCI). Infiltrating macrophages adopt a pro-inflammatory phenotype while resident astrocytes adopt a neurotoxic phenotype at the injury site, both of which contribute to neuronal death and inhibit axonal regeneration. The cytokine interleukin-4 (IL-4) has shown significant promise in preclinical models of SCI by alleviating the macrophage-mediated inflammation and promoting functional recovery. However, its effect on neurotoxic reactive astrocytes remains to be elucidated, which we explored in this study. We also studied the beneficial effects of a sustained release of IL-4 from an injectable biomaterial compared to bolus administration of IL-4. APPROACH: We fabricated a heparin-based coacervate capable of anchoring and releasing bioactive IL-4 and tested its efficacy in vitro and in vivo. MAIN RESULTS: We show that IL-4 coacervate is biocompatible and drives a robust anti-inflammatory macrophage phenotype in culture. We also show that IL-4 and IL-4 coacervate can alleviate the reactive neurotoxic phenotype of astrocytes in culture. Finally, using a murine model of contusion SCI, we show that IL-4 and IL-4 coacervate, injected intraspinally 2 days post-injury, can reduce macrophage-mediated inflammation, and alleviate neurotoxic astrocyte phenotype, acutely and chronically, while also promoting neuroprotection with significant improvements in hindlimb locomotor recovery. We observed that IL-4 coacervate can promote a more robust regenerative macrophage phenotype in vitro, as well as match its efficacy in vivo, compared to bolus IL-4. SIGNIFICANCE: Our work shows the promise of coacervate as a great choice for local and prolonged delivery of cytokines like IL-4. We support this by showing that the coacervate can release bioactive IL-4, which acts on macrophages and astrocytes to promote a pro-regenerative environment following a spinal cord injury leading to robust neuroprotective and functional outcomes.

Global, asynchronous partial sweeps at multiple insecticide resistance genes in Aedes mosquitoes.

Aedes aegypti (yellow fever mosquito) and Ae. albopictus (Asian tiger mosquito) are globally invasive pests that confer the world's dengue burden. Insecticide-based management has led to the evolution of insecticide resistance in both species, though the genetic architecture and geographical spread of resistance remains incompletely understood. This study investigates partial selective sweeps at resistance genes on two chromosomes and characterises their spread across populations. Sweeps at the voltage-sensitive sodium channel (VSSC) gene on chromosome 3 correspond to one resistance-associated nucleotide substitution in Ae. albopictus and three in Ae. aegypti, including two substitutions at the same nucleotide position (F1534C) that have evolved and spread independently. In Ae. aegypti, we also identify partial sweeps at a second locus on chromosome 2. This locus contains 15 glutathione S-transferase (GST) epsilon class genes with significant copy number variation among populations and where three distinct genetic backgrounds have spread across the Indo-Pacific region, the Americas, and Australia. Local geographical patterns and linkage networks indicate VSSC and GST backgrounds probably spread at different times and interact locally with different genes to produce resistance phenotypes. These findings highlight the rapid global spread of resistance and are evidence for the critical importance of GST genes in resistance evolution.

Longevity of hymenopteran parasitoids in natural versus agricultural habitats and implications for biological control.

Agricultural habitats are frequently disturbed, and disturbances could have major effects on species in upper trophic levels such as hymenopteran parasitoids that are important for biological control. A strategy for conservation biological control is to provide a diversified agricultural landscape which increases the availability of resources such as sugar required by parasitoid biological control agents. Here, we ask whether parasitoids occurring in agriculture benefit from sugar resources more or less than parasitoids occurring in natural habitats surrounding agricultural fields. We collected parasitoids from agricultural alfalfa fields, field margins, and natural prairies, and in the lab we randomly divided them into two treatments: half were given a constant supply of a sugar source to test their residual lifespan, and half were given neither sugar nor water to test their hardiness. Collected individuals were monitored daily and their day of death recorded. Parasitoids receiving a sugar source lived substantially longer than those without. Parasitoids collected in prairies lived longer than those from alfalfa fields in both the residual lifespan and hardiness treatments, with parasitoids from field margins being intermediate between them. Furthermore, the benefits of a sugar source to increase longevity was lower for parasitoids collected in agriculture than in natural habitats. This suggests that, even though parasitoid biological control agents benefit from sugar resources, their short lifespans make the benefit of sugar resources small compared to parasitoids that occur in natural habitats and have longer lifespans, and are adapted to consistent sugar sources.

Pregnancy Outcomes in Patients Treated with Upadacitinib: Analysis of Data from Clinical Trials and Postmarketing Reports.

BACKGROUND AND OBJECTIVE: Upadacitinib is indicated for diseases affecting persons of childbearing potential including rheumatoid arthritis, psoriatic arthritis, axial spondyloarthritis, atopic dermatitis, Crohn's disease, and ulcerative colitis; however, teratogenicity was observed in animal studies. Given the potential for human fetal risk, pregnancy avoidance measures were required during clinical trials. This analysis describes pregnancy outcomes in patients exposed to upadacitinib during pregnancy. METHODS: Clinical trial and postmarketing cases of in utero exposure to upadacitinib were identified in AbbVie's safety database through 25 April, 2023. Analysis of clinical trial cases and postmarketing reports are presented separately; prospective and retrospectively reported pregnancy outcomes are integrated for each. Descriptive rates are presented to summarize outcomes. RESULTS: There were 128 maternal upadacitinib-exposed pregnancies with known outcomes identified; 80 and 48 pregnancies were reported in clinical trials and the postmarketing setting, respectively. In clinical trials (mean in utero exposure of 5 weeks, 3 days), live births (54%), spontaneous abortions (24%), elective terminations (21%), and ectopic pregnancy (1%) were reported. There was one report of a congenital malformation: a 35-week infant with an atrial septal defect. In postmarketing cases, live births (46%), spontaneous abortions (38%), elective terminations (15%), and ectopic pregnancy (2%) were reported. CONCLUSIONS: As the data are limited for in utero exposure to upadacitinib, definitive conclusions cannot be drawn regarding the effect of upadacitinib on pregnancy outcomes. Rates of adverse pregnancy outcomes with upadacitinib exposure were comparable to rates observed in the general population or patients with autoimmune inflammatory diseases. To date, no apparent evidence of teratogenicity exists in the analyses of human pregnancies exposed to upadacitinib during the first trimester.

Highly Enantiomerically Enriched Secondary Alcohols via Epoxide Hydrogenolysis.

In this article, we report the development of ruthenium-catalyzed hydrogenolysis of epoxides to selectively give the branched (Markovnikov) alcohol products. In contrast to previously reported catalysts, the use of Milstein's PNN-pincer-ruthenium complex at room temperature allows the conversion of enantiomerically enriched epoxides to secondary alcohols without racemization of the product. The catalyst is effective for a range of aryl epoxides, alkyl epoxides, and glycidyl ethers and is the first homogeneous system to selectively promote hydrogenolysis of glycidol to 1,2-propanediol, without loss of enantiomeric purity. A detailed mechanistic study was conducted, including experimental observations of catalyst speciation under catalytically relevant conditions, comprehensive kinetic characterization of the catalytic reaction, and computational analysis via density functional theory. Heterolytic hydrogen cleavage is mediated by the ruthenium center and exogenous alkoxide base. Epoxide ring opening occurs through an opposite-side attack of the ruthenium hydride on the less-hindered epoxide carbon, giving the branched alcohol product selectively.

Predictability of ecological and evolutionary dynamics in a changing world.

Ecological and evolutionary predictions are being increasingly employed to inform decision-makers confronted with intensifying pressures on biodiversity. For these efforts to effectively guide conservation actions, knowing the limit of predictability is pivotal. In this study, we provide realistic expectations for the enterprise of predicting changes in ecological and evolutionary observations through time. We begin with an intuitive explanation of predictability (the extent to which predictions are possible) employing an easy-to-use metric, predictive power PP(t). To illustrate the challenge of forecasting, we then show that among insects, birds, fishes and mammals, (i) 50% of the populations are predictable at most 1 year in advance and (ii) the median 1-year-ahead predictive power corresponds to a prediction R 2 of only 20%. Predictability is not an immutable property of ecological systems. For example, different harvesting strategies can impact the predictability of exploited populations to varying degrees. Moreover, incorporating explanatory variables, accounting for time trends and considering multivariate time series can enhance predictability. To effectively address the challenge of biodiversity loss, researchers and practitioners must be aware of the information within the available data that can be used for prediction and explore efficient ways to leverage this knowledge for environmental stewardship.

RBM10 loss induces aberrant splicing of cytoskeletal and extracellular matrix mRNAs and promotes metastatic fitness.

RBM10 modulates transcriptome-wide cassette exon splicing. Loss-of-function RBM10 mutations are enriched in thyroid cancers with distant metastases. Analysis of transcriptomes and genes mis-spliced by RBM10 loss showed pro-migratory and RHO/RAC signaling signatures. RBM10 loss increases cell velocity. Cytoskeletal and ECM transcripts subject to exon-inclusion events included vinculin (VCL), tenascin C (TNC) and CD44. Knockdown of the VCL exon inclusion transcript in RBM10-null cells reduced cell velocity, whereas knockdown of TNC and CD44 exon-inclusion isoforms reduced invasiveness. RAC1-GTP levels were increased in RBM10-null cells. Mouse Hras G12V /Rbm1O KO thyrocytes develop metastases that are reversed by RBM10 or by combined knockdown of VCL, CD44 and TNC inclusion isoforms. Thus, RBM10 loss generates exon inclusions in transcripts regulating ECM-cytoskeletal interactions, leading to RAC1 activation and metastatic competency. Moreover, a CRISPR-Cas9 screen for synthetic lethality with RBM10 loss identified NFkB effectors as central to viability, providing a therapeutic target for these lethal thyroid cancers.

Glucose transporter 1 is essential for the resolution of methicillin-resistant S. aureus skin and soft tissue infections.

Skin/soft tissue infections (SSTIs) caused by methicillin-resistant Staphylococcus aureus (MRSA) pose a major healthcare burden. Distinct inflammatory and resolution phases comprise the host immune response to SSTIs. Resolution is a myeloid PPARγ-dependent anti-inflammatory phase that is essential for the clearance of MRSA. However, the signals activating PPARγ to induce resolution remain unknown. Here, we demonstrate that myeloid glucose transporter 1 (GLUT-1) is essential for the onset of resolution. MRSA-challenged macrophages are unsuccessful in generating an oxidative burst or immune radicals in the absence of GLUT-1 due to a reduction in the cellular NADPH pool. This translates in vivo as a significant reduction in lipid peroxidation products required for the activation of PPARγ in MRSA-infected mice lacking myeloid GLUT-1. Chemical induction of PPARγ during infection circumvents this GLUT-1 requirement and improves resolution. Thus, GLUT-1-dependent oxidative burst is essential for the activation of PPARγ and subsequent resolution of SSTIs.

Whole genome sequencing for copy number variant detection to improve diagnosis and management of rare diseases.

First-line genetic investigations for rare neurological and developmental conditions have limitations in their ability to detect and characterize copy number variants (CNVs). Whole genome sequencing (WGS) offers potential advantages over other methods of CNV analysis. We aimed to demonstrate the utility of CNV detection using WGS through description of three clinical cases. WGS analysis was undertaken in three patients presenting to a national rare disease service, in whom a genetic aetiology remained uncertain after gene panel testing or microarray based comparative genomic hybridization (array CGH). In all three cases, WGS identified CNVs and confirmed zygosity and pathogenicity, resulting in genetic diagnoses of PRKN-related Parkinson disease, TAOK1-related neurodevelopmental disorder, and AP1G1-related Usmani-Riazuddin syndrome. This case series demonstrates the value of WGS analysis in identifying or better characterizing CNVs that were missed or deemed of uncertain significance using conventional methods of testing. Importantly, our approach facilitated accurate genetic diagnosis and counselling for the families involved.

Synthesis and Cheminformatics-Directed Antibacterial Evaluation of Echinosulfonic Acid-Inspired Bis-Indole Alkaloids.

Synthetic efforts toward complex natural product (NP) scaffolds are useful ones, particularly those aimed at expanding their bioactive chemical space. Here, we utilised an orthogonal cheminformatics-based approach to predict the potential biological activities for a series of synthetic bis-indole alkaloids inspired by elusive sponge-derived NPs, echinosulfone A (1) and echinosulfonic acids A-D (2-5). Our work includes the first synthesis of desulfato-echinosulfonic acid C, an α-hydroxy bis(3'-indolyl) alkaloid (17), and its full NMR characterisation. This synthesis provides corroborating evidence for the structure revision of echinosulfonic acids A-C. Additionally, we demonstrate a robust synthetic strategy toward a diverse range of α-methine bis(3'-indolyl) acids and acetates (11-16) without the need for silica-based purification in either one or two steps. By integrating our synthetic library of bis-indoles with bioactivity data for 2048 marine indole alkaloids (reported up to the end of 2021), we analyzed their overlap with marine natural product chemical diversity. Notably, the C-6 dibrominated α-hydroxy bis(3'-indolyl) and α-methine bis(3'-indolyl) analogues (11, 14, and 17) were found to contain significant overlap with antibacterial C-6 dibrominated marine bis-indoles, guiding our biological evaluation. Validating the results of our cheminformatics analyses, the dibrominated α-methine bis(3'-indolyl) alkaloids (11, 12, 14, and 15) were found to exhibit antibacterial activities against methicillin-sensitive and -resistant Staphylococcus aureus. Further, while investigating other synthetic approaches toward bis-indole alkaloids, 16 incorrectly assigned synthetic α-hydroxy bis(3'-indolyl) alkaloids were identified. After careful analysis of their reported NMR data, and comparison with those obtained for the synthetic bis-indoles reported herein, all of the structures have been revised to α-methine bis(3'-indolyl) alkaloids.

Temporal and spatial dynamics within the fungal microbiome of grape fermentation.

Over 6 years, we conducted an extensive survey of spontaneous grape fermentations, examining 3105 fungal microbiomes across 14 distinct grape-growing regions. Our investigation into the biodiversity of these fermentations revealed that a small number of highly abundant genera form the core of the initial grape juice microbiome. Consistent with previous studies, we found that the region of origin had the most significant impact on microbial diversity patterns. We also discovered that certain taxa were consistently associated with specific geographical locations and grape varieties, although these taxa represented only a minor portion of the overall diversity in our dataset. Through unsupervised clustering and dimensionality reduction analysis, we identified three unique community types, each exhibiting variations in the abundance of key genera. When we projected these genera onto global branches, it suggested that microbiomes transition between these three broad community types. We further investigated the microbial community composition throughout the fermentation process. Our observations indicated that the initial microbial community composition could predict the diversity during the early stages of fermentation. Notably, Hanseniaspora uvarum emerged as the primary non-Saccharomyces species within this large collection of samples.